平成26年度
次世代医療機器・再生医療等製品
評価指標作成事業
生体吸収性ステント
審査WG報告書
平成27年3月
審査WG座長 中村 正人
東邦大学医療センター 大橋病院
内科学講座 循環器内科
目次
Ⅰ
委員構成 .............................................................................................................. 1
Ⅱ
議事概要 .............................................................................................................. 3
Ⅲ
委員報告
Ⅲ-1
DES と比較して期待される BVS のメリットと懸念材料
(中村座長) ......................................................................................... 11
Ⅲ-2
材料(ポリマー)(山岡委員) ............................................................... 17
Ⅲ-3
生体吸収性金属材料の現状と課題(山本委員)..................................... 23
Ⅲ-4
生体吸収性ステントの In vitro 評価(岩﨑委員) ................................. 33
Ⅲ-5
In vivo 評価について(中澤委員) ........................................................ 41
Ⅲ-6
イメージングによる評価(新家委員) ................................................... 47
Ⅲ-7
臨床的観点から考えられる構造的問題点(挽地委員) .......................... 53
Ⅲ-8
Biodegradable Vascular Scaffolding (BVS) Clinical Trials
(宮内委員) ......................................................................................... 57
Ⅳ
資料
Ⅳ-1
生体吸収性材料関連規格リスト.............................................................. 67
Ⅳ-2
厚生労働省医薬食品局審査管理課長通知
薬食審査発第 0904001 号
「冠動脈ステントの承認申請に係る取扱いについて」 ............................... 71
Ⅳ-3
Public Workshop — ASTM-FDA Workshop on Absorbable Medical
Devices: Lessons Learned from Correlations of Bench Testing and
Clinical Performance, November 28, 2012 ................................................ 81
Ⅳ-4
Guidance for Industry and FDA Staff Non-Clinical Engineering
Tests and Recommended Labeling for Intravascular Stents and
Associated Delivery Systems ..................................................................... 85
Ⅳ-5
Guidance for Industry
Coronary Drug-Eluting Stents —
Nonclinical and Clinical Studies DRAFT GUIDANCE .......................... 113
Ⅰ
委員構成
委員(○:座長)
○
岩﨑 清隆
早稲田大学理工学術院 先進理工学研究科 共同先端生命医科学専攻 教授
新家 俊郎
神戸大学大学院医学研究科 内科学講座 循環器内科学分野 准教授
中澤 学
東海大学医学部 内科学系 循環器内科学 講師
中村 正人
東邦大学医療センター 大橋病院 内科学講座 循環器内科 教授
挽地 裕
佐賀大学医学部 循環器内科 准教授
宮内 克己
順天堂大学医学部大学院医学研究科 循環器内科学講座 先任准教授
山岡 哲二
国立循環器病研究センター研究所 生体医工学部 部長
山本 玲子
物質・材料研究機構 MANA-ナノライフ分野 生体機能材料ユニット
バイオメタルグループ グループリーダー
厚生労働省
磯部 総一郎 大臣官房 参事官(医療機器・再生医療等製品審査管理担当)
近藤 英幸
医薬食品局 医療機器・再生医療等製品担当参事官室
医療機器規制国際調整官
金川 幸紀
医薬食品局 医療機器・再生医療等製品担当参事官室 医療機器指導官
間々田 圭祐 医薬食品局 医療機器・再生医療等製品担当参事官室 主査
独立行政法人
医薬品医療機器総合機構
木下 勝美
医療機器審査第一部 部長
方 眞美
医療機器審査第一部 審査役
相澤 浩一
医療機器審査第一部 審査役代理
桜井 淳
医療機器審査第一部 審査専門員
大内 貴司
医療機器審査第一部 審査専門員
竹下 康平
医療機器審査第一部 審査専門員
高橋 彩来
医療機器審査第一部 審査専門員
宮崎 生子
規格基準部 部長
松岡 厚子
規格基準部 医療機器基準課 テクニカルエキスパート
事務局
新見 伸吾
国立医薬品食品衛生研究所 医療機器部長
宮島 敦子
国立医薬品食品衛生研究所 医療機器部 室長
迫田 秀行
国立医薬品食品衛生研究所 医療機器部 主任研究官
Ⅱ
議事概要
平成26年度 次世代医療機器・再生医療等製品評価指標作成事業
生体吸収性ステント審査ワーキンググループ 第1回会議 議事概要
開催日時:平成26年8月25日(月)15:00-17:15
開催場所:TKP品川カンファレンスセンター カンファレンスルーム4D
(東京都港区高輪3-26-33 京急第10ビル)
出席者(敬称略)
委員
:岩﨑清隆(早稲田大学)
、新家俊郎(神戸大学)、中澤学(東海大学)
中村正人(東邦大学)
、挽地裕(佐賀大学)、宮内克己(順天堂大学)
山岡哲二(国立循環器病研究センター研究所)、山本玲子(物質・材料研究機構)
欠席委員 :なし
オブザーバ:松崎邦男、岡崎義光(産業技術総合研究所)
厚生労働省:金川幸紀、間々田圭祐(医療機器・再生医療製品審査管理室)
PMDA :方眞美、相澤浩一、竹下康平、高橋彩来(医療機器審査第一部)
松岡厚子(規格基準部)
事務局
:新見伸吾、宮島敦子、迫田秀行(国立医薬品食品衛生研究所)
配布資料
資料1 第1回WG会議議事次第
資料2 次世代医療機器評価指標作成事業について
資料3 委員名簿
資料4 メーリングリストについて
資料5 生体吸収性ステントの開発状況
資料6 厚生労働省平成 15 年 9 月 4 日付通知「冠動脈ステントの承認申請に係る取扱いについ
て」
資料7 FDA ガイダンス「Non-Clinical Engineering Tests and Recommended Labeling for
Intravascular Stents and Associated Delivery Systems」(2010/4/18)
資料8 FDA ガイダンス「Coronary Drug-Eluting Stents — Nonclinical and Clinical Studies
DRAFT GUIDANCE」(2008/3/26)
資料9 評価項目対応表
資料10 COI について
参考資料 平成 24 年度 次世代医療機器評価指標作成事業 重症下肢虚血分野審査 WG 報告書
概要
配布資料の確認に引き続き、厚生労働省より挨拶及び事業説明があり、当事業での成果は順次
通知という形になり実際の審査で活用されていることなどが紹介された。
座長挨拶及び各委員の自己紹介に引き続き、委員より情報提供があり、以下のような内容の報
告があった。
中村座長「DES と比較して期待される BVS のメリットと懸念材料」
ステント治療は手技成功率が高いものの、再狭窄が問題であったため、薬剤溶出性ステント
(DES)が開発された。しかし、DES では遅発性のステント血栓症のリスクが残ること、新規
の動脈硬化が形成する可能性があり、しかも通常の Bare Metal Stent より早期に生じる可能性
があることが指摘されている。また、永久に残存することから、破断の可能性や、血管の形態
への影響、血流への影響等が永続的に残り、これらが有害事象につながる危険性がある。生体
吸収性ステントでは、このような長期のリスクがなく、追加で処置が可能である等のメリット
がある。一方で、強度不足、強度が維持される期間が不明なこと、厚さ、過拡張による破損の
可能性、DES より長期の抗血栓剤投与の必要性、視認性の悪さ等が欠点として挙げられる。
中澤委員「報告されている pre clinical study の成績」
動物モデルは臨床の結果を予測するものであるが、モデルの選択と観察のタイミングにより、
差がなくなってしまう場合があるので注意が必要である。DES では、豚を使用したモデルで 1
年後に炎症反応が見られ、晩期の評価に活用できる。ウサギを使用したモデルで、内皮化の良
否が評価でき、遅発性血栓症の発生頻度とも関連性が見られる。吸収性ステントは、ウサギを
使用した試験で、消失するまでにおよそ 4 年かかることがわかっている。動物モデルでは、吸
収過程及び生体反応の評価ができるが、動物における生体反応は人間のおよそ 6 倍の速度であ
り、一方吸収速度は変わらないと考えられることから、注意が必要である。
新家委員「報告されている imaging の成績」
Imaging の手法としては、OCT(光干渉断層法)
、IVUS(血管内超音波検査)、CAG(冠動
脈造影)
、MSCT(マルチスライス CT)
、MRI(核磁気共鳴画像法)、Angioscopy(血管内視鏡)
等がある。このうち OCT は、分解能が 10-20 um であり、吸収性ステントの観察に適している。
吸収性ステントと DES の臨床成績を比較すると、吸収性ステントでは急性期合併症の発生率が
高い可能性があり、その原因としては、デリバリーの困難さが考えられる。過拡張すると破損
のリスクがあるため、圧着が不十分になる場合がある。オーバーラップができない、側枝の閉
塞リスクが高いという問題が指摘されている。血管径にあったサイズを選択し、前拡張や後拡
張を適切に行う必要がある。ポリマー製吸収性ステントでは造影で撮影しても写らないが、OCT
では圧着不良等の確認が可能である。
山岡委員「ポリマー系吸収性材料について」
吸収性ステントの応用部位としては、血管、気管、食道、消化管、胆管等が考えられている。
血管ステントへの適用としては、DES の薬剤溶出部分への適用、全吸収性ステント、ステント
グラフト、カバードステントが考えられている。強度不足が最大の課題である。繊維状にする
と配向化等により強度を出しやすいが、繊維を編んで機器を作製すると、オーバーラップした
部分で内膜肥厚が起き、問題となる。ポリマーは溶けてなくなるイメージではなく、分子量が
落ちて構造が壊れても、物質自体は長期間残存する。残存物は炎症反応の原因になる他、血中
への流出の危険性や、血栓症の原因になる可能性がある。その他のポリマー系吸収性ステント
の問題点としては、分解産物による生体反応、クリープによる Radial force の低下、強度不足
を補うためのストラットの厚さが考えられる。
山本委員「メタル系吸収性材料について」
メタル系吸収性材料としては、マグネシウム合金、純鉄、鉄合金、純亜鉛が研究されている。
マグネシウム合金は、血管ステントや骨接合材としての応用が検討されており、ステントの臨
床試験も行われている。吸収速度が速いことが課題である。マグネシウムイオンは血中濃度が
高く、排泄速度も速いため、毒性の問題はないと思われるが、他に添加されている金属の毒性
については情報が乏しく注意が必要である。純鉄はステントの動物試験が行われたが、吸収速
度が遅く、血中ではイオンとしてほとんど存在しないため、さびが沈着するなどの問題がある。
純亜鉛はワイヤーの埋植試験が行われたところである。不純物により炎症反応が出たり、分解
速度に影響が出たりする可能性がある。ガイドラインや規格で定められた in vitro における金
属の溶解試験法では、生体内での金属の腐食反応の機構を再現していない場合があり、注意が
必要である。
情報提供に関連して質疑応答があった後、座長より、本ワーキンググループでは冠動脈を中心
とした血管ステントを対象とすること、ポリマー製及び金属製の吸収性ステントを対象とし、骨
格が残るものは対象としないこと、薬剤を含む製品は対象とするが、薬剤部分の評価は対象外と
することが提案され、了承された。また、製品開発が企業を中心に行われていて情報が乏しく、
情報収集が必要であることから、本年度は情報収集を行い、来年度末の評価指標案の作成を目指
すことが提案され、了承された。
初めて臨床試験を行う際にはリスクを伴うため、小規模な臨床試験(Feasibility study)を行
ってから大規模な臨床試験(Pivotal study)を行うことが一般的であるとの指摘があった。従っ
て、検討すべき評価項目としては、非臨床試験、動物実験、小規模臨床試験、大規模臨床試験で
構成されることになるとの意見があった。また厚生労働省より、薬事法改正に伴い市販後調査に
おける評価項目についても検討をお願いする可能性があることのコメントがあった。
今年度の会議日程を、10 月 20 日(月)及び 12 月 15 日(月)の 15 時 30 分から 17 時 30 分と
して、会議を終了した。
平成26年度 次世代医療機器・再生医療等製品評価指標作成事業
生体吸収性ステント審査ワーキンググループ 第2回会議 議事概要
開催日時:平成26年10月20日(月)15:30-17:20
開催場所:TKP品川カンファレンスセンター カンファレンスルーム4F
(東京都港区高輪3-26-33 京急第10ビル)
出席者(敬称略)
委員
:岩﨑清隆(早稲田大学)
、新家俊郎(神戸大学)、中澤学(東海大学)
中村正人(東邦大学)
、挽地裕(佐賀大学)、宮内克己(順天堂大学)
山岡哲二(国立循環器病研究センター研究所)、山本玲子(物質・材料研究機構)
欠席委員 :なし
オブザーバ:花田幸太郎、岡崎義光(産業技術総合研究所)
厚生労働省:近藤英幸(医療機器・再生医療等製品審査管理室)
PMDA :方眞美、相澤浩一、桜井淳、竹下康平、高橋彩来(医療機器審査第一部)
松岡厚子(規格基準部)
事務局
:新見伸吾、宮島敦子、迫田秀行(国立医薬品食品衛生研究所)
配布資料
資料1 第2回WG会議議事次第
資料2 第1回議事概要(案)
資料3 厚生労働省 平成 20 年 4 月 4 日付通知「次世代医療機器評価指標の公表について」別添
1「次世代型高機能人工心臓の臨床評価のための評価指標」
資料4 ワークショップ資料(ASTM-FDA Workshop on Absorbable Medical Devices: Lessons
Learned from Correlations of Bench Testing and Clinical Performance (2012/11/28)、
Workshop Standardization of Absorbable Metals for Medical Devices (2013/11/4))
資料5 評価指標案の項目のイメージ(たたき台)
資料6 報告書構成(案)
概要
配布資料の確認に引き続き、前回会議議事概要の確認を行った。1 か所の修正を行い、会議の
終了をもって了承となった。
引き続き、委員より情報提供があり、以下のような内容の報告があった。
挽地委員「臨床的観点から考えられる構造的問題点」
慢性完全閉塞の場合には、吸収性ステントでは充分な Radial force が得られるか不安がある。
急性心筋梗塞の場合には、再灌流させると血管径が次第に大きくなることから、不完全圧着が
生じる可能性がある。これに対して過拡張をすると破損する可能性があるため、サイジングが
難しい。吸収性ステントを留置後数か月以内に、末梢側に対して追加治療を行うと、先に留置
していた吸収性ステントが動く可能性があることが報告されている。CT により観察ができない
ため、慢性期の評価方法が課題である。
分岐部に吸収性ステントを設置した場合、ステントのストラットが何らかの組織に覆われる。
ストラットの間隔が狭いと、膜状になり(Neointimal bridge)、側枝の入り口が狭くなる場合
がある。そこで、ステント留置後、側枝に向かって拡張をすることが考えられるが、吸収性ス
テントでは破損を生じる可能性がある。
岩﨑委員「in vitro 実験系について」
金属製ステントで使用される金属材料に比べると、吸収性ステントで使用されるポリマーで
は、引張強度は数%程度、破断伸びは数%から十数%程度である。従って、吸収性ステントでは
不完全圧着や破断のリスクが金属製ステントより高く、血栓症や、血管拡張保持力の低下が生
じるリスクがあると考えられる。血管を模擬した透明のファントムを使用することにより、不
完全圧着や、過拡張による破断、リコイルの評価などが可能である。テーパ血管に留置する場
合の径の差の許容範囲や適切なステントサイズの選択の評価も必要と思われる。実臨床では側
枝の拡張が必要になる可能性があることから、側枝の拡張の影響も評価しておくべきである。
生体吸収性ステントに特有の評価試験法としては、狭窄血管モデルでの経時的な拡張保持力性
能評価試験や、生理的拍動数や溶液、流れ環境を再現した耐久性評価試験が考えられる。
情報提供に関連して質疑応答及び討論を行った。Radial force の評価については、金属製ステ
ントを対象とした現行の試験法では不十分で、検討が必要との意見があった。過拡張による破損
を防ぐため、拡張限界についてしっかり評価すべきとの意見があった。Neointimal bridge につい
ては、最近になってようやく観察が可能になったものであり、まだ情報が不足している、また、
動物実験による再現も容易ではないとの意見があった。側枝の拡張が臨床上必要になる可能性が
あることから、側枝の拡張限界について何らかの評価はしておくべきとの意見があった。
金属製ステントの疲労強度評価は加速して行っているが、吸収性ステントの場合は、実時間で
行うことになるとの意見があった。また、吸収性ステントに加わる力により分解速度に影響があ
るとの指摘があった。ステントが破損した場合、その時期、破損する場所、破損した後の形状も
重要との意見があった。
続いて、2012 年に FDA で開催された吸収性の医療機器に関するワークショップについて紹介
があった。インターネットからプレゼンテーションの内容が見られることから、各自が関係する
と思われるところを確認して頂き、FDA のワークショップで問題となっている点及び検討事項に
ついて次回会議で要約して頂くことになった。
報告書の構成案について確認し、各委員の執筆内容について、次回の会議で紹介して頂くこと
にした。報告書の原稿締め切りは、2 月 15 日とした。
今年度の会議日程を、12 月 15 日(月)の 15 時 30 分から 17 時 30 分と確認して、会議を終了
した。
平成26年度 次世代医療機器・再生医療等製品評価指標作成事業
生体吸収性ステント審査ワーキンググループ 第3回会議 議事概要
開催日時:平成26年12月15日(月)15:30-17:00
開催場所:TKP品川カンファレンスセンター カンファレンスルーム4F
(東京都港区高輪3-26-33 京急第10ビル)
出席者(敬称略)
委員
:岩﨑清隆(早稲田大学)
、新家俊郎(神戸大学)、中澤学(東海大学)
中村正人(東邦大学)
、挽地裕(佐賀大学)、宮内克己(順天堂大学)
山本玲子(物質・材料研究機構)
欠席委員 :山岡哲二(国立循環器病研究センター研究所)
オブザーバ:花田幸太郎、岡崎義光(産業技術総合研究所)
厚生労働省:金川幸紀(医療機器・再生医療等製品審査管理室)
PMDA :相澤浩一、桜井淳、大内貴司、高橋彩来(医療機器審査第一部)
事務局
:新見伸吾、宮島敦子、迫田秀行(国立医薬品食品衛生研究所)
配布資料
資料1 第3回WG会議議事次第
資料2 第2回議事概要(案)
資料3 ワークショップ資料(ASTM-FDA Workshop on Absorbable Medical Devices: Lessons
Learned from Correlations of Bench Testing and Clinical Performance (2012/11/28))
資料4 報告書構成(案)
資料5 生体吸収性材料関連規格リスト
資料6 ISO/TR 37137:2014 Cardiovascular biological evaluation of medical devices - Guidance for
absorbable implants(抜粋)
資料7
ISO/TS 17137:2014 Cardiovascular implants and extracorporeal systems - Cardiovascular
absorbable implants(抜粋)
資料8 ASTM ASTM F3036 - 13 Standard Guide for Testing Absorbable Stents(抜粋)
(当日配布)宮内委員プレゼンテーション資料
概要
配布資料の確認に引き続き、前回会議議事概要の確認を行った。特にコメントはなく、会議の
終了をもって了承となった。
引き続き、PMDA 及び委員より情報提供があり、以下のような内容の報告があった。
PMDA 高橋様「生体吸収性ステントの審査について」
医療機器の審査は一般的に、製品のコンセプトの確認、製品の特性や性能設計の確認、製品
のコンセプトの実現の確認という流れで行われている。その中でまず確認するのが、その製品
の臨床的位置づけである。具体的には、既存製品等と比較して、予想されるベネフィットとリ
スクとしてどのようなものがあるか確認を行う。例えば、生体吸収性ステントの場合は、薬剤
溶出型ステントとの比較が考えられる。
次に、これらのベネフィットとリスクを正確に見積もる。ベネフィットは臨床的アウトカム
が既存製品に対し非劣性であることを示す必要がある。また、製品特有のコンセプトがある場
合は、期待される臨床的ベネフィットを確認する必要がある。安全性については、既存製品と
比べ大きく劣らないことが大前提だが、既存製品に劣る場合は臨床的アウトカムの向上又は新
たな臨床的ベネフィットの検証必要になる。
非臨床評価では、安定性や生体適合性の確認が必要と思われる。また、材料の特性や分解機
構、吸収過程を考慮したベンチ試験や動物試験等が必要となると思われる。基本的性能は非臨
床試験で評価し、臨床試験では手術の成功、吸収性ステントの物性及び生体反応による影響、
再治療時の有害事象等について評価を行うことになると思われるが、非臨床評価と臨床評価の
切り分けは難しい問題と思われる。また、材料により生体反応は異なるため、試験系の統一や
規格値の設定は難しいと思われる。
宮内委員「BVS (Biodegradable Vascular Scaffolding) Clinical Trial」
生体吸収性ステントの臨床試験としては、ABSORB という一連の臨床試験が行われており、
先行した一部の試験において結果が出ている。安全性の Clinical Endpoint としては、MACE
(Major Adverse Cardiac Events)
、TLF(Target Lesion Failure)
、TVF(Target Vessel Failure)
が用いられている。最初の臨床試験(Cohort A)における MACE は 5 年で 3.4 %で既存製品と
ほぼ同等であり、基本的な安全性は担保されたと言える。ただし、単群試験或は歴史的対照を
使用していること、単純病変を対象としていることなどに注意が必要である。
一方、生体吸収性ステントでは、設置後 3 年から 5 年で血管が広がることが報告されており、
生体吸収性ステント特有のベネフィットである可能性がある。
続く臨床試験(ABSORB EXTEND)では、より複雑な病変も対象とし、歴史的対照を使用
して試験を行っている。3 年の観察により、安全性について非劣性が示されている。
続く臨床試験(ABSORB II)では、薬剤溶出型ステントを対照とした臨床試験で、試験治療
患者と対照治療患者を 2 : 1 で割り付けている。1 年の結果で非劣性が示されている。また、狭
心症の発生が有意に低下しており、吸収性ステント特有のベネフィットである可能性がある。
狭心症の発生を主評価項目とした臨床試験も始まっている。
ヨーロッパでは認可されたため、レジストリーが稼働している。30 日以内の血栓症が多い等、
従来の臨床試験の結果に比べ有害事象の発生率は高いようであるが、既存製品と比べ大きく上
昇しているわけではないようである。
情報提供に関連して質疑応答及び討論を行った。30 日以内の血栓症については、ラーニングカ
ーブがある可能性が指摘されているとの意見があった。また、症例選択により成績向上の可能性
もあるのではないかとの意見があった。
次に、FDA で開催された吸収性の医療機器に関するワークショップについて、委員より以下の
ような内容の調査報告があった。
山岡委員(事務局代読)
吸収性ポリマーについては、縫合糸を対象とした規格等の文書があるがステントについての
記載は無い。分解性についてはポリマー材料ごとに文書があるが、その試験方法に関するコン
センサスは特にない状況である。ポリマーの分解性には様々な因子が影響し、定量的な相関性
もないため、材料ごとに評価する必要がある。形状や動き、応力等も分解性に大きな影響を与
える。
山本委員
金属材料の製造工程によっても分解特性は影響を受ける。リン酸緩衝水溶液を使用した試験
結果の報告があったが、生体内環境を十分模擬できているとは言えない。標準材料の作製の提
案もあったが、分解特性には不純物の影響が大きく、品質管理が困難なため、議論は進んでい
ない。また、ドイツで 2013 年 11 月に開催された吸収性メタル医療機器に関するワークショッ
プの内容について問い合わせをしたが、情報は得られなかった。
岩﨑委員
吸収性ポリマーでは、応力負荷環境下の方が分解速度は速くなる。ステントの場合は、流れ
や拍動の影響を考慮する必要がある可能性がある。温度を上げると分解速度は上昇する。加速
試験としての妥当性については、検証が必要と思われる。
続いて、報告書の構成案及び原稿締め切り(2 月 15 日)を確認した後、来年度の活動方針につ
いて議論を行った。ISO 及び ASTM 規格の紹介があった。報告書の作成作業終了後、今年度の議
論及びこれらの資料を参考にしながら項目出しを行い、来年度一年をかけて評価指標案を作成す
ることし、会議を終了した。
Ⅲ
委員報告
Ⅲ-1
DES と比較して期待される BVS のメリットと懸念材料
東邦大学医療センター
大橋病院
中村
正人
1.はじめに
冠動脈インターベンション(percutaneous coronary intervention、PCI)の歴史は常に限界へ
の挑戦であるが、この歴史の中の一里塚といえばステントの登場、薬剤溶出性ステント(drug
eluting stent、DES)の登場であろう。そして、生体吸収性ステント(bioabsorbable stent)に
よって新たなページが書き加えられようとしている。
PCI の歴史は 1970 年代後半、バルーン拡張術によってはじまり、この時代を経ていわゆるニ
ューデバイス時代へ至った。このニューデバイス時代には各種デバイスが開発され臨床応用がす
すめられたが、この中で最終的に勝ち残ったのがステントであった。この 30 年間ステントを中心
として開発がすすめられてきたといっても過言ではない。また、この時期には定量的な冠動脈造
影が標準となり、デバイス間の優劣がサイエンティフィックに論じられることになった。ステン
トによって再狭窄のリスクは著しく軽減したものの、ステント留置後に生じるステント再狭窄は
依然として 20-10%に見られ、PCI のアキレス腱と称された。この再狭窄の問題を解決するため
の開発がすすめられ DES が誕生した。最初に登場したのは sirolimus eluting stent(SES)であ
るが、2000 年より開始された最初の多施設比較検討試験 RAVEL1)では再狭窄率、late loss、ステ
ント血栓症すべて“ZERO”であったことからゼロトライアルとも称され、その成績に世界は驚愕し
た。すべてが解決されたと思われた瞬間であった。しかし、適応が拡大されると様々な問題がク
ローズアップされることになり、DES 自体の改良が、重ねられた。また、金属が体内に遺残しな
いステントの開発も進められ実臨床での使用が始まっている。完全に生体吸収されるステントは
理論的には非常に多くの利点を有すると考えられる。一方、吸収される過程で従来のステントと
は異なった事象が生じることも懸念される。したがって、従来のステントとは異なった審査が必
要となるであろう。このため、本邦における生体吸収性ステントの評価指標を作成することを目
的として、本評価指標作成ワーキンググループ(WG)が立ち上がった。
2.DES 開発の軌跡と問題点
当初、DES 最大の関心事はベアメタルステント(bare metal stent、BMS)よりもステント血
栓症のリスクが著しく高くなるのではないかという懸念であった。実際、そのリスクについての
報告が相次いだ。剖検例による病理学的検討からは、内皮化の遅延および不均一な内皮化、ポリ
マーに対する過敏反応、mal-apposition、内皮機能障害などが報告された。これらの現象は、い
ずれも超遅発性ステント血栓症の誘因となりえるものであった。また、ステントの内側に生じる
新たな動脈硬化病変(neoatherosclerosis)は、DES では BMS よりも早期により高頻度に認めら
れると報告された。このような内皮化障害を背景とした病態が DES の一つの懸念材料である。一
方、DES によって高度屈曲病変、長区間のびまん性病変など複雑病変を積極的に治療するように
なると、BMS 時代にはあまり問題とされなかったステントの破断、血管 geometry の変化が新た
な問題として浮かびあがった。このため、これらの点を改善するための開発がすすめられ第 2 世
代 DES が誕生した。その進化は、主としてポリマーの生体適合性ならびに抗血栓性の改良と、材
質、プラットフォームの改良と言える(図1)
。
図1 ステントストラットの比較 2)。DES は材質の改良によってより金属
量の少ない、薄いストラットのステントになってきている。結果、構造の
改良と相まってステントの血管追従性は著しく改善された。
血管追従性の改良によって複雑病変へのアプローチがより簡便になり、ステント破断などのリ
スクも著しく軽減された。しかし、ステント破断の問題はステントが金属である以上完全に解決
することは困難である(図2)
ポリマーの改良によってステント血栓症の懸念も払しょくされた。急性冠症候群のような血栓
が関与する病態であっても DES のほうが BMS よりもステント血栓症のリスクが低いと報告され
ている(図3)
。
次なる改良は、生体吸収性ポリマーの登場である。安定したポリマーであっても過敏反応を惹
起するリスクは皆無でないということから、生体吸収されるポリマーによる DES の開発が進めら
れ、今後はこの種の DES が主流になると予想されている。
図2 第 2 世代の DES であっても、ステント破断はあり、その場合のイ
ベントリスクは高くなる 3)。
図3 心筋梗塞に対する BMS と DES; メタ解析の結果 4)。DES は BMS
よりも安全性が優れている。
3.生体吸収性ステント開発の原動力
薄いステントストラット、生体吸収性ポリマー、薬剤量の減量と DES の開発は急速に進み、金
属アレルギー、late catch up、ステントの破断、超遅発性ステント血栓症などのリスクは著しく
低減した。しかし、金属が残存するため完全に解決されたわけではない。また、バイパス吻合の
妨げになる、再治療の妨げになるなどの問題点も残存する。このため、完全に生体で吸収性され
るステントの開発がすすめられた。コンセプト自体は決して最近のものではないが、臨床使用に
は限界があるとされ開発はストップしていた。しかし、薬剤溶出の技術と統合することによって
一気に現実的なデバイスとして再度注目されることになった。異物が残らないことにより想定さ
れるメリットとしては下記の項目が挙げられる。最大の差異は血管反応性を保持できるか否か、
血管反応性保持による長期的なイベント回避の可能性であろう。動脈硬化は血管の shear stress
と関係し、pulsatile で周期的な血流は血管の安定に関係するからである。
1)超遅発性ステント血栓症、遅発性ステント血栓症のリスク軽減
2)永続的な側枝閉塞のリスク軽減
3)Late catch up がない
4)ポリマーや金属に対する慢性炎症が少ない
5)mal-apposition、neoatherosclerosis の軽減
6)血管の geometry を維持して、新規病変の発現を減ずる
7)血管内皮機能の温存、vasomotion の温存
8)造影 CT など検査の妨げにならない
9)外科手術の妨げにならない
10)次の PCI の妨げにならない
11)内腔の拡大、血管の代償性リモデリング
12)狭心症の軽減
4.生体吸収性ステントで懸念されること
生体吸収性ステントは狭窄病変を拡張する医療機器であるため、血管の弾性収縮に抗してある
一定期間血管を保持する能力が要求される。血管保持の必要性がなくなった後には吸収され、異
物による副作用のリスクが消失する。これが理想の姿である。したがって、生体吸収性ステント
であっても十分な radial force が必要であり、吸収の過程でステントの integrity が問われる。し
たがって、吸収のスピードが適切でないと早期の合併症が増加する。ステント破断は radial force
を失うことになり、DES と同様に再狭窄の頻度、ステント血栓症の頻度が高くなるものと考えら
れる。ステント破断は様々な局面で想定される。ステントの拡張限界を超えて過拡張した場合、
側枝を拡張してステントの構造が変形した場合、石灰化病変などでステントが不均等に拡張した
場合などである。吸収される過程でステントが破断した場合、末梢塞栓を生じないかといった懸
念もある。Radial force を維持するためステントのストラットが厚くなるが、PCI 手技自体の難
易度が高くなり、不十分拡張のリスクが高まる。ステントストラットが厚い場合には側枝閉塞、
周術期心筋梗塞のリスクも高くなる。ポリマーによる生体吸収性ステントでは視認性が劣るため、
over-lap させ複数のステントを留置することが困難であろうし、ステントのストラットが厚いと
オーバーラップ部位ではさらに 2 重で厚くなる。現状、これら新規デバイスが不向きな病変は①
静脈グラフト、
②高度石灰化病変、
③抗血小板薬 2 剤併用療法(dual antiplatelet therapy、DAPT)
の継続服薬が不可能、④術前血流が TIMI<3 などが指摘されている。
5.現在、臨床使用されている生体吸収性ステント
現在、20 社以上が臨床応用をめざし、開発を進めている。生体吸収性ステントは用いられる材
料によって、①ポリ乳酸(poly lactic acid、PLLA)と co-polymer、②Thyrosine polycarbonate、
③金属に大別される。最も応用が進んでいるのが PLLA であり、次いで応用されているのがマグ
ネシウム合金による生体吸収性ステントである。その他に polylactic anhydride などが試みられ
ている。なお、個々のデバイスによって光干渉断層法(optical coherence tomography、OCT)
などのイメージング像も異なる。
現在、臨床が試みられている吸収性ステントの構造を図4に示す。
図4 現在臨床応用されている生体吸収性ステント 5)。
6.本審査 WG における検討対象
生体吸収性ステントは、食道、肝胆膵などの管腔臓器と冠動脈、末梢動脈など血管ステントが
ありえるが、本審査 WG では冠動脈ならびに末梢動脈に対する血行再建治療のための医療機器を
対象とした。また、構造物が完全に吸収され、消退する医療機器を対象とした。したがって、生
体吸収性ポリマーを用いた DES は、ポリマー消退後に金属製のステントが残存するため対象に含
まれない。また、一定期間血管を保持ずる能力を有するもの(ステント)が対象であり drug coated
balloon(DCB)も対象しないこととした。
この新たなデバイスは、従来の金属ステントとまったく異なった効果が期待される。それは、
主として長期的なメリットである。一方、主な欠点は構造や材質に伴うものであり、固有な合併
症、手技に伴うものを含め比較的短期的に出現する。したがって、新たな視点にたった preclinical
データが必要であり、基本的性能を臨床導入前に如何に評価するかが問われる。また、臨床試験
におけるチェックすべき観察項目も従来の DES とは異なったものが必要であろう。
文献
1)Morice et al. A randomized comparison of a sirolimus-eluting stent with a standard stent
for coronary revascularization. N Engl J Med. 2002 Jun 6;346(23):1773-80.
2)Foin N et al. Impact of stent strut design in metallic stents and biodegradable scaffolds.
Int J Cardiol. 2014 Dec 20;177(3):800-8
3)Kuramitsu S et al. Incidence and clinical impact of stent fracture after everolimus-eluting
stent implantation. Circ Cardiovasc Interv. 2012 Oct;5(5):663-71
4)Sabaté M et al. Comparison of newer-generation drug-eluting with bare-metal stents in
patients with acute ST-segment elevation myocardial infarction: a pooled analysis of the
EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial
INfArcTION) and COMFORTABLE-AMI (Comparison of Biolimus Eluted From an
Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial
Infarction) trials. JACC Cardiovasc Interv. 2014 Jan;7(1):55-63
5)Wiebe J et al. Current status of bioresorbable scaffolds in the treatment of coronary artery
disease. J Am Coll Cardiol. 2014 Dec 16;64(23):2541-51
Ⅲ-2
材料(ポリマー)
国立循環器病研究センター研究所・生体医工学部長
山岡
哲二
1.生体吸収性医療機器
ポリ乳酸などのポリαヒドロキシ酸を基本構造とした生体吸収性縫合糸の国内市場は約 200 億
円と大きい。非吸収性縫合糸の約 2 倍の市場を有しているにもかかわらず、その 9 割が輸入品で
あり、国内での規制整備は進んでいない。図1にポリαヒドロキシ酸の化学構造を示した。その
分解特性は、何れも非酵素的加水分解であるが、化学構造などにより分解速度は大きく異なる。
1990 年はじめに報告された組織工学的手法を用いた軟骨再生においても、生体内安全性が担保さ
れていたこれらの高分子の中で、ポリグリコール酸(図1中上段、R=H)不織布がスキャホー
ルドとして使用された。
同様の理由から、吸収性ステントの材料としてポリαヒドロキシ酸が注目されたのは納得でき
るが、生分解性に加えて、柔軟性、結紮性、破断強度、などの特性が要求される縫合糸と、血管
拡張性維持のための持続的ラジアルフォースが要求されるステントでは、その要求特性が大きく
異なることは明白である。しかしながら、そのストラット基本部材に関する規格でさえも、具体
的参考資料となる規格やガイドラインは国内に存在しない。海外でも、同様に吸収性ステントに
対するガイドラインの重要性が認識されており、近年、その整備作業が進みつつある。
R
O
O
O
O
Sn(C7H15COO)2
O
C
C
n
R
R
DexonTM etc.
Polyglycolide : R = H
Polylactide : R = CH3
Polylgractin : R =H, CH3
Glycolide : R = H
Lactide : R = CH3
O
O
H
O
VicrylTM
O
OCH2CH2OCH2C
O
O
n
O
O
O
+
O
PDSTM
Polydioxanone
O
O
O
OCH2 C
O
OCH2CH2CH2OC
m
n
Poly(ester carbonate)
Polyglyconate
MaxonTM
O
O
O
OCH2 C
+
O
O
O
OCH2CH2CH2CH2CH2C
m
n
O
O
Polyglecaprone
TM
Monocryl
図1 生分解性縫合糸に利用されるポリ-α-ヒドロキシ酸
2.生体吸収性医療機器に関する規格
(1)JIS
吸収性医療機器に該当する JIS 規格は、腸線縫合糸(surgical sutures catgut)に関する JIS
T4102 のみである。目標吸収期間を約 1 週間とした無加工 A 型から、特殊処理により吸収期間を
2、3、4 週間と制御した、B 型、C 型、D 型と、その素材と吸収速度に関する規格である。吸収
期間とは、腸線が体内で吸収され、縫合目的を失うまでの期間であり、したがって、体内に物質
が残存している状況である。その他、繊維径、引っ張り強さ、結び目の引っ張り強さ、包装など
が記載されている。
(2)ISO
ISO では生体吸収性ステントの規制に関連すると考えられるものが幾つか存在する。
ISO10993-6(Framework for identification and quantification of potential degradation
products)では、吸収性か非吸収性にかかわらず、塊状体、多孔質体、液体、ペースト、微粒子
などを埋入した際の局所反応の評価法に関して記載されている。また、分解性であるがゆえに局
所反応だけでは不十分であることから、分解産物の体内への拡散を考慮して、分解性材料埋入時
の全身反応試験法、あるいは、分解試験デザインが ISO10993-9 に記述されている。また
ISO10993-13 では、生体模倣環境下での分解産物生成量の定量法などに関して言及されている。
ISO/TS17137 では一般的な分解性材料に関する規制が記載されている。しかしながら、いずれの
場合にもステントを対象としたものではなく、ステントが留置される生理的環境を十分に反映し
たテスト法を新たに策定する必要があり、ISO TC150/SC2/WG7(Cardiovascular absorbable
implants)および、TC194 において同内容に関する検討が進んでいるので、継続的に情報を収集
する必要がある。
(3)FDA-CFR1)
吸収性縫合糸に関しては、表1に示したようなレギュレーションが存在する。
表1 吸収性縫合糸に関する FDA-Code of Federal Regulations
Absorbable Polydioxanone Surgical (PDS) Suture
21CFR§878.4840
Absorbable Poly(glycolide/L-lactide) Surgical Suture
21CFR§878.4493
Absorbable Gut Suture
21CFR§878.4830
(4)ASTM
ASTM F2902(Standard Guide for Assessment of Absorbable Polymeric Implant)において
は、成形加工、デバイス物性、パッケージングや滅菌など基本的特性が、また、AFTM F1635 で
は、 in vitro 分解性テストに関して、さらに ASTM F1983 では、in vivo 生物学的安全性試験に
関する標準化が進んでいるが、現状では吸収性ステントに特化されたものとはなっていない。
3.生体吸収性高分子の分解と国内での認可状況
(1)ポリ-α-ヒドロキシ酸の一般的分解特性
図1に示された生体吸収性高分子やその共重合体の分解挙動の研究は、古くから盛んに行われ
てきた。何れも、自然界では微生物分解や酵素的分解も報告されているが、生体内では非酵素的
単純加水分解が中心である。分解に影響を与える材料側の要因として、図1に示したような化学
特性(組成、分子量、表面特性)
、物理特性(形状、結晶性、配向性、形状)
、加工方法(吐出、
遠心、アニーリング、溶媒キャスト、混合)、添加物(薬物、タンパク質、複合材料)などが知ら
れている。ポリ乳酸(図1中、R=CH 3 )に比較してポリグリコール酸(図1中、R=H)の
分解速度は極めて大きく、その共重合組成により分解速度が調整可能であると同時に力学特定も
大きく変化する。図2には、共重合体の一つである、乳酸-カプロラクトン共重合体の分解挙動を
示した。分解速度の遅いポリ-ε-カプロラクトンとの共重合により、ポリ乳酸の分解は早くなる。
これは、共重合による結晶性が低下するために、加水分解速度が上昇したためである。その他、
分解試験に用いる環境の pH や温度など、分解条件が大きく影響する。
図2の縦軸は重量低下が示されているが、その分解による重量減少と強度低下は大きく異なる。
一般的に、これらポリ-α-ヒドロキシ酸の分解挙動は、「溶解」のようなイメージではない。分子
鎖の化学分解により、分解初期において材料にクラックが生じて力学強度が大きく低下する。続
いて、図2に示すような重量低下が起こる。すなわち、生体吸収性ステントにおいては、ラジア
ルフォースが大きく低下した(あるいは消失した)後にも、血管内腔あるいは血管壁内に微細物
質が残存して分解が継続するために、分子量低下、重量現象、力学強度低下、など多角的な指標
から検討しなければ、ステントの機能性と、残存炎症性に与える影響を検討することは困難であ
る。また、構造とこれらの分解挙動の一般的相関性は得られていないので、素材ごとにデータを
取る必要がある。
(2)生体吸収性ステントの分解
Soares らは、図3のように、ステントの形状が分解に与える影響をシミュレートしている 2)。
特に応力集中部位や可動域での分解が加速され、ステント強度の支配要因となることから、上述
の一般的分解試験とは異なる系の構築が必要である。
しかしながら、例えばステント形状に成形した後の in vitro、in vivo テストは煩雑かつ一般性
に欠けることから、図4に示すような、加重下での in vitro テストの有効性を検証することが必
要である 2)。
図2 ポリ乳酸、ポリグリコール酸、および、ポリ乳酸/ポリ-ε-カプロラクトン共重
合体の共重合体の加水分解による重量低下
図3 ステントの形状が分解に与える影響の計算例 2)
図4 加重下における分解試験の例 2)
(3)国内で認可状況が公開されている分解性医療機器の例 3)
以下の 3 例は PMDA 開発前相談 HP に審査報告書が公開されている例である。上述のごとく、
国内では生体吸収性材料そのものに対する、規制などが整備されていないことから、これらの専
攻する医療機器の許認可状況を集約する必要があろう。
A.
ハイドロキシアパタイトとポリ L 乳酸との複合体からなる骨接合用スクリュー、ピン、
ワイヤーがタキロン社から販売されているスーパーフィクソーブ TMである。分解速度だ
けでなく分解により生じる粒状産物が周囲組織に与える影響についても PMDA からの
指摘も記されたようで、上述の局所生体応答として、ステントにも重要な項目であろう。
B.
。
最近、PGA を主体とする神経誘導管が東洋紡から販売された(ナーブリッジ TM)
ISO10933-1 に準拠した生物学的安全性試験を進めたようであるが、ポリαヒドロキシ
ル酸重合時に用いられるスズ触媒の安全性も注目されている。
C.
グンゼ株式会社は、ポリグリコール酸、あるいは、ポリ乳酸とポリカプロラクトンとの
共重合体からなる埋入型医療機器を幾つか販売しているが、平成 12 年に人工硬膜を申請
し、平成 19 年に承認されている(シームデュラ TM)。先に欧州 CE マークを取得してい
たが、かなりの一般的項目に関するデータが要求されたようである。
(4)リスク
ステントが分解性であるが故の大きなリスクファクターとしては、初期の急速な強度低下によ
るラジアルフォースの減弱あるいは消失が大きい。分解に伴う周囲組織の pH 低下は、用いる物
質量が小さいこと、分解が比較的遅いこと、血流に接していることから、その影響は極めて小さ
いと考えられるが定量的考察は必要であろう。さらに、分解産物が血管内腔皮に露出するか、血
管壁内に埋没するかは、遠位での塞栓に繋がるリスクファクターとして考察する必要がある。
4.おわりに
分解性高分子の生体内利用においては、分解による医療機器としてのパフォーマンスの低下の
みならず、分解中の分解産物顆粒などに対する生体反応も重要な検討要因である。複雑な形状に
基づく、応力集中や継続的な動きによる分解加速現象も知られているが、全てを生体内で進める
事は困難である。主に吸収性縫合糸に対して作成されてきた標準化仕様をベースにして、ステン
ト独自の環境因子が分解等に与える影響を評価するための単純な in vitro 試験の標準化が必要と
考えられる。
文献
1)http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm312601.htm
2)Soares JS, Rajagopal KR, Moore JE Jr., Deformation-induced hydrolysis of a degradable
polymeric cylindrical annulus., Biomech Model Mechanobiol., 2010, 9(2):177-86.
3)中岡竜介、生体吸収性材料を用いた医療機器の安全性評価:薬事医承認審査時における留意
点、進化する医療用バイオベースマテリアル第 6 編 27 章、CMC 出版、2014 年
Ⅲ-3
生体吸収性金属材料の現状と課題
(独)物質・材料研究機構 国際ナノアーキテクトニクス研究拠点
生体機能材料ユニット
山本
玲子
1.生体吸収性金属材料とその特徴
生体吸収性金属材料として純鉄やマグネシウム合金を適用する試みは、今世紀に入り冠動脈ス
テント応用を中心に本格化した。これまでに、生体吸収性金属材料としてマグネシウムおよびそ
の合金、鉄およびその合金、亜鉛について検討が進められている。これらの金属材料には、1)
生体必須元素であり、体内における存在量が比較的大きいため、溶出イオンが生体に及ぼす影響
、水と反
が小さいと期待されること、さらに2)純金属の標準電極電位は卑であり(表 11)参照)
応して容易に腐食する、という特徴がある。2)の特性を生体内における分解性として利用する
ものである。
これらの金属(M)の水溶液中の腐食反応を以下に示す。
M + 2H 2 O → M2+ + 2OH- + H 2 ↑
鉄の場合、酸性溶液中では上記の反応が進むが、中性溶液では次のように溶存酸素がないと腐
食しない 2)。
2Fe + 2H 2 O + O 2 → 2Fe2+ + 4OHいずれの場合も腐食反応の進行に伴い OH-が生じるため、溶液の pH が上昇する。それに伴い、
腐食生成物[M(OH) 2:金属水酸化物]が金属表面を覆い拡散障壁層を形成するため、次第に腐食速
度が低下する。すなわち、これらの金属の体内における分解速度は、埋入環境における腐食生成
物の生成状況に依存する。
体液は種々の無機塩やアミノ酸・タンパク質等の有機物を含む溶液であり、その pH は部位に
より異なるがほぼ一定に保たれている。例えば血液の pH は主として炭酸緩衝系により、7.4 に維
持されている 3)。大気中における炭酸ガス濃度は約 0.04%であるが、動脈血中の濃度は約 5%と
100 倍以上高い 3),4)。血中に溶け込んだ炭酸ガスは炭酸脱水素酵素の働きにより重炭酸イオンとの
平衡状態にあり、血液の pH 恒常性維持に貢献している。一方、体組織中の酸素濃度は大気中の
1/4 以下である 4)。
体液中の無機塩・有機物は、これらの金属の腐食生成物形成に大きな影響を及ぼす。マグネシ
ウムの腐食を例に説明すると、食塩水中では腐食の進行に伴い OH-が生成し、溶液の pH が上昇
する。すると、溶液中の溶解度が低下するため、水酸化マグネシウムが金属表面に析出(沈殿)
する。このときの pH は 11 から 12 である。しかし、血漿と同等組成の疑似体液中では、より難
溶性のリン酸塩、炭酸塩が pH8 前後で析出する。したがって、マグネシウムの疑似体液中の腐食
速度は血漿と同濃度の食塩水中の約 1/50 である 5)。しかし、血流等によって溶出イオンが金属表
表 1 各種金属の標準電極電位 1)
元素名
電極反応
金
白金
水銀
銀
銅
水素
すず
ニッケル
コバルト
インジウム
鉄
ガリウム
クロム
亜鉛
マンガン
ジルコニウム
チタン
アルミニウム
マグネシウム
ナトリウム
カルシウム
カリウム
リチウム
Au3+ + 3e- → Au
Pd2+ + 2e- → Pd
Hg2+ + 2e- → Hg
Ag+ + e- → Ag
Cu2+ + 2e- → Cu
2H+ + 2e- → H 2
Sn2+ + 2e- → Sn
Ni2+ + 2e- → Ni
Co2+ + 2e- → Co
In3+ + 3e- → In
Fe2+ + 2e- → Fe
Ga3+ + 3e- → Ga
Cr3+ + 3e- → Cr
Zn2+ + 2e- → Zn
Mn2+ + 2e- → Mn
Zr4+ + 4e- → Zr
Ti2+ + 2e- → Ti
Al3+ + 3e- → Al
Mg2+ + 2e- → Mg
Na+ + e- → Na
Ca2 + 2e- → Ca
K+ + e- → K
Li+ + e- → Li
標準電極電位
(V vs SHE)
1.50
0.987
0.854
0.800
0.521
0.00(基準)
-0.136
-0.250
-0.277
-0.342
-0.44
-0.53
-0.74
-0.763
-1.18
-1.53
-1.63
-1.66
-2.37
-2.71
-2.87
-2.93
-3.05
面近傍から除去される場合、あるいは疑似体液の緩衝作用により pH が上昇しない場合には、金
属表面に析出する腐食生成物・難溶性塩の量が減少し、結果として腐食速度の低下度が変化する。
すなわち、これらの金属の生体内における分解速度を推測するためには、生体内と同様の環境に
おいて、体液の組成や緩衝能、血流や総体液量などを考慮する必要がある。
生体吸収性材料の分解特性評価に限らず、生物学的安全性評価においても生体内と同様の環境
を考慮することは重要である。なぜならば、生体吸収性金属材料の安全性は溶出物の濃度に依存
し、その推定には材料の生体内における分解速度の推定が必須だからである。この点は従来の生
体吸収性高分子・セラミックス材料と同じであるが、生体吸収性金属材料の体内における分解機
序は、既存の生体吸収性材料とは異なる点に留意が必要である。例えば生体吸収性高分子材料で
あるポリ乳酸について、リン酸緩衝液浸漬に伴う強度低下が、ラット体内(軟組織中)埋植にお
ける強度低下と一致するという報告があり 6)、そのため分解特性評価法として in vitro リン酸緩
衝液浸漬試験が ISO にて推奨されている 7)。ポリ乳酸の生体内における分解機序は加水分解であ
り、生体吸収性金属材料のように試料表面に腐食生成物層が形成され、分解反応が妨げられるこ
とがないため、生体内環境をリン酸緩衝液で模擬可能と推測される。
したがって、繰り返しになるが、生体吸収性金属材料については、生体内における分解機序が
異なる生体吸収性高分子の分解特性評価法を適用してはいけない。同じく、従来の高耐食性金属
材料(既に実用化されているチタン合金・ステンレス鋼・コバルト-クロム合金等)に対する耐
食性試験法の適用も不適切である。従来の高耐食金属材料については、耐食性が高ければ高いほ
ど望ましいという観点から、体内よりも過酷な条件として生理食塩水中あるいは 1%乳酸溶液中で
のアノード分極試験等が実施されてきた。しかし、生体吸収性金属材料については、このような
生体内とはかけ離れた環境における試験結果は生体内環境における重要な分解速度制御因子(例
えば炭酸緩衝系、リン酸、有機物など)が含まれておらず、生体内における分解速度との相関性
が得られないことは明白である。
2.生体吸収性金属材料ステントの開発状況
(1)マグネシウムおよびその合金
マグネシウム合金のステント応用については、ドイツのビオトロニーク社にて WE43 系合金に
よる開発が進められており、既に臨床例が報告されている 8)-11)。WE43 系合金製ステントの最初
の臨床例は、安全性確認に主眼を置いた下肢の虚血症例への適用であった。20 名の患者に 23 個
のベアメタルステントが埋入されたが、ステント埋入にともなう急性毒性は認められず、ステン
トは 6 週間以内に分解したと報告されている 8)-10)。ベアメタルステントの安全性が確認されたた
め、続いて冠動脈領域での埋植も実施された。63 患者に 71 ステントが埋入されたが、術後 12 ヶ
月で Target Lesion Revascularization(TLR)が 45%に至り、従来のステンレス製ベアメタルス
テント(28%)および薬剤溶出ステント(6%)よりも悪い結果となった 11)。WE43 系合金ステ
ントは埋入後 4 か月以内に分解したと推測されている。これらの臨床例から、WE43 系合金ステ
ントが血管狭窄部位の拡張を維持する期間の不足が示唆される。そこで、ステントの分解期間を
延長するために生体吸収性高分子被覆を施し、抗がん剤徐放と組み合わせた薬剤溶出ステントが
それによると、
埋入 12 ヶ月後の時点で Late Lumen
開発された。
既に、
臨床例も報告されている 12)。
Loss (LLL)が 0.52±0.39 mm であり、ベアメタル時の結果よりも改善されたが、先行する生体吸
収性高分子製ステント(0.27±0.32 mm)には及ばない 13)。そのため、図 1 に示すように、現在
さらなる拡張維持期間の延長を目指し、ストラット形状の変更、生体吸収性高分子コーティング
厚さの向上や抗がん剤の種類の変更などの改良が進められている 13)。
動物埋入例については、WE43 系合金のブタ・ミニブタ埋入例 14)-18)に加え、生体吸収性高分子
被覆 AZ31 合金のウサギ埋入例 19)が報告されている。WE43 系合金製ベアメタルステントのブタ
埋入例では、
埋入 28 日での内皮化および埋入 3 ヶ月でのストラット消失が報告されている。一方、
AZ31 合金製ステントのウサギ埋入例では、ポリマー被覆のない、表面リン酸処理のみのステント
について、105 日でのストラット消失が報告されている 19)。
図 1:WE43 系マグネシウム合金製ステントの変遷 13)
A: ベアメタルステント、B: 薬剤徐放ステント DREAMS 1G(1st generation)
、C: DREAMS 2G
、D: WE43 系マグネシウム合金ステントの分解挙動を示す模式図。DREAMS
(2nd generation)
1G では、ポリ乳酸-ポリグリコール酸共重合体コーティング層にパクリタクセルを含浸。
DREAMS 2G では、ポリ乳酸コーティング層にシロリムスを含浸。コーティングの厚さも 7 µm
に増加させ、タンタル製マーカーも付与された。
(2)鉄およびその合金
前術したようにマグネシウム合金製ステントの臨床例では、体内における血管拡張維持期間の
不足が示唆される。そこで、マグネシウムよりも強度が高く、また腐食速度も小さい鉄を生体吸
収性ステントとして応用する試みが複数の研究グループにて検討されている。しかしながら、ま
だ臨床例は報告されていない。
純鉄製ステントのウサギ動脈への埋入実験では、ステントの分解量が小さく、18 ヶ月経過後で
も分解速度の測定が不可能であったと報告されている 20)。しかし、ストラット周辺には茶色の腐
食生成物およびそれを貪食するマクロファージ像が観察され、軽い局所的な炎症反応が認められ
た 20)。鉄は体液中の溶解度が低いため、ステント周辺部からイオンの状態で拡散するとは考えに
くく、体外への排出が起こりにくいと予想される。ブタへの埋植実験においても、埋入 14 日後か
ら茶色の腐食生成物が確認されている 21),22)。埋入 1 ヶ月後から、網内系、すなわち細胞貪食によ
り処理される様子が観察された 22)。埋入 3 ヶ月後の時点では、脾臓内における腐食生成物の局所
的に堆積が認められるが、重篤な鉄の過剰症は見られないと報告されている 22)。ステントとして
の鉄埋入量は、動物個体全体に鉄過剰症を引き起こす量よりもはるかに小さいため、局所的な影
響で留まるのであろう。埋入されたステントは、12-18 ヶ月においても強度を保っており、内皮
化され血栓形成もないことが報告されている 20),22)。
鉄ステントの分解期間の減少を目指し、窒化処理により強度を上げストラット厚さを 70 µm ま
で低減したステントが開発されているが、これまでのところミニブタへの 28 日間埋入試験結果し
か報告されておらず 23)、分解速度についてのデータは得られていない。
(3)亜鉛およびその合金
生体吸収性金属材料のステント応用において、これまでの臨床例、動物埋入例から、マグネシ
ウム合金では強度維持期間が短く、鉄では分解期間が長過ぎることが推測される。そこで、両者
の中間の分解速度であることを期待し、亜鉛の適用が検討されている。亜鉛は生体必須元素では
あるが生体内の存在量はマグネシウムよりも小さく、血漿中濃度は 12-18 µM とマグネシウム
(0.5-1 mM)の 1/30 程度である 24),25)。さらに、報告されている亜鉛の過剰症発症時の血漿中濃
度は 31.5-640 µM であり、通常の血漿中濃度の 2 倍程度である。すなわち、体内における亜鉛濃
度の安全域が小さいことに留意が必要である 25)。
純亜鉛ワイヤのラット腹腔動脈への埋入例によると、顕著な毒性反応はなく、埋入 1.5 ヶ月後
の分解速度は 20 µm/year 以下と報告されている 26)。しかしながら、純亜鉛の引張強度は純マグ
ネシウム同様~120 MPa と低く、合金化が必須である。
3.生体吸収性金属材料ステント開発における課題
生体吸収性金属材料ステントによる血行再建治療の成功には、埋入時および体内での分解に伴
う機械的強度が重要であり、そのためには材料の分解特性制御が鍵となる。生体吸収性金属材料
の分解特性制御には、不純物の削減、金属組織制御、合金化、表面処理(生体吸収性高分子との
複合化を含む)等が有効である。現在開発が進められているマグネシウム合金についても、今後
検討が進む可能性のある鉄および亜鉛についても、血管ステントとして実用化されるのは純金属
ではなく合金と考えられる。合金開発およびその組織制御により、材料の機械的特性や分解特性
を望ましいものに制御できる可能性があるが、従来の医療用金属材料以上に安全性への配慮が必
要である。というのは、従来の非吸収・高耐食性金属材料とは異なり、生体吸収性金属材料は最
終的には体内で全て分解する。したがって、マグネシウムや鉄などの主要元素だけでなく、合金
化のために添加された元素も体内に排出されるため、これら添加元素の安全性も考慮しなければ
ならない。例えば現在冠動脈ステント応用が進められている WE43 系マグネシウム合金には、イ
ットリウムやミッシュメタルと呼ばれる希土類元素の混合物が合わせて 7 重量%(1 g 当たり 0.07
g)含まれている。マグネシウムは生体必須元素であり、一部のマグネシウム塩が薬として利用さ
れていることもあり、体内存在量や排泄経路、過剰症を示す濃度など、ヒトについて色々なデー
タが得られている。一方、希土類元素については、ごく一部の元素は 19 世紀末から工業応用され
ていたが、その他多くの元素については第二次世界大戦後であり、個々の元素についての毒性デ
ータはほとんど得られていないのが現状である。一部の元素については有機錯体の形で造影剤と
して臨床応用されているが、他の元素についてはヒトに関するデータはほとんどない。
元素の利用の開始が近現代である場合、毒性報告例が少ないことが多いが、これは決して毒性
がない、という意味ではない。むしろ、安全性未確認の部分が多い、と捉えるべきである。毒性
報告例があれば、どの程度の量を摂取した際に問題が生じるかの予測が可能だが、データがなけ
ればリスクの推定はできない。ステント応用の場合、埋入量は他のデバイス(例えば骨折固定材
など)よりも小さいとはいえ、口からではなく体内に直接埋入されるため、安全性未知の元素の
使用は慎重に進めるべきである。
生体吸収性金属材料ステントの開発を進めるために現時点で予想される課題として、1)開発
目標となる仕様が不明であること、2)in vitro および in vivo データの不足、ならびに3)評価
法が未確立であること、があげられる。1)については、生体吸収性高分子材料ステントがごく
最近海外にて上市されたばかりであり、その特性(強度保持期間約 6 ヶ月、分解・消失まで約 2
年)が冠動脈ステントにとって最適設計なのか否かは不明である。さらに、疾患タイプや患者の
個人差等により最適な特性が変化する可能性がある。実際に、強度特性については生体吸収性高
分子ステントと非吸収性金属ステントでは大きく異なっており、素材として、あるいは製品とし
て目指す仕様が明らかになっているとは言い難い。
2)
、3)に関しては1.でも述べたように、生体吸収性金属材料の分解特性およびその機序が
従来の生体吸収性高分子材料や非吸収性金属材料と異なることに由来する。生体吸収性金属材料
の生体内分解特性は環境に敏感であり、その評価には従来の単純な環境では不十分であり、より
生体内に近い環境が求められる、というだけのことである。現時点ではまだ in vitro の評価条件
の確立には至っていないが、それゆえ海外では in vitro の評価を不要とすべし、という意見もあ
る。しかし、開発プロセスにおいて、候補材の絞り込みや素材・加工材の品質確認のための in vitro
評価は必須である。なんでもかんでも動物試験で確認すればよい、という考え方は、近年の動物
愛護運動の高まりや細胞培養法を初めとするバイオ関連技術の進展に逆行している。実際に、医
療材料の評価手法として動物を用いた試験は万能ではなく、その結果は必ず臨床結果と一致する
とは限らない。要は開発プロセスにおいて in vitro 評価と in vivo 評価をいかに上手く組み合わせ
て利用するか、であり、分解特性評価環境の確立は必須である。
この点は分解特性の評価だけでなく、生物学的安全性評価についても同様である。既存の生物
学的安全性評価手法は、基本的に溶出物の Hazard Identification に主眼を置いているため、材料
からの溶出物濃度が最大となるように抽出液を作製、それを用いて細胞・動物試験を行うという
構造である。しかし、そのために既存ガイドラインが推奨する抽出液作製条件は、実際の生体内
における使用条件とはかけ離れた過酷な環境となっている。繰り返しになるが、生体吸収性材料
の安全性は溶出物濃度に依存するため、生体内に近い環境で試験をしないと、材料が生体内で使
用可能かどうかの判断はできない。ガイドラインが推奨する抽出溶媒は水や生理食塩水であり、
試験によっては培養液も使用可だが、抽出液を動物へ投与する場合には生理食塩水に限定される。
しかし、先述したように、生体吸収性材料の生理食塩水中の分解速度は疑似体液中の数十倍であ
り、ガイドラインに従って生体吸収性金属材料の生物学的安全性を評価すると、使用可能な材料
までも使用不可と判断されかねない。
このような評価法に関する課題を解決するためには、速やかな生体吸収性金属材料の生体内分
解特性評価条件の確立と、生物学的安全性評価における抽出液作製条件の見直し(生体吸収性金
属材料に適用可能な条件の明示)が求められる。両者に共通する点として、1)試験溶液・抽出
溶媒は体液になるべく近い組成の溶液(炭酸緩衝液である必要がある)とすること、2)試験・
抽出環境は体内同様の 5%炭酸ガス環境とすること、そして3)生体内で溶出物が体液中に速やか
に拡散することを十分考慮して試料/抽出溶媒比を決定すること、があげられる。
1)に関しては、マグネシウムの腐食において、血清タンパク質に分解抑制効果が確認されて
おり 5)、動物血清あるいはヒト血漿をモデルに開発された Eagle’s Minimum Essential Medium
に血清を添加して用いるなどが望ましい。動物へ投与する場合は、タンパク質等の有機物が含ま
れると滅菌操作が難しくなるため、ISO10993-15:2000(Annex C)にあるように、人工血漿(無
機塩のみ)を用いるのも一案である。2)については細胞培養等に広く用いられている 5%炭酸ガ
スインキュベータの利用で解決可能である。3)については、どのような部位に埋入することに
なっても、基本的に生体内の全組織には毛細血管網により血流があるため、総循環体液量を考慮
して試験溶液・抽出溶媒量を決定することになる。しかし、例えば成人の血漿量は体重の約 5%、
細胞外液量は約 15%であり、そのままのスケールで実施するとなると 1 L 以上の疑似体液が必要
になる。生物学的安全性評価のための抽出液作製においては、例えば 1/100 にスケールダウンし
て実施した場合には安全率 100 を掛けている、との解釈も可能と考えられる。一方、生体吸収性
材料の分解特性においては、成人の状況を念頭に十分量の試験溶液を用いること、および単位表
面積当たりの試験溶液量が分解速度に及ぼす影響を検証することで対応可能と考えられる。
4.おわりに
生体吸収性金属材料およびその血管ステント応用について、開発の現状と課題について概説し
た。上述したように、いずれの材料についてもまだまだ研究開発の段階ではあるが、実用化まで
の開発プロセスにおいて、生体内分解性・生物学的安全性評価手法の確立は非常に重要である。
今後、本事業を通してこれらの課題が解決され、我が国における生体吸収性材料製医療デバイス
の早期実現に貢献できれば幸いである。
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25)高木洋治, 山東勤弥, 李鐘甲, 根津理一郎, 岡田正;”XI 栄養療法(経腸栄養、静脈栄養)
とミネラル・微量元素”, 鈴木継美, 和田攻編「ミネラル・微量元素の栄養学」, 第一出版, 東京,
pp.135-156(1994).
26)Bowen PK, Drelich J, Goldman J; Advanced Materials 25:2577-2582(2013).
Ⅲ-4
生体吸収性ステントの In vitro 評価
早稲田大学理工学術院
先進理工学研究科
共同先端生命医科学専攻
岩﨑
清隆
1.はじめに
生体吸収性ステントは、永久留置型の金属製ステントと比較して体内で分解され血管内に最終
的に異物が残らないというこれまでにない画期的な特徴を有する。永久留置型の薬剤溶出型金属
ステントにおいて課題としてある、不完全な内膜被覆による長期に渡る血栓症のリスク 1),2)、ステ
ントの疲労破断に起因する再狭窄や血栓症のリスク 3)-5)が低減される可能性が期待できる。その反
面、ステントの材料、設計、厚さで決まる力学的特性が永久留置型金属製ステントと比較して小
さく 6)-8)、早期分解による血管拡張不全やステント断裂による再狭窄や血栓症のリスクがある。狭
窄病変を拡張し、生体血管内で晒される負荷がステントに作用する環境での経時的な血管拡張力
に関する性能、また、in vivo を想定した負荷環境での経時的な分解や破断の関係の特徴を示す耐
久性は生体吸収性ステントの評価項目として重要であり、in vitro 試験法の開発は重要かつ急務で
ある。本項では、永久留置型の金属製ステントで求められる評価に加え、生体吸収性ステントで
新たに必要と考えられる in vitro 評価についてまとめる。
2.生体吸収性ステント材料の力学的特性
生体吸収性ステントは、主にポリ乳酸やマグネシウム合金を利用して開発されている。化学組
成や製造方法等の違いにより、力学的特性や分解期間は表1のように異なる 6-8)。
(1)引張破断強度
引張破断強度はステントの破断耐久性に影響を及ぼす力学的因子である。引張破断強度に関し
ては、バルーン拡張型の冠動脈ステントに現在最も使用されているコバルトクロム合金と比較し
て、ポリ乳酸では 3~12%程度、マグネシウム合金では 15~35%程度である。同様に、自己拡張
型の大腿膝窩動脈ステントや頚動脈ステントに使用されているニッケルチタン合金と比較すると、
破断強度は、ポリ乳酸では 3~16%程度、マグネシウム合金では 16~48%程度である。
(2)引張破断ひずみ
引張破断ひずみは、例えば冠動脈ステントではステントを過拡張する際にステント破断が生じ
るまでの伸びの限界を示す力学的因子である。コバルトクロム合金およびニッケルチタン合金と
比較して、ポリ乳酸では 2~15%程度および 3~60%程度、マグネシウム合金では 4~44%程度お
よび 5~200%程度である。したがって、ステント留置時の初期拡張成功を獲得するために、ステ
ント材料の力学的特性を踏まえたステントの適正な拡張法と拡張限界に注意する必要がある。
表1 生体吸収性ステントと永久留置型金属製ステントに用いられる材料の力学的特性の比較
組成
引張弾性率
GPa
引張破断強度
MPa
引張破断
ひずみ %
分解期間
月
Poly(L-lactide)6)
3.1-3.7
60-70
2-6
>24
Poly(D,L-lactide)6)
3.1-3.7
45-55
2-6
6-12
Poly(glycolide)6)
6.5-7.0
90-110
1-2
6-12
50/50
D,L-lactidde/glycolide6)
3.4-3.8
40-50
1-4
1-2
82/18
L-lactide/glycolide6)
3.3-3.5
60-70
2-6
12-18
Mg alloy6)
40-45
220-330
2-20
1-3
Stainless steel 316L6)
193
668
40+
生体内で安定
Stainless steel 316L7)
193
595
60
生体内で安定
233
930
45
生体内で安定
243
1000
50
生体内で安定
Cobalt chromium6)
210-235
1449
≈40
生体内で安定
Platinum chromium7)
203
834
45
生体内で安定
Nitinol6)
45
120(austenite)
50(martensite)
700-1100
10-20
生体内で安定
690-1380
13-40
生体内で安定
Cobalt chromium
MP35N7)
Cobalt chromium
L6057)
Nitinol8)
3.生体吸収性ステントの拡張に関する検討項目
ステントの基本性能として拡張径がある。引張破断ひずみが本邦で臨床使用されて広く普及し
ている永久留置型の金属製ステントと比較して小さいため、生体吸収性ステントでは、過拡張に
対する制限があることに注意する必要がある。
(1)ステントが破断しない最大拡張径
血管は、一般に遠位部に行くにしたがって径が小さくなる。近位部と遠位部で血管径の差があ
る場合にはステントを血管壁へ圧着させるために、図1に示すようにバルーンによる後拡張が必
要となる場合がある。また、病変の特徴に応じてバルーンを過拡張する場合もある。ポリ乳酸ス
テントの臨床報告で、後拡張した際にステントが破断して、血管内腔側に倒れてきたという報告
がある 9)。したがって、ステント破断が起きない安全な拡張径の範囲を明示することが望ましい。
(2)分岐部血管にステント留置時にステントから側枝に向けてバルーンで後拡張した際のステ
ント破断しない最大拡張径
冠動脈ステントを用いた血管治療の中で分岐部血管は 15~20%を占めるといわれている 10)。
分岐部にステントを留置する際には、図2に示すように側枝に架かっているステントをそのまま
にして治療を終える場合と、側枝に架かっているステント部を拡張する場合がある 11)。側枝を拡
張する場合には、ステント破断を起こさない拡張径に関するデータを取得することが、安全な普
及に向けて望まれる。
遠位部(Distal)
近位部(Proximal)
図1 テーパ血管でのステントの後拡張
側枝を未拡張
側枝を拡張
図2 血管分岐部にステント留置時の側枝流入部に架かっているステント部の拡張の有無
4.生体吸収性ステントの経時的拡張保持力の評価
狭窄病変を拡張した生体吸収性ステントは、留置初期が最も血管拡張保持力があり、分解とと
もに最終的に血管拡張保持力はなくなる特徴がある。図3は継時的なステントの分子量、質量損
失、ステントの拡張保持力の関係の概念図を示したものである 6)。内膜で覆われる一定期間まで
必要な血管拡張力の経時的な特性を示す非臨床試験データの提示は、重要な評価項目である。以
下に、本試験における考慮すべき因子を示す。
ステントの
拡張保持力
最大
経時的な分解と拡張
質量損失
保持力の関係の評価
(分解量)
が必須
分子量
最小
0
12
体内埋め込み後の経過時間 月
24
図3 生体吸収性ステントの分子量,質量損失とステントの拡張保持力の
経時的変化の概略図(文献6を改変)
(1)溶液
分解性の評価では、溶液の pH、イオン構成・強度、温度を in vivo での生理的環境に合わせる
ことが重要である 12), 13)。溶液に関しては、ポリ乳酸を用いたステントに関して、リン酸緩衝生理
食塩水を用いた in vitro 試験とブタでの in vivo 試験で数平均分子量の低下の遷移傾向が類似する
結果が示されている 14)。マグネシウム合金では、リン酸緩衝生理食塩水を溶液として用いた in
vitro 試験では、
ラットでの in vivo 試験と比較して分解速度が顕著に早いことが示されている 15)。
血清が分解を抑制する因子であることがわかっており 16)、マグネシウム合金の試験では考慮すべ
き点である。
(2)狭窄血管モデル
狭窄部を拡張したステントは、図4に示すように血管壁から負荷を受けた状態で力が釣り合う。
応力が高くひずみが生じている部分は分解速度が速くなるため 14), 17)、in vivo を想定したステン
トへの負荷を組み込んだ試験が望まれる。
(a)ステント拡張前
(b)ステント拡張後
図4 狭窄血管でステント拡張後の力の釣り合い
(3)流れ環境
In vivo では常に拍動血流・血圧に晒されている。In vivo を想定した生理的な拍動数かつ流れ
環境での試験は、in vivo における分解過程を評価する上で重要な因子と考えられる。
5.生体吸収性ステントの耐久性評価
生体吸収性ステントに関しては、血管を拡張することが期待される一定期間、構造を保持する
ことを示す耐久性試験が必要である。In vivo で想定される負荷環境での試験が重要である。拍動
による血管の径方向の負荷は、冠動脈ステントの試験に関して『平成 15 年 9 月 4 日付薬食審査発
第 0904001 号』18)に記載されている最低限の基本的項目である。臨床では、図5に示すように、
心臓の収縮・拡張にともない冠動脈が繰り返し屈曲変形する部位でステントに疲労破断が起こる
ことが認知されている 4), 19), 20)。In vitro の繰り返し屈曲負荷を作用する加速耐久試験において、
各種ステントの臨床での破断傾向と合う結果が示されており 21), 22)、繰り返し屈曲負荷は構造保持
を示す耐久試験で検討すべき重要な因子である。
合わせて、溶液の pH、温度を生理的環境に合わせることが必要である。ポリ乳酸では、溶液
の温度を上げることで分解速度が上昇することがわかっている 23)。加速負荷試験を行う場合には、
材料の化学的な分解速度を負荷の加速条件と合わせることが重要であり、加速試験の妥当性を示
す必要がある。
図5 心臓の収縮・拡張にともなう冠動脈の繰り返し屈曲変形
6.おわりに
生体吸収性ステントの材料特性を踏まえたステントの拡張に関する検討項目、そして、生体吸
収性ステントの非臨床評価として新たに求められる経時的拡張保持力の評価試験、耐久性評価試
験についてまとめた。これらの in vitro 試験が生体吸収性ステントの迅速評価の一助となれば幸
いである。
文献
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Defining a Material Model for a Biodegradable Stent Fiber, Department of Health and
Human Services, Food and Drug Administration, Silver Spring, MD, 2012.
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認申請に係る取扱いについて、平成 15 年 9 月 4 日
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Ⅲ-5
In Vivo 評価について
東海大学
循環器内科
中澤
学
1.従来の冠動脈内デバイスの動物実験における評価
薬剤溶出ステントをはじめとする冠動脈内デバイスの動物実験を用いた評価には、豚の冠動脈
モデルがゴールドスタンダードとして長らく使用されてきた。しかし、近年はうさぎ腸骨動脈モ
デルも一定の信頼を得て、多く使用されている。
一般的に動物モデルではステント留置後 1 ヶ月後の新生内膜増殖抑制効果をもとに有効性を判
定する。しかし、長期的安全性の指標となる生体適合性に関しては、より長期(3 ヶ月~1 年)の
留置期間で評価する。特に薬物溶出、生体分解などの過程が関与する場合は、その過程が終了し
反応が沈静化するまでの期間を最低限評価する必要がある。また、ステントストラットの被覆化
(再内皮化)に関しては、増殖の緩徐なうさぎ腸骨動脈モデルを選ぶか、もしくはブタ冠動脈モ
デルでより早いタイミングでの評価を行うことが好ましい(2 週間後など)
。
モデルの特性として
ブタ冠動脈:

心臓の動きによる影響が判定できる(ステントの血管への追従性、フラクチャーなど
の評価に適する)

ステントを留置した周囲の組織への影響や(心筋の評価により)末梢塞栓などを評価
できる
うさぎ腸骨動脈:

豚冠動脈モデルに比して個体差が比較的少ない

比較的反応が緩徐であるため再内皮化などの評価に適する

飼育や実験が簡便である
などが挙げられる。
(図1)1)
2.実臨床での成績と動物実験での相関
適切なモデル、タイミング、評価方法を選択すれば、冠動脈内デバイスの実臨床における有効
性、安全性に関して、かなり相関があると考えられる。
たとえば、第一世代薬剤溶出ステントについて例を上げると、動物実験において CYPHER ス
テント(シロリムス溶出ステント)は炎症反応が強く、また晩期に増加する傾向があるのに対し
て、TAXUS(パクリタキセル溶出ステント)はフィブリンの沈着が強く出る症例が多いことが報
告されているが 2)、剖検例を用いた実臨床での生体反応を見てみると、かなり類似した反応が得
られていることが分かる(図2)3)。また、有効性の評価としても、うさぎ動脈硬化腸骨動脈モデ
ルを用いた実験では実臨床での新生内膜増殖抑制効果を非常によく反映した結果が得られること
が報告されている 4)。
一方で、古くはアクチノマイシン溶出ステントが豚冠動脈モデルにおいて留置後 28 日時点で有
意な内膜増殖抑制を認めたため、臨床治験がスタートしたが、その後動物モデルで 90 日後には著
しい炎症反応により Late catch-up(遅発性再狭窄)が見られ、同様に実臨床においてもステント
両端を中心とする再狭窄が認められたため承認が得られなかった。また、開発当初のシロリムス
溶出ステントを評価し有効性を示した豚冠動脈モデル実験において、留置後 28 日時点でのステン
トの内皮化を評価し、ベアメタルステントと違いはなかったと評価している 5)。しかし、後に実
臨床では治癒過程障害による遅発性血栓症が問題になっており 6, 7)、この事象についてはこの動物
実験では予知しきれなかったことになる。その後、うさぎ腸骨動脈を用いてこれらの薬剤溶出ス
テントの再内皮化が遅れることが示された 8)。
以上のように、適切なモデル、評価のタイミング、評価の方法が臨床成績を予知する上で非常
に重要であると考えられる。
3.生体吸収性ステントの場合の特殊性
これまでに、臨床応用されているアボット社の Absorb(エベロリムス溶出生体吸収性スキャフ
ォルド、bioresorbable scaffold、BRS)に関する動物実験が既にいくつか報告されている 9, 10)。
これらの実験でも検討されているとおり、生体吸収性ステントの吸収過程を詳細に検討する必要
が有り、その生体反応の変化などが主な評価対象となる。前述のとおり、デバイスの新生内膜抑
制効果や長期の生体適合性などについては評価可能であるが、下記が生体吸収性ステント評価の
際の特有の問題点として挙げられる(図3)
。
① 一般的に生体反応は動物の方が早いことが知られているが、デバイスの吸収速度は動物内
も人間内も概ね同じであると考えられる(ただし、下記 C も参照)。このため、反応と吸
収過程にギャップが生じ、このため動物実験における吸収過程と生体反応のタイミングが
どこまで人間の生体内の反応を反映するかが不明である。
② 一般的に用いられる動物モデルは病変モデルでないため、生体吸収性ステントで重要とさ
れる Radial force の評価が困難である(線維性プラークや石灰化プラークに対する拡張能
の評価が困難)
。
③ 生体吸収性ステントの吸収速度に影響する炎症細胞、留置部の pH、病変部の脂質の含有な
どが人体内の冠動脈病変と違うため、吸収速度が動物実験では若干異なる可能性がある。
図1 豚冠動脈およびうさぎ腸骨モデルの利点と問題点
図2 動物モデルと人間での局所反応の類似性
図3 生体吸収性スキャフォルドの吸収過程と炎症、フィブリン沈着 10)
図4 BVS と Xience の血管、内腔面積および狭窄度の経過 10)
文献
1)Nakazawa G, Finn AV, Ladich E, Ribichini F, Coleman L, Kolodgie FD, Virmani R.
Drug-eluting stent safety: Findings from preclinical studies. Expert Rev Cardiovasc Ther.
2008;6:1379-1391
2)Wilson GJ, Nakazawa G, Schwartz RS, Huibregtse B, Poff B, Herbst TJ, Baim DS, Virmani
R. Comparison of inflammatory response following sirolimus and paclitaxel drug-eluting
stents implanted in porcine coronary arteries. Circulation. 2009;In Press
3)Nakazawa G, Finn AV, Vorpahl M, Ladich ER, Kolodgie FD, Virmani R. Coronary
responses and differential mechanisms of late stent thrombosis attributed to
first-generation sirolimus- and paclitaxel-eluting stents. J Am Coll Cardiol.
2011;57:390-398
4)Nakazawa G, Nakano M, Otsuka F, Wilcox JN, Melder R, Pruitt S, Kolodgie FD, Virmani R.
Evaluation of polymer-based comparator drug-eluting stents using a rabbit model of iliac
artery atherosclerosis. Circ Cardiovasc Interv. 2011;4:38-46
5)Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou
G, Narayan P, Leon MB, Yeung AC, Tio F, Tsao PS, Falotico R, Carter AJ. Stent-based
delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation.
2001;104:1188-1193
6)Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P,
Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S,
Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and
paclitaxel-eluting stents in routine clinical practice: Data from a large two-institutional
cohort study. Lancet. 2007;369:667-678
7)Joner M, Farb A, Cheng Q, Finn AV, Acampado E, Burke AP, Skorija K, Creighton W,
Kolodgie FD, Gold HK, Virmani R. Pioglitazone inhibits in-stent restenosis in
atherosclerotic rabbits by targeting transforming growth factor-beta and mcp-1.
Arterioscler Thromb Vasc Biol. 2007;27:182-189
8)Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK,
Gold HK, Virmani R. Differential response of delayed healing and persistent inflammation
at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 2005;112:270-278
9)Onuma Y, Serruys PW, Perkins LE, Okamura T, Gonzalo N, Garcia-Garcia HM, Regar E,
Kamberi M, Powers JC, Rapoza R, van Beusekom H, van der Giessen W, Virmani R.
Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years
after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine
coronary artery model: An attempt to decipher the human optical coherence tomography
images in the absorb trial. Circulation. 2010;122:2288-2300
10)Otsuka F, Pacheco E, Perkins LE, Lane JP, Wang Q, Kamberi M, Frie M, Wang J,
Sakakura K, Yahagi K, Ladich E, Rapoza RJ, Kolodgie FD, Virmani R. Long-term safety of
an everolimus-eluting bioresorbable vascular scaffold and the cobalt-chromium xience v
stent in a porcine coronary artery model. Circ Cardiovasc Interv. 2014;7:330-342
Ⅲ-6
イメージングによる評価
神戸大学大学院医学研究科
内科学講座
循環器内科学分野
新家
俊郎
1.はじめに
生体吸収性ステントは、新しい冠動脈疾患の治療デバイスである。狭窄や閉塞を解除し、一定
期間冠動脈内腔を支持する(スキャホールド)役割を終えると、生体内に吸収されて血管は健常
な機能を回復することが期待される。生体吸収性ステントを用いた冠動脈インターベンション
(percutaneous coronary intervention、PCI)の潜在的利点としては以下の点が挙げられる。

不安定プラークのシーリング

金属ステント慢性期で見られるフラクチャーがない

血管形態が自然な形に戻り、生理的拡張能が回復する

慢性期に内腔が大きくなる

CT / MRI での血管評価が可能

超慢性期に PCI / 冠動脈バイパス移植術(coronary artery bypass grafting、CABG)によ
る再治療を妨げない

超遅発性血栓症、晩期再狭窄が少ない可能性

治療部位の新たな動脈硬化が少ない?
上記の長期的な利点が謳われる一方で、PCI 治療急性期の合併症が増加する可能性が指摘され
ており、冠動脈イメージングによる評価が重要である。
2.イメージングの種類
冠動脈イメージングとして、多数のデバイスの臨床的有用性が示されている(図1)。中でも、
生体吸収性ステントの留置手技時と慢性期の血管反応性を評価するデバイスとしては、光干渉断
層映像法(optical coherence tomography、OCT)の演じる役割は大きい。血管内超音波法
(intravascular ultrasound、IVUS)に比し約 10 倍の解像度(20 µm)を有し、特に生体分解性
ポリマーを用いたデバイスの可視化においては IVUS では描出困難なストラット断面像を明瞭に
描出できる(図2)
。
図1 冠動脈イメージングに使用されるデバイス
図2 冠動脈イメージング:生体吸収ステントをヒト冠動脈に留置直後の
OCT 及び IVUS 像。OCT では、ステントの横断面が明瞭に描出される。
3.報告されている成績
(1)前臨床:慢性期、超慢性期における病理所見との対比
すべての冠動脈拡張用デバイスがそうであるように、前臨床試験によって、その効果と安全性
が検証されてから臨床試験に移行する。生体吸収性ステントでは特に、慢性期の吸収過程を病理
学的に評価して、冠動脈イメージングとの対応が検討される。OCT はストラットの吸収過程とス
テント内の新生内膜増殖を正確に評価することが可能であり、前臨床試験の中でも頻用されてい
る。生体吸収性ステントはその分解吸収過程において、まず分子量の減少が起こり、ストラット
の量的減少が続く。この際にストラット内に平滑筋細胞など新生組織が入り込んでいくが、前臨
床試験で得た、病理所見と対応した OCT 画像は臨床試験に移行した際の重要な参照イメージとな
る。
また、長期の血管反応性を評価することもイメージングの役割として重要である。Lane LP ら
は、豚冠動脈モデルを用いて最長 42 ヶ月までの血管反応性を評価したが、生体吸収性ステントは
金属性薬剤溶出性ステント(drug eluting stent、DES)に比し、長期的な内腔面積の拡大を報告
している(図3)1)。
図3 薬剤溶出性生体吸収ステントおよび金属ステント留置後の経時的変
化:豚冠動脈モデルにおける、留置 1, 6, 12, 24, 30, 36, 42 ヶ月後の病理像
と対応する OCT 画像。OCT でも吸収過程を観し得る。
(2)臨床試験
1)急性期
現在一般臨床で使用されている生体吸収性ステントは、Abbott Vascular 社の BVS のみであ
るが、ステント留置時のいくつかの pit fall が報告されている。ストラットが金属製 DES に比
して厚いため、狭窄部へのデリバリーが困難、圧着不良が起こりやすい、小さな側枝閉塞をき
たしやすい、オーバーラップ留置時に内腔への突出が大きいなどが主な論点である。また、拡
張力がやや弱いため、拡張不良が起こりやすく、それを回避するためには病変の前拡張を大き
く行う必要がある。一方で、金属ほどの伸展能を有さない素材であるため、過拡張によるスト
ラット破断の危険があること(拡張限界の存在)も指摘されている。OCT を用いた臨床研究で
は、径の大きな冠動脈では圧着不良の頻度が高く、径の小さい血管では拡張不良とエッジ解離
が多く発生することが報告されている(図4)2)。報告によって結果に差があるものの、金属
製ステントに比して術後 30 日以内の早期ステント血栓症が多く発生する傾向にあり、留置手
技の最適化が進められている現状と思われる。
図4 生体吸収ステント留置直後の OCT 所見:定量的冠動脈造影による
最大血管径(DMAX)ごとに差異が認められる。大きな血管に対して生体
吸収ステントを留置すると圧着不良が高頻度に認められ、一方小さい血管
では拡張不良とエッジ解離が多く認められる。
2)慢性期
Abbott Vascular 社の BVS においては、最長 5 年程度までフォローアップした報告が散見さ
れる。OCT を用いると、新生内膜によるストラット被覆、吸収過程を観察していると考えられ
るストラットイメージの変化を可視化できる。留置 3-5 年後には、ストラット構造が新生内
膜と識別不能となり、均一な内膜肥厚として描出される。IVUS を用いた検討では、留置 6 ヶ
月後と 2 年後を比較して、スキャホールド面積と内腔面積の拡大が認められた 3)。金属ステン
トで見られるようなストラットによるアーチファクトが少ないため CT で内腔の評価が可能と
される。また、アセチルコリン負荷試験後の血管径の変化を測定して、内皮依存性血管拡張反
応が回復したとする報告や、パルポグラフィーを用いて、慢性期に生理的な血管捻弾性が回復
したとする報告がある。側枝入口部を覆っていたストラットが留置慢性期には消失し、新しい
側枝入口部が形成されるとするものもある。これまでのところ、いずれも長期的には生理的な
血管機能の回復を観察するとしている報告が多く、それらが狭心症症状の再発抑制に寄与して
いる 4)のか否か今後の検討が待たれる。
4.イメージングの評価指標として、追加考慮されるもの(今後の検討課題)
(1)前臨床
1)急性期:留置直後、早期のイメージングの報告は少ない
①
屈曲部に留置した場合の追従性
②
残存する拡張不良/ 圧着不良、エッジ解離の頻度
③
急性リコイル
④
前臨床試験での早期イベント例の病理学的検討、イメージングの収集
2)慢性期:実臨床を想定したモデルでの検討
①
障害血管モデル、動脈硬化モデルでの評価
②
オーバーラップ留置例、分岐部への留置、先細り(tapered)血管
③
Radial force の経時的変化の評価
(2)臨床試験
1)急性期:
①
留置手技と術者教育の標準化策の提示
②
留置直後イメージ:急性期リコイル、圧着度、組織逸脱/血栓形成
③
オーバーラップ留置例
④
分岐部留置例
⑤
ステント血栓症症例のイメージング
2)慢性期:
①
オーバーラップ留置例
②
分岐部留置例
3)イベント例:
①
イメージング評価
②
背景因子の検討
5.総括
生体吸収性ステントはその長期効果に期待が集まる一方で、急性期合併症が増加することが危
惧される。評価指標の作成に際しては、急性期の効果と安全性、慢性期の治癒過程の評価、両面
から検討する項目立てが必須と考えられる。OCT などのイメージングによる、留置手技のモニタ
リングと慢性期評価が必要である。
文献
1)Lane JP et al. J Am Coll Cardiol Cardiovasc Intv 2014;7:688-95
2)Gomez-Lara J et al. Eurointervention 2012;8:214-24
3)Ormiston et al. Circ Cardiovasc Interv. 2012;5:620-632
4)Serruys PW, et al. Lancet. 2015;385:43-54
Ⅲ-7
臨床的観点から考えられる構造的問題点
佐賀大学医学部循環器内科
挽地
裕
1.はじめに
既に EU 圏内では Biodegradable Vascular Scaffolding(BVS)が臨床使用されており、その
有効性が証明されるとともに今後解決すべき課題も示されてきた。この章では、メタルステント
と比較して BVS で臨床使用時/留置後中長期に懸念される問題点として、

サイズのミスマッチと過拡張による破損

留置後急性期・慢性期の評価方法

分岐部病変における BVS の経時的変化
の項目につき検討する。
2.サイズのミスマッチと過拡張による破損
(1)急性心筋梗塞
急性心筋梗塞の際には、閉塞した冠動脈の血管径が正常時より小さくなっていることが多々あ
る。再灌流を維持するために冠動脈ステントを留置するが、メタルステントであれば後拡張を追
加する事で血管壁にステントを圧着させる事が可能である。
しかし、BVS を用いた場合には推奨拡張径より 0.5 mm を超える過拡張を行うと構造が破断す
ることが確認されている。複数箇所で破断した際には、血管壁に対するラディアルフォースがな
くなる。また血管壁に BVS の構造物が不完全圧着し、血管壁内で遺残することになるため、留置
部位での血栓性が増す危険性が危惧される。
(2)労作性狭心症
冠動脈狭窄部位前後で血管径が 0.5 mm 以上異なる場合がある。さらに狭窄部を解除したこと
により末梢血管径が大きくなる場合がある。対照血管径を測定するために血管内エコー検査・
OCT/OFDI 等での計測を行う際にも狭窄解除前の計測では末梢側は小径に計測される。小さなス
テントを留置した際には、先に述べているような不完全圧着のままの BVS の遺残、過拡張にとも
なう BVS の破断が起こりうると危惧される。
3.留置後急性期・慢性期の評価方法
通常、冠動脈治療は連続透視撮影/記録を行える冠動脈造影装置による透視下で手技を行うのが
基本である。しかし、BVS はその材料の特性上、デリバリーシステムマウント時、あるいは拡張
後も透視下ではその本体を確認することは出来ない。確認できるのは両端の小さなゴールドマー
カーのみである。
ゴールドマーカーが着いていることにより冠動脈長軸方向におけるジオグラフィックミスは起
こりにくい。しかし、拡張したあと BVS の不完全拡張の有無、血管壁への圧着の程度を冠動脈造
影装置で確認することは出来ない。血管造影装置を使った様々な方法で留置した BVS を確認する
ためのソフトウェア開発が続けられているが、未だ確立されている方法はない。
血管内エコー検査では BVS は評価できないというのが定説である。実際には条件が良ければ留
置直後の BVS を観察することは可能である。しかし、慢性期を含めると BVS を留置した部位が
慢性的に観察できる方法には成っていない。
光干渉断層法(OCT/OFDI)は解像度が約 10-15 µm と IVUS の約 10 倍の高い分解能を有して
おり BVS を観察するために有用である。これを用いることで留置直後の BVS の不完全圧着や破
損を確認することが可能である 1)。しかし、検査時には血液を遮断する/あるいは造影剤へに置換
する必要があり、カテーテル検査と同じ侵襲を必要とする。従って慢性期の確認等で頻回に行う
わけには行かない。
冠動脈造影 CT 検査(MDCT)を用いることで、メタルステントであれば留置位置を明瞭に把
握することが出来る。しかし、MDCT を用いても BVS 本体を確認することは出来ない。両端の
ゴールドマーカーは確認できるため、再狭窄の有無を確認するためには造影剤を用いて撮影する
ことによりその内腔を計測することが可能であるが、BVS の変形については確認することは困難
である。また、両端マーカーのみしか認識されないため、複数の BVS を留置した際には、留置位
置を把握することが困難になるものと危惧される。
4.分岐部病変における BVS の諸問題
冠動脈分岐部病変は冠動脈治療の対象病変のおよそ 20%を占めている。本管に BVS を留置し
た場合側枝入口部が Jail(本管にステントが留置された際に側枝入口部にストラットがかかって
いる状態)される場合も当然多くなる。この時点で側枝の血流低下を認めれば、側枝側に向けた
拡張が必要になる。メタルステントであれば、この際に本管と側枝に向けて二本のバルーンで同
時拡張を行う拡張方法(Kissing balloon dilatation technique、KBT)を通常実施する。しかし、
BVS を本管に留置した際に側枝をいかに処理するかについては定かでない。懸念されるのは以下
の二点である。

KBT を行わない場合
側枝入口部には血管壁に圧着しない BVS のストラットが遺残する。留置後数ヶ月以降に未
圧着のストラットの表面には何らかの組織が付着し増生することが確認されている。さら
に数年以内に BVS が完全に消失した際に neointimal bridge として残る場合がある 2)。こ
れが臨床的に問題になりうるのかこれまで検討されておらず、対処の必要性も今後検討す
る必要がある。

KBT を行う場合
BVS のストラット越しにバルーンを拡張させるためストラットの破断を来す可能性が高い。
ベンチ実験では本管に BVS の留置後に本管を径 3.5 mm のバルーン、側枝を径 3.0 mm の
バルーンを用いて 5 気圧同時拡張することで、BVS のストラットが破断することなく側枝
に向けて BVS を変形させることが出来ている 1)。しかし、これ以上の拡張を行った場合に
は一部のストラットが破断する事が確認されている。一部分のみのストラット破断が臨床
的になるのかは不明である。
以上、今後 BVS を臨床使用するにあたり解決すべき問題を挙げた。
文献
1)Ormiston JA, De Vroey F, Serruys PW, Webster MW, Bioresorbable Polymeric Vascular
Scaffolds: A Cautionary Tale. Circ Cardiovasc Interv. 2011 Oct 1;4(5):535-8.
2)Okamura T, Garg S, Gutiérrez-Chico JL, Shin ES, Onuma Y, García-García HM, Rapoza
RJ, Sudhir K, Regar E, Serruys PW, In vivo evaluation of stent strut distribution patterns
in the bioabsorbable everolimus-eluting device: an OCT ad hoc analysis of the revision 1.0
and revision 1.1 stent design in the ABSORB clinical trial. EuroIntervention. 2010
Apr;5(8):932-8.
Ⅲ-8
Biodegradable Vascular Scaffolding (BVS) Clinical Trials
順天堂大学医学部医学研究科
循環器内科
宮内
克己
1.緒言
冠動脈インターベンションは現在薬剤溶出ステント(Drug-Eluting Stent、DES)として
Everolimus-Eluting Stent(EES)が最も臨床的に汎用されているが、ステントが異物として残
存することやポリマーによる炎症反応惹起が長期的には問題となる可能性がある。超遅発性ステ
ント血栓症や neoatherosclerosis という新たなプラークの進展などである。ステントが一定期間
に消失、すなわち異物がなくなるという観点から開発されたデバイスが Biodegradable Vascular
Scaffolding(BVS)である。理論的には異物やポリマーが消えれば、抗血小板薬の 2 剤併用は不
要となるか、抗血小板薬自体が不要となる可能性もあり、出血リスクは減少すると考えられる。
また、現在、DES は平均 4 本留置され、総ステント長は 100 mm に及ぶといわれているなかで、
長期の観察期間で再血行再建が必要になることもあり、その時にステントが消えていればバイパ
スを含む治療選択肢は多く、かつ容易となる。以上のように BVS への期待は高まるが、支えとし
て血管リモデリングを抑制するのがステントであり、それが消失することは血管が収縮するリス
クもはらんでいることになる。このような BVS の理論的な利点や欠点は臨床の場で検証する必要
があるが、実践で使用するなかで思いがけてない欠点や利点を見出すこともある。そこで、実際
の治験から欧州での実臨床での BVS の安全性から有益性までの治療成績を概説する。
2.臨床試験の目的とエンドポイント
現在、BVS の臨床試験は図1、2に示すような計画で進められている。検討事項は安全性と有
効性であるが、前者はイベントとして心血管事故やステント血栓症、後者は画像診断で内膜肥厚
や内腔面積であり、その結果を現在の標準治療である EES の成績と比較し、非劣勢を証明するこ
とが臨床試験の目的となっている。現在のステント臨床試験は 1 次評価項目として Target Lesion
Failure(TLF)、Major Adverse Cardiac Events(MACE)、Target Vessel Failure(TVF)のい
ずれかを用いることが多い。最も多いエンドポイントである MACE は心血管死亡、心筋梗塞、臨
床的虚血のある標的部位再血行再建(clinically-driven target lesion revascularization、CD-TLR)
の 3 イベント、TLF は心血管死亡と標的血管を責任病変とする心筋梗塞、CD-TLR と定義し、TVF
は CD-TLR の代わりに標的血管再血行再建(clinically-driven target vessel revascularization、
CD-TVR)とする。心血管事故が重要であることはいうまでもないが、血管内の情報、すなわち
留置部位の内腔や内膜肥厚の程度、血栓の有無、BVS の変化なども 2 次評価項目としている。こ
れは最近の画像診断デバイスの発展におうところが大で、血管内超音波(intravascular
ultrasound、IVUS)、VH(virtual histology)-IVUS、光干渉断層法(optimal coherence
tomography、OCT)、冠動脈 CT など様々な画像診断を駆使して経時的に観察している。
3.初期前向き臨床試験
ABSORB 試験
いわゆる FIM(First In Men)が ABSORB 試験であり、コホート A、B さらに B は画像診断
時期により B1、B2 に分けられている。コホート A は BVS の安全性を担保する目的で 2006 年に
30 例の低リスク患者に施行され、単純病変の初回病変へステント長 12 mm あるいは 18 mm の
BVS を単独で留置した 1)。追跡は 6 ヶ月、1 年、2 年時に冠動脈造影(CAG)、IVUS、VH-IVUS
などを施行した。MACE は 4 年の追跡で 3.4%、6 か月で 1 例のみ心筋梗塞を発症したが、6 か月
から 5 年までのイベントやステント内血栓症は 1 例も認めなかった。少数例かつ単純病変に施行
したとはいえ、BVS の安全性が担保できる妥当な臨床試験結果となった。また定量的冠動脈造影
法(quantitative coronary angiography、QCA)の 6 ヶ月後の評価では損失血管径は 0.44 mm
であり、これまで報告されている通常の金属ステント(BMS)の 0.8 mm に比べれば少なかった
が、Xience ステントでの 0.11 mm と比べれば大であった。その原因は内腔面積が留置直後に比
較して 11.8%減少していることによると考えられるが、内膜肥厚は少なく、血管がリモデリング
したためであった。この原因は早期に BVS の吸収が始まったことで、ステントの支えが減少した
ことによるリコイルに起因し、”scaffold shrinkage”と呼ばれている。この研究では BVS の内
腔狭窄の評価などに多くの画像を用いている。冠動脈 CT は内腔面積や狭窄度を DES では金属反
射で正確に評価できなかったが、BVS では QCA と比較し正確度に差異がないことが確認された。
IVUS 画像からはステントストラットに一致する高エコー輝度領域は留置直後から 6 ヶ月(18.5%
to 10.3%)、さらに 6 ヶ月から 2 年(10.3% to 7.7%)で減少したことから、BVS は 6 ヶ月という
短期から 2 年までで確実に吸収されていることが判明した。また、最少内腔面積や平均内腔面積
は留置直後から 6 ヶ月で減少するが、6 ヶ月から 2 年で増加したことから、”scaffold shrinkage”
は時間の経過とともに改善することが明らかになった 2-4)。
また、コホート B は BVS の形状や材質を一部変更して BVS の性能を向上させ、第 2 世代の
BVS1.1 で施行された試験である 5)。101 人の患者を 5 年間、QCA、IVUS、OCT 画像を用いて追
跡し、BVS の溶解過程を追跡する有効性かつ安全性を検証する試験である。CAG での 6 か月の
損失血管径(late lumen loss、LL)は 0.19 mm まで向上し、2 年、5 年での病変部位の狭窄度に
変化はなく、これまで報告されている Xience ステントと同等であった。また IVUS や OCT での
6 か月後の BVS 内腔面積減少率はそれぞれ 2.9%、1.9%と第 1 世代で問題となった”scaffold
shrinkage”も改善し、IVUS での 1 年時の新生内膜肥厚面積などの指標は図3に示すように、こ
れまでの Xience ステント試験と比較して遜色のないものであった 6, 7)。またコホート B の 101 例
の心血管イベントは MACE 10 例、TVF 13 例、non-Q 心筋梗塞 3 例、再血行再建 3 例で、心血
管死亡は 1 例も認めなかった 8)。これは BVS だけの結果であり、DES と比較できないことに問
題がある。そこで、これまで報告された Xience V 試験を歴史的コントロールとして、背景因子を
調整して予後を比較すると 3 年間で両群間のイベントに差は認めず、BVS の安全性が許容範囲で
あることが示された。また、BVS の消失は 2 年と 5 年の間で起こっていることも確認された。以
上の点から ABSORB A、B 試験をまとめると、1)BVS の安全性が短期から長期で確認された
こと、2)単純病変に留置すれば心血管事故が少ないこと、3)BVS が冠動脈内から消えること
などが明らかになった。
患者数を増やし多施設で実施されているのが ABSORB EXTEND 試験 9)である。BVS の安全性
を検証する目的で 450 人の患者を 2 年間追跡した前向き臨床試験である。いわゆるステント血栓
症は 1.1%、MACE は 6.7%に認めた。3 年まで追跡できた 250 人では心臓死 0.8%、心筋梗塞 4.0%、
TLR 6.0%、MACE 9.3%、TVF 10.1%、TLF 8.9%、ステント血栓症は 1.2%であった。この比率
が高いか低いかの客観性を検証する目的で、現在の DES の標準治療である Xience ステントをコ
ントロールに Propensity Score Matching という統計学手法を用いて予後を比較した 10, 11)。この
ABSORB EXTEND 250 例中の 174 例と Xience、Spirit I-III 試験の全患者 862 例中 290 例が
Propensity Score Matching の対象となり、両群の予後を比較した。結果は表1に示す通りステ
ント血栓症を含め MACE、MI、ID-TLR 再血行再建は観察期間 3 年で差は認めず、TVF は有意
に BVS 群で低率であった。この結果は後ろ向き解析であるという大きな限界はあるが、
Propensity Score Matching で背景因子を一致させたうえで BVS の DES に対する非劣勢を示し
ており、BVS が Xience ステントと同等の予後であることを示した臨床的意義は極めて高い。
4.初期前向き臨床試験
ABSORB 試験
次に必要な前向き臨床試験は BVS vs DES の head to head 試験であり、その意図に沿って企
画されたのが ABSORB II 試験である。この試験では BVS 335 人、Xience (EES)166 人に 2:1
で無作為化し、6 か月から 1-5 年追跡される予定である。既に 1 年時の追跡結果が報告されてい
る。表2に示すすべてのイベント(死亡、心筋梗塞、すべての再血行再建術率、ステント血栓症)
は両群間で差を認めなかった。この解析で注目すべきは狭心症の出現頻度で EES 25.6% に対し
BVS 16.4%と有意に低かったことである。ただ、その機序については不明である。
この試験結果をうけ、現在いくつかの大規模臨床試験が進行中である。一つは ABSORB III で
2000 人を対象に BVS:EES を 2:1 で割り付け、観察期間 5 年で TLF を 1 次評価項目とした BVS
の非劣勢を証明する試験である。ABSORB IV は 5000 人を対象に BVS と EES に割り付け、1
年以内の狭心症と 5 年での TLF を評価する。既に欧州では BVS は認可されたデバイスであり、
実臨床での登録研究も報告されている。1189 名が登録され、実臨床さながら、複雑病変患者も登
録され 6 ヶ月までの結果が報告されている。ただ気がかりな点は 30 日以内の血栓症が多く発生し
ていることである(図4)。BVS に適した病変選択を誤るあるいは手技上の注意を怠ると、ステ
ント血栓症のリスクがあることに留意しなければならないが、血栓症のリスクは多くの症例数を
積み上げていくことで明確になってくると考えられる。
5.臨床研究の総括
これまでの臨床試験結果からは BVS の心血管イベントやステント血栓症は第 2 世代 DES と同
等であることが明らかになっている。さらに表3に示すような BMS をコントロールとして第 1
世代 DES、第 2 世代 DES、さらに BVS を血管傷害の程度から neoatherosclrosis まで比較する
と興味深い。ステントによる血管傷害度や急性の血栓症は 4 群で差異はなく、炎症惹起や内皮細
胞機能障害は第 2 世代 DES で改善し、BVS でも悪化させないことがわかる。注目すべきは血管
リモデリングと血管拡張反応で、ステントを留置すれば DES の有無に関わらず血管の拡張性リモ
デリングは起こらないし、血管拡張反応も生じない。一方 BVS では血管リモデリングは長期で明
らかに改善し、血管拡張反応も維持される。Neoatherosclrosis は第 2 世代 DES で問題となるこ
ともあるが、BVS ではこの点について長期追跡のデータがないため不明と言わざるを得ない。
文献
1)Dudek D, Thuesen L, Webster MW, et al. A bioabsorbable everolimus-eluting coronary
stent system for patients with single de-novo coronary artery lesions (ABSORB): a
prospective open-label trial. Lancet. 2008; 371: 899-907
2)Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting coronary
stent system (ABSORB): 2-year outcomes and results from multiple imaging methods.
Lancet. 2009; 373: 897-910.
3)Onuma Y, Serruys PW, Ormiston JA, et al. Three-year results of clinical follow-up after a
bioresorbable everolimus-eluting scaffold in patients with de novo coronary artery disease:
the ABSORB trial. EuroIntervention. 2010; 6: 447-53.
4)Dudek D, Onuma Y, Ormiston JA, et al. Four-year clinical follow-up of the ABSORB
everolimus-eluting bioresorbable vascular scaffold in patients with de novo coronary artery
disease: the ABSORB trial. EuroIntervention. 2012; 7: 1060-1.
5)Onuma Y, Serruys PW, Gomez J, et al. Comparison of in vivo acute stent recoil between the
bioresorbable everolimus-eluting coronary scaffolds (revision 1.0 and 1.1) and the metallic
everolimus-eluting stent. ABSORB Cohort A and B investigators. Catheter Cardiovasc
Interv. 2011; 78: 3-12
6)Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting coronary
stent system for patients with single de-novo coronary artery lesions (ABSORB): a
prospective open-label trial. Lancet. 2008; 371: 899-907.
7)Serruys PW, Onuma Y, Ormiston JA, et al. Evaluation of the Second Generation of a
Bioresorbable Everolimus Drug-Eluting Vascular Scaffold for Treatment of De Novo
Coronary Artery Stenosis: Six-Month Clinical and Imaging Outcomes. Circulation. 2010;
122: 2301-12
8)Serruys PW, Onuma Y, Dudek D, et al. Evaluation of the second generation of a
bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary
artery stenosis: 12-month clinical and imaging outcomes. J Am Coll Cardiol. 2011; 58:
1578-88.
9)Abizaid A, Costa JR Jr, Bartorelli AL, et al. The ABSORB EXTEND study: preliminary
report of the twelve-month clinical outcomes in the first 512 patients enrolled.
EuroIntervention. 2014 Apr 29. pii: 20130827-06
10)Muramatsu T, Onuma Y, García-García HM, et al. Incidence and short-term clinical
outcomes of small side branch occlusion after implantation of an everolimus-eluting
bioresorbable vascular scaffold: an interim report of 435 patients in the ABSORB-EXTEND
single-arm trial in comparison with an everolimus-eluting metallic stent in the SPIRIT
first and II trials. JACC Cardiovasc Interv. 2013; 6: 247-57
11)Muramatsu T, Onuma Y, van Geuns RJ, et al. 1-year clinical outcomes of diabetic
patients treated with everolimus-eluting bioresorbable vascular scaffolds: a pooled analysis
of the ABSORB and the SPIRIT trials. JACC Cardiovasc Interv. 2014; 7: 482-93.
Ⅳ
資料
生体吸収性材料関連規格リスト
ISO
1.
ISO 10993-6:2007 Biological evaluation of medical devices -- Part 6: Tests for local
effects after implantation
2.
ISO 10993-9:2009 Biological evaluation of medical devices -- Part 9: Framework for
identification and quantification of potential degradation products
3.
ISO 10993-13:2010 Biological evaluation of medical devices -- Part 13: Identification
and quantification of degradation products from polymeric medical devices
4.
ISO 13781:1997 Poly(L-lactide) resins and fabricated forms for surgical implants -- In
vitro degradation testing
5.
ISO 15814:1999 Implants for surgery -- Copolymers and blends based on polylactide -In vitro degradation testing
6.
ISO 22794:2007 Dentistry -- Implantable materials for bone filling and augmentation in
oral and maxillofacial surgery -- Contents of a technical file
7.
ISO 22803:2004 Dentistry -- Membrane materials for guided tissue regeneration in oral
and maxillofacial surgery -- Contents of a technical file
8.
ISO 25539-3:2011 Cardiovascular implants -- Endovascular devices -- Part 3: Vena cava
filters
9.
ISO/TS
17137:2014
Cardiovascular
implants
and
extracorporeal
systems
--
Cardiovascular absorbable implants
10. ISO/TR 37137:2014 Cardiovascular biological evaluation of medical devices -- Guidance
for absorbable implants
JIS
1.
JIS T4101 医療用絹製縫合糸
2.
JIS T4102 腸線縫合糸
ASTM (standard)
1.
ASTM F603-12 Standard Specification for High-Purity Dense Aluminum Oxide for
Medical Application
2.
ASTM F619-14 Standard Practice for Extraction of Medical Plastics
3.
ASTM F748-06(2010) Standard Practice for Selecting Generic Biological Test Methods
for Materials and Devices
4.
ASTM F1634-95(2008) Standard Practice for In-Vitro Environmental Conditioning of
Polymer Matrix Composite Materials and Implant Devices
5.
ASTM F1635-11 Standard Test Method for in vitro Degradation Testing of
Hydrolytically Degradable Polymer Resins and Fabricated Forms for Surgical Implants
6.
ASTM F1983-99(2008) Standard Practice for Assessment of Compatibility of
Absorbable/Resorbable Biomaterials for Implant Applications
7.
ASTM F2150-13 Standard Guide for Characterization and Testing of Biomaterial
Scaffolds Used in Tissue-Engineered Medical Products
8.
ASTM F2212-11 Standard Guide for Characterization of Type I Collagen as Starting
Material for Surgical Implants and Substrates for Tissue Engineered Medical Products
(TEMPs)
9.
ASTM F2450-10 Standard Guide for Assessing Microstructure of Polymeric Scaffolds for
Use in Tissue-Engineered Medical Products
10. ASTM F2451-05(2010) Standard Guide for in vivo Assessment of Implantable Devices
Intended to Repair or Regenerate Articular Cartilage
11. ASTM F2502-11 Standard Specification and Test Methods for Absorbable Plates and
Screws for Internal Fixation Implants
12. ASTM F2721-09 Standard Guide for Pre-clinical in vivo Evaluation in Critical Size
Segmental Bone Defects
13. ASTM F2739-08 Standard Guide for Quantitating Cell Viability Within Biomaterial
Scaffolds
14. ASTM F2789-10 Standard Guide for Mechanical and Functional Characterization of
Nucleus Devices
15. ASTM F2883-11 Standard Guide for Characterization of Ceramic and Mineral Based
Scaffolds used for Tissue-Engineered Medical Products (TEMPs) and as Device for
Surgical Implant Applications
16. ASTM F2884-12 Standard Guide for Pre-clinical in vivo Evaluation of Spinal Fusion
17. ASTM F2902-12 Standard Guide for Assessment of Absorbable Polymeric Implants
18. ASTM F2942-13 Standard Guide for in vitro Axial, Bending, and Torsional Durability
Testing of Vascular Stents
19. ASTM F3036-13 Standard Guide for Testing Absorbable Stents
20. ASTM F3089-14 Standard Guide for Characterization and Standardization of
Polymerizable Collagen-Based Products and Associated Collagen-Cell Interactions
ASTM (Work item)
1.
WK41613 Revision of F2902 - 12 Standard Guide for Assessment of Absorbable
Polymeric Implants
2.
WK43150 Revision of F1983 - 99(2008) Standard Practice for Assessment of
Compatibility of Absorbable/Resorbable Biomaterials for Implant Applications
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Medical Devices
Public Workshop - ASTM-FDA Workshop on Absorbable Medical Devices:
Lessons Learned from Correlations of Bench Testing and Clinical Performance,
November 28, 2012
The Food and Drug Administration (FDA) is announcing a public Workshop entitled "ASTMFDA Workshop on Absorbable Medical Devices: Lessons Learned from Correlations of Bench
Testing and Clinical Performance." FDA is co-sponsoring the workshop together with ASTM
International, an organization responsible for the development and delivery of international
voluntary consensus standards.
The purpose of the workshop is to provide a forum for industry, academia, FDA to discuss
test methods for establishing correlations between in vitro and in vivo degradation of
absorbable implant devices, and the interaction of mechanical loading and mechanical
performance with degradation. While there will be an emphasis on cardiovascular
indications as part of a panel session, characterization techniques and experiences from
both cardiovascular as well as non-cardiovascular devices will be discussed and are
encouraged.
Date, Time and Location
Federal Register Notice1
Background and Discussion Topics
Agenda
Transcript
Program and Booklet
Contact Us
Date, Time and Location
This workshop was held November 28, 2012, beginning at 8:15AM at the following location:
FDA White Oak Campus
10903 New Hampshire Avenue
Building 31 Conference Center (Great Room, Room 1503)
Silver Spring, MD 20993
Background and Discussion Topics
Recent studies have identified promising results for the use of absorbable materials in
implantable devices for endovascular therapies such as fully absorbable cardiovascular
stents, where the stent platform degrades, as well as absorbable coatings. The use of these
materials for cardiovascular indications poses new risks due to the critical fatigue and
mechanical loading demands that the implant must withstand and perform. However, the
optimal preclinical/bench testing paradigm to predict clinical performance of fully
absorbable cardiovascular devices is not yet defined. This workshop will discuss the use of
absorbable materials (including synthetic polymers as well as erodible metals) in medical
devices across a broad range of indications with the aim of defining successful and
unsuccessful methods to predict clinical performance, and will subsequently apply these
methods to unique challenges for cardiovascular indications. Therefore, we invite presenters
to share their experience from cardiovascular and non-cardiovascular medical devices, as
well as devices that are fully absorbable, and devices with only a component or coating that
is absorbable. This workshop will bring together the expertise of academia and industry
professionals to define test methods as well as to educate and inform their colleagues in
industry, academia, and device regulation on the performance and predictability of
absorbable medical device degradation. Workshop participants will seek to define the critical
factors for preclinical/bench testing and clinical predictability. They will then apply lessons
learned from marketed devices for non-cardiovascular indications to the emerging uses of
absorbable devices to treat cardiovascular disease.
Topics to be discussed at the workshop include:
Correlations of in vitro and in vivo absorption
Quantitative characterization of absorption kinetics
Test methods to identify interactions of absorption with mechanical loading and
Test methods to assess mechanical performance of the absorbable product
The lessons learned from both early cardiovascular and well-established non-cardiovascular
device experiences will be presented. These lessons will be discussed in the context of
emerging cardiovascular uses of absorbable materials as part of a panel session at the end
of the workshop.
Agenda
Time
7:30-8:15
8:15-8:30
8:30-9:30
Registration
Subject
Opening Remarks2
Plenary Presentation
John Middleton, “Tailoring of Poly(lactide-co-glycolide) to Control
Properties”3
9:30-10:30 Session I: Considerations for Modeling Degradation in Vitro Moderator :
Hany Demian
Karen Burg, “Processing Considerations for Degradable Materials: The many
profiles of ‘polylactide’”4
Elizabeth M. Perepezko, “Establishing Accelerated In Vitro Aging Methods for
Evaluating Resorbable Polymeric Implants”
Jeremy Schaffer, “Corrosion and fracture behavior of bioabsorbable wires in
Bio-simulated fluid”
10:30-10:45Break
10:45-11:45Session II: In Vitro-In Vivo Correlation (IVIVC) & Predicting Corrosion
in Degradable Metals Moderator : Erica Takai
Frank Witte, “Current Opinion of the Science Community on Guidelines and
Testings of Biodegradable Metals”5
Yeohung Yun, “Testing Corrosion for Biodegradable Mg alloys: Science,
Current Methods, and Limitation”
John Disegi, “In Vitro Mechanical Property Degradation of 2.0 mm Dynamic
Compression Plates Fabricated from Absorbable Fe-28Mn Alloy”
11:45-13:00Lunch on your own Food for purchase will be available
13:00-14:45Session III: In Vivo Performance and In Vitro-In Vivo Correlation
(IVIVC) of Polymer Systems Moderator : Ji Guo
Kathryn Uhrich, “Polymorphine: a biodegradable drug delivery system for
extended analgesia”6
Meng Deng, “In Vitro and In Vivo Degradation of Absorbable Polymeric
Biomaterials: Experiences and Learning”7
Nathan Lockwood, “Characterization of Novel Degradable Polymers for Drug
Delivery Applications”
Renu Virmani, “Histopathologic results of bioabsorbable stent (BVS) in the
porcine model”
Yen-Lane Chen et al.,“Characterization of the In Vivo and In Vitro
Degradation of Poly(DL-lactic-co-glycolic acid) on a Drug-Eluting Stent”
14:45-15:00Break
15:00-16:20Session IV:Mechanical Interactions & Product Development
Considerations Moderator : Scott Anderson
Lisa Ferrara, 8“Mechanical Evaluation of Biodegradable Magnesium and
Magnesium Alloys: Identifying the Necessary Testing, Challenges, and
Pitfalls for Biomaterial Characterization9”
Danika M. Hayman and James E. Moore Jr., “Defining a Material Model for a
Bioresorbable Stent Fiber”10
Julia Fox et al., “Relationship between Mechanical Loading and Chemical
Degradation in Polymeric Bioresorbable Vascular Scaffolds”
Byron Hayes, “Standards Development in Absorbable Medical Devices”11
16:20-16:30Break
16:30-17:30Panel Discussion Moderator : Maureen Dreher12
Transcript
Transcript for November 2813
Program and Booklet
Workshop Program and Booklet14 (PDF)
Contact Us
For questions regarding workshop content please contact:
Maureen Dreher, Ph.D.
Center for Devices and Radiological Health
Food and Drug Administration
WO62-Room 2110
10903 New Hampshire Ave,
Silver Spring, MD 20993,
Phone: 301-796-2505
FAX: 301-796-9932
email: [email protected]
or
Erica Takai, Ph.D.
Center for Devices and Radiological Health
Food and Drug Administration
WO66-3622
10903 New Hampshire Avenue
Silver Spring, MD 20993
Phone: 301-796-6353
Fax: 301-796-9959
e-mail: [email protected]
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1. http://www.gpo.gov/fdsys/pkg/FR-2012-08-20/html/2012-20322.htm
2. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331541.pdf
3. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM335606.pdf
4. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331547.pdf
5. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331548.pdf
6. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331543.ppt
7. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331545.pdf
8. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM335604.pdf
9. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM335604.pdf
10. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM335605.pdf
11. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331546.pdf
12. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM331551.pdf
13. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM335036.pdf
14. /downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM329321.pdf
Interventional Cardiology Devices Branch
Peripheral Vascular Devices Branch
Division of Cardiovascular Devices
Office of Device Evaluation
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
For questions regarding this document contact Hina Pinto or Elizabeth Hillebrenner at 240-276-4222 or
[email protected] or [email protected]
This document supersedes the guidance “Non-Clinical Engineering Tests and Recommended Labeling for
Intravascular Stents and Associated Delivery Systems” dated January 13, 2005.
On August 30, 2013 FDA issued a draft guidance Select Updates for Non-Clinical Engineering Tests and
Recommended Labeling for Intravascular Stents and Associated Delivery Systems. When final, that
guidance document will update and augment (but not replace) this guidance.
Document issued on: April 18, 2010
Non-Clinical Engineering Tests and
Recommended Labeling for
Intravascular Stents and Associated
Delivery Systems
Guidance for Industry and FDA Staff
Additional copies are available from the Internet at:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0
71863.htm. You may also send an e-mail request to [email protected] to receive an
electronic copy of the guidance or send a fax request to 240-276-3151 to receive a hard copy.
Please use the document number (1545) to identify the guidance you are requesting.
Additional Copies
Comments and suggestions may be submitted at any time for Agency consideration to Dockets
Management Branch, Division of Management Systems and Policy, Office of Human Resources
and Management Services, Food and Drug Administration, 5630 Fishers Lane, Room 1061,
(HFA-305), Rockville, MD, 20852. When submitting comments, please refer to the exact title of
this guidance document. Comments may not be acted upon by the Agency until the document is
next revised or updated.
Public Comment
Preface
Contains Nonbinding Recommendations
INTRODUCTION............................................................................................................. 1
SCOPE ............................................................................................................................... 2
CONTENT AND FORMAT OF TEST DATA .............................................................. 4
Summary Reports .......................................................................................................................... 4
Test Reports.................................................................................................................................... 5
Test Protocols ................................................................................................................................. 6
NON-CLINICAL ENGINEERING TESTS ................................................................... 8
Material Characterization............................................................................................................. 8
Material Composition ...................................................................................................................... 8
Shape Memory and Superelasticity of Intravascular Stents............................................................. 9
Stent Corrosion Resistance .............................................................................................................. 9
Stent Dimensional and Functional Attributes ........................................................................... 11
Dimensional Verification............................................................................................................... 11
Percent Surface Area...................................................................................................................... 12
Foreshortening ............................................................................................................................... 12
Recoil for Balloon Expandable Stents ........................................................................................... 13
Stent Integrity ................................................................................................................................ 13
Radial Stiffness and Radial Strength ............................................................................................. 14
Radial Outward Force .................................................................................................................... 14
Mechanical Properties.................................................................................................................... 15
Stress /Strain Analysis ................................................................................................................... 16
Fatigue Analysis ............................................................................................................................ 19
Accelerated Durability Testing ...................................................................................................... 20
Particulate Evaluation .................................................................................................................... 21
Magnetic Resonance Imaging (MRI) Safety and Compatibility.................................................... 23
Radiopacity .................................................................................................................................... 25
Crush Resistance (Peripheral Indications Only) ............................................................................ 25
Kink Resistance (Peripheral Indications Only).............................................................................. 26
Additional Tests for Stents Intended for In-Stent Restenosis ........................................................ 26
Additional Tests for Stents Intended for Bifurcation Lesions ....................................................... 26
Delivery System Dimensional and Functional Attributes ........................................................ 27
Dimensional Verification............................................................................................................... 27
Delivery, Deployment, and Retraction .......................................................................................... 28
Balloon Rated Burst Pressure (Balloon Expandable Stents Only)................................................. 29
Balloon Fatigue (Repeat Balloon Inflations; Balloon Expandable Stents Only) ........................... 29
Balloon Compliance (Stent Diameter vs. Balloon Pressure; Balloon Expandable Stents Only)... 30
Balloon Inflation and Deflation Time (Balloon Expandable Stents Only) .................................... 31
II.
III.
A.
B.
C.
IV.
A.
1.
2.
3.
B.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
C.
1.
2.
3.
4.
5.
6.
I.
Table of Contents
Contains Nonbinding Recommendations
Precautions ................................................................................................................................... 40
MR Environment ......................................................................................................................... 41
Overview of Clinical Studies ....................................................................................................... 41
Adverse Events ............................................................................................................................. 42
Clinical Studies............................................................................................................................. 44
Principal Safety and Effectiveness Table................................................................................... 45
Patient Selection and Treatment ................................................................................................ 46
Directions for Use......................................................................................................................... 46
Patient Materials.......................................................................................................................... 47
E.
F.
G.
H.
I.
J.
K.
L.
M.
APPENDIX B: APPLICABLE STANDARDS......................................................................... 51
APPENDIX A: TEST SUMMARY CHECKLIST .................................................................. 48
Warnings....................................................................................................................................... 40
Contraindications......................................................................................................................... 40
Indications for Use ....................................................................................................................... 40
Device Description ....................................................................................................................... 39
LABELING ..................................................................................................................... 39
Biocompatibility ........................................................................................................................... 36
Shelf Life....................................................................................................................................... 35
Catheter Bond Strength.................................................................................................................. 31
Tip Pull Test................................................................................................................................... 32
Flexibility and Kink Test ............................................................................................................... 32
Torque Strength ............................................................................................................................. 32
Coating Integrity ............................................................................................................................ 33
Stent Securement for Unsheathed Stents ....................................................................................... 34
D.
C.
B.
A.
V.
E.
D.
7.
8.
9.
10.
11.
12.
Contains Nonbinding Recommendations
An intravascular stent is a synthetic tubular structure intended for permanent implant in
native or graft vasculature. The stent is designed to provide mechanical radial support
after deployment; this support is meant to enhance vessel patency over the life of the
device. Once the stent reaches the intended location, it is expanded by a balloon or selfexpanding mechanisms defined below.
Intravascular Stent
Intravascular stents are also known as endovascular stents or vascular stents. This
document uses the term “intravascular stent” to refer to intravascular, endovascular, and
vascular stents.
Definition of Terms Used in this Guidance
1
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should in Agency guidances means that something
is suggested or recommended, but not required.
This guidance provides FDA’s current thinking on non-clinical engineering tests that are
submitted in investigational device exemption applications (IDEs) and premarket approval
applications (PMAs) to support the safety and effectiveness of intravascular stents and their
associated delivery systems. This guidance also provides recommendations for labeling for
these devices.
I. Introduction
This guidance represents the Food and Drug Administration's (FDA's) current thinking on
this topic. It does not create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed on the title page of this
guidance.
Non-Clinical Engineering Tests and
Recommended Labeling for Intravascular
Stents and Associated Delivery Systems
Guidance for Industry and FDA Staff
Contains Nonbinding Recommendations
NIN
Stent, Superficial Femoral Artery
1
Refer to http://www.fda.gov/oc/ohrt/irbs/devices.html#risk.
2
Clinical studies conducted in the United States in support of a PMA approval must be conducted
under the Investigational Device Exemptions (IDE) regulation, 21 CFR Part 812. FDA believes
that the intravascular stents addressed by this guidance document are significant risk devices as
defined in 21 CFR 812.3(m), 1 and as such, are not exempt from the requirement to submit an
These devices require a premarket approval (PMA) application before marketing. See sections
513(a) and 515 of the Federal Food, Drug, and Cosmetic Act (the Act) and 21 CFR Part 814.
NIP
Stent, Iliac
Stent, Renal
NIM
NIO
Stent, Coronary
Stent, Carotid
MAF
Table 1: Product Codes for Stents Addressed in this Guidance
Product Code
Device
Intravascular stents, including balloon expandable and self-expanding stents, are class III devices
whose product codes are given in the table below.
This guidance document addresses self-expanding and balloon expandable extracranial
intravascular stents and their associated delivery systems. The scope includes extracranial
intravascular stents placed in coronary or peripheral arteries and saphenous vein grafts but is not
limited to stents used in these locations; other vascular indications outside of the intracranial
vasculature are also included.
II. Scope
Stent Delivery System
A stent delivery system delivers a stent to a target site and then deploys the stent.
A stent delivery system for a balloon expandable stent consists of a balloon catheter.
Self-expanding stent delivery systems may or may not include a balloon.
Self-expanding Stent
A self-expanding stent’s diameter increases from its pre-deployed size to its postdeployed size in the absence of balloon inflation or other mechanical assistance. The selfexpanding quality can result from material properties or geometry or both.
Balloon Expandable Stent
A balloon expandable stent is expanded by a balloon catheter. The diameter of the stent
increases as the balloon diameter increases. The stent remains expanded after deflation
of the balloon.
Contains Nonbinding Recommendations
IDE regulations (21 CFR 812)
Regulations governing institutional review boards (IRB) (21 CFR 56)
Informed consent (21 CFR 50). 2
3
You should review the statutory definition of applicable clinical trial to determine if your trial must be
registered to comply with the law. See PL 110-85, Section 801(a), (adding new 42 U.S.C. 282(j)(1)(A)).
http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf
Information can be submitted to ClinicalTrials.gov using the Protocol Registration System (PRS). For more
information visit the PRS Information Page.
3
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072193.pdf
and http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072196.pdf
2
This guidance document supplements other FDA publications on PMA, PDP, and IDE
applications and should not be construed as a replacement for those documents. For general
information about these applications, see the CDRH Device Advice web site given below:
x PMAs (21 CFR Part 814):
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour
Device/PremarketSubmissions/PremarketApprovalPMA/default.htm
Some of the tests (and labeling recommendations) in this guidance are relevant to covered (NIV),
drug-eluting (NIQ), and biodegradable stents, and stents used to treat aneurysms or dissections.
However, FDA recommends additional testing to fully characterize these devices. For drugeluting stents, please refer to the draft document Coronary Drug-Eluting Stents— Nonclinical
and Clinical Studies. 3 For other coated stents, FDA recommends that you assess the need for
additional testing to address coating characterization, coating integrity, and coating durability.
The Interventional Cardiology Devices Branch and the Peripheral Vascular Devices Branch are
available to discuss additional testing details for these stents and indications.
Non-vascular stents meant for use outside the vasculature are not included in the scope of this
document. This document also does not include stents used in the intracranial vasculature. You
should contact the Division of Reproductive, Abdominal, and Radiological Devices for
information about biliary stents, the Division of Anesthesiology, General Hospital, and Infection
Control Devices for information about non-vascular stents, or the Division of Ophthalmic,
Neurological, and Ear, Nose, and Throat Devices for information about stents used in the
intracranial vasculature.
After FDA has approved a device, clinical studies conducted in accordance with the indications
in the approved PMA, including clinical design validation studies conducted in accordance with
the quality systems regulation, are exempt from the investigational device exemptions (IDE)
requirements. However, such studies must be performed in conformance with the regulations
governing institutional review boards (21 CFR Part 56) and informed consent (21 CFR Part 50).
x
x
x
investigational device exemption (IDE) application (21 CFR 812.2(b), 812.20(a)(1). When an
IDE application is required, a sponsor must not begin a clinical trial in humans in the United
States until FDA has approved the application (21 CFR 812.20(a)(2), 812.42). Sponsors of such
studies must comply with the following:
Contains Nonbinding Recommendations
PDPs (21 CFR Part 814.19):
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour
Device/PremarketSubmissions/PremarketApprovalPMA/ucm048168.htm#pdp
IDEs (21 CFR Part 812):
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYour
Device/InvestigationalDeviceExemptionIDE/default.htm
maximum measured value (max)
mean
standard deviation of the test data (std. dev.).
x
x
x
Summary of Conclusions
You should summarize your conclusions regarding whether the results support the safety and
effectiveness of your device for each test.
minimum measured value (min)
x
Test Data Summaries
You should include test data summaries for all tests. The summaries should contain:
Test Summaries
You should briefly describe all tests performed.
4
Table of Contents
You should place a table of contents at the front of the document. Each line listing in the table of
contents should refer to major section titles and the page numbers where each section can be
found.
We recommend that you present test data in a summary that includes the elements described
below.
A. Summary Reports
III. Content and Format of Test Data
This guidance also cites a number of voluntary standards, many of which are recognized by FDA.
You may access a list of the FDA-recognized standards from the CDRH web site,
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. See also the guidance,
Recognition and Use of Consensus Standards,
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm077
274.htm.
x
x
Contains Nonbinding Recommendations
B. Test Reports
size (diameter, length, or other relevant dimensions) of all test specimens
rationale for the number of test specimens and sizes tested
whether the specimens represent the finished product
sterilization parameters and number of sterilization cycles applied to the test specimens.
x
x
x
x
specifications or acceptance and rejection criteria
a rationale for the specification or acceptance and rejection criteria based on the
clinical requirements of the device.
x
x
5
Conclusions
We recommend that you describe the conclusions drawn from the test results, and the clinical
significance of the conclusions.
Data Analysis
You should analyze the data, including any outlying points and anomalous results, and
explain whether the data meet the given acceptance criteria.
Test Results
You should summarize your test results and include statistical analysis when it is appropriate.
Raw Data
We recommend that you include all raw data in appendices or on a CD-ROM, or make the
raw data available for our review upon request.
an explanation of and rationale for critical test parameters
x
Test Parameters and Acceptance Criteria
You should report the test parameters and acceptance criteria that you use, including:
Protocol Deviations
You should describe any protocol deviations and their effect on the ability of the test data to
support the safety and effectiveness of the device.
Test Protocol
You should submit your test method or protocol. It should contain enough detail that an
individual familiar with intravascular stent testing will be able to interpret the test results.
number of test specimens
x
Test Specimen Information
Your test specimen description should include:
You should include full test reports for all tests performed. Your test reports should include the
sections described below.
Contains Nonbinding Recommendations
Intravascular stents have been in clinical use for over a decade and some designs are in their
fourth or fifth generation. Some attributes may not be modified when changes are made in the
design of a next-generation device. For a particular attribute, rather than providing original data
for a next-generation design, it may be appropriate to reference previously tested stents in the
6
Your explanation should include a rationale for why you do not think the test should be
performed in order to support the safety and effectiveness of your device. Your rationale should
clearly demonstrate, by reference to a Failure Modes and Effects Analysis (FMEA) or other risk
analysis method, that the particular test or data set is not necessary or appropriate to support the
safety and effectiveness of your device. Alternatively, you may identify measures you have
taken to mitigate the risks associated with the device in the failure mode that would usually be
evaluated using the test that you have not performed.
If you believe a test recommended in this guidance does not apply to your device, you should
include a heading for the test in your test summary, followed by an explanation of why the test is
not applicable. We will then be aware that you did not inadvertently omit it from your
application.
Several of the tests listed in this guidance do not apply to all intravascular stents and delivery
systems. The designs or clinical indications to which these tests do apply are noted in their
descriptions. We believe that each test helps to support the safety and effectiveness of
intravascular stents for their stated indication. Each test’s clinical or engineering significance is
described in Section V.
Occasionally, the worst performing combination of device configuration and physiologic
conditions occurs in the mid-range of the relevant variables. You should check for this situation
when developing your protocols to ensure that you test the worst performing combination.
Your test protocols should assess device performance when exposed to the most extreme clinical
conditions that your device is likely to experience. Both device configuration and physiologic
conditions affect the performance of devices in the human body. We recommend that you
evaluate extreme device dimensions, tolerances, sizes, and any other important device
parameters in your testing program. We also recommend that you examine the outer limits of
physiologic variables such as blood pressure, vascular compliance, and anatomic types. You
should clearly state all test conditions in the test protocol and support them with references to
applicable literature, standards, or both.
We are willing to informally review and provide comments on test protocols prior to conduct of
a test, if there are aspects of a particular test that you feel might benefit from FDA input. While
FDA does not approve test protocols, our input before testing may improve your ability to
demonstrate the performance characteristics of your device.
You should establish protocols for all experiments or computational analyses, including
acceptance criteria when applicable, before you perform the tests. Established test protocols help
to ensure consistent repetition of tests and allow comparison of data between test runs.
C. Test Protocols
Contains Nonbinding Recommendations
Stent
Stent Length
Diameter (mm)
8 12 18 24
(mm)
2.5
X
X
3.0
3.5
4.0
X
X
X = Recommended sizes for testing
Table 2: Four Corners Test Paradigm Example
7
You should test the full range of sizes that you intend to commercially distribute. The
recommended default paradigm is a 2 x 2 factorial of the largest and smallest diameters and
lengths, also known as the “four corners” paradigm for each different stent design. We
recommend a different set of sizes for some of the tests in Section V. Table 2 illustrates the four
corners concept for a typical coronary stent. If you do not test a device using the four corners
paradigm or the recommended sizes for a particular test, you should provide a scientific rationale
to support the sizes that you do test in the test summary and test protocols. For some tests, we
may recommend that you perform an analysis to identify the size or sizes that represent the worst
case.
All test samples should represent the finished product. Your devices should be sterilized by the
final production process, including repeat sterilization cycles. You should note any tests that use
samples that are not finished, sterilized product in the test summary and test protocols, and
explain why doing so does not affect the applicability of the test results to the evaluation of
safety and effectiveness of the device.
Sample Selection
You should use a statistically significant sample size whenever possible. When using a
statistically significant number of samples is not possible, you should provide a scientific
rationale to support the number of samples tested in your test summary and test protocols, and
provide reasonable assurance that the test results support the safety and effectiveness of the
device.
same device family. However, a reference to previous generic device experience, for example,
“alloy X has been used in stents,” generally is not adequate. If you choose to reference testing
previously performed on already marketed stents, you should explain why the previous testing is
relevant. If a particular attribute of the next-generation device is re-evaluated, a comparison of
the results to those of the previous generation may be helpful.
Contains Nonbinding Recommendations
We recommend that you provide documentation to certify that incoming raw
material conforms to specifications. We recommend that you submit supplier
certification, incoming quality control test results, or equivalent documentation.
Material Certification
Surface finish is known to affect other material properties for nitinol (e.g.
corrosion, nickel ion release). Therefore, for stents containing nitinol, we
recommend that you characterize the material surface of your finished product in
terms of passivation layer microstructure vs. depth. Special attention should be
paid to surfaces which might include heat-affected zones (e.g., from laser cutting),
or to geometric areas which may be affected differently by finishing (e.g., internal
angles).
We recommend that you provide detailed specifications for the chemical
composition or formulation of materials (or both) for any new materials, alloys, or
formulations with no history of use in intravascular stents or PTCA catheters.
Chemical Composition and Formulation
We recommend that you list formulations of all materials by generic name, for
example, 18 Cr-14 Ni-2.5 Mo stainless steel. We recommend that you reference
any applicable standard designations such as ASTM F138. 4
Generic Chemical Formulation
We recommend that you list materials by trade or common name, for example,
316L stainless steel.
Stent and Delivery System Materials
Recommendation
We recommend that you specify the device characteristics described below. If your
stent material is identical to your previously marketed stents, we recommend that you
identify the stent(s) and material(s) to which it is identical.
Significance
Material composition testing documents a baseline for evaluation of the effects of
future changes in materials.
1. Material Composition
8
ASTM F138 Standard Specification for Wrought 18Chromium-14Nickel-2.5Molybdenum Stainless Steel Bar and
Wire for Surgical Implants
4
Non-Clinical Engineering Tests
A. Material Characterization
IV.
Contains Nonbinding Recommendations
9
ASTM F2004 Standard Test Method for Determination of Transformation Temperature of Nickel-Titanium Alloys
by Thermal Analysis
6
ASTM F2082 Standard Test Method for Determination of Transformation Temperature of Nickel-Titanium Shape
Memory Alloys by Bend and Free Recovery
5
We recommend that you address the potential for fretting corrosion between two
stents since there is a reasonable expectation of stent overlap during clinical use
for most indications. We recommend that the examination of samples for fretting
corrosion be incorporated as part of fatigue/durability testing (see Section B.11.
Accelerated Durability Testing). You should ensure that overlapping stents are
in contact with one another and that the setup does not preclude micromotion
between strut elements. For coronary stents, because tortuosity of a target
deployment site could result in increased micromotion between components or
multiple stents, the mock deployment site should be bent to a worst-case clinically
relevant radius of curvature, which should be smaller than most anatomical
Fretting Corrosion
Recommendation
We recommend that you address the corrosion properties of your device described
below. If some of these characteristics do not apply to your device, we recommend
that you explain this in your application.
Significance
Stent corrosion can cause or contribute to premature stent failure. In addition,
corrosion byproducts may be toxic or cause other adverse biological and tissue
responses.
3. Stent Corrosion Resistance
We recommend that you describe the mode of action (e.g., thermal shape memory
or superelasticity) by which the stent transitions to the specified size and shape.
Mode of Action
We recommend using the methods described in ASTM F2004, 5 ASTM F2082, 6
or equivalent methods.
Austenite Finish Transition Temperature (Af)
Recommendation
We recommend that you document the following properties for any shape memory or
superelastic materials present in your stent.
Significance
The transition temperature of nitinol or other shape memory and superelastic
materials determines specific shape memory and superelastic properties.
2. Shape Memory and Superelasticity of Intravascular Stents
Contains Nonbinding Recommendations
10
Liao R, Green NE, Chen SY, Messenger JC, Hansgen AR, Groves BM, Carroll JD. Three – dimensional analysis
of in vivo coronary stent – coronary artery interactions. International Journal of Cardiovascular Imaging. 2004
Aug;20(4):305-13.
8
ASTM F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to
Determine the Corrosion Susceptibility of Small Implant Devices
7
You may use literature citations or previous experience with stents to address this
issue; however, the materials, design, and fabrication processes specific to your
stent may reduce or eliminate the applicability of generic literature. For example,
the pitting corrosion resistance of nitinol is sensitive to processing variables such
as heat treatment and electropolishing; therefore, for a nitinol stent, you should
characterize the corrosion potential of the finished stent.
If results do not indicate an acceptable pitting and crevice corrosion potential, you
should consider characterizing the corrosion potential of the finished, as
manufactured stent to determine if the corrosion potential of your stent is affected
by fatigue.
Results from testing through one year time equivalent should be provided in
support of an IDE application. Results from testing through ten years time
equivalent should be provided when they are available, but not later than at the
time of PMA submission.
We recommend that you characterize the corrosion potential of your stent with
any potential surface damage that may result from fatigue. We recommend
testing the same samples used in the fretting corrosion evaluation described above
according to the method in ASTM F2129. 8 Specifically, one stent from each
overlapping pair subjected to fatigue cycling should be evaluated for pitting and
crevice corrosion potential while the other stent from each pair is evaluated for
fretting corrosion as described above. Test reports for pitting and crevice
corrosion potential testing should include the recorded potentials as well as the
polarization curves.
Pitting and Crevice Corrosion Potential
Results from testing through one year time equivalent should be provided in
support of an IDE application. Results from testing through ten years time
equivalent should be provided when they are available, but not later than at the
time of PMA submission. A scientific rationale for the number of samples
evaluated for fretting corrosion should be provided.
We recommend conducting a visual (e.g., SEM) inspection of samples after
fatigue/durability testing for evidence of corrosion.
situations encountered in clinical use. For example, for most coronary
indications, FDA recommends a 15mm radius of curvature as this represents
worst case for 90% of the population based on published angiographic
measurements. 7 For other indications such as use in coronary bifurcations, please
provide a similarly robust clinical rationale for the radius of curvature selected.
Contains Nonbinding Recommendations
10
ASTM G71 Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes.
ASTM F2081 Standard Guide for Characterization and Presentation of the Dimensional Attributes of Vascular
Stents
9
We recommend that you measure and report the expanded diameter of balloon
expandable stents. You may do this as part of the process of creating a
compliance chart. See Section C. Delivery System Dimensional and
Functional Attributes, 5. Balloon Compliance.
Balloon Expandable Stents
We recommend that you provide dimensional specifications and tolerances for
un-expanded stents.
Un-expanded Stents
11
Recommendation
FDA recommends that you provide the information described below that applies to
your stent. We recommend the methods used in ASTM F2081 10 or their equivalents.
At a minimum, you should take measurements at each end and in the middle of the
stent and at two circumferential points 90Û apart (for a total of six measurements).
You should take additional measurements as appropriate based on device design.
Significance
Accurate stent dimensions help the physician to achieve proper stent sizing and
accurate placement in the body. They also affect the functional behavior of the stent.
1. Dimensional Verification
B. Stent Dimensional and Functional Attributes
Testing should be conducted even if an alloy conforms to a specific standard
because manufacturing processes can affect the galvanic corrosion potential of the
finished product.
If your stent contains more than one type of metal, such as a base stent material
with added marker bands, we recommend that you demonstrate the design’s
resistance to galvanic corrosion. If you expect that your stents will be overlapped
during clinical procedures, and the contacting or overlapping stents may be made
of different materials, we recommend that you address the potential for galvanic
corrosion between stents. In this case, we recommend that you use the marketed
stent with the highest galvanic coupling with your stent material in your
evaluation. We recommend the methods described in ASTM G71 9 or their
equivalents. These methods may be modified to provide for testing of finished
stents, for example, by incorporating the experimental setup described in
Appendix X3 of ASTM F2129.
Galvanic Corrosion
Contains Nonbinding Recommendations
We recommend that you apply the methods described in ASTM F2081 or their
equivalents.
Percent Foreshortening = 100 x (Change in Length ÷ Loaded Length).
12
We recommend that the reported value reflect the maximum nominal diameter. We
recommend that you report the results in terms of a percentage of the loaded length as
shown below:
Recommendation
FDA recommends that you report the decrease in length of the stent between the
catheter-loaded condition and the deployed diameters up to the maximum labeled
diameter.
Significance
Foreshortening, i.e., dimensional changes that may occur when deploying a stent,
influences final stent length. Knowledge of the foreshortening characteristics aids in
proper stent length selection and proper placement in the body.
3. Foreshortening
(The reference area is defined as the full cylindrical surface area at the expanded stent
diameter.) We recommend that you apply the methods described in ASTM F2081 or
their equivalents.
Percent Surface Area = 100 x (Area in Contact with Vessel ÷ Full Cylindrical Surface
Area)
Recommendation
We recommend that you report the percent surface area of the stent for both the
smallest and largest nominal expanded diameters for each stent design. We
recommend that you evaluate different lengths only if you expect that the percent
surface area varies significantly with stent length. We recommend that you measure
or calculate the contact area of the stent structure, and express the final value as a
percentage of the reference area, as shown below:
Significance
The area over which a stent contacts a vessel may affect the biologic response of the
vessel. The amount of open, non-contact area may influence tissue prolapse or
ingrowth.
2. Percent Surface Area
We recommend that you verify the unconstrained expanded diameter of selfexpanding stents with measurement data.
Self-Expanding Stents
Contains Nonbinding Recommendations
11
or their equivalents.
ASTM F2079 Standard Test Method for Measuring Intrinsic Elastic Recoil of Balloon expandable Stents
Recommendation
We recommend that you examine your deployed stent and report any evidence of
stent defects such as, but not limited to:
x cracks
x scratches
x permanent set
x coating delamination.
13
Significance
Stent defects, whether a result of manufacturing flaws or subsequent damage, can
contribute to clinical complications. Laser cutting or other manufacturing processes
may induce flaws that are not completely removed by polishing. Plastic deformation
during loading or balloon expansion may cause cracks or other damage. Selfexpanding stents that are stored loaded in a delivery system may exhibit permanent
set or changes in expansion characteristics as a result of time or sterilization or both.
5. Stent Integrity
We recommend the methods described in ASTM F2079
11
We recommend that you present the results as a percentage of the expanded diameter.
We recommend that you measure and report values for each labeled stent diameter.
If you expect that the percent recoil varies significantly with length, we recommend
that you evaluate recoil for different stent lengths at various points along the length of
the stent, including the ends. The number of locations along the length of the stent at
which recoil is measured should be determined by initial assessment of the stent
geometry.
Recommendation
We recommend that you report the measured change in diameter of your stent
between post-balloon expansion and after balloon deflation.
Significance
The recoil behavior of balloon expandable stents influences proper device selection,
sizing, acute post-implant results, and long-term clinical outcomes. Recoil is a
function of stent design and material selection; therefore, knowledge of stent recoil
helps to characterize the behavior of a particular stent design.
4. Recoil for Balloon Expandable Stents
See Section VIII. Labeling for recommendations on data presentation of the percent
foreshortening of self-expanding stents.
Contains Nonbinding Recommendations
radial strength, i.e., the pressure at which your stent experiences irrecoverable
deformation.
radial stiffness, i.e., the change in stent diameter as a function of uniformly
applied external radial pressure; and
14
Recommendation
We recommend that you measure the radial force exerted by self-expanding stents
against the vessel wall after deployment. If a particular stent size or model is
indicated for use in a range of vessel sizes, your assessment should cover the range of
possible vessel sizes, or should include a rationale for not assessing the entire size
range to be marketed. We recommend that you evaluate different stent lengths if you
expect that the radial force varies as a function of the total stent length. In addition, if
Significance
It is important to characterize the radial outward force of self-expanding stents.
Excessive radial force could injure the surrounding tissue, while a radial force that is
too low can result in incomplete apposition of the stent to the vessel wall.
7. Radial Outward Force
We recommend that you support the diameter or pressure range used in your tests for
radial stiffness. The diameter and pressure range will probably vary depending on
your stent’s intended target site.
FDA recommends that you measure and report values for each labeled stent diameter.
If you expect that the radial stiffness varies significantly with length, we recommend
that you also evaluate different stent lengths.
x
x
Recommendation
We recommend that you report a value for the following:
Significance
Radial stiffness and stent recoil determine the diameter of balloon expandable stents
deployed in compliant vessels. Radial stiffness and radial strength characterize the
ability of the stent to resist collapse under short-term or long-term external loads.
6. Radial Stiffness and Radial Strength
When you are looking for post-deployment damage, we recommend that you examine
or inspect:
x balloon expandable stents, after expansion to the largest diameter listed in
your labeling
x self-expanding stents, after expansion to the unconstrained diameter.
We recommend that you use optical or electron microscopy, or both to look for
defects. We recommend that you support the level of magnification that you use on
the basis of the size of the defect that your inspection attempts to detect.
Contains Nonbinding Recommendations
ultimate tensile strength (UTS)
yield strength (YS)
elongation
plateau stresses, for nitinol
elastic strain limits, for nitinol.
15
In addition, reporting other mechanical properties at previous stages of manufacture,
may allow characterization of your material for use in your stress/strain analysis. See
Section 9. Stress/strain Analysis. We recommend that you determine the stressstrain response, endurance limit, and post-processing mechanical properties through
physical experiments or computational models that simulate stent material properties,
manufacturing, and deployment processes. If you cite any quoted literature or
FDA also recommends that you report the stress-strain response of the stent after
deployment. We recommend that you present the stress-strain behavior in a plot
or graph that shows both loading and unloading. We recommend that you report
the following post-processing mechanical properties of your stent:
x UTS
x YS
x elongation
x elastic modulus
x Poisson ratio
x endurance limit
x plateau stresses, for nitinol
x elastic strain limits, for nitinol.
Post-Processing Mechanical Properties
x
x
x
x
x
Mechanical Properties of the Raw Material(s)
Recommendation
We recommend that you specify the mechanical properties listed below for the stent
raw material(s).
Significance
Raw material properties determine incoming material quality and uniformity, and
predict subsequent thermomechanical effects. Thermomechanical properties of the
implanted stent affect clinical performance, as well as stress and fatigue behavior.
8. Mechanical Properties
you expect that the radial force of your stent is not axially uniform (for example, if
your stent has a tapered length), we recommend that you measure the radial force at
multiple locations along the length of the stent. The specifications for radial outward
force should include both minimum and maximum values.
Contains Nonbinding Recommendations
x
We recommend that you provide a justification for the physiological
relevance of your vessel model parameters (e.g., vessel compliance).
If you do not model all of your stent sizes, we recommend that you
explain why the modeled stent size is the worst case with respect to
critical stresses. We recommend that you address the effect of
dimensional variation within allowable tolerances on the results of the
stress/strain analysis (i.e., maximum critical stress).
Model Geometry
We recommend that you clearly describe the stent and vessel geometry
used. If symmetry is used, we recommend that you explain why this is
appropriate for your model.
16
We recommend that you clearly identify and explain the sources and values of all
inputs and assumptions used to create the stress/strain analysis model. You
should identify any software used for analysis. We recommend that finite
element analysis reports include the element types used to model the stent,
loading surfaces, and boundary conditions. We also recommend that you indicate
if mesh refinement analysis was performed and clearly describe how you model
the surrounding vessel/tissue and the type of contact elements used. Specifically,
we recommend that you consider the following:
Computational Model and Inputs
Recommendation
FDA recommends that you include the following elements in your stress/strain
analysis and test report for each stent design.
Significance
Failure of a loaded stent may result in loss of radial support of the stented vessel or in
perforation of the vessel by the stent struts. Stress/strain analysis, combined with
fatigue analysis and accelerated durability testing, provides an indication of device
durability.
9. Stress /Strain Analysis
handbook values, we recommend that you explain how they are relevant to your
device. Since the material properties of nitinol are widely variable depending on
processing, we recommend for nitinol devices that you perform physical experiments
on actual post-processing samples to determine the mechanical properties of your
stent. We also recommend that you use and reference standard test methods
whenever possible, and describe any nonstandard test methods in detail.
Contains Nonbinding Recommendations
Material Properties (Constitutive Model)
We recommend that you clearly describe the material stress/strain
behavior of your stent in graphical and equation form. This discussion
should include, but is not limited to the following considerations:
o Linear vs. non-linear
o Isotropic vs. anisotropic
o Temperature-dependent behavior
o Raw vs. processed material.
Finite Element Analysis (FEA) Validation
We recommend that you validate your FEA (material properties,
geometry, and boundary conditions) with experimental bench testing. For
example, you could perform radial loading of your device and compare the
force-displacement results with FEA of a simulated radial loading
experiment.
x
x
If you believe that you do not need to model the entire stress history, we
recommend that you use material properties that are consistent with the starting
point of your analysis. We recommend that the material properties accurately
17
FDA recommends that you include the entire stress history of the device in each
loading step in order to incorporate the effects of residual stresses. The entire
stress history may include, but is not limited to:
x manufacturing (fabrication, annealing, electropolishing, heat-setting, etc.)
x loading onto the delivery system and/or crimping
x expansion/deployment (including over- or underexpansion into an elastic
vessel, if applicable)
x stent recoil
x physiologic loading conditions.
Stress/Strain History
Contact Elements
We recommend that you specify the type of contact defined between any 2
contacting bodies modeled in your analysis; e.g., the vessel and outer
surface of your stent.
We recommend that you perform a mesh refinement analysis to ensure
that the solution is independent of element size. If you do not believe
mesh refinement analysis is necessary for your model, we recommend that
you provide a justification for not conducting such an analysis.
Type of Element & Mesh Refinement Analysis
We recommend that you specify the number and type of elements used in
your mesh, including any mesh refinement in transition regions or regions
of complex geometry.
x
x
Contains Nonbinding Recommendations
18
We recommend that you identify the critical locations of stress or strain on the
stent using finite element analysis and address the effect of dimensional variation
within allowable tolerances on the results. We recommend that you report the
location and magnitude of all maximum tensile and compressive stresses or
strains as well as the stress-strain distribution using graphics. The stress or strain
measure used should be clearly defined (e.g., principal stresses, Von Mises
stresses, etc.). We recommend that you explain why the measure used is
reasonable considering your constitutive model. Additionally, we recommend
that you explain what safety issues may arise if the stent fails in the region of
maximum stress or strain.
Results: Stress or Strain Critical Locations and Magnitude
For non-coronary stents, long stents, and coronary stents used in other vessel
configurations such as bifurcation lesions, we recommend that you determine the
relevant loading conditions.
We believe that most coronary stents indicated for use in non-bifurcated vessels
should be modeled using radial dilation in a static bend to represent potential
tortuosity of the target lesion. We recommend that you perform your stress/strain
analysis such that the stent is in a mock deployment site bent to a clinically
relevant radius of curvature as described in Section IV. Non-Clinical
Engineering Tests A. Material Characterization 3. Stent Corrosion
Resistance – Fretting Corrosion. You may also wish to consider dynamic
bending to better evaluate the performance of your stent in clinical use conditions.
If you expect that your stents will be overlapped during clinical procedures, then
we recommend that you address the possibility of the additional stress
concentrations caused by overlapping stents.
We recommend that you address the list above as well as any other relevant
loading conditions when you develop the model for your stent.
The modeled physiologic loading mode will depend on the implantation site and
may include, but is not limited to the following:
x radial dilation
x torsion
x bending
x axial tension
x axial compression
x crushing, including focal, non-focal, or uniform radial compression.
Physiologic Loading Conditions
reflect the processing history of the stent as described in Section 8. Mechanical
Properties. We also recommend that you explain why the omitted loading steps
either do not affect the stent fatigue life or are accounted for in your model.
Contains Nonbinding Recommendations
Since the material properties of nitinol are widely variable depending on
processing, we recommend for nitinol devices that you perform physical
experiments on actual post-processed samples to determine the mechanical
properties of your stent, and use these values in your analysis.
19
We believe that most coronary stents indicated for use in non-bifurcated vessels
should be modeled using radial dilation in a static bend to represent potential
tortuosity of the target lesion. We recommend that you perform your stress/strain
analysis such that the stent is in a mock deployment site bent to a clinically
relevant radius of curvature as described in Section IV. Non-Clinical
Engineering Tests A. Material Characterization 3. Stent Corrosion
Resistance – Fretting Corrosion.
If you expect that your stents will be overlapped during clinical procedures, we
recommend that you address the possibility of the additional stress concentrations
caused by overlapping stents.
FDA recommends that you use the mean and alternating stresses/strains obtained
from the stress/strain analysis as input for the fatigue life determination. We
recommend that you clearly identify and support all inputs and assumptions used
in your analysis. If you use literature values for any material properties, we
recommend that you identify the source of the data and support that your values
correspond to the as-implanted condition of the material.
Inputs and Assumptions
If you do not analyze all stent sizes, we recommend that you explain why the
modeled stent size is the worst case for fatigue life.
Modeled Stent Sizes
Recommendation
FDA recommends that you determine the fatigue resistance of the stent to physiologic
loading using a Goodman analysis or another fatigue life analysis method. We
recommend that your test report include the following elements.
Significance
Failure of a stent due to fatigue may result in loss of radial support of the stented
vessel, thrombus formation or focal restenosis, or in perforation of the vessel by the
stent struts. Fatigue analysis, combined with stress/strain analysis and accelerated
durability testing, provides an indication of device durability.
10. Fatigue Analysis
If you choose to perform a strain-based analysis instead of a stress-based
analysis, we recommend that you explain why the strain-based analysis is
more appropriate for your device.
Contains Nonbinding Recommendations
20
We recommend that you test the durability of your stent to the equivalent of ten
years of real-time use under pulsatile flow and physiologic loading that simulates
blood pressure conditions in the human body. We believe that ten years of
durability data provides sufficient proof of safety of the device for most patients.
If you perform a rigorous and conservative fatigue analysis that indicates an
acceptable analytical safety factor, you may propose to complete long-term
durability testing concurrent with clinical trials and to submit the final results
Test Duration
We recommend that you select and support the stent size or sizes tested based on
the stress and fatigue analyses or other factors. We recommend that the sizes
tested represent the worst case fatigue life of your device.
Sizes Tested
We recommend that you consider a stent as one test specimen when you report
reliability calculations and results. We recommend that you consider the stent as
one test specimen regardless of the symmetries present in apices, repeat units, or
struts of the stent.
We recommend that you determine sample size based on your fatigue analysis,
including boundary conditions, loading conditions, safety factors, and any other
relevant factors.
Sample Size
Recommendation
FDA recommends that accelerated durability testing of your stent address the
following issues.
Significance
Accelerated durability testing validates fatigue analysis. It evaluates failure modes
such as fretting, abrasion, wear, and fracture. Durability testing can help in the
identification of device conditions, such as manufacturing anomalies, that were not
modeled using analytical or computational methods.
11. Accelerated Durability Testing
If you choose to perform a strain-based analysis instead of a stress-based
analysis, we recommend that you explain why the strain-based analysis is
more appropriate for your device.
We recommend that you provide a Goodman diagram or other graphic that
compares the stresses at critical locations in the stent to the mechanical properties
of the stent material. We recommend that you report fatigue safety factors in a
table and explain how the safety factors were calculated.
Results
Contains Nonbinding Recommendations
21
Particulate matter can be generated by the manufacturing process or from the
breakdown of any coating (e.g., hydrophilic coating) or from the stent platform, stent
delivery system, or product packaging. If particles are introduced in the bloodstream
during stent delivery or deployment, they may present an embolic risk to the patient.
Significance
12. Particulate Evaluation
We recommend that you relate the outcome of your test to the stress and fatigue
analysis results.
Results
Deployment Site
The testing should be relevant for your intended clinical use and condition. For
example, we believe that most coronary stents indicated for use in non-bifurcation
vessels should be deployed in a mock vessel bent to a clinically relevant radius of
curvature as described in Section IV. Non-Clinical Engineering Tests A.
Material Characterization 3. Stent Corrosion Resistance – Fretting
Corrosion.
If you expect that your stents will be overlapped during clinical procedures, we
recommend that you address the possibility of the additional risk of stent failure
caused by wear or other factors. Therefore, you should test overlapping stents as
part of the durability experiment.
Overlapping Stents
Stent systems should be tracked through a clinically relevant test fixture prior to
deployment.
We recommend that you address any other types of cyclic loading, such as
bending, that you anticipate your stent will experience when used as intended, and
incorporate these types of loading into your testing where possible. We
recommend that you explain the clinical relevance of the loading conditions used
for the accelerated durability testing. If the conditions you choose differ from the
loading conditions that you modeled in the stress and fatigue analyses, we
recommend that you report and explain the differences.
FDA recommends that you perform long-term durability testing that models the
physiological loads and boundary conditions that your stent is likely to experience
under its intended use.
Loading and Boundary Conditions
when they are available, but not later than at the time of PMA submission. In this
case, results from testing through a minimum of one year time equivalent should
be provided in support of an IDE application.
Contains Nonbinding Recommendations
12
ASTM F2394 Standard Guide for Measuring Securement of Balloon Expandable Vascular Stent Mounted on
Delivery System
22
Test Methods
We recommend using an in vitro model intended to mimic in vivo physiologic and
anatomic worst-case conditions (e.g., tortuous path, aqueous environment) to
evaluate particulates. For coronary indications, FDA recommends the tortuous
path described by Figure X2.4 of ASTM F2394 12 . If you expect your stents may
be deployed in an overlapped configuration during clinical procedures, we
recommend that you measure particulates generated during deployment of two
overlapping stents in a mock vessel. For coronary stents, the mock vessel should
be bent to a clinically relevant radius of curvature as described in Section IV.
Non-Clinical Engineering Tests A. Material Characterization 3. Stent
It may be possible to combine the Particulate Evaluation with Delivery,
Deployment and Retraction testing (see Section IV. Non-Clinical Engineering
Tests C. Delivery System Dimensional and Functional Attributes 2. Delivery
Deployment and Retraction) and/or with Coating Integrity testing (see Section
IV. Non-Clinical Engineering Tests C. Delivery System Dimensional and
Functional Attributes 11. Coating Integrity) but you should take care to ensure
that only minimal additional handling of the test samples is required for the
coating integrity evaluation such that particulates are neither lost nor generated.
Test Samples
You should conduct all testing on the finished product subject to all
manufacturing processes including sterilization. You should evaluate a robust
number of stents from multiple stent lots (minimum of 3 batches) and specify the
number of samples (we recommend that a sample equals one stent, not a strut or
portion of a stent) used, the stent size(s), and the number of stent lots for each test.
We recommend that you implement a sampling plan to examine multiple lots of
product to assess both inter- and intra- lot variability. You should perform testing
on sizes that represent four corners of the stent design (see Table 2 above) as well
as an intermediate size. You should provide a scientific or statistical justification
for the selection of samples.
Recommendation
We recommend that you measure the total number of particulates and size of the
particulates generated during the simulated delivery and deployment of all coronary
stents and any other stents that are determined to be high particulate risk based on a
risk analysis that takes into account the clinical setting and susceptibility of the end
organ to damage from emboli.
Measurement of the total quantity and size of particulates a device system may
generate is an indication of embolic risk. Therefore, evaluation of particulate
generation, size, and its potential impact on the end organ served by the stented
vessels is critical.
Contains Nonbinding Recommendations
13
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm107705.htm
We recommend that you report details of the test environment, such as, but not
limited to:
x magnetic field strength in Tesla (T)
x maximum spatial gradient
Test Environment
Recommendation
FDA recommends that you address the issues affecting safety and compatibility of
your stent in the MRI environment as described in the Guidance for Industry and
FDA Staff: Establishing Safety and Compatibility of Passive Implants in the
MR (Magnetic Resonance) Environment. 13
23
Significance
MRI of patients with stents poses the following potential hazards:
x movement of the implant, resulting in tissue damage or misplacement
x heating of the implant and subsequent tissue damage
x image artifacts that may render the MR images uninterpretable or misleading.
13. Magnetic Resonance Imaging (MRI) Safety and Compatibility
You should describe and validate particle counting and sizing methods. We
recommend that a known amount of various particle sizes be introduced into the
test setup and the amount of particles recovered quantified. The number of
particles recovered should closely approximate the number artificially introduced
into the system. For a system to be considered validated, •90% recovery should
be demonstrated for the •10μm and •25μm size ranges.
Validation
Corrosion Resistance – Fretting Corrosion. The stent should be in direct
contact with the simulated vessel without the use of other coatings, lubricants,
sheaths, or protective wraps between the stent and the simulated vessel. To
ensure measurement of the total number of particles that could be potentially
introduced into the bloodstream, the stent delivery system should be inserted into
the text fixture to the extent which it would be inserted in clinical use and
expanded to rated burst pressure (for balloon-expandable stents) or the maximum
labeled diameter (for self-expanding stents). Additionally, any accessory devices
required for the placement of the product should be used in this evaluation. The
total number of particulates including those from the stent, delivery system, and
accessory devices should be reported in each of three size ranges: •10μm,
•25μm, and at the largest size for which validation yields •75% recovery. At a
minimum, the largest size should be •50μm. Appropriate precautions should be
implemented to ensure that the particles are suspended during sampling for
particle counting and sizing to minimize artifacts from the test system.
Contains Nonbinding Recommendations
maximum time rate of change of magnetic field (dB/dt)
local specific absorption rate (SAR) at the position of the stent in the
phantom
calorimetric assessed phantom averaged whole body specific absorption
rate.
heating data versus time
close-up photos of temperature probe placement
overview photos of the placement of the stent in the phantom
details about the phantom gel
details about the pulse sequence
temperature increase at the location of the stent but without placing the
stent in the gel
close-up photo of the stent including the stent dimensions
B1rms according to IEC 60601-2-33.
24
Because the potential for device heating is impacted by the relationship between the
conductive length of the device and the wavelength of the RF, higher magnetic field
strengths do not necessarily result in worst-case test conditions for a particular device.
Therefore, we recommend that you test your device at all field strengths for which
you are seeking MR Conditional labeling. Given the prevalence of 1.5 T and 3.0T
MR systems, we recommend that, at a minimum, you test your device using both of
these systems unless you are able to provide compelling evidence that a particular
system represents a worst-case situation for your device. If you anticipate that your
stents will be overlapped during clinical procedures, we recommend that you consider
the total length of overlapping stents in your determination of worst case test
conditions and test accordingly.
Please note that for radiofrequency (RF) heating testing using the phantom described
in ASTM F2182 or equivalent, anatomical positioning of the stent in the phantom
does not reliably predict the implant heating in the patient. Therefore, you should
provide calorimetry data to demonstrate that your test conditions are applicable to
reasonable worst-case clinical conditions for heating.
central axis of the bore of the scanner.) The magnetically induced torque is a function
of the field strength, and so should be measured where the static magnetic field is the
greatest, within the bore of the magnet. Note that the physical locations of the
maximum torque and displacement force will almost certainly be different. You
should perform all testing on finished devices.
We recommend that the magnetically induced deflection force for a stent composed
of ferromagnetic material be determined at the location where the spatial gradient of
the magnetic field is a maximum. The magnetically induced deflection force for a
stent composed of paramagnetic material should be determined at the location where
the product of the magnitudes of the magnetic field and the spatial gradient of the
magnetic field ( B ’B ) is a maximum. (It is possible that this location is off the
x
x
x
x
x
x
x
x
x
x
x
Contains Nonbinding Recommendations
We recommend that you report the change in unloaded stent dimensions after the
application and removal of all of the specified loads and displacements.
25
Recommendation
FDA recommends that you demonstrate the ability of your stent to recover its desired
size and shape after application and removal of external loads, deformations, or both.
We recommend that you support the nature, location, and extent of all external loads
and deformations based on the intended implantation site, for example, the carotid or
femoral arteries. Testing may include the application of focal loads, axially
distributed loads, or both, depending on the target vasculature.
Significance
Peripheral stents in some anatomic locations may experience external, non-cardiac,
focal, or distributed loads. These loads could cause stent deformation and, possibly,
adverse clinical consequences.
15. Crush Resistance (Peripheral Indications Only)
We recommend that you provide a qualitative or quantitative indication of the
visibility of the stent on real-time and plane film x-ray. It is acceptable to use data
from images of animal implants, in vitro phantoms, or equivalent models.
Recommendation
FDA recommends that you evaluate the radiopacity of your stent at the smallest
diameter and the shortest length during the following stages in the life of the stent:
x delivery
x deployment, if separate from delivery
x after implantation.
Significance
Stent visibility using angiographic or radiographic imaging or both generally assures
proper stent placement and allows follow-up and secondary treatment.
14. Radiopacity
We recommend that your labeling contain information for the patient and medical
personnel about any potential hazards associated with MRI as a result of the presence
of the implanted stent. See Section VIII. Labeling for examples of language
describing the MRI compatibility of stents in labeling.
There is a large variability across available MR scanners of the actual specific
absorption rate (SAR) delivered. In general, the actual SAR delivered is much lower
than the value displayed on the scanner console. Therefore, we recommend that you
determine the actual SAR delivered to your stent during testing by calorimetry and
report this in the labeling.
Contains Nonbinding Recommendations
26
Recommendation
If you intend to label your stent for use in bifurcation lesions, we recommend that you
simulate the target deployment site with a mock vessel which includes the following
features:
x parent vessel bend at a clinically relevant radius of curvature (as described in
Section A. 3),
Significance
Stents designed for placement in coronary bifurcation lesions may be subjected to
different loading conditions which could result in different corrosion potential, stress,
fatigue, wear, coating damage, and particulate generation due to anatomical
constraints and stent to stent interactions.
18. Additional Tests for Stents Intended for Coronary Bifurcation Lesions
Recommendation
If you intend to label your stent for in-stent restenosis, we recommend you repeat the
following tests within an expanded stent (i.e., with 100% overlapped stent pairs):
x Fretting Corrosion (refer to Section A.3)
x Stress/Strain Analysis (refer to Section B.9)
x Fatigue Analysis (refer to Section B.10)
x Accelerated Durability Testing (refer to Section B.11)
x Particulate Evaluation, if appropriate for the indications for use (refer to
Section B.12).
Significance
Deployment of stents within previously implanted stents to treat in-stent restenosis
could result in increased corrosion potential, stress, fatigue, wear, coating damage,
and particulate generation due to stent to stent interactions.
17. Additional Tests for Stents Intended for In-Stent Restenosis
Recommendation
We recommend that you determine the smallest radius of curvature that your stent
can withstand without kinking, and demonstrate that the stent recovers its original
size and shape after testing. We recommend that you support the nature, location,
and extent of all external loads and deformations based on the intended implantation
site, for example, the carotid or femoral arteries.
Significance
Peripheral stents used in some anatomic locations will bend during normal body
motion, such as knee flexion. Such bends could cause stent deformation and possible
adverse clinical consequences.
16. Kink Resistance (Peripheral Indications Only)
Contains Nonbinding Recommendations
14
a bifurcation angle representative of the most challenging anatomical situation
likely to be encountered in clinical use, and
additional treatment of parent and/or side-branch vessels per expected clinical
use, with simulated angioplasty and/or stenting if the bifurcation stent allows
side-branch access.
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070984.htm
27
Recommendation
We recommend that you provide dimensional specifications and tolerances for your
device as manufactured. At a minimum, we recommend that you report effective
length, shaft inner and outer diameter, and crossing profile.
The crossing profile is defined as the maximum diameter found between the proximal
end of the mounted stent and the distal tip of the delivery system. Testing should
address potential differences in crossing profile that may exist in the circumferential
Significance
Stent delivery system dimensions influence the ability of the device to track to and
across lesions.
1. Dimensional Verification
C. Delivery System Dimensional and Functional Attributes
Additionally, if the bifurcation stent allows for side-branch access, compatibility
testing should be performed to ensure the stent does not cause balloon rupture of a
PTCA catheter. We recommend you evaluate the Balloon Rated Burst Pressure and
Balloon Fatigue of PTCA catheters within your expanded stent. For more
information, please refer to Section IX.C. Additional Tests for Catheters Intended
for In-Stent Restenosis or for Stent Expansion following Stent Deployment from
the Class II Special Controls Guidance Document for Certain Percutaneous
Transluminal Coronary Angioplasty (PTCA) Catheters. 14
The following test methods should be updated to include the alternative target
deployment site described above:
x Fretting Corrosion (refer to Section A.3)
x Stress/Strain Analysis (refer to Section B.9)
x Fatigue Analysis (refer to Section B.10)
x Accelerated Durability Testing (refer to Section B.11)
x Particulate Evaluation (refer to Section B.12)
x Delivery, Deployment, and Retraction (refer to Section C.2).
The selection of the radius of curvature of the mock vessel and of the bifurcation
angle should be supported by an analysis of clinical images from representative target
vessels or referenced literature.
x
x
Contains Nonbinding Recommendations
28
It may be possible to combine Delivery, Deployment and Retraction testing with
Particulate Evaluation (see Section IV. Non-Clinical Engineering Tests B. Stent
Dimensional and Functional Attributes 12. Particulate Evaluation) and/or with
Coating Integrity (see Section IV. Non-Clinical Engineering Tests C. Delivery
System Dimensional and Functional Attributes 11. Coating Integrity), but you
should take care to ensure that only minimal additional handling of the test samples is
required for the coating integrity evaluation such that particulates are neither lost nor
generated.
We recommend that this simulated use testing be performed by tracking the device
through an in vitro fixture that mimics challenging in vivo physiologic and anatomic
conditions (e.g., a tortuous path, aqueous environment), to the extent that the device
would enter a patient in clinical use. For coronary indications, FDA recommends the
tortuous path described by Figure X2.4 of ASTM F2394. For peripheral indications,
please provide an appropriate justification for your final model, including schematics
of the fixture and a clinically-based discussion of why it provides a sufficiently
challenging model for device tracking. We recommend that you conduct all testing
on complete sterilized assemblies with mounted stents and any accessory devices that
would be used in a typical clinical procedure (e.g., introducer or guiding catheter),
using worst-case sizes (e.g., smallest guiding catheter ID). We also recommend that
you thermally equilibrate all test samples in a 37°C saline bath. You should report
any abnormality or difficulty observed during the simulated procedure, as well as any
damage observed on the stent, delivery system, or any of the accessory devices. We
recommend that you measure and report the diameter and axial location of the largest
deflated balloon profile (including the inner member or wire). This information can
be used to determine the extreme dimensions of compatible accessory devices (i.e.,
minimum internal diameter), which should be identified in the labeling.
Recommendation
FDA recommends that you conduct testing to demonstrate that the delivery catheter
can safely and reliably deliver the stent to the intended location and that the stent is
not adversely affected by the delivery catheter, both during deployment and
withdrawal.
Significance
The delivery catheter should safely and reliably deliver the stent to the intended
location according to the instructions for use, without damage to the stent.
2. Delivery, Deployment, and Retraction
direction. For these situations, we recommend that you evaluate the crossing profile
of your delivery system along different longitudinal paths (e.g., rotating test sample
90 degrees for measurements). We recommend that you report the crossing profile in
the instructions for use, the outside package labeling, or both. We recommend the
methods described in ASTM F2081 or their equivalents.
Contains Nonbinding Recommendations
X
Stent Length
(mm)
8
12 18
X
24
X
X
X
X
Significance
Balloons on stent delivery systems are often inflated multiple times during clinical
use. Failure of the balloon to withstand multiple inflations could lead to device
failure or vessel damage.
4. Balloon Fatigue (Repeat Balloon Inflations; Balloon Expandable Stents Only)
29
We recommend that you record the pressure at which the device failed and the failure
mode. We also recommend that you calculate RBP as the pressure at which 99.9% of
the balloons will survive with 95% confidence based on statistical analysis of the test
data. We recommend that you specify RBP in the device labeling.
We recommend that you record as test failures any loss of:
x integrity of the balloon, such as a rupture or leak
x pressure due to failure of the balloon, shaft, or seals.
We recommend that you test according to the example in Table 3 for each balloon
size with a different labeled RBP. We recommend that you test balloons that are not
constrained by any test fixture such as tubing, and that you inflate the balloons
incrementally until failure.
Stent
Diameter
(mm)
2.5
3.0
3.5
4.0
Table 3: Stent Delivery Sizes to Test for RBP
Recommendation
We recommend that you test balloons with mounted stents that are not constrained by
any test fixture, such as tubing. If the entire range of device sizes will have a single
labeled RBP; we recommend that you conduct testing on the longest length of every
balloon diameter, plus the smallest diameter at the shortest length and the largest
diameter at the shortest length. Table 3 illustrates the recommended test matrix for a
stent design that ranges in diameter from 2.5 to 4.0 mm and ranges in length from 8 to
24 mm.
Significance
The rated burst pressure (RBP) is the pressure at which 99.9% of balloons can survive
with 95% confidence. Failure of a balloon to survive at the RBP could result in
device failure or vessel damage.
3. Balloon Rated Burst Pressure (Balloon Expandable Stents Only)
Contains Nonbinding Recommendations
30
Recommendation
FDA recommends that you test balloon sizes as illustrated in Table 3, and that you
test multiple product lots. We recommend that you explain why you chose the test
sample size. We recommend that you include data showing inflation pressure versus
balloon diameter over the full range of recommended inflation diameters, and report
the final results in the instructions for use, the outside package labeling, or both. A
graphical or tabular presentation (i.e., a compliance chart) is desirable.
We recommend that you identify the nominal inflation pressure and RBP, as shown in
the example below. The compliance chart may include pressures up to (but not
exceeding) 25% above the RBP, if you provide data and statistics demonstrating that
99% of the balloons will not fail at the listed pressure with 95% confidence. We also
recommend that you describe how you performed any data rounding and show all
instances. Table 4 below shows an example of a compliance chart for a stent with
Significance
The diameter of a deployed balloon expandable stent varies with the balloon inflation
pressure. A compliance chart in the labeling that relates stent diameter to balloon
pressure guides selection of stent size to fit the target lesion. Incorrect selection of
stent size may lead to device failure or vessel damage.
5. Balloon Compliance (Stent Diameter vs. Balloon Pressure; Balloon Expandable
Stents Only)
We recommend that you test balloons with mounted stents that are not constrained by
any test fixture such as tubing and that you inflate the balloons in increments until
they reach the RBP. For each sample we recommend that you hold the RBP for 30
seconds (or the time specified in the instructions for use), deflate the balloon, and
inflate it again to the RBP, for a total of 10 cycles. Note that the number of cycles
recommended for this testing is different from our recommendations for balloon
catheters indicated for angioplasty (PTCA catheters). This difference is intentional
and reflects the likely number of inflations that would occur with use of a stent
delivery system versus a stand-alone PTCA catheter. We recommend that you report
any loss of pressure, whether due to failure of the balloon, shaft, or proximal or distal
seals, as a test failure. We recommend that you record all failure modes, and that
your results demonstrate that 90% of the balloons will survive the test with 95%
confidence.
Recommendation
FDA recommends that you determine the repeatability, to 10 inflations, of successful
balloon inflation to the RBP. We recommend that your sample dimensions follow the
four corners paradigm:
x largest diameter/longest length
x largest diameter/shortest length
x smallest diameter/longest length
x smallest diameter/shortest length.
Contains Nonbinding Recommendations
Stent Nominal Diameter
where x = stent inner diameter at the given pressure
3.0 mm Stent Inner
3.5 mm Stent Inner
4.00 mm Stent Inner
Diameter (mm)
Diameter (mm)
Diameter (mm)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
31
Recommendation
We recommend that you test the bond strength at locations where adhesives, thermal
fusion, or other joining methods are used for bonding components of the delivery
system. Prior to evaluating tensile strength, we recommend you precondition
catheters by tracking through a tortuous path fixture, as described above in Section 2.
Delivery, Deployment and Retraction). We recommend that testing demonstrate
Significance
Failure of bonds in the delivery catheter could lead to device failure or vessel
damage.
7. Catheter Bond Strength
Recommendation
FDA recommends that you demonstrate, using techniques recommended in your
instruction manual (e.g., pre-dilation), that the balloon inflates and deflates within
acceptable times, and provide the clinical basis for your acceptance criteria. We
recommend that you test the largest diameter at the longest balloon length, and
evaluate which other sizes to test. We also recommend you specify the balloon
deflation times in your labeling. Please observe and describe any interference with
balloon deflation or delivery system extraction from the deployed stent.
Significance
Balloons occlude the target vessel and obstruct blood flow while inflated. Inflation
and deflation times affect occlusion time. Excessively slow inflation or deflation of a
balloon could lead to prolonged ischemia and damage to the end organ.
6. Balloon Inflation and Deflation Time (Balloon Expandable Stents Only)
9.0
10.0
11.0
12.0
13.0
14.0
15.0
16.0*
*RBP
Pressure
(atm)
Table 4: Sample Compliance Chart for a Balloon Expandable Stent
3.0 mm, 3.5 mm, and 4.0 mm diameters, with a RBP of 16 atmospheres (atm). The
nominal diameter occurs at 9.0 atm.
Contains Nonbinding Recommendations
32
FDA recommends that you measure the torque strength of the stent delivery system
when the distal tip is not free to rotate, by rotating the proximal end of the catheter
until failure. We recommend that you precondition delivery systems prior to
evaluating torque strength by tracking through a tortuous path fixture, as described
above in Section 2. Delivery, Deployment and Retraction. We recommend that
you report the number of rotations to failure and the failure mode for each sample
tested. Additionally, we recommend that you test the delivery system in a fixture that
Recommendation
Stent delivery systems may be subjected to torsional forces during use. Even nonfixed wire delivery systems could be subject to torsional forces if the tip is
inadvertently caught on a previously deployed stent, calcified lesion, etc. Inability to
withstand torsional forces that are typical of clinical use could lead to device failure
or vessel damage.
Significance
10. Torque Strength
FDA recommends that you conduct testing which demonstrates that the stent delivery
system will not kink at a bend radius that is appropriate for the intended anatomy.
We recommend that you consider wrapping the catheter around a series of mandrels
with successively smaller radii until the catheter kinks or the lumen collapses. We
also recommend you provide the clinical basis for your acceptance criteria.
Recommendation
Stent delivery systems may be subjected to tight angulations in tortuous vasculature
during use. Inability to withstand flexural forces that are typical of clinical use could
lead to device failure or vessel damage.
Significance
9. Flexibility and Kink Test
Recommendation
For devices with one or more joints in the distal tip (e.g., spring or nose-cone tips),
FDA recommends that you determine the tensile force that will separate the distal tip
from the catheter. We recommend that you precondition catheters prior to tip pull
testing by tracking through a tortuous path fixture, as described above in Section 2.
Delivery, Deployment and Retraction.
Significance
Failure of bonds in the distal tip could lead to device failure or vessel damage.
8. Tip Pull Test
that all bonds can withstand tensile forces greater than those that may be experienced
during clinical use. We also recommend you provide the clinical basis for your
acceptance criteria.
Contains Nonbinding Recommendations
33
In your coating integrity test reports you should include a detailed discussion of
the surfaces using any practical methods to quantify defects. This may include
counting the number of total defects per unit area, measuring representative defect
areas, and measuring worst-case defect areas. You should support your
Interpretation of Data
Coating integrity is considered a characterization test. Acceptance criteria are not
required; however, you should provide an interpretation of the data.
It may be possible to combine the Coating Integrity Evaluation with Delivery,
Deployment and Retraction testing (see Section IV. Non-Clinical Engineering
Tests C. Delivery System Dimensional and Functional Attributes 2. Delivery
Deployment and Retraction) and/or with Particulate Evaluation (see Section IV.
Non-Clinical Engineering Tests B. Stent Dimensional and Functional
Attributes 12. Particulate Evaluation) but you should take care to ensure that
only minimal additional handling of the test samples is required for the coating
integrity evaluation such that particulates are neither lost nor generated.
Test Samples
You should conduct all testing on the finished product subject to all
manufacturing processes including sterilization. You should provide a scientific
or statistical justification for the sample size for each test. We recommend that
you implement a sampling plan to examine multiple lots of product (•3) to assess
both inter- and intra-lot variability. You should perform testing on sizes that
represent four corners of the stent design (see Table 2 above) as well as an
intermediate size.
We also recommend that you describe the physical structure of the coating, such
as coating thickness, and indicate its chemical identity.
Coating Description
We recommend that you describe the clinical purpose and intended function of
the coating, such as enhanced radiopacity, thromboresistance, or lubricity.
FDA recommends that you address the aspects described below for any coatings
applied to the surfaces of your product.
Recommendation
Significance
Unintended delamination or degradation of a coating may lessen its benefit or
otherwise negatively impact its clinical performance.
11. Coating Integrity
simulates the anatomy of the aortic arch and coronary arteries. We also recommend
you provide the clinical basis for your acceptance criteria.
Contains Nonbinding Recommendations
34
Recommendation
FDA recommends that you measure the force that will dislodge the stent from the
delivery system under clinically relevant conditions. We recommend that the test
simulate the intended use, including insertion through a tortuous path that simulates
the vasculature proximal to and including the lesion site. We recommend that the
tortuous path be sized appropriately for the stent size being tested. We recommend
that you submit a photo, diagram, or description of the tortuous path, including
dimensions. For coronary indications, FDA recommends the tortuous path described
by Figure X2.4 of ASTM F2394. For peripheral indications, please provide the
clinical basis for your final model. We recommend that the stent sizes tested
represent the worst case stent securement for your design. We recommend that you
explain why your results are applicable to all sizes of your stent, including those not
tested for stent securement.
Significance
Dislodgment of the stent prior to deployment can result in stent embolization. Stents
without sheaths may dislodge if they catch on tortuous anatomy, guide catheters, or
other devices.
12. Stent Securement for Unsheathed Stents
Simulated Use Coating Integrity
We also recommend that you evaluate the coating integrity after simulated use,
via visual assessment. Devices should be tracked through a tortuous path fixture
(as described above in Section 2. Delivery, Deployment and Retraction) and
then expanded in air or an aqueous medium to the maximum labeled diameter
described in the Instructions for Use prior to visual inspection. You should also
assess the impact of simulated use on the functional aspects of the coating.
Baseline Coating Integrity
We recommend that you conduct a visual assessment of the coating integrity on
all appropriate surfaces of the delivery system before stent deployment to
establish a baseline for comparison to coating characteristics after testing
performed under other conditions. We recommend that you appropriately
quantify characteristics such as continuity and voids in the coating, as described
above.
We recommend that you address the aspects described below for any coatings
applied to the surfaces of your product.
discussion with representative images (including worst-case) at a sufficient
magnification to characterize the defects. Multiple magnifications may be needed
to visualize and adequately characterize the product. The discussion of acceptable
coating integrity should include a justification that the number and size of defects
observed will not impact clinical performance.
Contains Nonbinding Recommendations
35
To evaluate device functionality, we recommend that you repeat the following bench
tests on aged devices:
x Stent Dimensional Verification (refer to Section B.1)
x Stent Foreshortening* (refer to Section B.3)
x Radial Outward Force* (refer to Section B.7)
x Particulate Evaluation (refer to Section B.12)
x Delivery System Dimensional Verification (refer to Section C.1)
x Delivery, Deployment, and Retraction (refer to Section C.2)
x Balloon Rated Burst Pressure (refer to Section C.3)
x Balloon Fatigue (refer to Section C.4)
x Balloon Compliance (refer to Section C.5)
x Balloon Inflation and Deflation Time (refer to Section C.6)
x Catheter Bond Strength (refer to Section C.7)
x Tip Pull Test (refer to Section C.8)
x Flexibility and Kink Test (refer to Section C.9)
x Torque Strength (refer to Section C.10)
x Coating Integrity (refer to Section C.11)
Recommendation
We recommend that shelf life testing address package integrity to ensure sterility, as
well as stable device functionality over the expected life cycle.
Significance
Aging can potentially affect the performance of the materials of construction for the
stent and delivery system.
D. Shelf Life
Withdrawing a stent delivery system into a guiding catheter, arterial sheath, or
hemostasis valve could result in stent dislodgement. We recommend testing the
stent by attempting to withdraw the un-deployed stent into a guide catheter or
other opening of the smallest size for an accessory device recommended in the
instructions for use.
Dislodgement by Reverse Motion
Advancing a stent delivery system across a tight lesion could result in stent
dislodgement. We recommend testing the stent by passing it through a simulated
tight lesion in the tortuous path.
Dislodgement by Forward Motion
FDA recommends that you address the modes of dislodgement as described below:
Contains Nonbinding Recommendations
15
Stent Securement for Unsheathed Stents (refer to Section C.12)
*only repeat testing on aged stents if self-expanding
36
determine the appropriate amount of test material as outlined in ISO 10993-12
or an equivalent method, using surface area to extractant volume ratios (mass
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080735.htm
x
Sample Preparation
It is important to understand how the test samples compare to the final sterilized
product. For biocompatibility testing conducted using extraction samples, we
recommend that you:
Differences in formulation, processing or sterilization that could affect
biocompatibility of the final product may warrant additional biocompatibility testing.
Recommendation
We recommend that you determine the biocompatibility of all patient-contacting
materials present in your device. If your materials are identical in composition and
processing methods to materials with a history of successful use in cardiovascular
product applications, you may reference the appropriate literature or previous testing
experience. We recommend that you test novel materials, i.e., those with no history
of successful prior use according to the methods in the FDA-recognized version of
relevant ASTM, USP, and ISO standards. In addition, we recommend that you
follow the guidance Use of International Standard ISO-10993, 'Biological
Evaluation of Medical Devices Part 1: Evaluation and Testing 15 to identify the
types of tests that should be considered.
Significance
Stents and delivery systems contain patient-contacting materials, which when used
for their intended purpose, i.e., contact type and duration, may induce a harmful
biological response.
E. Biocompatibility
We recommend that you provide the protocol used for your shelf life testing, the
results of the testing, and the conclusions drawn from your results. If you use devices
subjected to accelerated aging for shelf life testing, we recommend that you specify
the way in which the device was aged. Since stent delivery systems contain
polymeric materials, you should plan to conduct testing on real-time aged samples to
confirm that accelerated aging is reflective of real-time aging. This testing should be
conducted in parallel with PMA review and approval, with results submitted in a
post-approval annual report.
Additional tests may be recommended for certain devices, depending on their design,
materials (alloys), or manufacturing processes.
x
Contains Nonbinding Recommendations
describe the condition of the extraction vehicle (e.g., color, presence of any
particles)
explain any changes in the post-extraction vehicle (compared to preextraction)
describe the details of storage conditions, if applicable.
x
x
x
37
Delivery Systems
Because delivery catheters are externally communicating products in contact with
cardiovascular tissue and circulating blood, with a temporary duration of contact (<24
hrs), we recommend the following tests be considered:
x cytotoxicity
x sensitization (guinea pig maximization with both polar and non-polar extracts)
x irritation (or intracutaneous reactivity)
x acute systemic toxicity
x material-mediated pyrogenicity
Stents
Because stents are implanted products in contact with cardiovascular tissue and
circulating blood, with a permanent duration of contact (>30 days), we recommend
the following tests be considered:
x cytotoxicity
x sensitization (guinea pig maximization with both polar and non-polar extracts)
x irritation (or intracutaneous reactivity)
x acute systemic toxicity
x material-mediated pyrogenicity
x hemocompatibility [hemolysis, in vivo thrombogenicity, and direct contact
complement activation (C3a and SC5b-9)]
x sub-chronic toxicity
x genotoxicity (bacterial reverse mutation assay, mammalian cell in vitro assay,
and in vivo cytogenetics assay in rodents)
x chronic toxicity
x implantation
x carcinogenicity.
If extraction samples are not used immediately, we recommend that you follow the
storage conditions described in ISO 10993-12 or an equivalent method. We also
recommend that you explain how storage does not affect your test results.
use both polar and nonpolar extractants
x
to extractant volume ratios should only be used if surface area cannot be
calculated)
Contains Nonbinding Recommendations
17
16
ASTM F2065-00e1 Alternative Pathway Complement Activation in Serum by Solid Materials.
ASTM F1984-99 (2003) Whole Complement Activation in Serum by Solid Materials.
38
In addition, you may assess in vivo thrombogenicity during preclinical animal
testing in lieu of a separate canine in vivo thrombogenicity test. If a 4 hour canine
in vivo thrombogenicity study is needed (e.g., due to the use of novel materials
never before used in a medical devices or questionable findings from the vascular
Immunology testing should appropriately address the various complement
activation pathways. We recommend that you assess in vitro C3a and SC5b-9
fragment activation using standard testing methods, such as those outlined in
ASTM F2065-00e1 16 and ASTM F1984-99 (2003) 17 , or an equivalent method.
Alternatively, you may provide a rationale for omitting this testing, if all the
materials used in the formulation and processing of the device have a history of
previous use in blood-contacting devices with similar contact duration.
Hemocompatibility
For blood-contacting devices (regardless of contact duration), we recommend that
you consider hemolysis, immunology (complement activation), and in vivo
thromboresistance.
x
We recommend either that you run concurrent controls, or that the test laboratory
run controls within 3 months of the test samples. We also recommend you
provide protocols and results from positive control testing to confirm that you
used the same methods for both the positive control testing and the test samples.
Sensitization (Guinea Pig Maximization Method)
We recommend that test reports confirm that all female animals used in the
testing are not pregnant, as pregnancy can reduce the ability of a female animal to
detect a sensitization response.
x
Additional Considerations
x Cytotoxicity
We recommend that extractions be conducted at 37°C for 24 hours using a vehicle
with both mammalian cell culture media (MEM) and 5% serum, as these
materials will allow for extraction of both polar and nonpolar constituents from
the test sample.
hemocompatibility [hemolysis, in vivo thrombogenicity, and direct contact
complement activation (C3a and SC5b-9))
x genotoxicity (bacterial reverse mutation assay, mammalian cell in vitro assay,
and in vivo cytogenetics assay in rodents).
Additional testing may be requested to fully characterize the toxicology profile,
depending on the materials of use.
x
Contains Nonbinding Recommendations
18
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm
We recommend that you describe the stent and delivery catheter, including the stent
material, whether the stent is balloon expandable or self-expanding, etc. You should
consider including a table with the following attributes, as appropriate:
x available stent diameters and lengths
x guiding catheter/sheath compatibility
x deployment and RBPs
x percent stent free area.
A. Device Description
FDA recommends that labeling for extracranial intravascular stents include the sections
described below. Some of these recommendations may also be relevant to covered, drugeluting, and biodegradable stents; however, FDA recommends additional labeling, not
described in this document, for those devices. The Interventional Cardiology Devices
Branch and the Peripheral Vascular Devices Branch are available to discuss labeling for
those stents and indications.
General labeling requirements for medical devices are described in 21 CFR Part 801.
Additional information may be obtained from Device Advice. 18 You must submit all
proposed labeling in your PMA [21 CFR 814.20(b)(10)].
V. Labeling
39
Nickel ion release
For devices containing nitinol, we recommend that you consider the potential for
nickel ion release from your device. Specifically, if you cannot demonstrate that
your nitinol device exhibits sufficient corrosion resistance as well as an adequate
passivation layer, we recommend that you quantify nickel ion release from your
device over time. Testing can be performed by measuring concentrations of
nickel leached from the device into a fluid with physiologic temperature and pH.
x
Material-mediated Pyrogenicity
We recommend that you assess pyrogenic responses to chemical leachants over
the duration of device contact with the patient. We recommend that you assess
material-mediated pyrogenicity using traditional biocompatibility extraction
methods, such as those outlined in the USP 28 <151> Rabbit Pyrogen Test (e.g.,
50°C for 72 hours; 70°C for 24 hours; or 120°C for 2 hours) or an equivalent
method. You should consider that temperatures above 37°C may result in
toxicities not representative of the final product.
x
animal studies), we recommend the study be conducted in a venous,
unheparinized model.
Contains Nonbinding Recommendations
need for appropriate anticoagulation or antiplatelet therapy or both
recommendation that when multiple stents are used, they should be of similar
composition
fact that long-term outcomes following repeat dilatation of endothelialized stents are
unknown.
x
x
x
x
lack of long-term safety and effectiveness data
lack of safety and effectiveness data for special patient populations
need for appropriate physician training
anatomical or physiological limitations on the effectiveness of the device.
40
You should include as precautions information regarding any special care physicians or
others should exercise for the safe and effective use of the device. Additionally, you should
include any limitations on the use of a device for reasons including, but not limited to:
E. Precautions
x
x
x
We also recommend that you include warnings to address the:
We believe a warning is also appropriate when the device is commonly used for a disease
or condition for which there is a lack of valid scientific evidence of effectiveness for that
disease or condition or use of the device is associated with a serious risk or hazard.
We recommend that you include an appropriate warning if there is reasonable evidence
of an association of a serious hazard with the use of the device. A causal relationship
need not have been proved.
D. Warnings
We recommend that you include contraindications to the use of the device.
Contraindications describe situations in which the device should not be used because the
risk of use clearly outweighs any possible benefit.
C. Contraindications
We recommend that proposed labeling reflect the precise indications for use statement
that is the subject of the application. The general statement of the “Indications for Use”
identifies the target population in which sufficient valid scientific evidence has demonstrated
that the device as labeled will provide clinically significant results and at the same time does
not present an unreasonable risk of illness or injury associated with the use of the device.
B. Indications for Use
We recommend that you describe any ancillary or accessory devices that are packaged
with your stent system when no separate labeling is available. An example would be a
description of an embolic protection system that is packaged with your stent delivery
system. You may add additional information where appropriate.
Contains Nonbinding Recommendations
19
the number of patients enrolled
the number of investigational sites both inside the United States (US) and outside
the United States (OUS)
the primary study endpoint or endpoints
the amount of available follow-up
the total planned follow-up.
x
x
x
x
x
41
the design of the study, including any randomization, blinding, and the control or
controls used
x
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm107705.htm
whether the study was a pivotal, supporting, or feasibility study
x
You should provide a narrative description of the pivotal study or studies and any
supporting or feasibility studies relevant to the stent. The narrative should be brief, and
should include the following information for each study:
G. Overview of Clinical Studies
The effect of heating in the MRI environment for overlapping stents or stents with
fractured struts is not known.
In addition to the labeling recommendations in the Guidance for Industry and FDA
Staff: Establishing Safety and Compatibility of Passive Implants in the MR
(Magnetic Resonance) Environment, FDA recommends that your labeling also
describe whether you determined the effect of heating in the MRI environment for
overlapping stents or stents with fractured struts. If you have not determined what
those effects are, we recommend that your labeling reflect this, for example:
Overlapping Stents or Stents with Fractured Struts
We recommend you follow the labeling guidelines given in Guidance for Industry
and FDA Staff: Establishing Safety and Compatibility of Passive Implants in
the MR (Magnetic Resonance) Environment 19
F. MR Environment
The safety and effectiveness of the XYZ coronary stent system has not been
established in patients with recent acute myocardial infarction.
or
The safety and effectiveness of the ABC (coronary or peripheral) stent system has not
been established in patients beyond x (months/years) of follow-up.
Stent handling, stent placement, stent system removal, and any post-implant precautions
are appropriate for inclusion in this section. Additionally, you should address length of
follow-up or use in special patient populations, for example:
Contains Nonbinding Recommendations
+
Any patients not evaluated during the analysis
window, but that had the specified adverse
event between treatment and the analysis
window
x
major adverse cardiac events (MACE), which includes:
o death
o Q-wave myocardial infarction (MI)
o non-Q-wave MI
o emergent coronary artery bypass grafting (CABG)
o target lesion revascularization (TLR)
You should separate in-hospital events from out-of-hospital events (through X
days or months), for categories such as:
Coronary Indications
We have provided a list of suggested elements for inclusion, below. Additional
elements may be appropriate given the specific vessel or vessels to be stented.
42
You should include an adverse events table that captures data through the longest
available follow-up for the study. You should also provide protocol definitions for
adverse events as footnotes, or a reference to definitions included with the Principal
Safety and Effectiveness Table.
You may also use an alternative approach known as “intent-to-treat” analysis, in
which any patients not evaluated during the analysis window are assumed to have had
an adverse event. If your trial involves substantial numbers of crossover patients, an
intent-to-treat analysis may be more appropriate. In this analysis, adverse events
would be assigned to the original treatment group regardless of actual treatment
received or time at which the adverse event occurred.
The numerator consists of the number of patients presenting with the adverse event
during or before the analysis window.
The number of
patients evaluated
during the analysis
window
In this approach, the numerator consists of the number of patients presenting with the
adverse event during or before the analysis window. For each adverse event, the
denominator consists of:
Observed Adverse Events
You should provide a brief narrative statement about the source or sources of the
adverse event experience followed by results in a tabular format. In the table, we
recommend that you present adverse events using a “per protocol” (also known as an
“evaluable”) approach.
H. Adverse Events
Contains Nonbinding Recommendations
target lesion failure (TLF)
target vessel failure (TVF)
target vessel revascularization (TVR)
TVR, non-TLR
stent thrombosis (acute, subacute, late)
cerebro-vascular accident (CVA)
bleeding complications
vascular complications
43
Potential Adverse Events
You should include potential adverse events associated with stenting of the intended
coronary or peripheral vessel or vessels.
You should separate events at specific time points (e.g. 30 days, 1 year) and
cumulative events for categories such as:
x major adverse event (MAE) – may be study specific
o death
o stroke
o Q-wave MI (in-hospital)
o non-Q-wave MI
o end organ injury or ischemia or both
o TLR
o target limb amputation
x TVF
x TVR
x TVR, non-TLR
x stent thrombosis (acute, subacute, late)
x bleeding complications
o access site
o non-access site
x vascular complications
o perforation
o aneurysm
o pseudo-aneurysm
o dissection
Peripheral Indications
x
x
x
x
x
x
x
x
Contains Nonbinding Recommendations
whether the study is controlled
which type of controls were used
if the study results were compared to a performance goal
how any performance goals were derived.
x
x
x
x
vessel type, (i.e., de novo or restenotic)
type of evaluations (clinical, telephone, angiographic/intravascular ultrasound
follow-up).
x
x
age
race
gender
percentage of smokers
incidence of hyperlipidemia
previous MI
diabetes
x
x
x
x
x
x
x
44
vessel size
x
Demographics
You should describe characteristics of your patient populations that could affect the
results of the study, including:
vessel location
x
You should include a brief description of patient entry criteria, such as:
You should also describe the success criteria for the trial (i.e., superiority or noninferiority when compared to the control).
whether the design is randomized or non-randomized
x
Design
You should describe your study design. The following is a partial list of elements
that may be appropriate to your design:
Conclusions
You should briefly state the study outcome or outcomes.
Purpose/Objective
You should state the intent of the study, including the primary endpoint or endpoints.
You should include additional specifics about the clinical studies described in the section
titled “Overview of Clinical Studies,” above. We suggest the following format:
I. Clinical Studies
Contains Nonbinding Recommendations
any other important covariates.
Examples of Kaplan-Meier survival endpoints
x “Freedom from MACE” for coronary and peripheral stenting studies
x “Patency survival” for peripheral stenting studies
45
In some instances, it may be appropriate to provide a graphical presentation of the most
appropriate Kaplan-Meier survival endpoints (see examples of these endpoints below)
and accompanying life tables. We believe that statistical comparisons between groups, as
presented in a Kaplan-Meier presentation, are only appropriate for randomized trials.
The review branches are available to advise you on this issue.
You should provide Kaplan-Meier estimates for relevant endpoints in your safety and
effectiveness table, which may include, but are not limited to:
x MACE-free survival
x MAE-free survival
x TVF-free survival
x TVR-free survival
x TLR-free survival
x primary, primary assisted, and secondary patency survival.
We recommend that you present the clinical outcomes in a tabular format as
“effectiveness measures” and “safety measures,” separately or combined. Your data
presentation should follow the same approach used for adverse event reporting (for
example, per protocol or intent-to-treat). You should include protocol definitions for
terms used in the table.
J. Principal Safety and Effectiveness Table
You should refer to the Principal Safety and Effectiveness Table, which is described
in the next section of this guidance.
The X stent demonstrated a lower rate of TVF as compared to the control group
(X% vs. Y%, P<0.001).
Results
You should briefly describe the results of the study, including whether the primary
endpoint or endpoints were met, for example:
Methods
You should describe any use of a Clinical Events Committee, a Data and Safety
Monitoring Board, and/or a core laboratory for adverse event adjudication, as
appropriate.
x
Contains Nonbinding Recommendations
You should include a compliance chart that provides the average stent inner
diameter following deployment at various pressures derived from bench testing.
You should display the data as determined from testing. However, if you round
the data, you should footnote the chart to indicate that the data is rounded. We
recommend the format presented in Table 4 (see Section IV. Non-Clinical
Engineering Tests, B. Stent Dimensional And Functional Attributes, 4.
Recoil For Balloon Expandable Stents).
Compliance Chart (Balloon Expandable Stents Only)
Pre-mounted Balloon Expandable Stents
46
You should include directions for proper preparation and use of the device in this section
of the labeling. If multiple delivery systems are available, you should clearly indicate
differences specific to the delivery system. An example would be to indicate the
difference between an over-the-wire (OTW) and a rapid exchange (RX) delivery system.
L. Directions for Use
We recommend that this section provide information related to individualization of
treatment.
K. Patient Selection and Treatment
If clinical results in the updates raise a safety or effectiveness concern when
compared to the initial results of your study, we recommend that you update the
labeling to reflect this new information.
If such an update is not listed as a condition of approval, you may provide the
updated labeling in your annual report, as long as the updated information is based on
the endpoints and follow-up schedule prospectively defined in your clinical study
protocol. For updates that relate to new indications, see 21 CFR 814.39. The
labeling should indicate which data were added or updated after the initial device
approval.
Updates to Principal Safety and Effectiveness Table
For some devices, updates to the Principal Safety and Effectiveness Table to reflect
additional clinical follow-up beyond the primary follow-up interval are identified as a
condition of PMA approval. In this case, the updated labeling should be submitted as
a PMA supplement.
If you provide a survival graph, it should include error bars representing a standard error
(SE) of ± 1.5. The scale should either begin on the y-axis at a value greater than zero –
we recommend using a value around 50 - 60% – or indicating a break in the scale to
illustrate the differences in survival curves, if applicable.
Contains Nonbinding Recommendations
21
47
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070782.htm
ASTM F2503 Standard Practice for Marking Medical Devices and Other Items for Safety in the Magnetic
Resonance Environment
22
IEC 60601 Medical electrical equipment – Part 2-33: Particular requirements for the safety of magnetic resonance
equipment for medical diagnosis
20
For MR Conditional stents, we recommend you include the bulleted points from the
Guidance for Industry and FDA Staff: Establishing Safety and Compatibility of Passive
Implants in the MR (Magnetic Resonance) Environment. In addition, we recommend
you include the following:
x
the appropriate MR safety icon and term from ASTM F2503 21
x
if applicable, a statement similar to the following: Patients with the device may
safely undergo MRI for (insert appropriate term: "Normal Operating Mode" or
"First Level Controlled Operating Mode") of the MR System as defined in IEC
60601-2-33 22
x
a statement about the image artifact
x
a recommendation that patients register the conditions under which the implant can
be scanned safely with the MedicAlert Foundation (www.medicalert.org) or
equivalent organization.
You should provide all patient materials, such as the patient guide and implant card, that you
will make available. See also Guidance on Medical Device Patient Labeling, 20
M.Patient Materials
If you base your values on mathematical calculations, you should indicate this in a
footnote to the table. See Section IV. Non-Clinical Engineering Tests, B. Stent
Dimensional And Functional Attributes, 3. Foreshortening, for information on
testing stent percent foreshortening.
Percent Foreshortening (Self-Expanding Stents Only)
You should provide a table that shows:
x vessel lumen diameter
x unconstrained stent diameter
x percent foreshortening.
Contains Nonbinding Recommendations
Stent
Dimensional and
Functional
Attributes
Material
Characterization
Kink Resistance (peripheral indications only)
Crush Resistance (peripheral indications only)
Coating Durability (coated stents only)
Radiopacity
MRI Safety and Compatibility
Particulate Evaluation
Accelerated Durability Testing
Fatigue Analysis
Stress/strain analysis
Radial Outward Force
Radial Stiffness and Radial Strength
Stent Integrity
Recoil for Balloon Expandable Stents
Foreshortening
Percent Surface Area of the Stent
Dimensional Verification
Corrosion Resistance
Mechanical Properties
Material Composition
Shape Memory and Superelasticity
Test
Appendix A: Test Summary Checklist
(continued on next page)
Page 48
Sizes Tested
and Sample
Sizes
Test Method or
Standard
Reference
Accept/Reject
Criteria
Results
Shelf Life
Delivery System
Dimensional and
Functional
Attributes
Delivery System Dimensional Verification
Particulate Evaluation
Stent Recoil
Stent Foreshortening
Stent Dimensional Verification
Packaging
Stent Securement for Unsheathed Stents
Coating Integrity
Torque Strength
Flexibility and Kink Test
Tip Pull Test
Catheter Bond Strength
Balloon Inflation and Deflation Time
(balloon expandable stents only)
Balloon Compliance (Stent Diameter vs.
Balloon Pressure) (balloon expandable
stents only)
Balloon Fatigue (balloon expandable stents
only)
Balloon Rated Burst Pressure (balloon
expandable stents only)
Delivery, Deployment, and Retraction
Dimensional Verification
Test
Page 49
Sizes Tested
and Sample
Sizes
Test Method or
Standard
Reference
Appendix A: Test Summary Checklist (continued from previous page)
Accept/Reject
Criteria
Results
Biocompatibility
Biocompatibility
Stent Securement for Unsheathed Stents
Coating Integrity
Torque Strength
Flexibility and Kink Test
Tip Pull Test
Catheter Bond Strength
Balloon Inflation and Deflation Time
Balloon Compliance
Balloon Fatigue
Balloon Rated Burst Pressure
Delivery, Deployment, and Retraction
Page 50
Page 51
G71 Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes
F2503 Standard Practice for Marking Medical Devices and Other Items for Safety in the
Magnetic Resonance Environment
F2394 Standard Guide for Measuring Securement of Balloon Expandable Vascular Stent
Mounted on Delivery System
F2182 Standard Test Method for Measurement of Radio Frequency Induced Heating Near
Passive Implants During Magnetic Resonance Imaging
F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization
Measurements to Determine the Corrosion Susceptibility of Small Implant Devices
F2082 Standard Test Method for Determination of Transformation Temperature of NickelTitanium Shape Memory Alloys by Bend and Free Recovery
F2081 Standard Guide for Characterization and Presentation of the Dimensional Attributes of
Vascular Stents
F2079 Standard Test Method for Measuring Intrinsic Elastic Recoil of Balloon expandable
Stents
F2065 Alternative Pathway Complement Activation in Serum by Solid Materials
F2004 Standard Test Method for Determination of Transformation Temperature of NickelTitanium Alloys by Thermal Analysis
F1984 Whole Complement Activation in Serum by Solid Materials
F138 Standard Specification for Wrought 18Chromium-14Nickel-2.5Molybdenum Stainless
Steel Bar and Wire for Surgical Implants
ASTM Standards
IEC 60601 Medical electrical equipment – Part 2-33: Particular requirements for the safety of
magnetic resonance equipment for medical diagnosis
IEC Standard
10993 Biological Evaluation of Medical Devices
A list of FDA-recognized standards is available at
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm
ISO Standard
Appendix B: Applicable Standards
3/26/2008
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health (CDRH)
Center for Drug Evaluation and Research (CDER)
March 2008
Combination Products
For questions regarding this draft document contact (CDRH) Ashley Boam at 240-276-4222 or
(CDER) Devi Kozeli at 301-796-2240.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of availability that publishes in the Federal
Register.
This guidance document is being distributed for comment purposes only.
DRAFT GUIDANCE
Coronary Drug-Eluting Stents—
Nonclinical and Clinical Studies
Guidance for Industry
3/26/2008
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health (CDRH)
Center for Drug Evaluation and Research (CDER)
March 2008
Combination Products
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Education, and Radiation Programs (OCER)
Division of Small Manufacturers, International and Consumer Assistance (DSMICA)
Center for Devices and Radiological Health
Food and Drug Administration
1350 Piccard Drive (HFZ-220)
Rockville, MD 20850-4307 U.S.A.
http://www.fda.gov/cdrh/ggpmain.html
Email: [email protected]
Fax: 301.443.8818
(Tel) Manufacturers Assistance: 800.638.2041 or 301.443.6597
(Tel) International Staff Phone: 301.827.3993
Additional copies are available from:
Coronary Drug-Eluting Stents
Guidance for Industry
Draft — Not for Implementation
Contains Nonbinding Recommendations
PRODUCT DEVELOPMENT PATHWAYS FOR DRUG ELUTING STENTS ...... 6
The DES Development Pathway — Overview ............................................................................ 6
Stent Platform .................................................................................................................................. 8
Delivery System................................................................................................................................ 8
Polymer/Carrier............................................................................................................................... 8
Drug Substance................................................................................................................................ 9
Factors Influencing Development: Local and Systemic Exposure ........................................... 9
A.
1.
2.
3.
4.
5.
6.
3/26/2008
V.
Clinical Pharmacology and Clinical Tolerance and Safety Information ................................ 13
C.
Physical and Chemical Characterization ...................................................................................... 17
Elucidation of Structure................................................................................................................. 17
Manufacturer ................................................................................................................................. 17
Manufacture and Control .............................................................................................................. 18
Specifications ................................................................................................................................. 18
Reference Standards ...................................................................................................................... 19
CMC for the Drug Substance Component ................................................................................ 17
CMC INFORMATION .................................................................................................. 16
Single IV Dose-Escalation Study ................................................................................................... 15
Multiple IV Dose-Escalation Study................................................................................................ 15
Mass Balance Study ....................................................................................................................... 15
In Vitro and In Vivo Metabolic Studies.......................................................................................... 15
Bioanalytical Methods ................................................................................................................... 16
Nonclinical Pharmacology and Toxicology................................................................................ 12
B.
1.
2.
3.
4.
5.
General Considerations ............................................................................................................... 10
A.
IV.
SYSTEMIC PHARMACOLOGY, TOXICOLOGY, AND SAFETY DATA FOR
THE DRUG SUBSTANCE ALONE ......................................................................................... 10
C.
1.
2.
3.
4.
1. Drug Substance................................................................................................................................ 7
2. Finished DES ................................................................................................................................... 8
B. Factors Influencing Development: Prior Information on Components.................................... 8
A.
III.
C.
Product Classification ..................................................................................................................... 3
IDE Application Requirements ........................................................................................................ 3
IND Application Requirements ....................................................................................................... 4
PMA Application Requirements...................................................................................................... 4
Master Files ..................................................................................................................................... 4
Letters of Authorization (LOA) ........................................................................................................ 5
Least Burdensome Principles........................................................................................................ 6
Application Requirements............................................................................................................. 3
1.
2.
3.
4.
5.
6.
Regulatory Basis ............................................................................................................................ 2
B.
BACKGROUND ............................................................................................................... 2
II.
A.
INTRODUCTION............................................................................................................. 1
I.
Appropriate Validated Models....................................................................................................... 42
Standards for Evaluation ............................................................................................................... 42
Study Duration ............................................................................................................................... 44
Biological Response....................................................................................................................... 45
Drug Dosage Safety Margin .......................................................................................................... 45
Overlapping Stents......................................................................................................................... 46
Long Stents..................................................................................................................................... 46
Clinical Pharmacology and Drug Release Kinetics .................................................................. 47
1. Clinical Pharmacology Information .............................................................................................. 47
2. Drug Release Kinetic Information ................................................................................................. 47
1.
2.
3.
4.
5.
6.
7.
Animal Safety Studies.................................................................................................................. 41
Manufacturing — Quality System (QS) Regulation and Current Good Manufacturing
Shelf life testing ............................................................................................................................ 52
3/26/2008
VIII. CLINICAL ASSESSMENT OF DRUG-STENT COMBINATIONS ........................ 53
Package Integrity ......................................................................................................................... 52
D.
Sterilization................................................................................................................................... 52
C.
B.
Practice (CGMP) Regulations ............................................................................................................. 51
A.
VII. FINISHED PRODUCT MANUFACTURING, STERILIZATION, PACKAGE
INTEGRITY, AND SHELF LIFE............................................................................................. 51
E.
D.
C.
Coating Characterization .............................................................................................................. 33
Coating Integrity............................................................................................................................ 34
Particulate Matter Characterization ............................................................................................. 36
Corrosion Potential of a DES ........................................................................................................ 40
Degradable coatings...................................................................................................................... 40
Biocompatibility ........................................................................................................................... 41
Engineering Evaluation ............................................................................................................... 32
1.
2.
3.
4.
5.
B.
NONCLINICAL STUDIES OF THE FINISHED DES .............................................. 32
Summary Tables .......................................................................................................................... 32
A.
VI.
1. Description of the DES .................................................................................................................. 20
2. Product Development..................................................................................................................... 20
3. Physical and Chemical Characterization ...................................................................................... 22
4. Components and Composition ....................................................................................................... 22
5. Manufacturer ................................................................................................................................. 25
6. Manufacturing Process and Controls ............................................................................................ 25
7. Packaging System .......................................................................................................................... 26
8. Finished Product Specifications .................................................................................................... 27
9. Stability .......................................................................................................................................... 30
10. Labeling .................................................................................................................................... 31
11. Environmental Assessment........................................................................................................ 31
7. Container/Closure System ............................................................................................................. 19
8. Stability .......................................................................................................................................... 19
B. CMC for the Finished Product ................................................................................................... 19
Draft — Not for Implementation
Draft — Not for Implementation
TABLE OF CONTENTS
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
Study Designs ............................................................................................................................... 55
D.
Follow-Up from Clinical Studies ................................................................................................ 64
Peri-Approval Studies ................................................................................................................. 70
Next Generation DES .................................................................................................................. 71
C.
D.
3/26/2008
BIBLIOGRAPHY ....................................................................................................................... 82
GLOSSARY OF TERMS........................................................................................................... 75
APPENDIX A .............................................................................................................................. 73
COMPANION DOCUMENT ........................................................................................ 72
Adverse Event Reporting ............................................................................................................ 68
B.
IX.
Postapproval Studies ................................................................................................................... 65
A.
VIII. POSTAPPROVAL CONSIDERATIONS .................................................................... 65
G.
1. Analysis Cohorts ............................................................................................................................ 62
2. Poolability Considerations for DES Studies.................................................................................. 62
F. Adjunctive Pharmaceutical Regimens ....................................................................................... 63
E.
Objectives for DES Trials ........................................................................................................... 54
C.
Superiority Study............................................................................................................................ 55
Noninferiority Study....................................................................................................................... 56
Endpoints for DES Trials............................................................................................................... 57
Considerations for DES incorporating an unstudied drug ............................................................ 59
Blinding Concerns in DES Clinical Studies................................................................................... 60
Independent Oversight of Drug-Eluting Stent Trials..................................................................... 61
Statistical Analysis Plan .............................................................................................................. 61
Intended Use................................................................................................................................. 54
B.
1.
2.
3.
4.
5.
6.
General Considerations ............................................................................................................... 53
33
34
35
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
5
6
7
8
9
10
11
12
4
3
2
1
INTRODUCTION
3/26/2008
1
1
This guidance has been prepared by a working group that included members of the Center for Devices and Radiological
Health (CDRH), Center for Drug Evaluation and Research (CDER), and Office of Combination Products (OCP) in the
Office of the Commissioner at the Food and Drug Administration.
2
For purposes of this guidance, sponsor refers to any person who takes the responsibility for and initiates a clinical
investigation; applicant refers to any person who submits an application, amendment, or supplement to obtain FDA
approval of a new medical product or any other person who owns an approved application. Sponsor is used primarily in
relation to investigational device exemption (IDE) applications and applicant is used primarily in relation to premarket
approval (PMA) submissions.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The
The associated companion document provides additional information that may be useful, including
suggested contents of investigational and premarket approval applications; various examples (e.g.,
example of a DES clinical study summary, a commitment table, test article certification);
information on good animal husbandry, biocompatibility considerations, and issues related to U.S.
and OUS (outside the U.S.) studies; and labeling recommendations. The companion document is
intended to be used together with this guidance.
This guidance is intended to provide recommendations to sponsors or applicants2 planning to
develop, or to submit to FDA, a marketing application for a coronary drug eluting stent (DES). The
guidance discusses the data and clinical studies needed to support such an application. This guidance
does not discuss noncoronary DESs (e.g., peripheral drug-eluting, nonvascular biliary stents) or
stents that contain biological product components such as cell or gene therapy or therapeutic
biological products such as monoclonal antibodies. The guidance makes recommendations for stents
made from metallic stent substrates, but does not provide complete information for degradable stents
or stents made from other material substrates (e.g., polymer or ceramics).
I.
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current
thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
Guidance for Industry1
Coronary Drug-Eluting Stents —Nonclinical and Clinical Studies
Draft — Not for Implementation
Draft — Not for Implementation
A.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
BACKGROUND
Regulatory considerations that are unique to DES combination products
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Regulatory Basis
3/26/2008
2
In response to several requests for designation under 21 CFR 3.7, the Agency determined that for
current DESs where the device component maintains coronary artery patency and the drug
component augments the safety and/or effectiveness of the uncoated (bare) stent by preventing
DESs are combination products subject to section 503(g) of the Federal Food, Drug, and Cosmetic
Act (the Act) (21 U.S.C. 353(g)), because they are a combination of two different types of regulated
components (a device and a drug) that are physically and/or chemically combined and produced as a
single entity (21 CFR 3.2(e)(1)). A combination product is assigned to an Agency component, such
as the Center for Devices and Radiological Health (CDRH) or the Center for Drug Evaluation and
Research (CDER), for premarket review and regulation based on a determination of the product’s
primary mode of action.
A.
We encourage sponsors and applicants to consult closely with FDA during development of a DES.
How to characterize the drug-device combination product, including the
chemical/physical/mechanical properties of the DES, the nonclinical local vascular and
regional myocardial toxicology, and the clinical performance of the drug-stent combination
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How to characterize the drug substance, including chemistry, nonclinical systemic and local
tissue pharmacology and toxicology, and how to evaluate the potential for and consequences
of systemic clinical exposure
After briefly discussing some general FDA jurisdictional considerations related to this drug-device
combination product, the guidance clarifies a number of issues related to the development of DESs
including the following:
Coronary stents are implantable devices that are placed percutaneously in one or more coronary
arteries to maintain patency. DESs incorporate a pharmacologically active agent (drug) that is
delivered at the site of stent deployment and is intended to reduce the incidence of restenosis due to
neointimal hyperplasia associated with bare metal stenting. In many cases, the drug is incorporated
into and released from a polymeric coating of sufficient capacity to accommodate the selected dose
and to modulate its delivery at the intended site of action and for the intended duration. The
chemical, physical, and mechanical attributes of the polymer coating system are important for stent
deployment, biocompatibility, and stability. To perform a regulatory assessment of a DES, FDA
would review data from a comprehensive evaluation of individual components (drug, polymer, and
stent), as well as from a comprehensive evaluation of the finished drug-device combination product.
II.
use of the word should in Agency guidances means that something is suggested or recommended,
but not required.
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Product Classification
Application Requirements
IDE Application Requirements
IDE regulations (21 CFR 812)
Regulations governing institutional review boards (IRB) (21 CFR 56)
Informed consent (21 CFR 50) 4
3/26/2008
3
See “Jurisdictional Update: Drug-Eluting Cardiovascular Stents,” http://www.fda.gov/oc/combination/stents.html.
This Jurisdictional Update discusses DESs for which the primary mode of action is the action of the device component in
maintaining vessel patency. However, a DES for which the primary mode of action is attributable to the drug component
would be assigned to CDER.
4
You should review the statutory definition of applicable clinical trial to determine if your trial must be registered
to comply with the law. See PL 110-85, Section 801(a), (adding new 42 U.S.C. 282(j)(1)(A)).
http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf
Information can be submitted to ClinicalTrials.gov using the Protocol Registration System (PRS). For more information
visit the PRS Information Page (http://prsinfo.clinicaltrials.gov).
5
FDA intends to develop guidance on pre-submissions.
3
FDA strongly encourages sponsors to use pre-submission interactions to obtain informal guidance
regarding product development prior to submission of an original IDE application.5 FDA comments
provided to sponsors during the pre-submission process are informal input, intended to facilitate
open communication between the sponsor and the Agency. Pre-submission interactions for a DES
can be broad-based, or can focus on particular areas, such as engineering testing, CMC testing, or
The companion document contains a listing of the elements FDA recommends be included in an
original IDE application.
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FDA has determined that DESs pose a significant risk as defined in 21 CFR 812.3(m), and as such,
are not exempt from the requirement to submit an investigational device exemption (IDE)
application (21 CFR 812.2(b), 812.20(a)(1). When an IDE application is required, a sponsor must
not begin a clinical trial in humans in the United States until FDA has approved the application (21
CFR 812.20(a)(2), 812.42). Sponsors of such studies must comply with the following:
2.
Coronary DESs, where the device component provides the primary mode of action, are regulated as
Class III devices that require the submission and approval of a premarket approval (PMA)
application prior to commercial marketing in the United States. To meet the standard for approval,
the PMA application must contain (or include by reference) valid scientific evidence to provide a
reasonable assurance of safety and effectiveness of the DES when used in accordance with its
labeled indication (21 U.S.C. 360c(a)(1)(C), 360c(a)(2)-(3)). Such evidence will usually consist of
nonclinical, animal, and human clinical testing.
B.
restenosis, the device mode of action is the primary mode of action.3 Therefore, the premarket
review and regulatory responsibility for these coronary DESs has been assigned to CDRH with
significant consultation from CDER.
Draft — Not for Implementation
Draft — Not for Implementation
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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IND Application Requirements
PMA Application Requirements
Master Files
Letters of Authorization (LOA)
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7
See FDA guidance on Drug Master Files and the Introduction to Master Files for Devices for more information on the
submission of DMFs and MAFs
With a right to reference authorization letter, FDA will not discuss the contents of the referenced
submission with the third party applicant. In the event there are outstanding or unresolved issues
related to FDA’s review of the referenced submission, the Agency will inform the third party
applicant of the general nature of the outstanding issues that must be adequately addressed by the
An LOA may grant FDA either the right to reference or the right to reference and discuss the
information included within one regulatory submission (e.g., NDA, IND, ANDA, DMF, MAF, IDE,
PMA) in support of another regulatory submission (e.g., IDE, PMA).
An LOA authorizes FDA, in its review of an application such as an IDE or PMA, to refer to
information contained in another regulatory submission such as an NDA, IND, ANDA, DMF, MAF,
IDE, or PMA. As part of its review of an IDE or PMA for a DES, FDA will review information
from a referenced file only when the IDE or PMA applicant submits an LOA from the holder of that
file, authorizing FDA to refer to the file in support of the IDE or PMA application. The extent of
access granted to the IDE or PMA applicant is typically a business arrangement between the
respective parties. An LOA may give the applicant the authority to rely on all of the information in a
regulatory file, or, if the right to reference is not totally inclusive, on only specific portions of the
file. A copy of the LOA should be included as part of the original IDE and subsequent PMA
applications, with the original LOA submitted to the DMF. (Please refer to Section V.A of the
Guideline for Drug Master Files for specific information to be included within an LOA.)
6.
We have not issued guidance on the content of Device Master Files. In general, we will not accept a
submission as a MAF if it is not substantive in nature and does not contain information that may
reasonably be regarded as trade secret or confidential commercial information.
We recommend that a sponsor intending to reference (or file) a DMF allow for sufficient time for the
Drug Master File Staff to administratively determine the adequacy of the DMF and assign a DMF
number before an IDE is submitted, given the 30-day review timeframe for IDE applications.
Additionally, sponsors who reference a DMF or MAF as a source of supportive data for an IDE or
PMA should clearly identify the specific volume and page number of the referenced information for
ease of review.
As outlined in Section IV.C of the Guideline for Drug Master Files, each DMF should contain only
one type of information and all supporting data. If the DMF is administratively incomplete or
inadequate, it will be returned to the submitter with a letter of explanation from the Drug Master File
Staff, and it will not be assigned a DMF number. If you intend to submit a DMF that does not
conform to the Guideline for Drug Master Files, we recommend that you contact the appropriate
review division or Drug Master File Staff before making the submission.
from the holder of the DMF or MAF, which authorizes FDA to refer to the master file in support of
that application.9
See the CDER guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase
1 Studies of Drug.
See guidance for industry and FDA staff, Premarket Approval Application Modular Review.
8
Ibid.
6
Drug Master Files (DMFs) and Device Master Files (MAFs) permit the submission of proprietary
information to FDA so that parties other than the owners of that information may rely on it. With
the permission of the holder of that master file, a third party applicant may rely on the information in
that master file to support the third party’s application to FDA (e.g., IDE or PMA), even though the
contents of the master file remain proprietary to the holder of the master file (See 21 CFR 314.420,
814.3(d), 814.9(a)). The Agency will not review a DMF or MAF in support of a third party’s
application unless the third party applicant submits in its application a letter of authorization (LOA)
5.
Because of the extensive amount of nonclinical information that is typically needed (especially when
the drug component is a new molecular entity, or NME, that has never been the subject of a new
drug application) coupled with the relatively long primary endpoint timeline for a DES (e.g., 12
months or longer), applicants may wish to consider using the Modular PMA application program.7
A modular PMA application is a compilation of discrete sections, or modules, submitted at different
times, as each is completed. Together the modules make up a complete application. The potential
advantage associated with the modular approach is that if any deficiencies in a particular section are
noted by FDA, the applicant may be able to resolve them earlier in the review process than would
occur with a traditional PMA application, where a complete application is submitted in a single
submission.8
To meet the standard for approval, a PMA application must provide reasonable assurance of the
safety and effectiveness of the finished DES (21 USC 360c(a)(1)(C)). See the companion document
for a list of the elements FDA recommends be included within an original PMA application.
4.
Preclinical and clinical evaluation of the drug substance alone (e.g., not delivered via a stent) may be
appropriate to fully characterize potential toxicities (see Section IV. below). Human studies of an
investigational drug in the United States must be conducted under an IND application (21 CFR Part
312). The IND application should specify that the eventual intended use of the drug is to be in
combination with a stent.6
3.
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Draft — Not for Implementation
clinical protocols. Sponsors should clearly identify questions or particular items they would like to
have addressed as part of the pre-submission interaction. It may be appropriate to meet or hold presubmission discussions with Agency staff more than once, at different stages of the development
process.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Least Burdensome Principles
PRODUCT DEVELOPMENT PATHWAYS FOR DRUG ELUTING STENTS
The DES Development Pathway — Overview
3/26/2008
6
The developmental process typically begins with selection of the drug, polymer or other carrier (if
applicable), and stent platform. The stent platform may be chosen for its previously demonstrated
performance, or it may be a new design developed specifically for use as a DES. In selection of the
polymer or other carrier, considerations will include the following:
A.
An overview of a potential development pathway is described directly below. The following
sections discuss the factors that can affect the development pathway for a DES as well as how the
amount of new information to be generated will be affected by both the extent of prior information
on each of the components and the need to understand local and potentially systemic effects of the
drug. Sponsors and applicants should carefully consider all of the information in this section in
determining the appropriate development pathway for a particular DES.
The development of a new DES calls for a thorough exploration of the safety of all of the relevant
components of the product intended for clinical use (e.g., stent, polymer/carrier, and drug), the
composite finished DES, and the delivery system. DES development can present numerous
challenges in that the action of the finished product (such as drug release profile) will affect the
evaluations to be conducted on the individual components, especially the drug substance. However,
testing of the finished product should be limited to in vitro and animal testing until sufficient safety
information is generated to support the introduction of the DES into humans under IDE.
III.
The issues identified in this guidance document are issues we believe should be addressed before a
coronary DES can be marketed. In developing this guidance, we carefully considered the relevant
statutory criteria for Agency decision making. We believe that we have identified the least
burdensome approach to resolving the issues presented in the guidance. If, however, you believe
that there is a less burdensome way to address an issue, we recommend you follow the procedures
outlined in the guidance for industry A Suggested Approach to Resolving Least Burdensome Issues.
C.
A right to reference and discuss authorization letter allows FDA to review the reference submission
as part of the third party’s application, and permits FDA to discuss information within the referenced
submission with the third party applicant. In the event that there are outstanding issues arising from
FDA’s review of the referenced submission that directly apply to the third party’s IDE or PMA, this
permission to discuss permits the Agency to discuss these issues directly with the IDE or PMA
applicant instead of requiring FDA to discuss specific issues solely with the holder of the referenced
submission.
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The ability to control drug elution
The compatibility of the polymer with the arterial tissue
The ability of the polymer to conform to the stent platform without significant delamination
upon stent delivery and deployment
Drug Substance
3/26/2008
7
Information regarding the drug substance may be available to the IDE or PMA applicant through the
right to reference a third party’s IND or NDA. However, if the referenced submission does not
relate to intravenous or intra-arterial administration of the drug, as would be delivered by a coronary
DES, FDA may require that additional information related to intravascular safety be included in the
IDE and PMA applications. In some situations, particularly when the right of reference is not
available and a sponsor is relying on information in the public domain, additional studies (e.g., drug
interaction) may help the sponsor adequately support the safety of the drug, polymer, or stent
When needed, these single and multiple IV dose escalation studies, conducted in healthy volunteers,
will provide critical safety information about the drug and its potential toxicities in humans. The
NOAEL determined in the animal studies described above should be used to select the starting dose.
These studies, in addition to metabolic studies, which are intended to describe the distribution,
metabolism, and excretion characteristics of the drug, should be performed prior to initiation of
human clinical studies of the DES under an IDE.
Developmental animal studies of the DES are encouraged to provide an understanding of the local
and systemic exposure to the drug substance. Even if the amount of drug available systemically is
below the limit of detection of the assay used, the potential for toxicity may still exist. Therefore,
animal toxicology studies of the drug substance may be important to fully understand the potential
for adverse effects following stent implantation. If implantation of the DES results in significant
systemic exposure, data from human safety studies, specifically, single and multiple IV dose
escalation studies, should be provided (previously conducted or new). If implantation of the DES in
animals does not result in significant systemic exposure, data from human safety studies should not
generally be needed (see Section IV.B. on how to determine when systemic exposure is considered
to be significant).
The drug substance should be carefully characterized through evaluation of its chemistry,
mechanism of action, and safety profile. In vitro and animal testing will reveal the types of toxicities
that may result from the drug and the exposure levels at which those toxicities occur. Animal
toxicology testing should establish the No Observed Adverse Effect Level (NOAEL), the highest
exposure at which no adverse effects occur.
1.
Whether previously studied or newly developed, the drug substance is intended to limit the growth
of excess neointimal hyperplasia after the injury caused by the stenting procedure without preventing
ultimate re-endothelialization of the stented artery. Selection of the drug dose, both total dose and
dose density, is critical. The amount of drug to be delivered should be carefully evaluated to ensure
that the lowest effective dose is chosen to minimize potential toxicities. Sponsors are encouraged to
consider dose-ranging studies of the DES in animals and possibly in humans to aid in identification
of an optimal dose.
x
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Draft — Not for Implementation
Draft — Not for Implementation
referenced application holder, but will not identify the specific issues. Alternately, if the holder of
the referenced submission chooses not to address outstanding issues, the third party applicant could
potentially generate the requested data independently.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Finished DES
1.
Stent Platform
Factors Influencing Development: Prior Information on Components
Delivery System
3/26/2008
3.
Polymer/Carrier
8
Delivery system testing should be carried out as described in section VI.B. below. Evaluation of
aspects such as delivery and handling characteristics, when previously studied in conjunction with a
bare metal or other previously approved stent, can be incorporated by reference; however, delivery
system testing that incorporates the drug-eluting stent (e.g., deployment, balloon burst) should be
conducted using the intended DES and delivery system combination.
2.
Stent platforms used in a DES may be chosen based on previously used bare metal stents or may be
developed expressly for use in the DES. If nonclinical testing has been performed on the platform as
a bare metal stent, much of this information may be incorporated by reference. Certain additional
testing on the finished DES, such as coating integrity and particulate matter evaluation, should also
be carried out. Additionally, the sponsor/applicant should consider whether the coating process or
other manufacturing steps will affect the stent integrity or corrosion resistance and repeat appropriate
bench testing (see Section VI.B.) as necessary.
B.
More specific recommendations regarding each of these development steps can be found in the
following sections of this document.
The clinical study program should include the pivotal trial(s) to support marketing approval,
extended follow-up of the patients in the pivotal trials following the primary endpoint evaluation,
and appropriate postapproval studies.
Evaluation of the finished DES in humans should include meaningful clinical information related to
stenting outcomes, as well as a systemic pharmacokinetic (PK) study. If significant systemic drug
exposure occurs as a result of DES implantation (see Section IV.B. below), a careful evaluation of
factors that may affect exposure, such as concomitant drugs and comorbidities (such as renal or
hepatic failure), should be carried out.
The finished DES and its delivery system should be fully characterized. Characterization will
include engineering studies, biocompatibility evaluation, animal studies, and development of
complete chemistry, manufacturing and controls (CMC) information, including sterilization,
packaging, and shelf life/stability testing.
2.
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Drug Substance
Factors Influencing Development: Local and Systemic Exposure
9
For the purpose of this guidance, drug substance is considered the active pharmacological agent.
3/26/2008
10
Second, it has been our experience that in certain situations (i.e., multiple stents, major active
metabolites), systemic drug exposure from a stent, or stents, can cause systemic toxicities.
First, although the total dose of drug on a DES is almost always much lower than that given in a
systemic administration (e.g., orally or by injection), the exposure at the artery wall may be many
times higher than the blood levels achieved after an oral or injected dose. Therefore, the potential
toxicity at the coronary wall at the DES implantation site and within the coronary vascular bed and
myocardium distal to the DES implantation site should be studied. Animal studies of the finished
DES will be critical to this understanding, but as is typical of animal toxicology studies, it is also
important to assess the potential toxicity of exposure to higher doses than in the finished DES.
Animal studies of local doses well above those expected from a DES to examine the safety margin
over the doses that will be used in human DES implants should be completed.
For any DES, the primary exposure to the drug substance will occur at the coronary artery wall
directly apposed to the stent and downstream in the stented vessel and myocardium. Exposure in the
rest of the body will be much lower. At first glance, this could suggest that evaluation of the
systemic toxicity of the drug substance alone should not be necessary and that the animal and
clinical testing of the finished DES should be sufficient to demonstrate preliminary safety of the
DES. However, several factors challenge this conclusion.
C.
The amount of new evidence needed to support the safety and effectiveness of a DES will be
determined by the amount of existing information about each of the components and, particularly,
the drug substance. For a DES using a studied drug, that is, a molecular entity that has been
previously approved or studied under IND (i.e., has an approved NDA or ANDA, or has undergone
human clinical studies under an active IND), the information on systemic use described below may
be available for the DES manufacturer to incorporate by reference. An unstudied drug that is a
molecular entity that has not been approved for use in humans or that does not have study
information available should undergo testing as described in Section IV below to develop this
information before human testing of the DES.
An understanding of the systemic pharmacology and toxicology of the drug substance10 and its
metabolism in the body is essential to guide the design of the clinical studies of the DES with respect
to monitoring for adverse events. Given this aim, testing should be performed prior to initiation of
an IDE for the DES.
4.
As described in section V below, a full physicochemical description of any polymers used as drug
carriers should be provided either in the original application or by reference to DMFs, MAFs, or
other sources. Any change in the properties of the polymer due to the incorporation of the drug
substance within the polymer or the application of the polymer to the stent should be evaluated.
Draft — Not for Implementation
Draft — Not for Implementation
component of a DES. FDA should be consulted on the need for additional studies in this situation
(See also Section IV. below).
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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SYSTEMIC PHARMACOLOGY, TOXICOLOGY, AND SAFETY DATA FOR THE
DRUG SUBSTANCE ALONE
General Considerations
3/26/2008
10
A first step in characterizing a drug involves performing systemic nonclinical pharmacology and
toxicology studies of the drug substance using in vitro (cell culture) or in vivo (animal) models.
These nonclinical studies help provide an understanding of the metabolism of the drug, its
distribution and accumulation (e.g., in the regional myocardium or other important organs), and
whether the effects of the drug might be significantly affected by the presence of certain enzymes.
Animal testing will also help assess potential toxicities that cannot be identified during clinical trials
and will define the No Observed Adverse Event Level (NOAEL), which is used to determine the
starting dose for human safety studies (see Section IV.B.). In some cases, animal testing may
establish that an adequate factor of safety exists between the levels of drug exposure likely to be
reached in humans and the levels of exposure at which toxicities are seen in animal studies. In some
situations, when a sufficient safety margin exists, this testing may support the conclusion that human
intravenous safety studies would not be necessary to ensure safety of clinical systemic exposure. In
addition to determining the severity of the observed toxicities in animals and a careful definition of
the local, regional, and systemic adverse effects in animals, it is important to define the slope of the
A.
FDA believes that systemic pharmacology, toxicology, and safety data on a drug substance to be
incorporated in a stent are needed to fully understand the safety profile of the finished DES.
Nonclinical, and often clinical, studies should be performed as part of the effort to demonstrate the
safety of a DES.
IV.
In summary, a manufacturer of a new DES should establish preliminary evidence of the safety of the
DES prior to beginning human clinical trials (under an IDE, or under an IND if intravenous clinical
study of the drug substance alone is needed). A complete assessment of safety and effectiveness of
the DES should be submitted in the PMA application. Recommended testing to address issues
related to systemic pharmacology, toxicology, and safety of the drug substance follows. FDA
remains open to alternative methods to obtain this information as well to other considerations, such
as when the drug incorporated in the DES has known toxicities that may require modifications to the
recommendations below.
Furthermore, there is a greater need for information about the safety of the drug component prior to
beginning clinical studies of a DES because of the permanence of the DES. In addition, the planned
DES clinical trials may not explore the full range of clinical use likely to occur after marketing
approval, and there is a need to consider whether this more extensive use of permanent implants may
place patients at risk. As a result, an appropriate understanding should be gained of the safety of the
drug component prior to clinical studies with a DES.
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Determining when human safety studies are needed – PK parameters and the NOAEL
Determining when human safety studies are needed – calculating the safety factor
3/26/2008
12
11
The DES should initially be studied in an animal model to inform the design of the animal IV toxicology study.
See the CDER guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase
1 Studies of Drug.
11
Because multiple stents are commonly used in humans, the exposure parameter (generally,
x
If the parameter that best predicts toxicity is AUC, it is important to base any comparisons on AUCs
integrated over the same or nearly the same time courses. Empirically, we recommend a comparison
based on AUC0-24h.
Another consideration for the relevance of a preclinical model is the possibility of species-specific
metabolism. If a metabolite is prominent in humans, but not in the animal, the resulting NOAEL
may not be pertinent to human exposure. If a sufficiently sensitive assay is available, it may be
appropriate to do a microdose study in humans12 to confirm similar metabolism.
When considering the relevance of a preclinical model for intravenous administration, the exposure
should, ideally, resemble the exposure from a DES. Release of drug from a DES can generally be
expected to follow two-phase kinetics—a first-order (or relatively fast) process with a time constant
on the order of hours and a zero-order (or very long time constant) process. the preclinical
intravenous exposure intended to match this would include infusion over several hours (first-order
phase) followed by a lower prolonged or repeated infusion (if the half-life in plasma is much less
than the release rate from a DES).11 We recognize, however, that mimicking the time course of
release from the stent can greatly complicate the animal study. Furthermore, matching the DES
release should not be necessary when toxicity is likely to be mostly related to Cmax and the AUC
over the first several hours, and the safety margin related to this period is of greatest concern. In such
cases, preclinical assessment following a single bolus administration should be acceptable.
In such cases, preclinical assessment following a single bolus administration should be acceptable.
A second important consideration is identifying the preclinical toxicity that establishes the NOAEL.
Usually, this is based on testing in the most sensitive species and on the adverse effect seen at the
lowest dose.
When deciding whether human intravenous safety studies also will be needed, one should first
consider what pharmacokinetic parameter—Cmax (maximum concentration) or AUC (area under
the curve describing concentration versus time) over some specific time—should be the basis of the
safety factor. If the parameter that best predicts toxicity is AUC (which is most likely the case), it is
important to base any comparisons on AUCs integrated over the same or nearly the same time
courses.
x
relationship between toxicity and exposure over a broad range of doses, extending to levels in excess
of the dose anticipated for use in humans.
Draft — Not for Implementation
Draft — Not for Implementation
Therefore, it is crucial to have information gathered under acute and chronic conditions on the
systemic safety and toxicity profiles of the drug to be used in a DES system prior to initiating
clinical studies.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Nonclinical Pharmacology and Toxicology
3/26/2008
12
See also Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics
in Adult Healthy Volunteers at http://www.fda.gov/cder/guidance/5541fnl.htm.
13
The timing and types of studies that should be performed are described in International Conference
on Harmonisation (ICH) M3, Timing of Pre-clinical Studies in Relation to Clinical Trials.
Toxicology studies in two species, including one non-rodent species, should be designed to describe
For an unstudied drug that has never been studied in humans, preclinical safety testing and
pharmacology studies should be conducted to fully characterize the drug-related effects, metabolites,
and toxicities of the drug administered intravenously (IV). Studies should be designed to describe
desired as well as off-target pharmacology and also potential drug toxicities; data from these studies
should be used to select safe starting doses for clinical trials.13
B.
Where reference rights are unavailable, a sponsor may be able to use information in the public
domain (e.g., published literature) in support of an application. When a DES relies for approval on
data in a previously approved application for the drug substance to which the sponsor has an LOA,
or on literature in the public domain, the sponsor or applicant should demonstrate that the active
ingredient of the DES is the same as the active ingredient in the reference drug.
For a previously studied drug, much of the information discussed below may be available for
incorporation in an IDE or PMA application through a right to reference or other means. However,
in some cases, gaps in the preexisting safety data may be identified. For example, for a drug that has
been developed for oral administration, additional nonclinical testing pertaining to the intravenous
route (e.g., hypersensitivity, hemocompatibility) may not have been performed and should be
conducted.
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The NOAEL for the most sensitive relevant toxicity (in the monkey) occurs at a472
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dose that produces AUC0-24h = 4500 ng-h/mL. If a single 40 mm DES in the mini474
pig produces AUC0-24h = 3 ng-h/mL; 120 mm of stent would be expected to yield
an AUC0-24h of 9 ng-h/ml, still just 1/500 of the NOAEL. Absent other factors, it475
may be reasonable to conclude that no intravenous study in humans would be 476
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necessary before the first DES implantation in humans.
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x Previously studied drugs
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Clinical Pharmacology and Clinical Tolerance and Safety Information
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13
For an unstudied drug, the need for studies to elucidate the distribution, metabolism, and excretion of
the drug, and any intrinsic or extrinsic factors that could affect exposure should be carefully
assessed. Some of the metabolic information can be based on in vitro methods, notably the role of
CYP450 enzymes in metabolism; some can be obtained from studies on the DES. As already
mentioned, in some cases, human studies involving micro-doses may facilitate the assessment of the
drug’s pharmacokinetics.
In general, for drugs that are well understood no additional clinical pharmacology studies are
warranted since all the factors that affect a drug’s safety and efficacy from a systemic point of view
will already have been well characterized. If a drug has been previously studied and the resulting
information is available, these studies need not be repeated. However, if the DES will incorporate a
total amount of drug higher than that used in previous studies of the drug alone or result in higher
sustained levels, additional information would be necessary to address the safety of the higher dose.
Human safety studies of the drug alone in healthy volunteers can provide critical information
regarding the tolerability, safety, and pharmacokinetics of a drug substance. Whether such studies
are needed will depend on the systemic exposure that will arise from the stent and how this
compares with the exposure seen in animal studies, specifically the NOAEL, of the most sensitive
species.
The decision tree provided in this section describes the clinical pharmacology (CP) studies that
should be considered for the assessment of the drug substance during the development of a DES.
The key focus of the tree is the initial determination about whether the drug is an unstudied drug,
about which little is known, or a previously studied drug, about which there already is a thorough
understanding and adequate information with an appropriate safety profile is referenced in the
application.
C.
Other recommended toxicology studies are designed to assess potential toxicities that may not be
monitorable in clinical studies. For example, tests for potential genetic toxicity (ICH S2A and S2B),
tests for reproductive toxicity (ICH S5), and safety pharmacology studies (ICH S7A and S7B).
Tests for the assessment of potential carcinogenicity are also described in the ICH guidances (S1A
and S1B). However, if drug exposure to the local tissue is shown to last less than six months,
carcinogenicity studies will generally not be required. Note that finished product biocompatibility
testing does not obviate the need for safety and pharmacology testing of the drug substance alone.
a maximum tolerated dose (MTD) and determine the NOAEL. The duration of these studies should,
at a minimum, span the length of time the DES is estimated to release drug in vivo. The minimum
duration should be two weeks for a DES without a polymer or other drug carrier, which could be
considered as a single IV dose drug study. The NOAEL from the IV studies should provide
significant safety multiples over the clinical systemic exposure from multiple DES implants.
Draft — Not for Implementation
Draft — Not for Implementation
AUC0-24h) measured from implantation of the DES in the animal model should be adjusted to reflect
the use of 120 mm of stented length as a likely maximum length to be encountered in common
clinical use. In a vast majority of cases, if the safety factor (ratio of the NOAEL AUC0-24h level in
the animal to the corresponding exposure AUC0-24h in humans) is a factor of 100 or more, DES
clinical studies can be initiated without a prior intravenous administration human safety study. This
conclusion is based on the observation that >100 fold increase in sensitivity to toxic effects in
humans versus animals is extremely unusual for drugs. See the following example.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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YES
YES
No additional CP studies
are needed
NO
No additional CP
studies are needed
Studied Drug
Safety
Concerns
NO
Single IV Dose-Escalation Study
Multiple IV Dose-Escalation Study
Mass Balance Study
15
3/26/2008
14
In Vitro and In Vivo Metabolic Studies
3/26/2008
14
4.
We note that single and multiple ascending dose studies are small and quite well monitored, and the insight into
human toxicity can be quite valuable.
14
The mass balance study should be based on the drug substance tagged with a radioactive label (i.e.,
C, 3H) to allow for sensitive monitoring of the distribution patterns of the tested drug after its
intravenous administration. Blood (plasma or serum as appropriate), urine, and fecal samples should
be collected and assayed for radioactive label. Other routes of elimination should be monitored as
appropriate. Both the parent drug substance and any metabolites present should be identified.
We suggest that a mass-balance study be performed to define and assess the systemic exposure, the
disposition and pathways of elimination (including metabolism and excretion), and pharmacokinetic
measures or parameters of the drug substance administered intravenously.
3.
If the time course for release from a DES is long, data from a multiple IV dose- or from a continuous
infusion dose-escalation study to mimic the stent exposure should be provided.
2.
If a single IV dose-escalation study is indicated, the selected initial dose should be based on the
NOAEL information from the animal nonclinical studies. The drug should be given via intravenous
administration (if feasible). This study should be designed to collect information on the drug
substance’s tolerance, safety, and pharmacokinetics following administration of single doses and
escalating up to the maximum tolerated dose. The exposure should be engineered to resemble that
produced by the DES.
1.
For unstudied drugs, testing to elucidate the distribution, metabolism and excretion characteristics of
the drug are essential in understanding the safety and efficacy profile of this new entity.
The usual next steps in developing a DES that incorporates an unstudied drug would involve single
and multiple ascending dose studies. If the systemic exposure to the drug from a DES (or from
multiple DESs) is sufficiently low (i.e., a reasonable safety factor exists between the NOAEL and
the expected systemic exposure in man based on animal studies of the DES), such studies would
probably not be informative.14 However, it should be noted that an adequate assessment of systemic
exposure from the DES in an animal model can only be made if the release characteristics of the
drug are well-characterized and have been shown to have minimal variation from stent to stent.
If human PK data (using the DES) are available from previously conducted studies outside the
United States, these data may provide a direct measure of systemic exposure (instead of the indirect
measure based on animal data on the DES) and further determine whether such a substantial
separation from toxicity causing concentrations exists. On the other hand, for DES where
appreciable systemic drug concentrations can reasonably be expected and for drugs with animal or
human toxicities that occur at only slightly above the anticipated human exposures, the full range of
studies to evaluate the consequences of systemic exposure to the drug would be warranted. Animal
Significant systemic exposure may not have been observed in animal studies of the DES, in part
because the number of stents that can be implanted in an animal is limited. The potential for
multiple stent use in routine clinical practice should be considered when determining whether a
single IV dose escalation human study is needed to understand the systemic levels at which toxicities
are first observed. Absent other factors that increase concern, a separation between the NOAEL
established in the most sensitive animal species and the systemic exposure that could be reached of
two orders of magnitude could mitigate the need for human studies of systemic drug safety.
- First DES clinical trial
- Multiple IV dose safety/ tolerance/PK study
* These studies can be conducted in parallel
NO
YES
Human data (or animal data on the absence of
human data) showing systemic levels with
multiple DES
- Single IV dose tolerance study
- In vitro metabolic studies
Safety
Concerns
Multiple IV dose safety/
tolerance/ PK study
>100 times
CLINICAL STUDIES
<100 times
NOAEL Safety Margin
Unstudied Drug
Drug Substance
Integration of CP to the Development of DES
toxicology studies will then also serve to determine what is considered to constitute an initial safe
dose for human systemic drug safety studies.
Draft — Not for Implementation
Draft — Not for Implementation
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Bioanalytical Methods
CMC INFORMATION
CMC for the Drug Substance Component15
Physical and Chemical Characterization
2.
Elucidation of Structure
General description (e.g., appearance, color, physical state)
Melting or boiling points
Optical rotation
Solubility profile (aqueous and nonaqueous, as applicable)
Solution pH
Partition coefficients
Dissociation constants
Identification of the physical form (e.g., solid-state form, solvates, and hydrates) that will be
used in the manufacture of the finished product
17
3/26/2008
16
3/26/2008
Manufacturer
15
See the CDER guidance Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug
Substances. Another drug substance guidance is forthcoming that, once finalized, will supersede this guidance.
16
See the CDER guidance Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of
Drug.
3.
The chemical structure of the drug substance should be confirmed using physical and chemical
techniques, such as elemental analysis, mass spectrometry (MS), nuclear magnetic resonance (NMR)
spectroscopy, ultraviolet (UV) spectroscopy, infrared (IR) spectroscopy, X-ray crystallography, and
other tests (e.g., functional group analysis, derivatization, complex formation).
x
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The chemical structure of the drug substance (including stereochemistry), molecular formula, and
molecular weight should be provided. All appropriate names or designations for the drug substance
should be listed (e.g., USAN, Chemical Abstracts, IUPAC, code number). The physicochemical
properties of the drug substance should be described and should include, but not be limited to,
information on the following, as appropriate:
1.
The following items should be included for the drug substance in both the IDE and PMA
submissions. When submitting an IND (e.g., when the drug substance is an unstudied drug and
human safety studies will be conducted in the United States), guidance on Phase 1 (CMC section)
should be carefully consulted.16
A.
validation is incomplete, and the acceptance criteria for the finished product tests are still tentative,
provided all parameters that relate to safety are well characterized. The sponsor/applicant is strongly
encouraged to meet with the Agency before the initial IDE submission, during development and
before submitting a PMA application to discuss critical drug-related issues and the information
needed at various stages of development.
In general, the information for the drug substance component is expected to be similar for both IDE
and PMA submissions. However, it is recognized that the finished product is still under
development at the time of the initial IDE submission. Consequently, clinical trials may be allowed
to proceed even though manufacturing processes are not fully optimized, analytical methods
Because the product described in an initial IDE application will be permanently implanted into
patients with potentially life-threatening coronary artery disease, the CMC section should address all
of the items that would be provided in a PMA application. However, the level of detail and the
degree of documentation will differ in that the information for the IDE will focus more on patient
safety and product development and less on product and process controls.
This section provides guidance on the information to be submitted regarding the chemistry,
manufacturing, and controls (CMC) aspects of (1) the drug substance and (2) the finished product,
followed by the information needed for (3) the engineering evaluation. The information can be
provided in the submission, or incorporated by reference to another regulatory submission (e.g.,
DMF, NDA, ANDA, PMA, MAF) with copies of the LOA provided in the relevant section of the
IDE or PMA application. All of the topics described for the drug substance and finished product
should be included for both IDE and PMA submissions.
V.
Validated bioanalytical methods should be used when evaluating the concentrations of the drug and
its metabolites in the clinical pharmacology and metabolic studies. Information on the validation of
assays can be found in the guidance Bioanalytical Method Validation.
5.
Information on the design and data analysis of the metabolic studies can be found in guidances In
Vivo Drug Metabolism/Drug Interaction Studies and Drug Metabolism/Drug Interaction Studies in
the Drug Development Process: Studies In Vitro.
In vitro metabolic studies can frequently serve as an adequate screening mechanism to assess the
contribution of cytochrome P450 on the metabolism of the drug, so that subsequent in vivo testing
will be unnecessary. In contrast, when positive findings of active or toxic metabolites arise in in
vitro metabolic studies, we recommend that drug interaction information be obtained from the
clinical trials using a drug interaction-population PK approach.
In vitro metabolic studies designed to assess the P450 metabolizing enzymes of the drug as well as
to characterize the P450 isoenzymes that are inhibited or induced by the drug should be conducted so
that the clinical implications of interactions can be assessed later in the DES clinical studies.
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Draft — Not for Implementation
Draft — Not for Implementation
Since an integral part in understanding the safety of an unstudied drug is determining its metabolic
pathway and whether there is formation of any active/toxic metabolites, the Agency recommends
that a drug’s metabolism and metabolic pathway, as well as the activity of major metabolites, be
assessed relatively early in development of the DES.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Manufacture and Control
Specifications
3/26/2008
18
See ICH Guidance Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and Drug
Products: Chemical Substances.
18
See ICH Guidances Q2A Text on Validation of Analytical Procedures and Q2B Validation of Analytical Procedures:
Methodology.
17
Analytical procedures, including validation information, for each of the tests proposed in the
specification should be described in detail. If the analytical procedure is in the current version of the
United States Pharmacopeia (USP) or other FDA-recognized standard reference (e.g., AOAC
International Book of Methods), details need not be provided. Analytical procedures should be
validated to demonstrate that the methods are suitable for their intended use. Validation should
include experimental data (e.g., representative chromatograms with peak identification).18
Specifications are established to control the quality of the drug substance and should focus on those
characteristics necessary to ensure the safety and efficacy of the finished product. The specifications
should include all tests, analytical procedures, and associated acceptance criteria to which each batch
of a drug substance will conform over its retest period/shelf-life.17 Acceptance criteria are numerical
limits, ranges, or other measures for the tests described. We recommend that the information be
presented in tabular form.
5.
Specifications, certificates of analysis, and quality or grade of the starting materials, reagents,
solvents, and auxiliary materials that will be used to manufacture the drug substance (including
deriving it from a biological source) should be provided. When appropriate, specific tests and
acceptance criteria to control microbial contamination in materials derived from biological sources
should be included in the specifications.
Process controls used to monitor and adjust the manufacturing process should be provided and
include in-process tests and acceptance criteria. These controls should ensure that intermediates and
drug substance will conform to their established specifications.
The description of the manufacturing process should include a flow diagram and a narrative of the
processes and process controls that will be used to manufacture the drug substance. The flow
diagram should include each manufacturing step with chemical structure, solvents, reagents,
auxiliary materials, critical operating parameters, and expected yield. A narrative description of the
sequence of manufacturing steps and the scale of production should be provided in more detail than
that given in the flow diagram.
4.
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6.
Reference Standards
Batch identity (i.e., batch number) and size
Date of manufacture
Site of manufacture
Manufacturing process (e.g., synthetic route A)
Intended use (e.g., clinical, nonclinical, stability)
Results for each parameter tested; tabular format is recommended
Container/Closure System
Stability
CMC for the Finished Product
19
See ICH guidance Q1A(R2) Stability Testing of New Drug Substances and Products.
3/26/2008
19
For the purpose of this section, the phrase finished product refers to a packaged and sterilized DES
that contains all the materials (e.g., drug and polymer coating materials) applied to or incorporated
within a bare metallic stent substrate and the stent delivery system. The following sections discuss
the information on the finished product that should be submitted in support of an IDE or PMA
B.
Stability data should be generated in accordance with ICH guidances.19 The studies conducted,
protocols used, and the results of the studies should be summarized. The discussion should include
(1) a summary of stability batches tested, storage conditions used, attributes tested, acceptance
criteria, test schedule, and analysis of all available data (including a summary of the statistical
analysis if performed) and (2) conclusions regarding the storage conditions and retest or expiration
dating period, as appropriate. Data regarding stability under stressed (e.g., pH extremes, oxidation,
heat, light) conditions should also be provided. We recommend that the results of stability studies be
presented in tabular form.
8.
A description of the container closure system for the drug substance should be provided, including
the identity of materials of construction for each primary packaging component and specifications.
7.
Information on the reference standards or reference materials used for testing the drug substance
should be provided. A reference standard obtained from an official source should be identified. A
reference standard not from an official source should be appropriately characterized. A list of any
available reference standards for impurities should be included.
x
x
x
x
x
x
Acceptance criteria should be primarily based on consideration of safety, efficacy,
manufacturability, and stability. The justification for the acceptance criteria can be demonstrated by
batch analysis data for all relevant batches, e.g., nonclinical, clinical, and primary stability batches.
The batch analysis reports should include:
Draft — Not for Implementation
Draft — Not for Implementation
The name, address, and manufacturing responsibility should be provided for each facility (including
contract manufacturers and testing laboratories) that will be involved in the manufacturing or testing
of the drug substance. The addresses should be those of the locations where the relevant
manufacturing or testing operation will be performed. Registration numbers (i.e., CFN, FEI
numbers) should be provided to facilitate CGMP inspections.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
Description of the DES
Product Development
3/26/2008
20
See the CDER guidance for industry Submitting Documentation for the Manufacturing of and Controls for Drug
Products (1987). Another drug product guidance is forthcoming that will supersede the 1987 guidance.
20
Key physicochemical characteristics (e.g., solubility, hydrophobicity, stability) of the
drug substance should be discussed and those characteristics that can influence the
performance and manufacturability of the finished product should be assessed. The
compatibility of the drug substance with the excipients in the finished product should
also be addressed, and if there is any evidence of physical or chemical
incompatibility, justification for using the component should be provided.
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Drug Substance
x
This section should contain information on the development studies conducted to establish that the
components of the finished DES, the formulation, manufacturing process and controls, and
packaging system are appropriate for the purpose specified in the application. The studies included
in this section can be distinguished from controls used for routine batch release. Additionally, this
section should identify and describe the formulation and process attributes, including critical
parameters that can influence batch reproducibility, product performance, and quality. Development
reports allow the Agency to understand critical variables and focus attention on high-risk aspects of
a product and process.
a.
Components of the Finished DES Product
2.
A detailed description of the finished DES should be provided and should include the proprietary
name, model numbers, stent sizes, product code, and intended use. Detailed engineering drawings
should also be provided. In addition to a detailed written description, a cross-sectional schematic of
the stent platform, coating layers (e.g., primer layer, polymer/drug layer, drug-free polymer topcoat)
and stent delivery system should also be included that pictorially depicts the coating and drug
distribution across the stent geometry (e.g., length, circumference, strut sides, adluminal, abluminal).
The schematic should also include a description of the drug release mechanism. The total drug
content (μg/stent) and drug dose density (μg/mm2) should also be provided for each stent size.
1.
application. Section V.B. provides recommendations on the chemistry, manufacturing, and
controls information on the finished product from a drug perspective. Section VI.B. (Engineering
Evaluation) provides recommendations regarding assessment of coating integrity and Section VII.A.
(Manufacturing -- Quality System (QS) Regulation and Current Good Manufacturing Practice
(CGMP) Regulations) provides recommendations for additional manufacturing and quality control
information needed for the finished product from a QS regulation/CGMP regulation perspective.
You may wish to provide all of this information relating to the drug and device constituent parts of
the combination product in one section of the PMA or separately with cross-reference to the other
sections as appropriate.
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Stent Substrate and Delivery System
Formulation Development
Manufacturing Process Development
The selection of the manufacturing process with emphasis on understanding its critical
aspects should be described. Manufacturing process development generally starts with the
identification of critical quality attributes of the finished product, which are necessary for its
desired performance. Manufacturing process options in conjunction with appropriate control
c.
Since a DES is formulated to provide extended release of the drug substance, a description of
the drug release mechanism (e.g. erodible polymer matrix, diffusion) should be provided.
The development of target release rates of the drug from the polymer matrix should be
discussed. The applicant should provide a scientific rationale for the selection of the final
formulation by evaluating appropriate models for drug release. The applicant should show
how the formulation and product construction were chosen, incorporating the principles of
modern pharmaceutical development practices, Quality System regulations, and/or Design
Control requirements as appropriate.22,23,24
b.
The design of and the rationale for the selection of the key elements of the stent
substrate21 (e.g., materials, surface characteristics and area, cell structure, engineering
performance), which can influence the performance and manufacturability of the
finished DES, should be discussed. The applicant should also describe the
components and design elements of the stent delivery systems used for stent
deployment in the coronary vasculature.
x
3/26/2008
21
See Guidance for Industry and FDA staff on Non-Clinical Tests and Recommended Labeling for Intravascular Stents
and Associated Delivery Systems.
22
See also the CDER guidance for industry PAT — A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance.
23
See ICH Guidance Q8 Pharmaceutical Development.
24
See 21 CFR 820.30 for more detailed Design Control requirements.
21
Excipients
The choice of excipients (e.g. polymer carriers), their concentrations, and the
characteristics that can influence the finished product performance or
manufacturability should be discussed. The applicant should demonstrate an
understanding of the effects of excipient variability on the critical quality attributes of
the finished product. Since organic solvents are usually employed to dissolve both
the drug substance and polymer carrier to form a coating solution, the rationale for
choice of solvent should be provided. The ability of functional excipients (e.g.
antioxidants) to perform throughout the intended shelf life of the DES should also be
discussed.
x
Draft — Not for Implementation
Draft — Not for Implementation
838
805
806
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Packaging System Development
Physical and Chemical Characterization
Components and Composition
22
See 21 CFR 820.30 for more detailed Design Control requirements.
3/26/2008
25
4.
Note: These tests are a subset of testing recommendations provided in Section VI.C of this guidance
for the mechanical/engineering performance tests for the finished DES.
A detailed description of the physical and chemical tests performed to characterize the finished
product should be provided. The physical, chemical, and mechanical characteristics of a DES are
critical to ensure finished product quality and performance. Physical and chemical characterization
of a DES should include tests for surface coat composition, coating/carrier thickness and uniformity,
and coating/carrier erodability as applicable. These tests are useful for characterization and may be
provided as one-time tests—not to be confused with routine control and release testing.
The morphology of the solid drug-polymer carrier system in the finished product should be
described (i.e., dispersed drug phase, continuous separate drug phase, reservoirs). Micrographs of
the surface and full thickness cross-section of the coating should be provided. The micrographs will
aid in gaining an understanding of the drug release process, which may have implications for coating
durability and particulate matter formation.
3.
The applicant should describe how the packaging system was selected and designed to
provide protection and maintain sterility throughout the shelf life of the finished product.
The suitability of the packaging system should be demonstrated with respect to protection
from moisture, oxidation, and light, and compatibility of materials with all components of the
finished product.
d.
928
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3/26/2008
Component Function
Component Controls
Name and address of the supplier
COA from the supplier
Results from any additional testing
x
23
Name and address of the supplier
For each noncompendial excipient, detailed information should be provided in the
submission or in an MAF/DMF and should include the following:
x
x
x
Compendial excipients should comply at a minimum with the monograph standard in
the official compendium and be identified as such. The monograph tests may not be
sufficient or appropriate for use in a DES and additional testing may be needed,
especially for the polymer/carrier (see below). When analytical procedures from an
official compendium or other FDA recognized standard references (e.g., AOAC
International Book of Methods, analytical procedures from EP or JP that are
interchangeable with a USP General Chapter) are used, they should be verified as
suitable under actual conditions of use. The following information should be
provided for each compendial excipient:
(ii) Excipients
See Section V.A.
(i) Drug Substance
The applicant should identify all component tests that the finished product manufacturer will
routinely perform as well as test results that will be accepted from the excipient and drug
substance manufacturer (Certificate of Analysis, COA). At a minimum, the finished product
manufacturer must perform an appropriate component identification test (21 CFR
211.84(d)(2)).
b.
The function (i.e., role) of each ingredient in the formulation should be described.
Ingredients that are used in the manufacture but are not intended to be part of the finished
product (e.g. solvents) should be identified as processing agents.
a.
A qualitative and quantitative list of drug substance(s) and excipients making up the finished product
should be provided. We recommend including a detailed components and composition table per unit
and per batch for each stent configuration to be marketed. Ingredients used in the manufacture of the
finished product, regardless of whether or not they appear in the finished product, such as solvents,
should be identified. Ingredients of human or animal origin should also be identified and their use
supported with appropriate safety information.
Draft — Not for Implementation
Draft — Not for Implementation
strategies that can reliably result in finished product with critical quality attributes within
acceptable ranges should be considered. Critical process parameters that should be
controlled or monitored to ensure batch-to-batch reproducibility and to minimize intra-batch
variability should also be discussed. This approach demonstrates knowledge and
understanding of the product and associated processes, which in turn provides greater
assurance of product quality. The benefits of having an efficient and reliable process, with
reduced reliance on end-product testing, include enhanced manufacturing efficiency and a
reduced risk of producing a poor quality product. These concepts, when implemented, would
be a significant advantage to stent manufacturers who typically produce small batch sizes.
Operations using process analytical technologies (PAT)25 that measure an endpoint indicating
the manufacturing process (e.g., coating) is under control are preferable to a measurement of
a quality attribute on representative samples. Generally, this allows for adjustments to
process parameters to mitigate anticipated variation in raw materials, equipment,
environment, or other conditions.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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3/26/2008
Method of manufacture (e.g. flow chart, all components used in the
manufacturing)
Specifications and validation of analytical procedures
COA from the supplier
Additional information as appropriate (e.g. safety data for novel excipients)
Description and function of polymer (including a rationale for each component, if
a co-polymer)
Polymer characterization and properties
Chemical structure (monomer fractions, if co-polymer)
Identity test (matches infrared or NMR reference spectrum) and any other
acceptance tests with associated analytical methods
Average MW, MW range, and MW distribution (including MW methodology
validation)
Glass transition temperature (Tg) (and melting temperature, Tm, if applicable)
Density
Residual levels of catalysts, solvents, impurities, and monomers
Composition by weight percentage (if polymer carrier is a blend)
Sampling and storage conditions
Stability (e.g., measurement of polymer molecular weight, resistance to oxidation,
light, heat, ionizing radiation)
x
x
x
x
24
Name and address of the supplier
Method of manufacture (e.g., laser cutting for stent)
Specifications and validation of analytical procedures
COA from the supplier or incoming receiving specifications if no COA provided
The following detailed information for each component used in the fabrication of the
stent substrate and its delivery catheter system should be provided:
(iii) Stent Substrate and Delivery System
It is important to note that although an MAF/DMF may be referenced for the
polymer, the MAF/DMF might not contain sufficient and/or appropriate information
to support omission of testing on the finished product. For example, the MAF/DMF
may only provide certificate of analysis (COA) information about the chemical
properties of the unprocessed polymer, but additional data on the polymer following
the intended processing/manufacturing (including sterilization) should be provided.
Many of these items should be tested on a routine basis as part of the polymer
specifications and adequate justification should be provided for any exclusions.
x
x
x
x
x
x
x
x
x
x
x
Manufacturer
Manufacturing Process and Controls
Depiction of differences in manufacturing processes for the catheters (e.g., Over-TheWire versus Rapid eXchange)
x
1055
1056
3/26/2008
25
A statement should be provided that ruminant-derived materials from bovine spongiform encephalopathy (BSE)
countries as defined by the U.S. Department of Agriculture (9 CFR 94.11) are not used or manipulated in the same
facility.
Differentiation of manual versus automated processes
x
1054
Sterilization (identify method) and packaging steps
x
1052
Any end-process (reliability) testing conducted prior to product release
In-process testing (identify method) and the manufacturing step where it is performed
x
1051
x
Critical processing steps that may have an influence on the chemical or physical
properties of the stent, polymer, or drug (e.g., application of coating, including any
primers or coupling agents, use of oxygen scavengers or antioxidants, crimping of stent
onto catheter, heat sets, use of sheath protectors)
x
1053
Steps where materials enter the process (e.g., catheters, stents, polymers)
x
26
Flow Diagram
A flow diagram (or series of flow diagrams) should be provided that includes all the steps in
the manufacturing process for the finished DES. The diagram should include the following:
a.
A complete description of the manufacturing process and controls (or a reference to this information)
should be provided within this section of an application to provide a thorough understanding of the
critical attributes that should be assessed at final product release and to assess the potential impact of
changes made in the manufacturing procedures used during the course of product development. A
discussion of any differences between the manufacturing process to be used for the marketed product
and any used to produce batches for clinical efficacy and/or primary stability studies should be
addressed in the PMA application. This should include an evaluation of how the differences will not
adversely affect the performance of the product. (See also Section VII.A below.)
6.
The name, address, and manufacturing responsibility should be provided for each facility (including
contract manufacturers and testing laboratories) that will be involved in the manufacturing or testing
of the finished product.26 Addresses should be provided for the locations where the relevant
manufacturing or testing operation will be performed. Registration numbers (i.e., CFN, FEI
numbers) should be provided to facilitate GMP inspections. This information may be submitted in
the Manufacturing -- Quality System (QS) Regulation and Current Good Manufacturing Practice
(CGMP) Regulations section (see Section VII.A. below) and incorporated by reference or
reproduced here for ease of review.
5.
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Draft — Not for Implementation
Draft — Not for Implementation
Since most DESs use a polymer matrix as a carrier or barrier for the drug release,
special attention should be paid to this component. In addition to the items listed
above, the following information should also be included for the polymer:
x
x
x
x
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Description of the Manufacturing Process
Process Controls
Sterilization Process
Packaging System
3/26/2008
26
A description and the following information on each component of the primary packaging system for
the finished product should be provided:
x Supplier/manufacturer
x Composition
x Quality/grade of materials
x Schematic drawing including dimensions, tolerances, etc.
x Specifications
7.
See Section VI.C for engineering test methods to evaluate the effect of sterilization on the
coating characteristics.
The sponsor should clearly identify the method of sterilization (e.g., ethylene oxide, E-beam
radiation, gamma) along with the specific parameters (e.g., concentrations, humidity, time,
and temperatures) and an assessment of its effect on the finished product. The assessment
should address the effects on such elements as coating integrity, drug substance, and polymer
carrier stability.
d.
In some cases, results from in-process controls can be used in lieu of finished product testing.
This approach, however, should be supported with data that demonstrate a clear relationship
between in-process testing and the critical quality attributes of the finished product.
Controls used to monitor the manufacturing process should be described, including operating
parameters, environmental controls, and process/in-process tests. A description of critical
process controls (as justified in section V.B.2.c. Manufacturing Process Development)
should include tests, analytical procedures, limits (ranges), or other acceptance criteria.
c.
A description should be provided of the entire manufacturing process, including packaging,
which should illustrate the sequence of steps undertaken and the scale of production. The
description should include equipment identified by type (e.g., coating process chambers) and
capacity. Any novel processes or technologies (e.g., coating methodology) should be
described in detail.
b.
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Finished Product Specifications
Batch identity (i.e., batch number) and size
Date of manufacture
Site of manufacture
Manufacturing process
Intended use (e.g., clinical, stability)
Results for each parameter tested, in tabular format
3/26/2008
27
See ICH guidances Q2A Text on Validation of Analytical Procedures and Q2B Validation of Analytical Procedures:
Methodology.
27
A batch is defined as a quantity of DES produced according to a single manufacturing order during
the same cycle of manufacture. A batch should be made with only one lot of coating solution.
Combining stents having different expanded diameters into one batch would only be appropriate
x
x
x
x
x
x
The analytical procedures and their validation27 should be described in detail for each test listed in
the specifications. Acceptance criteria should be primarily based on consideration of safety,
efficacy, manufacturability, and stability. The justification for the acceptance criteria can be based
upon batch analysis data for all relevant batches (e.g., nonclinical, clinical, and primary stability
batches). Ideally, the data should be representative of batches of finished product manufactured
using different lots of drug substance, polymer, and coating solution. The sampling plan should be
described. The batch analysis reports should include:
When product knowledge and process understanding have been demonstrated in the application, and
relevant in-process control strategies are being implemented routinely, it may be possible to use inprocess tests in lieu of traditional off-line end-product testing. In addition, PAT, if applied, can serve
as a basis for real-time release of the finished product to demonstrate that each batch conforms to
established regulatory attributes. It should be emphasized that any alternate proposals to endproduct testing should be discussed with the Agency during development and regulatory approval
obtained before implementation.
Regulatory specifications should be provided for the finished product; these specifications apply to
every batch at release and throughout shelf-life. A specification consists of a list of tests, references
to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or
other criteria for the tests described. An example of a regulatory specification table is provided in
Appendix A. Finished product specifications should focus on those characteristics found to be
useful in ensuring product quality as it relates to safety and efficacy. Testing should be performed on
every batch of the finished product after packaging and sterilization. All testing should be
performed on expanded stents, unless otherwise justified. To ensure that the regulatory specifications
are met throughout the shelf life, tighter acceptance criteria may be established for product release.
8.
The same type of information should be provided for functional secondary packaging components as
well. For nonfunctional secondary packaging components (e.g., those that do not provide additional
protection), only a brief description is necessary.
Draft — Not for Implementation
Draft — Not for Implementation
We recommend that the diagram be color-coded (and/or shape-coded) to differentiate
materials, processes, and inspection steps.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Using in-process testing as a substitute for some release tests (e.g. residual solvents). In
these cases, the tests should still be listed in the finished product specifications with
appropriate notation.
Using the same test samples for several release tests (e.g. identification, assay, and content
uniformity).
Using a smaller number of samples than recommended by USP for certain tests (e.g. content
uniformity) with tighter acceptance criteria.
Using quality by design principles, which rely less on end-product testing and more on
building quality into the product and process design.
3/26/2008
Appearance
Identification
Assay
28
A specific, stability-indicating assay to determine content should be included for all drug
substances in the finished product. In many cases, it is possible to employ the same
procedure (e.g., HPLC) for assay of the drug substance and quantitation of impurities.
c.
Identification testing to establish the identity of the drug substance in the finished product
should be specific (e.g., infrared spectroscopy or a chromatographic method in combination
with an additional test such as UV diode array or MS) and able to discriminate between
compounds of closely related structure that are likely to be present. Identification solely by a
single chromatographic retention time, for example, is not regarded as being specific.
However, the use of two chromatographic procedures, where the separation is based on
different principles, or a combination of tests into a single procedure, such as HPLC/UV
diode array, HPLC/MS, or GC/MS, is generally appropriate.
b.
A qualitative description of the finished DES should be provided. Any visualization or
imaging methods adequate to ensure that the DES meets its specifications should be
included.
a.
General tests that are expected to be included in the specifications for a finished DES are listed
below. A tabular format similar to the example shown in the Appendix A is recommended for
presentation of the specifications.
x
x
x
x
Because DES batch sizes are typically small and end-product testing consumes a large quantity of
test samples, the applicant may consider any of the following alternative approaches:
1187
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3/26/2008
Impurities and Degradation Products
Content Uniformity
Drug Release
Package Integrity and Sterility
Endotoxins
29
A test procedure and acceptance criteria for endotoxins, using a procedure such as the
Limulus Amoebocyte Lysate (LAL) test, should be included in the specification.
h.
The tests and methods demonstrating the integrity of the microbiological barrier of the
packaging system should be well defined and scientifically justified. Sufficiently sensitive
packaging integrity testing may reduce the need for end product sterility testing.
A test procedure and acceptance criterion for evaluation of sterility testing and package
integrity should be included. When test methods differ significantly from compendial test
methods, a demonstration of the equivalency to the compendial method should be provided.
Parametric release can be proposed when appropriate data are generated during development
and validation.
g.
The specification should include a test for in vitro drug release. The test should be performed
over a sufficient period of time and include a sufficient number of time points to correlate to
in vivo release. The test is generally used as a quality control tool and should be
discriminatory. The results should ideally be reported as percent of label claim released per
unit time. See section VI. E. for additional details regarding in vitro elution testing.
f.
This test assesses drug content variation from stent to stent within a batch and is to be
distinguished from uniformity along an individual stent length. The latter is typically a onetime test to establish coating uniformity. The method and limits established in USP <905>
Uniformity of Dosage Units are considered appropriate for determining content uniformity
within DES batches.
e.
Any impurities, degradation products, and/or residual solvents are included in this category.
We recommend sponsors refer to the ICH Q3B guidance covering finished product
impurities. Appropriate stability-indicating analytical methodology should be used to
monitor degradation products and acceptance limits should be defined for individual
specified degradation products, both identified and unidentified, unspecified degradation
products, as well as total degradation products.
d.
When use of a nonspecific assay can be justified, other supporting analytical procedures
should be used to achieve overall specificity. When the assay is not stability indicating, a
separate impurity assay can be employed. A specific procedure should be used when there is
evidence of inactive ingredient interference with the nonspecific assay.
Draft — Not for Implementation
Draft — Not for Implementation
when the stents originated from the same diameter tubing, have the same design/platform, and only
differ in the balloon diameter to be used. Combining stents of different lengths into one batch is
discouraged.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
1233
1234
1235
1236
1237
1238
1239
1240
1241
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Particulate Matter—Batch Release
Additional Testing
Stability
Labeling
Environmental Assessment
3/26/2008
31
See ICH guidance Q1A(R2) Stability Testing of New Drug Substances and Products.
See section VI. B for test method considerations for particulate matter testing as part of the stability protocol.
3/26/2008
29
An Environmental Assessment or request for a waiver (with justification) should be submitted (21
CFR 814.20(b)(11)).
11.
Detailed guidance on labeling and examples of text that can be used are included in the stand-alone
companion document. CMC information should appear in the Description sections of the label.
10.
If different finished product manufacturing sites will be used, appropriate release/stability data to
ensure the consistency and equivalency of the finished product should be generated. Generally realtime, room temperature data should be used to establish a DES shelf life. However, based on the
quality of the data (e.g., accelerated, long-term testing) provided by the applicant, a reasonable
extrapolation of data may be considered to assign the shelf life. It is recommended that simulated
transportation/shipping studies also be conducted as a one-time test to support excursions that may
occur during distribution of a DES.
30
30
Appearance
Assay/drug content
Impurities/degradation products
In vitro drug release
Particulate matter30
In addition, some tests, such as sterility, and package integrity, should be performed at release,
annually, and at expiry.
x
x
x
x
x
In general, the following tests should be performed at each of the preselected stability time points on
a minimum of three finished product batches to generate the primary stability data used to support an
expiration date:
For each set of stability data provided, the sponsor should identify the packaging system, the batch
number and scale, manufacturing date and site, the manufacturing process and formulation. For ease
of review, the Agency recommends that all stability information be provided in tabular format. See
Appendix A for an example of a stability table.
Stability testing should be conducted under ICH recommended conditions at room temperature
(25oC/60% RH or 30oC/65% RH) and accelerated conditions (40qC/75% RH).29 If long-term testing
is conducted at 25oC/60% RH and a significant change as described in ICH Q1A(R2) is observed in
the results obtained for a DES tested under accelerated conditions, additional testing using
intermediate conditions (30oC/65% RH) should be conducted and evaluated against significant
change criteria.
See ICH guidance Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products.
28
A stability protocol should be provided that includes storage conditions, time points, test parameters,
analytical methods, and acceptance criteria. The formal stability protocol can include an appropriate
matrixing and bracketing design. At a minimum, the protocol design should include the extremes (in
terms of both stent dimensions and total drug load) as well as an intermediate size to provide
assurance of consistent behavior across the entire proposed matrix of DES sizes to be
commercialized.28 If there are design differences (e.g., multiple stent platforms) within the proposed
DES matrix, the sponsor should bracket each design or provide a scientific rationale to support the
applicability of the sizes that are tested for the entire product matrix. We recommend that stability
testing include samples from a minimum of three finished product batches for each size tested.
Stability testing is performed to support the establishment of a shelf life or expiration dating period
for a DES (See also Section VII.C below). Stability studies should also be conducted during
investigational phases to support product stability for the duration of clinical trials.
9.
Additional testing of the finished DES may be necessary to address unique characteristics of
an individual DES. Examples include tests for polymer molecular weight, residual
monomers, catalysts, or other additives.
j.
This test evaluates the presence of sub-visible particulate matter. Particulate matter may
include particles shed from the formulation components as well as extraneous particles from
the stent platform, stent delivery system, packaging, and environmental factors. Appropriate
testing and acceptance criteria should be established for particulate matter. See section VI.B
for analytical procedures for characterizing particulate matter.
i.
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1314
1315
Draft — Not for Implementation
Draft — Not for Implementation
Note: All blood-contacting cardiovascular devices and combination products should be nonpyrogenic regardless of whether any claims regarding their non-pyrogenic status are made in
the labeling. Pyrogenicity testing is used to help define limits to protect patients from the
risk of febrile reaction. Pyrogenic responses to gram-negative bacterial endotoxins can be
tested using standard methods such as the USP Bacterial Endotoxins Test (<85>) using LAL.
Pyrogenic responses to leachables over the implant life can be tested using a materialmediated pyrogenicity test. See the companion document (Section titled “General
Biocompatibility Considerations”) for additional specifics on materials-mediated
pyrogenicity testing.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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A.
Summary Tables
NONCLINICAL STUDIES OF THE FINISHED DES
Engineering Evaluation
3/26/2008
32
See guidance for industry and FDA staff on Non-Clinical Tests and Recommended Labeling for Intravascular Stents
and Associated Delivery Systems.
31
The battery of tests and content and format of test data outlined in FDA’s guidance document on
bare metal intravascular stents and their associated delivery systems31 are relevant for this guidance
and for DES development. FDA recommends that sponsors complete all tests outlined in that
guidance on the finished DES intended for commercialization. Additionally, for those tests that
evaluate characteristics that could be affected by the addition of the drug and/or drug coating,
sponsors should compare those results with the performance characteristics of the bare metal stent
system in a side-by-side fashion. If a test article other than the finished, sterilized DES (e.g., bare
metal stent, prototype, coupon) is used for a specific test, a scientific rationale should be provided
for the applicability of the test article.
B.
In the event that the DES evaluated in nonclinical or clinical studies differs from the DES that is
intended for commercialization, the sponsor/applicant should provide an appropriate justification for
the applicability of testing provided. This justification, which can include additional limited testing,
can be referred to as a bridging document. FDA will assess the significance of any such differences
when determining whether sufficient information has been provided to support initiation of a clinical
study (IDE) or whether valid scientific evidence has been submitted to provide reasonable assurance
of safety and effectiveness for a PMA application.
Also for ease of review, FDA recommends that a one-page summary of significant trial design
parameters for each clinical study conducted in support of either the IDE and/or PMA applications
be provided. The companion document includes more details regarding this recommendation.
FDA recommends that a master table be compiled to summarize all mechanical performance,
animal, and clinical testing that has been conducted in support of the DES to either be tested
clinically (under the IDE) or commercialized (for the PMA application) in the United States. An
example of the parameters to be captured in tabular format as part of the master table has been
included in the Companion Document to this guidance. The master table should be provided and
updated, as necessary, for both IDE and PMA applications. To enable the integration of the master
table into the regulatory submission, the sponsor/applicant may decide to divide the table into more
discrete units (e.g., separate tables for engineering, PK, pharmacology/toxicity studies for the drug
substance, and animal studies in support of the DES). This table, or set of tables, will greatly aid in
the sponsor’s and the Agency's assessment of whether sufficient supportive acute and chronic safety
and/or effectiveness data have been provided for the proposed DES as part of both the IDE and PMA
reviews.
VI.
Test protocols
3/26/2008
1.
Coating Characterization
33
The term coating may refer to the drug carrier (usually polymeric, but not limited to such), the drug
itself if it is solely coated onto the stent platform, any other coating, or the drug carrier even if it is
incorporated onto the stent in a geometry other than a coating.
Extreme device dimensions, tolerances, sizes, and any other important device parameters should be
evaluated. We also recommend that the outer limits of physiologic variables, such as blood pressure,
vascular compliance, and anatomic types, be examined. All test conditions should be clearly stated
in the test protocol and supported with references to applicable literature, standards, or both.
Occasionally, the worst performing combination of device configuration and physiologic conditions
occurs in the mid-range of the relevant variables. This should be considered when developing
protocols to ensure that the worst performing combination has been evaluated.
Test protocols should assess the worst-case conditions that the DES is likely to experience in clinical
practice. Both device configuration and physiologic conditions can affect the performance of a DES.
In addition to the test data (summaries are not typically sufficient), detailed test protocols, which
include the loading parameters, test conditions, samples tested, acceptance criteria, and conclusions
drawn for each of the tests performed on finished, sterilized product, should be provided for FDA
review. A brief description of the derivation or development of the test method, or identification of
other applications in which the method has been previously used should be included.
x
Since unintended delamination or premature dissolution of a DES coating may influence its clinical
performance and/or mechanical integrity, additional evaluations and suggested modifications to the
battery of traditional engineering testing as outlined in the guidance document referenced above
should be taken into consideration for a DES.
A thorough description of the entire manufacturing process should be provided for review. This
description should clearly indicate whether any modifications have been made to the native stent
platform (e.g., texturizing of the stent surface, use of coupling agents, polishing) to facilitate coating
deposition/adhesion onto the stent substrate. The potential effect of additional processing steps on
the durability of the stent substrate as well as the coating should be evaluated.
FDA recommends that the final, finished DES be evaluated to determine the initial performance
characteristics of the DES. However, if there are any differences between DES tested for initial
characterization, clinical builds (DES used in the human studies) and the DES sought to be
commercialized (due to scale up of the manufacturing process), the changes should be clearly
documented and, as a part of the PMA submission, appropriate additional testing should be
conducted or a scientific rationale provided to demonstrate that these modifications will not affect
the safety and effectiveness of the DES.
Draft — Not for Implementation
Draft — Not for Implementation
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
Chemical identification of particles recovered as part of particulate matter testing (see
Section VI.D.3 below)
x
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3/26/2008
34
For this section of the guidance, acute refers to any time up through expansion and deployment of
the DES, whereas chronic refers to any time after assessment of the initial stent deployment in a
simulated vessel throughout the lifetime of the implant.
Furthermore, FDA recommends that coating integrity be evaluated by testing under certain
conditions before and after aging (at a minimum, the product should be aged to the requested shelf
life). These samples do not need to be real-time aged, but can be subjected to accelerated aging
conditions.
As part of this testing, it is recommended that a sampling plan be implemented to examine multiple
lots of DES as well as comparing regions of high stress/strain versus low stress/strain areas to assess
both inter- and intra-lot variability. A sufficient number of images should be provided so that FDA
can make an assessment of consistency.
The acute and chronic integrity of coating on the stent substrate should be assessed to provide
reasonable assurance that the coating is able to sustain its integrity according to its design
specifications. The Agency requests that the sponsor qualitatively and quantitatively determine
whether subjecting a DES system to expansion, deployment, and repetitive cycling modalities as
experienced in the clinical setting will influence the ability of the coating to interact appropriately
with the stent substrate. Part of this evaluation will entail determining whether there are areas where
the coating has not been adequately deposited onto the substrate (e.g., defects such as bare spots or
webbing due to manufacturing) versus areas in which the coating may have physically dislodged
(e.g., delaminated) from the substrate due to being subjected to mechanical forces.
Coating Integrity
Adhesion of the coating to the stent substrate. We recommend a quantitative characterization
of the adhesion strength. If the coating consists of multiple layers (e.g., primers), we
recommend that a quantitative test be performed to determine the cohesive strength between
the layers.
x
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2.
Coating thickness and uniformity along the stent length (both abluminal and adluminal
surfaces, if relevant), circumferentially, and along the sides of the struts.
x
Specifically, testing should be provided to address each of the following issues as part of
characterization studies:
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As part of the overall coating characterization of a finished DES, the sponsor should conduct
additional studies on a one-time basis as part of the product assessment to establish an understanding
of their DES system as well as appropriate baseline data. FDA believes that adequate baseline
characterization of a DES may help the sponsor identify potential coating integrity concerns earlier
rather than later in the development process. It should be noted that the tests recommended to
characterize the coating and to assess acute and chronic coating integrity are not typically considered
quality control (QC) tests; however, tests for particulate matter recommended in Section VI.B.3.iii
are suggested as part of the QC assessment as described.
2. We recommend that testing be conducted with stents in a bent configuration, with a clinically
relevant radius of curvature.
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Chronic coating integrity
3/26/2008
35
The sponsor should consider the following when designing tests to appropriately demonstrate the
chronic coating integrity of a DES:
Chronic coating integrity or, for a degradable polymer system, the loss of coating integrity over time,
can be assessed by performing accelerated durability testing in a simulated in vivo environment. It
is highly recommended that the visual integrity of a DES after 30 and 400 million cycles of fatigue
testing (representing approximately 1 and 10 years of equivalent implant time) be compared to
baseline data in a side-by-side fashion. For degradable polymer systems, timepoints for evaluation
may be specific to the expected degradation profile. A detailed fatigue test protocol, clearly
describing the test equipment, aqueous environment, frequency, loading parameters, and mounting
of samples should be provided with the results from these tests.
x
Ideally, the coating should not significantly change in configuration or prematurely delaminate from
the stent substrate upon expansion or deployment.
Further visual characterization of the coating should be performed after deployment of the DES to
the maximum diameter as described in the Instructions for Use. If overexpansion of the DES (postdilatation) is to be allowed, this should be taken into consideration as part of this testing. It is
recommended that deployment be simulated in an in vitro model intended to mimic in vivo
physiologic and anatomic conditions (e.g., tortuous path, aqueous environment). The stent should be
in direct contact with the simulated vessel without the use of other coatings, lubricants, sheaths, or
protective wraps between the stent and simulated vessel. The rationale for the final model selected
should be provided.
Acute coating integrity of a DES should be assessed via some visualization method (e.g., scanning
electron microscope). The stents used for this characterization should be representative of the
finished product, subjected to all manufacturing processes, including sterilization. A visual
assessment of the coating integrity on all appropriate surfaces of the DES after expansion in air to
nominal diameter with characteristics appropriately quantified (e.g., continuity, voids) is strongly
recommended to establish a baseline for comparison to coating characteristics after testing
performed under other conditions.
1. The sponsor should clearly indicate whether the sample consists of single or multiple stents
along with a justification supporting test methods testing multiple samples. Since there is a
reasonable expectation that stents will be overlapped during some clinical procedures,
accelerated durability testing should be performed on multiple stents in an overlapped
configuration.
Acute coating integrity
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Draft — Not for Implementation
Draft — Not for Implementation
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
4. At a minimum, we recommend that these additional tests be performed on the finished DES
for the worst-case product sizes for each stent design to demonstrate that the acute and
chronic integrity of the coating has not adversely affected the characteristics of the DES
system.
5. This testing can be combined with fatigue testing intended to evaluate integrity of the stent
platform, if the apparatus can accommodate both tests.
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Particulate Matter Characterization
3/26/2008
Testing Considerations
36
2. Appropriate precautions should be implemented to ensure that the particles are
suspended during sampling for particle counting and sizing to minimize artifacts from
the test system. In our experience, particles > 50 μm have the tendency to settle
and/or stick to the reservoir between particle counting. We recommend running a
blank in which no stent is present and any particles present in the system are captured
and counted. These counts represent test artifact and should be subtracted from the
results when a stent (or stents) is introduced into the system
1. Particle counting and sizing methods should be described and validated. It is
recommended that as part of the method validation, a known amount of various
particle sizes be introduced into the test setup and the amount of particles recovered
quantified. The number of particles recovered should closely approximate the
number artificially introduced into the system.
The sponsor should consider the following when designing tests to appropriately determine
the number, size and/or type of particles for a DES system when subjected to the conditions
described in b-d below.
a.
FDA recommends measurement of particulate matter generated by breakdown of the coating or from
the stent platform, stent delivery system, and product packaging both at release and after aging.
Particulate matter testing serves multiple purposes: (1) it provides an indirect evaluation of the
coating integrity of the finished product and (2) it establishes the number of particles that can
potentially be introduced systemically using the stent system. FDA believes that the main purpose in
particulate matter testing for DESs is to provide a level of assurance of patient safety in terms of
total particulate matter introduced into the bloodstream. Therefore, since the concern applies to the
total number of particles released into the bloodstream, the test should apply to the entire stent
delivery system, not just the stent.
3.
Refer to the section immediately below for additional issues related to characterization of the coating
integrity of a DES.
3. If a product’s drug elution is completed in a short time relative to the intended lifetime of the
product, coating integrity test samples should be pre-eluted for a worst-case evaluation. This
is a particularly important consideration for those coatings that become porous over time
because of drug elution.
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3/26/2008
37
4. We recommend that for baseline, overexpansion, and simulated use conditions
described in sections b, c, and d immediately below, testing be performed on the
extremes (four corners size matrix — see example table, below) and an appropriate
intermediate stent size for the entire stent matrix proposed.
3. The number of samples (a stent, not a strut or portion of a stent) used, the stent size,
and the stent lot should be specified for each test. The selection of the samples
should be scientifically justified.
Draft — Not for Implementation
Draft — Not for Implementation
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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3/26/2008
X
21
24
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X
Characterization
Baseline (expansion to nominal diameter)
x
38
Over-expansion (maximum deployed diameter, including post-dilatation limits, as
specified in the IFU)
Such testing should involve expansion of the stent to its nominal diameter in a beaker of
solution. If the stent is not a balloon-deployed stent and is self-expanding, this condition and
the over-expansion condition described below may be equivalent and combined into one test
condition.
x
For the purposes of characterization of the finished, sterilized DES, particulate matter testing
should be performed and particles collected and appropriately measured for several different
test cases:
b.
Note: In the event that an accessory device (e.g., embolic protection, atherectomy) is
intended to be used in conjunction with a DES, the sponsor should provide appropriate
supportive engineering performance test data to ensure that the integrity of the coating is
maintained. We recommend that sponsors contact appropriate FDA staff to discuss
engineering testing recommendations.
8. We recommend that particulate matter results be provided in a side-by-side fashion
(e.g., comparing baseline and post-tracking deployment).
7. Appropriate acceptance criteria should be proposed for particles t 10 Pm and t 25
Pm. The sponsor should provide valid scientific evidence, including chemical
identification of the particles recovered to support the proposed specifications.
6. For each test performed, a robust number of stents from multiple stent lots (minimum
of 3 batches) should be evaluated.
5. For evaluation of particulate matter generated on fatigue testing, the worst-case
size(s) for each stent design should be tested. A justification for the sizes selected for
testing should be provided; the rationale may include information gained from the
finite element analysis.
Diameter
(mm)
2.5
3.0
3.5
4.0
LENGTH (MM)
8
11 15 18
X
X
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3/26/2008
Simulated use (e.g., during tracking and deployment)
Fatigue/durability testing
Quality Control
Stability
39
For stability testing, we recommend that aged samples be evaluated using the simulated use
test condition. If the over-expansion condition is used for quality control purposes,
additional testing using the simulated use condition should be performed on stability batches
at t=0. It is highly recommended that particulate matter generation over time be evaluated at
each time point in the stability protocol (instead of only at t=0 and t=proposed expiration
date). In the event that the particle counts continually increase with aging or fail to meet the
d.
If the amount of particulate matter recovered from over-expansion testing and simulated use
testing is substantially similar, either test may be used for quality control testing. However,
if these two test conditions resulted in different amounts of particulate matter, the more
challenging test, the simulated use condition, should be performed for quality control
purposes. In either case, the test should be performed on every batch of product
manufactured as part of batch release (see Section V.B.8 above for other parameters to be
measured for batch release).
c.
This testing should be performed with use of a test fixture as described in section B.2
(chronic coating integrity) above. Note that physiologically relevant worst-case conditions
should be applied. This should include multiple stents placed in an overlapped and bent
configuration. It is recommended that particulate matter generation be measured at multiple
time points, rather than at t=0 and 400 million cycles. One advantage of this approach is that
a pattern/trend of particulate matter generation can be described (e.g., plateaus, monotonic
increases). Depending on this trend, the sponsor may be able to determine the appropriate
number of fatigue cycles (which may be significantly less than 400 million) necessary to
demonstrate that the coating will not unintentionally break apart or, for a degradable polymer
system, to quantify the particulate matter generation associated with the degradation of the
polymer.
x
This testing should be performed with use of an in vitro model as described in section B.2
(acute coating integrity) above. Note that physiologically relevant worst-case conditions
should be applied. To ensure measurement of the total number of particles that could be
potentially introduced into the bloodstream, the stent delivery system should be inserted into
the text fixture to the point at which it would be inserted in clinical use.
x
This testing should involve expansion of the stent to the maximum diameter allowed, as
described in the post-dilatation limits in the IFU in a beaker of solution.
Draft — Not for Implementation
Draft — Not for Implementation
Example of Four Corners Size Matrix
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Corrosion Potential of a DES
Degradable coatings
3/26/2008
33
40
ASTM F746 Standard Test Method for Pitting or Crevice Corrosion of Metallic Surgical Implant Materials.
ASTM F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to
Determine the Corrosion Susceptibility of Small Implant Devices.
34
ASTM G71 Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes.
32
The durability of the degradable coating becomes important near the end of the coating lifetime
when degradation has weakened the coating. We therefore recommend that particulate matter
testing be conducted in fatigue testing for the life of the coating. The trend or pattern of particulate
matter generation as the coating degrades should be described. It may also be instructive to observe
If a DES has a degradable polymer carrier, the environments for the experimental tests described
above should be carefully taken into consideration since they may affect the interpretation of the
results. Therefore, we recommend that a full characterization be performed of the degradation
profile (both in vitro and in vivo) of the biodegradable polymer carriers. The resulting information
should be used to design the test environment for the evaluations described above, as well as to
assess the appropriate timelines for additional nonclinical studies (e.g., supportive animal studies,
elution characteristics).
5.
If a stent contains more than one type of metal, such as a laminate, we recommend that the resistance
of the stent to galvanic corrosion be demonstrated. If stents of different materials will be overlapped
during clinical procedures and the contacting or overlapping stents may be made of different
materials, we recommend that the potential for galvanic corrosion between stents be addressed. We
recommend testing according to the methods described in ASTM G71,34 or an equivalent method.
Sponsors can modify the method by incorporating the experimental setup described in ASTM
F2129.
Additionally, since there is a reasonable expectation of stent overlap during clinical procedures, the
potential for fretting corrosion between two DESs should also be addressed. The sponsor should
ensure that micromotion between strut elements is actually occurring. We recommend that the
sponsor incorporate examination of samples for fretting corrosion as part of fatigue/durability
testing. A scientific rationale for the number of samples evaluated for fretting corrosion should be
provided.
If the underlying stent substrate of the DES is metallic, FDA recommends that the sponsor evaluate
the effects of cracked or delaminated coatings on corrosion resistance. We recommend that
corrosion testing be performed after intentionally creating a defect in the coating, which exposes the
base stent substrate. We recommend testing according to the methods described in ASTM F746 32
or an equivalent method. The sponsor can modify the method by incorporating the experimental
setup described in ASTM F2129.33
4.
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Biocompatibility
Animal Safety Studies
41
ISO 10993-1 Biological evaluation of medical devices—Part 1: Evaluation and testing.
3/26/2008
35
Studies of stent + polymer (without drug) should be performed if safety concerns are observed with
the finished DES product so as to help identify whether pathologic changes are more likely due to
Animal studies should compare combinations of the stent components (i.e., bare stent, and stent +
polymer + drug) in both nonoverlapping and overlapping configurations. The sponsor should clearly
identify any differences (e.g., stent design differences, polymer thickness, drug amounts) between
the DES used for nonclinical studies and the proposed IDE study.
DES nonclinical in vivo safety studies conducted in appropriate validated healthy animal models are
intended to assess handling characteristics (delivery and deployment), the biological response to the
DES, drug effects, and stent-related pathology. In addition, these studies are used to identify
potential clinically relevant major adverse events that should be considered prior to beginning
human clinical trials or that may influence clinical study design. The design of these studies should
also evaluate stents that incorporate a safety margin over the highest drug dosage and greatest
polymer concentration intended to be evaluated in the IDE clinical study as well as for all reasonably
anticipated intended clinical uses of the DES.
Prior to undertaking GLP animal safety studies, pilot DES animal studies should be conducted to
evaluate the degree of systemic exposure, local vascular and regional myocardial levels of the drug
component of the stent. This information can be discussed with FDA and will inform the need for,
and extent of, separate studies or data on systemic clinical pharmacology.
D.
Biocompatibility testing should be conducted in accordance with ISO 10993.35 For certain tests,
evaluation of the stent should be carried out separately from the delivery system. For additional
considerations related to biocompatibility testing, refer to the companion document.
C.
It is also very important to characterize the effects of the sterilization processes on the coating,
because many processes (e.g., irradiation) reduce the molecular weight of the polymers, which may
allow an increase of elution at early stages of the product and reduce the effective lifetime of the
coating.
Shelf life/stability characterization becomes very important for degradable/resorbable polymers. For
example, exposure to humidity may begin the degradation process and therefore not only reduce the
shelf life, but increase the elution at early stages of the product and decrease the effective lifetime of
the coating.
the coating via visual/microscopic methods near the end of the coating lifetime to characterize the
pattern of degradation to understand the potential for increased particulate matter generation (e.g.,
Does the degradation occur preferentially at the surface or stent interface once some interface has
been exposed? Is the degradation patchy?).
Draft — Not for Implementation
Draft — Not for Implementation
acceptance criteria at the proposed expiration date, additional data will be available to
support a shorter expiration date for the DES.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Appropriate Validated Models
Standards for Evaluation
3/26/2008
42
The Agency recommends the use of, at minimum, general animal study guidelines, necropsy, and
arterial histopathology methods, including those described below. The study findings from each stent
Unless there is a specific reason to do otherwise, the stent should be implanted in an artery that has no
prior injury. Antiplatelet therapy should be administered based on the current clinical standard of care
and that to be used during the clinical study.
2.
Currently, there is no animal model that can both (1) replicate the heterogeneity of human
atherosclerotic coronary disease and (2) accommodate the sizes of catheters and stents used in
humans. Due to potential experimental complexity and in the absence of studies demonstrating
predictive capabilities, atherosclerotic animal models to test the safety and performance of these
products have not been routinely requested. However, although advanced stenotic atherosclerotic
lesions in animals may not be available, sponsors may consider DES implantation in modifications
of normal vessels (e.g., intimal lipid/inflammatory cell-rich or fibrotic lesions) to test device
performance in vascular environments that may be relevant to human use.
Because of the similarities in the size, anatomic distribution, and time-dependent progression neointimal
growth within stents in human coronary arteries, the swine model has historically been relied on for
testing of intracoronary devices. However, because of inherent differences between animal and human
vascular responses to stent implantation, animal testing is primarily focused on the evaluation of safety,
rather than sustained long-term efficacy. Small animal models (e.g., rabbit iliac artery) can provide
complimentary data on optimal dose finding and DES mechanism of action.
1.
Refer to the companion document for general recommendations regarding good animal husbandry.
Demonstration of probable product safety is currently considered to be the primary purpose of the
nonclinical animal studies. Demonstrating potential product efficacy (i.e., inhibition of neointimal
hyperplasia) is an important secondary endpoint. However, for any given drug-device combination,
the potential efficacy observed during animal studies should be appropriate to balance any potential
safety concerns that were observed during the same studies. Also, it is reasonable to presume that
the demonstration of the potential efficacy of a new DES in an animal model may assume increasing
importance over time if multiple DESs are approved for clinical use.
If observed pathologic changes are believed to be secondary to species-specific arterial responses, an
approved DES can be considered as an additional control treatment arm. Additionally, sponsors can
consider using an approved DES as a control treatment arm to demonstrate superiority of the test
DES with respect to sustained neointimal growth supression, more rapid stent endothelialization,
reduced fibrin deposition, improved vasomobility, reduced inflammation, and reduced positive
remodeling/stent strut mal-apposition.
We recommend pressure perfusion fixation and plastic embedding for stented arteries.
For stents < 30 mm in length, we recommend evaluation of a minimum of three sections per
stent (proximal, mid and distal), plus one section 5 mm beyond each end of the stent.
For stents > 30 mm in length, see section VI.F.7 of this guidance.
For arterial histopathologic sections, a descriptive histopathology report (including
micrographs illustrating the findings) and histomorphometric analysis as well as
interpretation of data are recommended. We also recommend a thorough evaluation of the
arterial biological response to the DES describing the following points.
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- Location and severity of dystrophic calcification
- Evidence of the loss of vessel wall structural integrity
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We recommend inclusion of a broad selection of representative, thoroughly described gross
photographs, radiographs (evaluating stent integrity, configuration, and extent of stent
overlapping), and photomicrographs of arterial cross sections from stented arteries in the
final pathology. We encourage the submission of representative photomicrographs
describing the histopathology scoring system used to describe the severity of histopathology
endpoints. In addition, thumbnail, low, and higher magnification photomicrographs of all
x
3/26/2008
We recommend that all pathology and histopathology reports be written by the examining
pathologists or clinicians and attached as an appendix to the final GLP study report.
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We recommend that you specifically evaluate and report the presence of mural thrombus
formation and evaluate the potential for thromboembolism and the significance of stentrelated embolic material in selected regions of organs perfused by the stented vessel. Stent
strut mal-apposition to the arterial wall should be reported. For the porcine coronary model,
in particular, the presence of granulomas should be noted.
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- Characterization of the inflammatory response and fibrosis within the neointima,
media, and adventitia
- Locations and amounts of fibrin
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- Alterations of the media (e.g., necrosis, thinning of media or loss of cellularity) and
adventitia
- The extent of endothelialization (scanning electron microscopy should be considered)
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- The morphologic features of the neointima and the extent of stent strut coverage by
neointima
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A complete general necropsy (gross and detailed histopathology) should be performed, as
well as gross and radiographic evaluation of stented vessels and the heart, including an
evaluation of vessel wall and stent structural integrity (e.g., strut fractures, polymer
fragments), assessment of stent malapposition, and multiple anatomical regional sections
from organs perfused by the stented artery.
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type (i.e., bare stent, stent + polymer + drug, and if indicated, stent + polymer) should be compared.
We recommend the following.
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Draft — Not for Implementation
Draft — Not for Implementation
the drug or the coating. The stent + polymer sample should include both biodegradable and nonbiodegradable polymer carriers as well as the primer layer.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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The non-stented adjacent arterial sections (5 mm proximally and distally) should undergo
comprehensive histologic evaluation including an assessment of arterial injury, neointimal
thickening, inflammation, and thrombus deposition.
Histomorphometric evaluation of sections is essential for the assessment of DES biological
response and safety. These measurements should minimally include the following:
neointimal area, neointima thickness at each strut site, medial area, internal and external
lamina area, lumen area and percent area stenosis. Measurements should be performed on
each stent section (proximal, middle, and distal), and a mean measurement for each
parameter for the entire stent should be reported. From these data, the percentage of the stent
narrowed by neointimal tissue (percent stent stenosis) can be calculated. A mean injury
score for each stent should be determined.
Study Duration
3/26/2008
44
In nonclinical studies at all time points, histology should be carefully evaluated for polymer
delamination from the stent.
In view of the mechanism of action of most DESs, longer term follow-up studies (e.g., beyond 6
months) are likely to be necessary to assess (1) chronic inflammatory reactions, (2) delayed or
incomplete endothelialization, (3) late stent thrombosis and restenosis, and (4) chronic biological
responses to the surface polymer after complete drug elution and, in the case where a biodegradable
polymer is used that takes longer than 6 months to fully degrade.
Animal studies designed to assess biological response and safety of the final clinical version of the
DES should be conducted prior to first in human use. At a minimum, 1- and 6-month studies are
suggested; 3-month animal data are optional, and depending on the results, may be sufficient to
begin a clinical feasibility trial.
3.
Following DES implantation, any sudden or unscheduled animal deaths should be vigorously
investigated for cause. In such cases, a thorough necropsy should be conducted, including
evaluating all stented arteries and specifying the cause of death. Any clinical problems (e.g., fever,
allergy, evidence of renal or hepatic dysfunction) should also be recorded. We recommend that
complete data on thrombus, myocardial infarction, aneurysm, and perforation be collected and
included with the pathology report within the IDE submission.
Quantitative coronary angiography (QCA) is recommended for appropriate stent diameter
implantation (stent to artery ratio) to avoid excessive vascular injury secondary to oversizing. The
use of intravascular ultrasound (IVUS) evaluation is recommended in a subset of animal studies to
demonstrate strut apposition to the arterial wall both post-procedure and at follow-up in a subset of
animals.
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Biological Response
Downstream and Edge Drug Effects
Drug Dosage Safety Margin
3/26/2008
45
The objective of studies of stents with higher drug and polymer dosages than will be applied to the
clinical or to-be-commercialized version of the stent is to establish a safety margin over and above the
dose intended for clinical use. These studies can reveal whether adverse effects are observed at higher
dosages, and at what dosage the effects are observed. The following drug formulation characteristics
5.
If long stents are evaluated separately (refer to section VI.F.7), this evaluation should be
completed both for standard length stents and for long stents.
In addition, the drug effects immediately proximal and distal to the stented segment of the
vessel (referred to as an edge effect) should be assessed. Using similar histopathology and
histomorphometric endpoints as described above (VI.C.2 and 4a), the findings should be
compared to the stent segment of the vessel.
It is important to evaluate whether a drug produces pathology in the tissue downstream from
the stent. Using the highest total drug dosage proposed for clinical use, a thorough gross and
histopathology evaluation of multiple anatomic regional sections of myocardium perfused by
the stented artery should be conducted to identify stent-related cardiac pathology (e.g.,
infarcts, thromboembolic material, myocardial necrosis and fibrosis).
b.
Study endpoints should focus on the characterization of localized drug effects within the vessel
wall of the stented vessel as well as immediately proximal and distal to the stented vessel segment
(i.e., to observe any potential edge effects). Evidence of DES-related drug effects and pathology
includes factors such as mural thrombus formation, fibrin deposition, inflammation (strut
associated; neointima, media, adventitia), granulomas, neointimal smooth muscle density, medial
necrosis and thinning, dystrophic calcification, endothelialization, vessel wall hemorrhage, and
neoangiogenesis. We recommend that a scoring system be used to record the incidence and
severity reported by stent segment region (i.e., proximal, mid, distal).
We recommend that a three-way comparison of the histopathological findings for the bare metal
stent, polymer-only stent (if indicated), and the polymer-drug stent combination be conducted at
appropriate time points, minimally to include 1 and 6 months. We recommend that at least six to
eight samples of each of the stent types be evaluated with a minimum of three to four animals per
time point. We recommend enrollment of extra animals in anticipation of possible early animal
deaths.
a.
Histopathology Endpoints Assessing Drug Effects
4.
Note: Given the differences in injury and healing responses between the animal models and humans,
in addition to inherent variability between the designs of different DES systems, a definitive longterm follow-up time point for animal model studies to assess late effects cannot be explicitly
recommended.
Draft — Not for Implementation
Draft — Not for Implementation
arterial sections should be included as an appendix in the final pathology report. To ease
review, we recommend providing all gross photographs, radiographs, and photomicrographs
in electronic format.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Dose density
Total dose loaded
Coating thickness
Amount of drug delivered to the tissues
Residual amount of drug on the stent
Release rate
Overlapping Stents
Long Stents
3/26/2008
46
A separate evaluation should be completed for the longest stent model if a long DES (i.e., >30 mm)
is to be marketed. Evaluation of angiography and histopathology is particularly important to
characterize the biological and drug response along the full length of the stent. Histopathology
sections should cut at approximately 10 mm intervals, plus one section 5 mm proximally and distally
beyond each end of the stent. The Agency will not routinely request comparisons to long stent
7.
Due to the likely possibility that multiple overlapping stents will be used, FDA recommends that
animal testing on overlapping stents be provided as part of the PMA submission whether or not
testing is included within the clinical study to provide a preliminary assurance of safety.
Since overlapping stents are commonly implanted in current clinical practice, animal studies should
be undertaken to evaluate the safety of overlapping DESs and provided as part of the IDE
submission. Stents overlapping by a minimum of 4 mm should be evaluated at 1 and 6 months
(optionally at 3 months), in a minimum of six stents per stent type. Histopathology sections should
be obtained from both overlapped and non-overlapped regions. Histopathology and
histomorphometric endpoints should be reported and compared by stent segment (i.e., proximal,
overlapped, distal stent).
6.
In animal studies intended to establish a safety margin, the dose density, amount of drug or polymer
loaded, and number of stents should be designed to justify a margin of safety over the proposed clinical
trial dose. In addition, drug release characteristics should be analyzed in relation to local tissue drug
concentration, vascular biological responses and local toxicity. The release rate is important because it
directly correlates with the local vascular toxicity. Additional animal studies should be carried out to
evaluate the safety of stents containing higher dosages of drug and polymer (i.e., a three- to ten-fold
margin over the intended drug dosage density of the final product) to evaluate whether the DES has an
appropriate local, regional, and (possibly) systemic safety margin with regard to drug dosage density. If
loading high drug concentrations onto the stent is technically difficult or significantly alters the
degradation profile for a degradable carrier, the Agency recommends evaluating regions of overlapped
stents to theoretically support safety margins. Evaluation of over-dosage stents should include the
longest, largest diameter stent, and if multiple stents are routinely used, the combined drug density of the
highest number of, and the longest, stents allowed in the planned human study.
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Clinical Pharmacology and Drug Release Kinetics
3/26/2008
Evaluation of the Systemic Pharmacokinetics of a DES
a.
Population-PK
Bio-Analytical Methods
Evaluation of In Vivo Drug Release
a.
47
The in vivo drug release information generated in the animal studies can be very useful (1) in the
design of the in vivo human PK assessment conducted as part of the clinical program (i.e.,
Drug Release Kinetic Information
2.
The evaluation of the samples collected during the PK study should be evaluated for drug
content using properly validated analytical methods. Additional information on validation of
methods can be found in CDER’s guidance for industry Bioanalytical Method Validation.
c.
A population PK-sparse sampling approach can also be used for the collection of clinical PK
data for the DES from patients enrolled in the clinical trials. See CDER’s guidance for
industry Population Pharmacokinetics.
b.
To obtain PK information at the highest possible drug exposure, it is recommended that the
PK evaluation occur in a trial including patients receiving multiple and overlapping stents.
The measures or parameters for the drug should include area under the plasma concentration
versus time curve (AUC), peak plasma concentration (Cmax), time to peak plasma
concentration (Tmax), elimination half-life (T1/2), and total clearance (Clt). If there are major
metabolites associated with the therapeutic or toxic effects of the drug, they should also be
determined.
The evaluation of the pharmacokinetics (PK) of a DES can be accomplished in one of the
trials of patients implanted with the DES. The sponsor should provide a detailed protocol
describing the design of the PK study. The in vivo drug release kinetic information
generated during the animal studies could be useful in designing the human PK study (i.e.,
appropriate PK sampling times, length of PK study).
Clinical Pharmacology Information
1.
This section provides suggestions on elements to consider in the assessment of the clinical
pharmacokinetics of a DES and on the evaluation of both in vivo and in vitro release characteristics
of the drug from a DES.
E.
controls. Results of the long DES may be compared to those observed for standard-length control
stents and DES.
Draft — Not for Implementation
Draft — Not for Implementation
should be used to describe a DES.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Drug Tissue Levels and Systemic Distribution
Evaluation of In Vitro Drug Release Kinetics
48
The in vitro drug release/elution kinetics should be evaluated under appropriate conditions
based on the mechanism of drug release and to emulate hydrodynamic considerations of stent
deployment. In vitro drug release kinetics characterization should provide valuable insight
on the time course of drug release and on the drug remaining on the stent. The relative
In vitro release testing is a powerful and useful tool for obtaining data related to a product’s
quality and, potentially, its clinical performance. The Agency considers the development of
acceptable, discriminating in vitro elution methodology and specifications as critical for the
adequate characterization of a DES product tested clinically as well as to validate consistency
in the commercially manufactured product. Because this testing serves multiple important
purposes, including use in DES characterization, batch release, and stability testing, the in
vitro elution method for the testing of the release of drug from the DES should be developed
and validated as early in the development process as possible and definitely prior to
submission of the PMA application.
b.
Assessments should include whether the drug’s concentration is uniform along the stent
length or preferentially distributed at either end. Evaluations should compare the terminal
elimination t1/2 of drug from stent to the true elimination t1/2 obtained after IV administration.
If drug release from the stent is slower than the elimination process (flip-flop phenomenon),
the rate limiting step is the release of drug from the stent.
The in vivo local and systemic drug kinetics of the DES to be used in the IDE clinical studies
and submitted in the PMA application for marketing approval (if there are modifications)
should be thoroughly characterized in an appropriate animal model. The release of drug
from the stent should be evaluated at specified time intervals covering the complete drug
elution profile (immediately after implantation until the drug is completely eluted from the
stent). Drug concentrations should be assessed in the blood, in arterial tissue, and in
myocardial tissue proximal and distal to the stent, as well as in remote tissue, such as the
liver, lung, and kidney. In the tissue surrounding the stent, the drug should be evaluated until
there are no longer detectable levels.
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The in vivo release of a drug can be divided into two types. First, the release can be directly
measured using the amount of drug remaining in explanted stents with respect to time until
complete drug elution profile is obtained. The release can also be measured using the blood
and/or tissue concentration data. The in vivo release profile generated using the first method
represents drug release from the stent to the surrounding tissues and systemic circulation
while that generated using the second method represents drug released from the stent and the
surrounding tissue into the systemic circulation.
Acceptance criteria should be set in a way to ensure consistent performance from lot
to lot.
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The establishment of at least three sampling times covering the initial, middle, and
terminal phases of the complete elution profile data should be selected. The
acceptance criteria ranges should be based on the overall elution data generated at
these times.
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Data from lots used in the clinical trials and stability studies, and also on to-bemarketed batches, should be used.
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The in vitro elution specifications should encompass the timeframe over which at
least 80 percent of the drug is eluted or where the plateau of drug elution is reached if
incomplete elution is occurring.
For the setting of the drug release/elution acceptance criteria, the following points should be
considered:
In vitro drug release kinetics should be reproducible between stents within a lot and between
manufacturing lots and should be stability-indicating. The chosen method should be
discriminatory and sensitive enough to reject lots that would have less than acceptable
clinical performance.
The elution profile should be complete and cover at least 80 percent of drug release of the
label amount or whenever a plateau is reached. We recommend use of at least six samples
per testing variable. The elution data (individual, mean, profiles) should be reported as the
cumulative percentage of drug eluted with time (the percentage is based on the product’s
label claim).
A detailed description of the optimal in vitro elution methodology and the developmental
parameters (i.e., equipment/apparatus, in vitro release media, agitation/speed, temperature,
pH, assay) that were used to identify this method as most appropriate should be submitted to
the Agency in the IDE. Also, the method validation information showing that the chosen
method is able to detect manufacturing changes (under meaningful testing) that may have an
effect on the release of the drug should be submitted. Validation studies are important for
identifying critical formulation and manufacturing variables during development,
establishing relevant controls for manufacturing, and developing a relevant stability
indicating test method for final product testing. An in vitro test method based on mechanism
of drug release can also be a valuable tool for ensuring unchanged performance of
manufactured lots.
solubility of the drug also determines the relative kinetics such that a more lipophilic drug
exhibits a longer time of elution. We recommend that the in vitro release profile generated
with the chosen method mimic the in vivo elution behavior of the drug from the DES. If this
is not possible (e.g., the in vivo release is limited), the in vitro method should be optimized
for its ability to detect manufacturing lots outside the boundaries established in the clinical
trials.
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Draft — Not for Implementation
Draft — Not for Implementation
appropriate PK sampling times, length of PK study), (2) in the development of in vitro release
methodology that mimics the in vivo drug release, and (3) in the development of an in vivo-in
vitro correlation (IVIVC).
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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The chosen acceptance criteria should not allow the release of any lots with elution
profiles outside those that were tested clinically.
In Vitro-In Vivo Correlation
Mechanism of drug release from the stent
Formulation and manufacturing process factors that influence the release kinetics
In vitro method conditions (e.g., hydrodynamics, media composition)
In vivo stent deployment factors
50
Once the in vitro and in vivo data sets are available, a mathematical model describing the
relationship between the in vitro and in vivo data sets should be developed. One mechanism
for determining whether a correlation exists between the in vitro release kinetics and the in
vivo tissue uptake is to plot the amount of drug released in vitro versus the amount released
in vivo at the same time points to see whether a point-to-point relationship exists (level A
correlation). When trying to develop such a relationship, the in vivo data set is fixed. Once
this information is generated, it establishes the relevant performance of the DES product. On
To obtain an in vitro-in vivo relationship, two sets of data should be collected. The first set
contains the in vitro data, usually drug release data from an elution test, and most often takes
the form of percentage of drug released as a function of time. The second data set contains
the in vivo data. For a DES, the in vivo release of a drug can be assessed by determining the
blood-drug concentration data and also by measuring the amount of drug remaining to be
released from the recovered stents. Although data from either or both methods can be used
in the development of an IVIVC, for a DES, the systemic drug levels might be very low or
below quantitation limit. Thus it becomes more feasible in constructing the IVIVC model to
use the in vivo release data from the explanted stents. A model that integrates both (i.e.,
mechanism of drug release and systemic drug concentration) may provide a means for
developing a physiologically based PK model for predicting drug disposition and for
establishing relevant mechanism based IVIVC.
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The ultimate goal of an in vitro-in vivo correlation (IVIVC) is to establish a meaningful
relationship between in vitro behavior of a DES product and in vivo performance of the same
product, which would allow in vitro release data to be used as a surrogate for in vivo
behavior. Thus, the main objective of developing and evaluating IVIVC is to empower the in
vitro release test to serve as a surrogate marker for in vivo bioavailability. One additional
primary purpose of establishing an IVIVC is to minimize the number of human studies
needed for the approval of scale-up and postapproval changes in manufacturing processes
(e.g., those that do not change the mechanism of release). We recommend that the following
factors be considered when establishing the IVIVC:
c.
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A.
Manufacturing — Quality System (QS) Regulation and Current Good
Manufacturing Practice (CGMP) Regulations
FINISHED PRODUCT MANUFACTURING, STERILIZATION, PACKAGE
INTEGRITY, AND SHELF LIFE
3/26/2008
37
51
See http://www.fda.gov/oc/combination/OCLove1dft.html.
The Agency has since announced its intent to issue a Proposed Rule on Current Good Manufacturing Practice for
Combination Products (72 Fed. Reg. No, 236 (2007), available at
www.RegInfo.gov/public/do/eAgendaViewRule?ruleID=279375.
38
See, e.g., guidance for industry Quality System Information for Certain Premarket Application Reviews,
www.fda.gov/cdrh/comp/guidance/1140.pdf, for more information.
36
A drug-device combination product must meet current good manufacturing practice requirements for
both the drug and device constituent parts of the combination product (e.g., 21 CFR 210/211 for
drugs, 21 CFR 820 for devices). For a discussion of the Agency’s current thinking on how to apply
these manufacturing requirements for a combination product, you may wish to refer to the draft
guidance for industry Current Good Manufacturing Practice for Combination Products, issued by
the agency in September 2004.36 The draft guidance describes a quality management framework for
combination products that, if properly implemented, would give manufacturers the flexibility to
select either the CGMP regulations (21 CFR 210/211) or the Quality System regulation (21 CFR
820) as their umbrella manufacturing operating system, provided their current good manufacturing
practice operating system incorporates key specific provisions pertaining to the other part of their
combination product.37 Under such an approach, if the Quality System (QS) regulation (21 CFR
820) is chosen as the umbrella set of regulations for the manufacturing operative system for a DES
product, complete manufacturing and quality control information for the DES product would be
provided pursuant to the QS regulation (see 21 CFR 814.20(4)),38 incorporating key, specific
provisions from the drug CGMP regulations (21 CFR 211). Likewise, if the CGMP regulation is
chosen as the umbrella manufacturing operating system, complete manufacturing and quality control
information should be provided for the DES product pursuant to the CGMP regulations (21 CFR
A PMA must include a complete description of the methods, facilities, and controls in sufficient
detail that FDA can make a knowledgeable assessment of the quality control used in producing the
finished DES (see 21 CFR 814.50). Although particular aspects of the manufacturing of the finished
DES are addressed in Section V.B., Chemistry, Manufacturing, and Controls, a full description of
the manufacturing methods, facilities, and controls must be provided at the time of the PMA
submission (see 21 U.S.C. 515(c)(1)(C)).
VII.
Additional information on the development and validation of an IVIVC can be found in
CDER’s guidance for industry In vivo/In vitro Correlations.
the other hand, the in vitro release profile may be modified through changes in the release
test conditions to obtain a consistent relationship between the percentage of drug released in
vitro and the fraction of drug released in vivo.
Draft — Not for Implementation
Draft — Not for Implementation
The applicant should note that an agreed upon in vitro elution test (i.e., specifications and
acceptance criteria) is critical as a quality control (QC) tool during the stability program and
establishment of the DES shelf life and is part of the QC tests performed for the release of
DES batches.
x
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Sterilization
Package Integrity
Shelf life testing
3/26/2008
52
FDA recognizes the following standards for steam, ethylene oxide, and radiation sterilization, respectively: ISO
11134, ISO 11135, and ISO 11137 (see guidance for industry Recognition and Use of Consensus Standards,
http://www.fda.gov/cdrh/ost/guidance/321.html.
40
ISO 2248 Packaging – Complete, filled transport packages – Vertical impact test by dropping; ISO 8318 Packaging
— Complete, filled transport packages and unit loads — Sinusoidal vibration tests using a variable frequency
39
In addition to the tests recommended to demonstrate stability of the DES discussed above (see
Section V.B.9), testing should also be performed to demonstrate that the functionality of the stent
and delivery system (i.e., mechanical performance), the coating integrity, and the package integrity
have not degraded over the requested shelf life. Testing should be performed on a finished,
sterilized DES product that has been manufactured and packaged in the same manner as intended to
be commercialized. Due to the presence of the polymer and drug components accelerated aging is
not appropriate for stability testing as described in Section V.B.9 above; however, testing to
establish the continued functionality of the stent and delivery system may be conducted using
samples subjected to accelerated aging. For certain tests, such as coating integrity, accelerated aging
conditions can have a significant detrimental impact on the DES such that real-time aging should be
considered.
D.
Additionally, appropriate testing should be conducted to evaluate the ability of the packaging to
withstand forces generated during shipping and distribution from the manufacturer to the end user.
Test methods such as those described in ISO 2248 and ISO 831840 may be appropriate.
Package integrity testing should be performed to demonstrate the ability of the package to maintain
the sterility of the product contained within it. Package integrity testing generally consists of a
whole package physical integrity test in conjunction with a seal integrity test. Some methods for
package integrity testing may be found in ISO 11607.
C.
The PMA application should identify the sterilization method and include the validation for the
sterilization method and the sterility assurance level (SAL) achieved. In general, sterile devices
would meet an SAL of 10-6, unless there is a substantial scientific justification provided for not being
able to achieve this level and for why patients would not be at increased risk. Sterilization validation
should be carried out in accordance with a recognized standard or equivalent method.39
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General Considerations
Clear statement of the intended use
Clinical development plan designed to develop the data needed to support the intended use
Study hypothesis(es)
Primary and secondary study endpoints for both safety and effectiveness
Criterion for study success, (i.e., which hypotheses must be met for the study to be
declared a success or win)
Allocation of Type I error (alpha) for primary and secondary hypotheses, as
appropriate
Plan for assessing safety in which all adverse events are identified and analyzed
Plan for assessing safety and effectiveness on the basis of an intent-to-treat population as
well as an evaluable population
Study design with inclusion/exclusion criteria
Case report forms
Statistical analysis plan
Risk/benefit analysis
Informed consent42
3/26/2008
42
53
See guidance on IDE Policies and Procedures, http://www.fda.gov/cdrh/ode/idepolcy.pdf.
You should review the statutory definition of applicable clinical trial to determine if your trial must be registered
to comply with the law. See PL 110-85, Section 801(a), (adding new 42 U.S.C. 282(j)(1)(A)).
http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf
41
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FDA believes that a clinical protocol for a coronary DES should include the following elements:
FDA encourages study sponsors to use the pre-submission process41 to gain informal feedback on
proposed clinical protocols for DES, including feasibility or pivotal studies. Additionally, although
FDA generally does not regulate device clinical studies performed outside of the United States, we
are willing to provide informal feedback on clinical protocols for OUS studies that are planned to
support either an IDE or PMA application.
Clinical trials of a new DES should not begin until the sponsor demonstrates that there is reason to
believe that risks to subjects are outweighed by the anticipated benefits to the subjects and the
importance of the knowledge to be gained. Depending on the amount of available information, a
feasibility study may be recommended to allow the collection of initial data in human subjects. If
feasibility (sometimes referred to as “first in human”) data are available from studies undertaken
outside the United States (OUS), additional data collection in a feasibility study in the United States
may not be necessary. However, the quality, applicability, and duration of such OUS feasibility
studies will be critical to assess whether these data can be considered directly or indirectly applicable
to the DES intended for clinical use in the United States. Such information should be reported in the
Report of Prior Investigation section of an IDE. The companion document includes an example of a
one-page summary that may be used for ease of review.
A.
VIII. CLINICAL ASSESSMENT OF DRUG-STENT COMBINATIONS
Draft — Not for Implementation
Draft — Not for Implementation
Parts 210 and 211), incorporating key, specific provisions from the device QS regulation (21 CFR
820).
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Data and Safety Monitoring Board (DSMB) charter
Balance of premarket and postapproval data development
Labeling that accurately presents any previously collected study data
Intended Use
Lesion types (e.g., de novo, in-stent restenosis)
Target population (e.g., stable angina, acute coronary syndrome (ST elevation myocardial
infarction, non-ST-segment elevation myocardial infarction, unstable angina)
Conditions for use
Anatomical sites of application of the DES (native coronary artery, saphenous vein or arterial
grafts, left main coronary artery, ostial, chronic total occlusion, bifurcation) and range of
lesion lengths and vessel diameters
Expected outcomes
Objectives for DES Trials
3/26/2008
54
Information can be submitted to ClinicalTrials.gov using the Protocol Registration System (PRS). For more information
visit the PRS Information Page (http://prsinfo.clinicaltrials.gov).
43
Although indications are commonly refined over time as clinical data from feasibility studies are analyzed, at the
pivotal trial stage of product development, the intended use and indications should be in reasonably sharp focus.
44
FDA statements available at http://www.fda.gov/cdrh/news/091406.html and
http://www.fda.gov/cdrh/news/010407.html. Panel summary and transcript available at
http://www.fda.gov/ohrms/dockets/ac/cdrh06.html#circulatory.
Following the approval of the first two coronary DES, data were collected that suggested a small but
significant increase in the rate of stent thrombosis associated with DES as compared to bare metal
stents, occurring after the first year of implantation. FDA convened an Advisory Panel meeting on
December 7 and 8, 2006, in an effort to fully characterize the risks, timing, and incidence of DES
thrombosis. Three topics were discussed by the experts on the panel, DES manufacturers, and
clinical investigators: (1) the rates of stent thrombosis and associated clinical sequelae (death and
MI) when DES are used in accordance with their labeled indications; (2) the rates of stent
thrombosis and associated clinical sequelae (death and MI) when DES are used in a broader, more
complex population of patients and lesions; and (3) the optimal duration of dual antiplatelet therapy
in patients who receive DES. More specific information about the meeting and the conclusions
reached are available on FDA’s Web site.44
C.
The intended use determines the objectives of the clinical trial, which are generally to demonstrate
the safety (i.e., associated morbidity and mortality) and effectiveness (i.e., associated patient benefit)
of the product for a defined clinical benefit in a target population under specific conditions of use.43 x
x
x
x
x
The sponsor should identify, as clearly and precisely as possible, the intended use of the DES. The
specific indications should include the following:
B.
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Study Designs
Superiority Study
3/26/2008
55
For a DES, an RCT study design could compare a DES, as the investigational device, to a bare metal
stent, as the control arm. However, the choice of control in a superiority design is not limited to a
bare metal stent. A sponsor may choose to evaluate the superiority of an investigational DES to an
active DES control (i.e., an FDA approved DES). The investigational DES should be shown to be
superior to the preselected control by a margin agreed to be clinically significant by the clinical
1.
Randomized controlled trials (RCTs) are the most appropriate trial design for a new DES, although
for certain additional indications beyond initial approval (e.g., additional stent diameters, lengths or
certain lesion types), other trial designs may be appropriate. Both superiority and noninferiority
RCTs can be used to support the safety and effectiveness of a DES.
D.
Clinical resistance to antiplatelet therapy (resistance to aspirin, clopidogrel, or both) may emerge as
an important risk factor for stent thrombosis. Evaluation of responsiveness resistance to antiplatelet
therapy may be a future recommended test. FDA is open to different approaches and trial designs to
address these critical questions. Suggested approaches are discussed in the sections to follow.
4. The following aspects of adjunctive antiplatelet therapy (APT) should be addressed.
x Describe the profile of patient compliance with recommended antiplatelet therapy
x Determine how often dual APT is being extended beyond the recommended duration
x Describe the frequency and duration of APT interruption
x Identify what, if any, bridging strategies during interruption were used
x Capture any and all invasive or surgical procedures that were deferred because of the need
for continued APT
x Define the rate of significant bleeding complications associated with APT
3. The rate of stent thrombosis over time should be addressed. For example, the rate of stent
thrombosis up to and after 1 year should be determined, including whether the rate increases,
decreases, or plateaus over time. Analyses should be presented for both patients receiving the
DES within the labeled indication and patients representing broader use of the product.
2. The rate of death and myocardial infarction (MI) should be determined. Not only are these
critical safety endpoints, but adequate precision around the rates of death and MI is needed to
understand the impact of stent thrombosis on the overall safety and effectiveness profile of a
DES.
1. The rates of critical clinical endpoints related to safety and effectiveness, such as death,
myocardial infarction, and need for revascularization should be determined.
As an outcome of that panel meeting, FDA recommends that all DES clinical programs address the
following questions as part of the information provided to demonstrate a reasonable assurance of
safety and effectiveness:
Draft — Not for Implementation
Draft — Not for Implementation
A number of the above elements are discussed in greater detail below.
x
x
x
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Noninferiority Study
57
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56
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Although a composite may not be the ideal primary endpoint, because the components have
different weights, the use of such a composite allows for trials of reasonable sample size to
be conducted. For example, a trial seeking to evaluate mortality would need tens of
Outcome drift can occur when successive generations of inferior devices are found to be non-inferior to the previous
generation as an active control, but might be inferior if tested against the original placebo treatment.
46
Cutlip et al., on behalf of the Academic Research Consortium. Circulation 2007:115;2344-2351. Clinical endpoints in
coronary stent trials: a case for standardized definitions.
45
Primary Endpoint – Clinical Endpoints
Historically, the conventional intracoronary device study endpoint has typically been a
composite endpoint (e.g., target vessel failure (TVF), which is a composite of death, nonfatal
myocardial infarction (MI), and target vessel revascularization (TVR) after an index stenting
procedure). The paper by Cutlip et al. referenced above recommends the use of a patientoriented composite including all death, MI, and TVR and a device-oriented composite
including cardiac death, target vessel MI, and TLR. We recommend the use of the deviceoriented composite as a primary clinical endpoint. Other endpoints may be appropriate for
specific studies; a clinical justification should be provided for the endpoint selected.
a.
FDA recommends that definitions for outcomes of interest (death, MI, Target Lesion
Revascularization (TLR), Target Vessel Revascularization (TVR), stent thrombosis) be standardized
in the protocol. One potential set of definitions can be found in Cutlip et al.,46 although alternate
definitions may be proposed with a clinical justification.
Based on the definition of effectiveness (21 CFR 860.7), the most direct method of providing valid
scientific evidence of effectiveness is to select an appropriate clinical outcome and design a study to
evaluate a statistically significant and clinically meaningful treatment effect.
Although the non-inferiority trial design is a strategy that could be used when a placebo-controlled
study cannot be conducted, there are some limitations to the noninferiority study design that should
be considered prior to adopting this approach. For example, selection of an appropriate delta value,
while ideally based on prior data and expectations of performance, should be determined by what is
a clinically meaningful definition of a delta, agreed to by the clinical community and FDA. In
addition, the trial design and analysis plan should take into consideration the potential for outcome
drift.
3.
Endpoints for DES Trials
device can still be considered to be noninferior to the control as long as the advantage of the control
over the investigational device is smaller than delta. Additionally, the delta should not be so large,
that in a direct comparison with the previous standard of care (in this case, bare metal stents), the
new treatment could be noninferior to the active control, but no longer superior to a bare metal stent
(so-called outcome drift45). To investigate whether the investigational device is noninferior to the
control, the appropriate null hypothesis is that the control is better than the investigational device by
at least delta, against the alternative hypothesis that the investigational device is not worse than the
control by delta. These two hypotheses are the essence of how FDA views noninferiority trials.
The quantification of delta should be clinically relevant and statistically feasible and should be
established through cogent discussion and agreement between the sponsor and the Agency. The
quantity needs to be sufficiently small so that, from a clinical point of view, the investigational
Although the noninferiority trial design is a strategy that could be used when a placebo-controlled
study cannot be conducted, there are some limitations to the noninferiority study design that should
be considered prior to adopting this approach. When a noninferiority study includes as a control a
DES that has not been directly compared to a BMS, the potential exists for a downward drift in the
true difference in safety and effectiveness between the investigational DES and a BMS. After serial
noninferiority studies, this so-called outcome drift could lead to a situation in which the
investigational DES could be found noninferior to the latest noninferior DES, but no longer superior
to a BMS, if such a direct comparison were made.
To investigate whether the investigational device is noninferior to the control, the appropriate null
hypothesis is that the control is better than the investigational device by at least the noninferiority
margin. The alternative hypothesis is that the investigational device is not worse than the control by
the noninferiority margin. These two hypotheses are the essence of how FDA views noninferiority
trials.
A noninferiority clinical trial usually refers to a study designed to show that an investigational
device is as effective, or almost as effective, as an approved device or a standard of care (active
control), from which it is then inferred that the investigational device is effective. In fact, the study
actually demonstrates that the investigational device is not inferior to the control by more than a
prespecified noninferiority margin delta. The margin delta used would be the largest acceptable
reduction in therapeutic response with the investigational device (i.e., the maximum tolerable
treatment difference such that the new device would still be considered sufficiently effective).
Before a noninferiority margin can be chosen, the treatment effect size for the active control device,
compared to the previous standard of care (BSM, in the case of DES), should be established based
on historical evidence of safety and effectiveness from controlled clinical trials. Subsequently, the
noninferiority margin for a new trial can be chosen based on clinical judgment regarding the
proportion of the initial effect size that should be maintained in the new comparison. It is also
critical to consider whether there is reason to believe that past examples of safety and effectiveness
would still be applicable to the current study (the constancy assumption). We recommend that
sponsors discuss selection of an appropriate noninferiority margin with FDA as the clinical study is
being designed.
The noninferiority, or equivalence, approach to study design has been used increasingly in clinical
trial settings where a placebo or previous standard of care as control is either unavailable or
unacceptable for logistical or ethical reasons. In this design, patients are randomized to
investigational DES or active DES control, as above, but the study hypothesis is noninferiority, not
superiority.
2.
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Draft — Not for Implementation
Draft — Not for Implementation
community and FDA. In a bare metal control trial, it may also be useful to include a third arm,
another DES; this enables assurance of comparability to other DESs.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Primary Endpoint – Nonclinical Imaging Endpoints
Primary Endpoint – Use of Multiple Endpoints
58
An alternative strategy is the use of appropriate composite or co-primary clinical and
imaging endpoints as outcome measures. For example, developing co-primary endpoints is
c.
It should be noted that there is a well-described impact of protocol-mandated angiography on
clinical revascularization rates. For this reason, we recommend that angiography and IVUS
be captured in a study separate from the pivotal trial or, if included in the pivotal trial,
protocol-mandated angiography should be scheduled after the 12-month clinical visit.
FDA believes that use of an imaging endpoint as the sole primary effectiveness endpoint in
pivotal DES trials is currently acceptable only for certain second-generation DESs, such as
iterative modifications from currently approved DESs and/or indication expansion, in
specific patient populations or in specific vessel or lesion types. For a novel DES, clinical
studies performed to support regulatory approval should include at least one study of
sufficient size that has as its primary endpoint a clinical endpoint and is appropriately
powered for statistical demonstration of superiority or non-inferiority against an appropriate
control. See Section VIII.D for more discussion of next-generation DESs.
Imaging-derived measures of restenosis, such as percent diameter stenosis and late lumen
loss, are potentially powerful effectiveness endpoints. Such outcome measures have the
advantage of providing quantitative data for the comparison of specific parameters of stent
performance, such as suppression of neointimal hyperplasia. Furthermore, they can provide
additional effectiveness data, even in patients who have not developed a major clinical
adverse event, and consequently have the potential to increase the sensitivity of outcome
measures between treatments. Imaging endpoints are commonly measured as continuous
variables and this powerful discriminatory advantage can be apparent with sample sizes
considerably smaller than typically needed for clinical endpoints. However, the use of these
potential imaging measures as primary endpoints does not preclude the need for evidence of
safety through evaluation of a clinical endpoint, such as death, MI, and/or TLR, either
individually or as a composite.
b.
The initial DES approvals were based on a primary endpoint assessment at 9 months postimplant. FDA currently believes that a 12-month primary endpoint, with a substantial
proportion of patients having 2-year data at the time of marketing application submission, is
critical to assess the potential for important adverse events such as stent thrombosis (and
related deaths and MIs) that may occur after 9 months. Patients in all trials to be used to
support approval of a PMA application should be consented at the time of enrollment for
follow-up to 5 years.
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Considerations for DES incorporating an unstudied drug
When a DES incorporates an unstudied drug, the data from a sufficient number of patients
exposed to the new DES should be collected for submission in the PMA. The number of
patients should be large enough to enable the detection with adequate precision of low
frequency adverse events (i.e., those occurring at a rate of 1 percent or less) that may be
associated with the unstudied drug. A single study or multiple studies (both randomized
trials and single-arm registry studies) can be used to complete this population.
4.
The secondary endpoints will, in most cases, not be descriptive and exploratory, not leading
to additional claims. If a formal comparison of treatment arms for a secondary endpoint is
desired, formal null and alternative hypotheses should be developed and pre-specified in the
protocol. If no pre-specified hypotheses are included in the protocol, p-values for such
comparisons will not be appropriate and should not be presented in labeling. If analyses
beyond descriptive statistics are planned for secondary endpoints, appropriate steps should be
taken to adjust for multiple comparisons and to preserve Type I error. Sponsors with studies
ongoing prior to the issuance of this guidance should discuss with FDA an appropriate
approach for presentation of such analyses in the labeling.
3/26/2008
59
Rocha-Singh, et al, Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol
stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv 2007;69(6):910-919
47
Secondary Endpoints
Separate from the primary endpoint chosen for effectiveness, we recommend collecting
additional vessel imaging information to evaluate healing and remodeling of the arterial wall,
including parameters such as stent apposition, aneurysm formation, edge effects, and
quantification of intimal proliferation, especially at the proximal and distal borders of an
implanted DES. Quantitative coronary angiographic (QCA) analyses should report stent,
lesion, and analysis segment parameters to assess the importance of any edge effects caused
by the drug. The angiographic analysis should also include review and analysis for stent
fracture; use of a grading system such as that described by Rocha-Singh et al.,47 may be
helpful for reporting the incidence and type of fracture, if observed. Side branch occlusion,
when observed, should also be reported.
d.
one potential method. If co-primary endpoints are proposed for the trial, the selection of the
noninferiority margin for the clinical endpoint may be less conservative than when used as a
stand-alone endpoint, reflecting the fact that additional information from another parameter
(such as angiograph) is being evaluated. When using co-primary endpoints, FDA
recommends that adequate adjustments for correlation between the endpoints and
preservation of type I error be carefully considered. Study success using co-primary
endpoints is typically defined as meeting both endpoints. Appropriate definitions for
superiority and for selection of noinferiority margins should be discussed with the Agency
when the use of multiple endpoints is contemplated.
Draft — Not for Implementation
Draft — Not for Implementation
thousands of patients to be enrolled to allow sufficiently powered hypothesis testing.
Although trials will not be powered to enable assessment of the individual components, FDA
will carefully consider the outcomes for each component of the composite when making our
assessment of the risk-benefit profile for the new DES.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Blinding Concerns in DES Clinical Studies
60
Nonetheless, because there is a potential for considerable investigator and/or patient bias
introduced by knowledge of treatment assignment, possibly confounding study outcomes and
diminishing the scientific validity of the study, the study design should incorporate blinding
to the maximum extent possible, maintaining the blind for patients (single-blind), follow-up
study investigators, and study staff to minimize the potential for bias and confounding. In
addition, increasing the objectivity of study parameters as much as possible and including
special analytical methods to evaluate for the potential influence of bias in study outcome are
potential ways to maximize the scientific validity of study design.
In a randomized controlled trial, the use of study blinding, or masking, further reinforces the
integrity of the random allocation of patient assignment and assessment of treatment effect.
In a superiority RCT study design using a DES and its corresponding bare metal stent, a
triple-blinded (i.e., patient, physician and monitoring committee are all blinded) study design
is logistically possible because of the physically similar appearance of the DES and bare
metal stents. However, for some medical devices, designing a double-blinded (i.e., patient
and physician are blinded to treatment assignment) or triple-blinded RCT can be impractical
and logistically impossible because of the physical characteristics and/or the mode of action
of the product (e.g., a DES versus coronary artery bypass grafting (CABG)). For
noninferiority study designs that are evaluating a DES with different platforms, the DES
might have different physical characteristics (e.g., radiologically and/or visually different in
appearance), making such study blinding logistically difficult to implement. Because certain
individuals involved in stent handling/implantation at the time of the index procedure will
have knowledge of treatment assignment.
5.
Sponsors with such DES are encouraged to meet with FDA prior to beginning clinical trials
to ensure that case report forms capture appropriate cardiac and non-cardiac safety
information.
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Independent Oversight of Drug-Eluting Stent Trials
Statistical Analysis Plan
48
Study hypotheses
Sample size calculation
Blinding
Number of proposed study centers
Study success criteria
Effectiveness patient populations (e.g., intent-to-treat, evaluable)
Pooling of data
Covariate adjustments
3/26/2008
61
Guidance for clinical trial sponsors on Establishment and Operation of Clinical Trial Data Monitoring Committees,
March 2006.
x
x
x
x
x
x
x
x
The proposed protocol should include a comprehensive statistical analysis plan with prospectively
defined methods to address the following:
E.
FDA strongly recommends that interpretation of data from tests such as angiograms, IVUS,
and ECGs be performed by independent core labs and that blinded adjudication of clinical
events be conducted by a clinical events committee (CEC Clinical adjudication committees
should be independent of core lab analysis centers to avoid potential bias. .
Many of the novel technologies employed in a DES have never been used previously in the
same combinations or anatomic locations in human beings. This fact raises new questions of
safety for participants in investigational DES trials. Given that most DESs under
development are intended to be permanent implants and that safe and reliable retrieval of
deployed stents is generally not possible, a heightened and constant vigilance during the
conduct of a DES trial is necessary. With this in mind, FDA strongly recommends the use of
data monitoring committees (DMC, also called data safety monitoring boards, or DSMBs)
for DES studies to keep track of and evaluate significant adverse events, including stent
thrombosis, in real time (i.e., as the study enrollment progresses).48 Sponsors are responsible
for ensuring proper monitoring of the investigations (21 CFR 812.40), and must select
monitors qualified by training and experience to monitor the investigational study (21 CFR
812.43(d)). Before the study begins, the DMC/DSMB charter should have an adequate
monitoring plan (e.g., number of predetermined meetings, timing of reports, appropriate
stopping rules, correspondence to FDA as appropriate) in place to adequately ensure that
patients are not subjected to undue risk. For sponsors conducting multiple trials with the
same investigational DES, FDA recommends that sponsors as part of their obligation to
monitor the studies, use the same DMC/DSMB for both studies or have a super-DMC/DSMB
that communicates with the DMC for each trial be considered. If this is not possible, the
sponsor should ensure that the DMCs/DSMBs for each of the studies communicate
frequently and regularly exchange safety information and ensure that all members of the
committee are apprised of the global safety data for the investigational DES.
6.
Draft — Not for Implementation
Draft — Not for Implementation
Also, certain additional safety data beyond what are typically collected in a stent trial should
be obtained and provided in the PMA to allow for analysis of potential drug-related adverse
events. The specific safety data to be collected will generally be specific to the drug
incorporated on the stent; however, the following are examples of typically requested
information:
x Liver enzyme values pre- and post-procedure and at appropriate follow-up
intervals
x Hypersensitivity reactions (definition should be pre-specified) including
symptoms, signs, and relevant laboratory values, treatment, and clinical course
x White blood cell counts to document the incidence of leukopenia
x EKG parameters
x EKG changes, particularly QT intervals
x Concomitant medications
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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1.
Analysis Cohorts
Stratification
Protocol deviations
Handling drop-outs and methods to address missing data
Analysis plan and statistical methods
Data auditing
Poolability Considerations for DES Studies
3/26/2008
x
x
x
62
Patient demographic and clinical characteristics
Geographic differences in medical practice
Differences in study protocol
When FDA considers foreign data as supportive evidence for U.S. product approval, a key
consideration in assessing the applicability of OUS studies in support of product safety and
effectiveness is to evaluate the generalizability of the OUS studies to the patient population and to
medical practice in the United States. Factors that FDA considers include, for example,
Pivotal studies of DES should be conducted at multiple investigational sites. Additionally, there can
be advantages to conducting multiple clinical studies of the same DES. Potential advantages to
combining data from different studies include having the ability to evaluate DES performance across
a broader population than can be achieved by one study and could increase generalizability of study
results because of wider demographic and geographic inclusion. Furthermore, demonstration of
comparable DES performance across different investigational sites and studies can permit more
robust conclusion of product safety and efficacy. However, when planning to conduct clinical
studies at multiple investigational centers, or in centers OUS (outside the United States), an analysis
of poolability of data should be included in the prospective analysis plan.
2.
Comparison of outcomes on the basis of intention-to-treat, per protocol, and as-treated patients
allows assessment of outcome robustness. Analysis details should be prospectively agreed to by the
sponsor and FDA.
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Adjunctive Pharmaceutical Regimens
63
Available at http://www.acc.org/qualityandscience/clinical/guidelines/percutaneous/update/index.pdf
3/26/2008
50
See draft guidance for industry and FDA staff on Coronary Drug-eluting Stents – Nonclinical and Clinical Studies:
Companion Document,” published together with this document.
49
At the December 2006 Circulatory System Devices Advisory Panel meeting on DES thrombosis ,
the Panel recommended that the labeling for the two approved DES include reference to the
AHA/ACC/SCAI practice guidelines. FDA agreed with this recommendation and both approved
DES Instructions for Use include this information. For this reason, for trials that use the CYPHER
stent or TAXUS stent as the control DES, we currently recommend that the prescribed antiplatelet
therapy follow the AHA/ACC/SCAI guidelines50; that is, patients should receive aspirin and a
minimum of 3 (CYPHER) or 6 months (TAXUS) of clopidogrel with therapy extended to 12 months
in patients at a low risk of bleeding. Despite the desire to have administration and use of dual
antiplatelet therapy, circumstances will cause some patients to have different regimens, and FDA is
particularly interested in how differences in duration affect patient outcome. Therefore, patients
should be carefully monitored and case report forms should be designed to capture compliance with
prescribed antiplatelet therapy and significant bleeding complications over the course of the trial.
Optimal duration of antiplatelet therapy and use of glycoprotein IIb/IIIa inhibitors and direct
thrombin inhibitor treatments in DES patients are currently unclear and may significantly affect
clinical outcomes. Consequently, to minimize confounding variables in the interpretation of the
study results, a uniform regimen of intra- and postprocedure concomitant medications should be
used. Careful consideration should be given to the optimal dosage and duration of antiplatelet
therapy for DES postimplantation, given the delay in endothelialization within DES compared to that
of bare metal stents and subsequent concerns regarding stent thrombosis due to premature
discontinuation of antiplatelet therapy.
F.
FDA is willing to comment informally on OUS study protocols through the pre-submission process.
Such comments may increase the likelihood that these data can be used to support a PMA
application.
Whether studies have been conducted solely in the United States or both in or out of the United
States, statistical analysis should examine the homogeneity of demographic and procedural
covariates across centers and geographical regions. Evaluation of interactions between treatment
and region is recommended. Furthermore, outcome comparability should be examined after
adjustment for covariate differences, using multivariate regression modeling and propensity scoring
methodology. In addition, sensitivity analysis should be performed to verify the robustness of any
statistical modeling using pooled data.
These factors have the potential to affect DES performance in terms of both safety and effectiveness.
Some examples of key factors that should be addressed when considering the poolability of results
and extrapolating study results to those expected in the United States can be found in the stand alone
companion document.49
Draft — Not for Implementation
Draft — Not for Implementation
The intention-to-treat population, which is defined as the cohort of all patients randomly assigned to
treatment in an RCT design, is usually the preferred population for superiority studies. Intention-totreat analysis allows for the evaluation of all patients who enroll in the study, even though some may
not complete the study (e.g., patients who are, for any reason, lost to follow-up, drop-outs, or
terminated by investigator). In an RCT design, the intention-to-treat principle means that any
comparison of the treatments is based on comparison of the outcome results of all patients in the
treatment groups to which they were randomly assigned. Within the protocol, the sponsor should
prospectively specify the analysis plans that will account for patients who do not complete the study.
The sponsor should also present analysis of the per protocol patient cohort (i.e., patients who enter
and complete the study according to protocol) and the as-treated patient cohort (recognizing such
analyses are subject to bias).
x
x
x
x
x
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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Follow-Up from Clinical Studies
3/26/2008
64
To minimize patient losses-to-follow-up, sponsors should request patient consent to five-year
follow-up at the time of enrollment in clinical studies. Additionally, the case report forms should
include the specific questions the sponsor or representative will ask the patient during telephone
During the PMA review, a three-month update of any additional clinical data must be submitted
(21 CFR 814.20(e)). The applicant must submit new information learned about the device from
ongoing or completed studies that may reasonably impact an evaluation of the safety and
effectiveness of the product or that may reasonably affect the draft labeling. Note that when
reasonably limited in scope, this update would be considered a minor amendment to the PMA.
Additional (i.e., later) endpoint evaluations, a significant increase in the number of evaluable
patients, or new analyses may be considered a major amendment requiring significant review. In
addition, as a condition of approval for a PMA application, applicants are required to submit updated
clinical reports to the Agency (§ 814.82 and 814.84)
At the time of PMA submission, all available long-term follow-up from the pivotal and
supplementary clinical studies should be provided to demonstrate the chronic performance of the
DES. Additionally, as part of the PMA review, the applicant is also required to submit a
bibliography of all published reports and other information relevant to an evaluation of the safety
and effectiveness of the device (see 21 CFR 814.20(b)(8)).
For purposes of regulatory approval, the current primary endpoint data for DES studies should be
collected over a period of approximately 12 months after implantation of the DES. However, DES
study length should be viewed in terms of the entire follow-up, which should extend through a 5year clinical follow-up period. Although the 12-month postimplantation endpoint might be
acceptable for a PMA submission, the study is not considered complete until study patients have
completed their long-term clinical follow-up as described in the protocol. At a minimum, this would
include annual follow-up telephone evaluations and, preferably, annual study visits, for five years in
a significant cohort of patients enrolled in the pivotal, feasibility, and/or any additional clinical
studies conducted to support product approval. During the long-term follow-up phase, the
occurrence and sequelae of late phenomena, such as incomplete stent apposition, late stent
thrombosis, and polymer compatibility issues, are important parameters that should be evaluated.
The actual duration of dual antiplatelet therapy and any interruptions should be captured as well (see
Section C above for objectives related to antiplatelet therapy).
Although nonclinical and clinical testing of DESs provide invaluable information on the short-term
safety and effectiveness of these products in a select patient population, such as that typically found
in the clinical trial setting, much information on the performance and safety profile of a DES can be
obtained only when the product moves into the larger, more diverse patient population after
marketing.
G.
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Postapproval Studies
3/26/2008
65
To evaluate the rate of cardiac death and MI, we suggest that the cohort of patients treated in
accordance with the labeled indications be pooled with the preapproval pivotal trial to reach a
sample size sufficiently large to provide adequate power to compare the rates of cardiac death and
target vessel MI for the new DES and the control stent used in the pivotal study and to rule out an
increased risk. This cohort of postapproval patients may be in a single-arm or randomized study,
and data pooling may be approached from either a frequentist or Bayesian perspective.
A sufficient number of patients should be enrolled to confirm that the upper bound of the one-sided
95 percent confidence interval around the observed rate of stent thrombosis between 12 and 24
months, 24 and 36 months, 36 and 48 months, etc. is ” 1 percent with at least 80% probability for
patients treated in accordance with the labeled indication. The total study sample size should be
sufficient to ensure a sufficient number of patients treated in accordance with the labeled indication
are available for analysis.
The postapproval study should have two primary goals: assessment of the rate of stent thrombosis
and assessment of the rate of cardiac death plus MI. As discussed above, the postapproval data
collected on currently approved DESs have signaled a potential increase in late stent thrombosis
after one year compared to bare metal stents. However, it is not known if this rate plateaus or
continues to increase over time, nor is the impact of stent thrombosis on rates of cardiac death and
MI completely understood. Therefore, one primary endpoint of the postapproval study should be
the rate of stent thrombosis after one year. As stent thrombosis is closely associated with cardiac
death and MI, a second primary endpoint of the postapproval study should be a comparison of the
rate of cardiac death and MI between the new DES and the control stent used in the pivotal study. To
gain a better understanding of these risks in the setting of actual clinical use of the product, FDA
recommends that postapproval data be collected on a series of patients who are consecutively
enrolled to avoid the introduction of selection bias.
Therefore, in addition to postapproval follow-up of clinical outcomes from the patients enrolled in
the preapproval clinical trials, the Agency will generally require the collection of additional
postapproval data for a DES (§ 814.82(a)(2)). Serious but rare DES-related adverse events that
might only be identified in a postapproval period include late stent thrombosis, drug interactions,
unforeseen complications of multivessel or overlapping stent placement, and experience with a DES
in different patient demographic subsets not adequately represented in preapproval studies (i.e., real
world use). A proposed postapproval study protocol should be included in the PMA application.
Postapproval surveillance provides a framework for assessing unanticipated risks secondary to
human factors, product manufacturing changes, or rare occurrences in real-world patient
populations.
A.
VIII. POSTAPPROVAL CONSIDERATIONS
follow-up to ensure that appropriate information is being collected and to minimize bias since
treatment assignment may be known upon disclosure of the primary endpoint results.
Draft — Not for Implementation
Draft — Not for Implementation
Eventual product labeling should include both the prescribed antiplatelet therapy and patient
compliance with that therapy as experienced in the clinical trials and should clearly specify the risks
of premature antiplatelet medication discontinuation.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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66
Patient characteristics
x Patients with diabetes, further characterized as insulin-requiring or noninsulin-requiring
x Patients with renal insufficiency, further characterized as creatinine clearance (rCl) using the
Cockcroft-Gault equation (CrCl > 60 mL/min, CrCl • 30 and ” 60 mL/min, CrCl < 30
mL/min)
x Degrees of left ventricular (LV) dysfunction (ejection fraction < 30%, 30-40%, > 40%)
x Patients with 3 vessel disease
Demographics
x Age (age < 65 years; age • 65 years)
x Sex (male, female)
x Race and ethnicity
The statistical plan should include planned descriptive statistics on certain subgroups of interest
including:
A postapproval study protocol should include the following elements:
x Study hypothesis(es) - Primary and secondary endpoints
x Study design with inclusion and exclusion criteria
x Definitions for outcomes of interest
x Sample size calculation
x Statistical analysis plan
x Informed consent document
x DMC/DSMB information
x Case report forms
x Types of participating centers (e.g., teaching vs. non-teaching, location, size, primary vs.
referral center and so on)
x Data monitoring procedures, including whether a CEC will be used
x Detailed study timeline, including enrollment goals (for sites, physicians and study subjects)
and a plan in case enrollment goals are not met.
x Interim and final report schedule
All patients should be consented for five years of follow-up. If stent thrombosis rates are
demonstrated to plateau or decrease in prior years, shorter follow-up may be sufficient.
Alternatively, if stent thrombosis rates continue to increase, longer term follow-up or specific
labeling changes may be appropriate.
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Patients with 2 vessel disease including proximal left anterior descending coronary artery
disease
3/26/2008
x
x
x
x
x
67
BMS or DES (name of stent, length, and diameter)
Postdilatation (balloon diameter and lengths used as well as the postdilatation atmospheres
achieved)
Clarification of antithrombotic regimen received prior to initial stenting, including doses
(aspirin, Plavix), including clarification of whether or not patient received a loading dose of
Plavix and what the actual dose was.
Antithrombotic regimen the patient was on at discharge (ASA, Plavix)
Patient compliance with antiplatelet therapy and significant bleeding complications
For patients who experience stent thrombosis, in addition to the above characteristics, the following
additional information should be reported:
Case report forms should capture patient compliance with prescribed antiplatelet therapy and
significant bleeding complications.
Lesion characteristics
x Lesions in the setting of acute ST elevation myocardial infarction (STEMI)
x Percutaneous coronary interventions within 36 hours of non-STEMI ACS
x Lesion length (” 20 mm, 21-30 mm, 31-40 mm, > 40 mm)
x Vessel diameter (2.0 - ” 2.5 mm; 2.6 – 2.9 mm; 3.0 - ” 3.5 mm, and > 3.5 mm)
x Ostial lesions
x Bifurcation lesions
x Trifurcation lesions (i.e., left main coronary artery, left circumflex coronary artery, left
anterior descending artery, and ramus intermedius)
x Thrombus-containing lesions
x Lesions with residual dissection post stenting
x Left main coronary artery (LMCA) lesions
x Include whether disease was ostial, mid, or terminal and whether or not it involved the
ostial LAD +/- LCFX
x Chronic total occlusions (CTO)
x Saphenous vein grafts (SVGs)
x Arterial grafts (internal mammary artery, radial artery, gastroepiploic artery)
x Post-brachytherapy
x Instent restenosis (ISR) (BMS)
x Instent restenosis (ISR) (DES)
x Overlapping BMS
x Overlapping DES
x Overlapping BMS and DES
x Non-overlapped multiple stents (in the same vessel or in different vessels)
x Intravascular ultrasound guidance for initial stent deployment
x
Draft — Not for Implementation
Draft — Not for Implementation
Additionally, postapproval studies to date have demonstrated that routine clinical use of DESs
typically includes the treatment of patients outside of the labeling indications, including higher risk
patient and lesion subsets. Based on this previous experience, FDA recognizes that a postapproval
study of consecutively enrolled patients is likely to include patients representing a broader use of the
product and recommends that data from such patients be analyzed separately to better understand
whether significant safety issues exist in the treatment of these patients.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
Any discontinuation of Plavix and/or aspirin and whether or not there was premature
discontinuation of these medications
Adverse Event Reporting
or
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Results in permanent impairment of a body function or permanent damage to a body
structure
Is life threatening, even if temporary in nature
3/26/2008
68
Each constituent part of a combination product is governed by a different set of postmarket reporting requirements
(for drugs, 21 CFR Parts 310 and 314, and for devices 21 CFR Part 803). This is the case for a DES product. The
Agency has announced its intention to issue a Proposed Rule, Postmarket Safety Reporting for Combination Products
that would clarify the postmarketing safety reporting requirements for combination products (72 Fed. Reg. No. 82,
22515 (2007). The proposed rule would provide a framework for the reporting of adverse events for combination
products and specify the circumstances in which following one set of postmarket safety reporting regulations (e.g., 21
CFR 803) generally would meet the requirements of another set and the circumstances in which these requirements
would be supplemented with specific reporting provisions applicable to the constituent part of the combination product.
x
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x
Serious injury/(Serious illness) (§803.3(aa)(1)) is an injury or illness that:
Because a DES is regulated under the device provisions of the Act, the adverse event and device
defect reporting requirements for devices are applicable.51 The medical device reporting (MDR)
requirements mandate that manufacturers report to the Agency (1) all device-related deaths and
serious injuries and (2) all malfunctions of the device or similar device that would be likely to cause
or contribute to a death or serious injury if the malfunction were to recur (21 CFR 803.3).
B.
Sponsors should contact the CDRH review division for more information on the use of these studies
to support additional indications. For more information on postapproval studies, see the CDRH
guidance for industry and FDA staff on Procedures for Handling Post-Approval Studies Imposed by
PMA Order.
(1) An event that user facilities become aware of that reasonably suggests that a device has or may
have caused or contributed to a death or serious injury
or
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or
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3/26/2008
The malfunction involves a long-term implant or a device that is considered to be lifesupporting or life-sustaining and thus is essential to maintaining human life.
ƒ
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The consequences of the malfunction affect the device in a catastrophic manner that may lead
to a death or serious injury.
The chance of a death or serious injury occurring as a result of a recurrence of the
malfunction is not remote.
A malfunction results in the failure of a device to perform its essential function and
compromises the device’s therapeutic, monitoring, or diagnostic effectiveness, which could
cause or contribute to a death or serious injury, or other significant adverse device
experiences required by regulation (the essential function of a device refers, not only to the
device’s labeled use, but for any use widely prescribed within the practice of medicine).
x
x
ƒ
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A malfunction is reportable if any one of the following is true:
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(ii) Has malfunctioned and that the device or a similar device marketed by the manufacturer
or importer would be likely to cause or contribute to a death or serious injury if the
malfunction were to recur.
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Furthermore, as explained in the Preamble to the FR Notice of December 11, 1995, Vol. 60, No.
237, relating to 21 CFR Part 803 – in Comment 12:
or
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(i) May have caused or contributed to a death or serious injury
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(2) An event that manufacturers or importers become aware of that reasonably suggests that one of
their marketed devices:
An MDR reportable event (§ 803.3) means:
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Performance specifications include all claims made in the labeling for the device. The intended
performance of a device refers to the intended use for which the device is labeled or marketed, as
defined in 21 CFR 801.4.
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Necessitates medical or surgical intervention to preclude permanent impairment of a body
function or permanent damage to a body structure
A malfunction (§803.3(m)) means the failure of the device to meet its performance specifications or
otherwise perform as intended.
x
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Draft — Not for Implementation
Draft — Not for Implementation
Effective postapproval identification of product risks relies on active collaboration of manufacturers,
regulatory bodies, and healthcare facilities to detect and report product-related injuries and other
adverse events. Although data collected as part of postapproval studies can and should be submitted
to the FDA in postapproval reports to the PMA, sponsors should note that, to support an expansion
in indications, they should conduct the study under an approved IDE. FDA is willing to consider the
implementation of nested studies, with protocols approved under an IDE, within postapproval
studies to support certain additional indications, such as long lesions and patients with two-vessel
coronary artery disease. A prospective, hypothesis-driven analysis plan should be provided for FDA
review in an IDE application or IDE supplement prior to initiation of the overall postapproval study.
Alternatively, sponsors may choose to pursue additional indications in separate studies under an IDE
to evaluate these uses in the intended patient population.
x
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Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
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The manufacturer takes or would be required to take action under section 518 or 519(f) of the
Act as a result of the malfunction of the device or other similar devices.
Peri-Approval Studies
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FDA strongly encourages sponsors to select a broad cross-sectional distribution of institutions (e.g.,
geographic location, private versus public versus academic hospitals, volume of procedures) to
address generalizability of the study findings. The main impetus for the peri-approval approach has
been to facilitate the enrollment of patients and streamline completion of the study so that both the
FDA and the applicant can assess patient safety in a real-world scenario in a timely manner to
support the total product life cycle of the DES.
To minimize this delay, FDA has encouraged PMA applicants to submit the postapproval study
protocol earlier in the PMA review process. If FDA has reached the conclusion that the PMA will
be approved (e.g., only minor issues such as labeling are pending), the postapproval study protocol
can be approved in advance of the PMA approval. A protocol for such a peri-approval study can be
submitted as an IDE supplement. Upon IDE approval, the study can begin enrolling under the IDE
with a prespecified patient limit, with the remainder of patients enrolled after PMA application
approval. Consequently, the peri-approval study does not obviate the need for the collection of
information after the initiation of marketing. The IDE approval does, however, enable a sponsor to
ensure that IRB review/approvals are in place and selected sites are eligible for active enrollment of
patients at the time of PMA application approval.
FDA has typically required postapproval studies for DESs. However, when the postapproval study
protocol was approved only at the time of the PMA approval, FDA found that there were significant
delays in beginning enrollment in the study due to delays in awaiting IRB review and approval.
There was also confusion on the part of some IRBs regarding the rationale for an additional study of
an approved product. The delays in enrollment and data collection in this scenario meant that an
important source of postmarket data was unavailable to the manufacturer and to FDA for multiple
months following PMA approval.
C.
Adverse events reported through MDR are shared with CDER so that drug-related aspects of
postapproval adverse events reported to CDRH can be evaluated.
Instructions for completing MedWatch Form 3500A are available at
http://www.fda.gov/medwatch/report/instruc_10-13-06.htm. MedWatch Form 3500A is available at
http://www.fda.gov/medwatch/safety/3500a.pdf.
Next Generation DES
Is this a first generation DES, a combination of new and old technologies, or essentially a
design iteration?
Has the delivery catheter been modified (e.g., distal tip or other elements)?
Is the drug formulation the same or different (e.g., change in polymer/drug ratio, increased or
decreased drug content)?
Have any of these modifications resulted in alterations to the release kinetics (e.g., amount or
significant modifications in profile)?
Have there been any modifications in any critical manufacturing parameters (e.g., coating
application, new sources of heat or humidity, sterilization method)?
Does the new product still meet the original product specifications?
How robust are the in vitro test methods and quality control specifications used to assess
product variability to ensure product quality and consistency?
x
x
x
x
x
x
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The significance of the changes in a DES system for a second generation DES will directly influence
the amount of additional nonclinical and/or clinical testing needed to support the safety and efficacy
If the stent substrate has changed, what specifically has been altered (e.g., stent substrate
material only (from 316L to CoCr); geometry elements, such as strut thickness, which can
lead to differences in surface area; and/or a change in the drug density and/or drug content)?
x
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Which components of the DES system have stayed the same and/or which have been
changed? Be sure to consider both intentional and unintentional changes that may have
occurred.
If the answer to “is this a first generation DES?” is no, some additional questions to address
include:
x
Some examples of questions for the sponsor or applicant to address regarding design modifications
to a DES that may affect rate and/or extent of drug elution include, but are not limited to, the
following:
DES candidates may employ a range of new and old technologies, making classification of a nextgeneration DES dependent on the specific components and/or modifications to the product. Unlike
second-generation bare metal stents, in which modifications in a product line were limited to either
the stent substrate (e.g., geometry, such as strut thickness, cell configuration, material), or delivery
catheter, for DES, manufacturers should carefully consider that planned modifications to the stent
substrate or polymer carrier may have unintended or unanticipated effects on other product
performance parameters (e.g., changes in drug density, total drug load, elution kinetics) and on the
overall safety and effectiveness of the finished product. Additionally, if a sponsor wants to make a
manufacturing change in the coating process, depending on the change, it may be necessary to
perform additional studies to ensure safety and/or effectiveness for the modified product if the rate
and/or extent of drug elution is materially affected.
D.
x
2964
2965
2944
2945
2946
2947
2948
2949
2950
2951
2952
2953
2954
2955
2956
2957
2958
2959
2960
2961
2962
2963
Draft — Not for Implementation
Draft — Not for Implementation
For more information see the Medical Device Reporting (MDR) Web site at:
http://www.fda.gov/cdrh/mdr/, and you may direct questions regarding MDRs to the Reporting
Systems Monitoring Branch at 240-276-3464.
x
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
Suggested elements for an IDE application
Suggested elements for a PMA application
Example master table
Example 1-pager describing DES clinical studies
Example commitment table
General biocompatibility considerations
Example test article certification
General guidelines regarding good animal husbandry
Factors affecting poolability of US and OUS studies
Guidance on labeling for a DES
x
x
x
x
x
x
x
x
x
x
2995
2996
2997
2998
2999
3000
3001
3002
3003
COMPANION DOCUMENT
3/26/2008
72
To facilitate the use of this guidance, a stand alone companion document is available to be used
together with this guidance. It is posted with this guidance on the FDA Web site. The companion
document contains the following:
IX.
of a modified DES. FDA encourages sponsors and applicants to discuss with the Agency proposed
changes to their DES and appropriate testing to validate those changes.
3008
3009
3010
3011
3012
3013
3004
3005
3006
3007
Shelf Life :
NMT 3500 particles t 10 Pm
NMT 300 particles t 25 Pm
NMT 0.5 EU/mL
Pass
NMT 1.2%
NMT 200 ppm
Release :
NMT 2500 particles t 10 Pm
NMT 200 particles t 25 Pm
NMT Q3B identification threshold
NMT 0.5%
NMT 0.6%
NMT 0.3%
LAL (USP <85>)
USP <71>
GC
Light obscuration as per USP
<788>
HPLC
HPLC
HPLC
Visual/Microscopic
HPLC with diode array detection
Analytical Procedure
3/26/2008
73
10% - 20%
2 hours
USP <724>
20% - 50%
4 hours
40% - 70%
8 hours
> 80%
24 hours
1
In the table above, all numerical limits and the time points in the drug release test are for illustrative purposes only.
2
Relative retention time
3
Example of an attribute for which tighter release limits are assigned in order to maintain a safety margin so that
the product remains within the approved shelf life acceptance criteria for that attribute.
Endotoxins
Sterility or package
integrity
Drug Release
Any individual
unspecified impurity
Total impurities
Residual Solvent A
Particulate Matter3
Degradant A
Impurity B
Degradant at RRT2 0.8
Content Uniformity
Degradation
Products/Impurities
USP <905>
Conforms to visual/microscopic description
Retention time of the major peak in the
chromatogram of the assay preparation
corresponds to that in the chromatogram of the
standard preparation obtained as specified in the
assay in combination with UV
90% - 110% of label claim
Appearance
Identification Tests
Assay (Drug content)
Acceptance Criteria1
Tests
Below is an example of a regulatory specification table for the finished DES product.
APPENDIX A
Draft — Not for Implementation
Draft — Not for Implementation
2984
2985
2986
2987
2988
2989
2990
2991
2992
2993
2994
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
3025
3026
3027
3028
3018
3019
3020
3021
3022
3023
3024
3014
3015
3016
3017
3/26/2008
Criteria*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12
Criteria*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
74
*Same as regulatory specifications
X indicates testing is performed at this time point.
Appearance
Identity
Assay (drug
content)
Impurities
Individual
Total
Drug Release
Particulate matter
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Accelerated (40 C/75%RH) Stability Testing Protocol
Time Points (months)
Acceptance
0
1
3
6
o
*Same as regulatory specifications
X indicates testing is performed at this time point.
** FDA recommends testing for particulate matter at every time point, but if testing is conducted less
frequently, the expiration date will be limited by the latest time point at which particulate matter testing
was conducted with passing results.
Appearance
Assay (drug
content)
Impurities
Individual
Total
Drug Release
Particulate
matter**
Endotoxins
Sterility
Tests
Long Term (25oC/60%RH) Stability Testing Protocol
Time Points (months)
Acceptance
0
3
6
9
3029
3030
3031
3032
3033
3034
3035
3036
3037
3038
3039
3040
3041
3042
3043
3044
3045
3046
3047
3048
3049
3050
3051
3052
3053
3054
3055
3056
3057
3058
3059
3060
3061
3062
3063
3064
3065
3066
3067
3068
3069
3070
3071
3072
3/26/2008
Cohesion: The sticking of a surface to itself
75
Coating: The drug carrier (usually polymeric, but not limited to such), the drug itself if it is
solely coated onto the stent platform, any other coating, or the drug carrier even if it is
incorporated onto the stent in a geometry other than a coating.
Cmax: PK parameter, maximum observed blood concentration
Clinical batch: Batch used to support the efficacy, safety, bioavailability, or bioequivalence of a
product
Bias (statistical and operational): The systematic tendency of any factors associated with the
design, conduct, analysis, and evaluation of the results of a clinical trial to make the estimate of a
treatment effect deviate from its true value. Bias introduced through deviations in conduct is
referred to as operational bias. The other sources of bias listed above are referred to as
statistical bias.52
Batch: A specific quantity of a drug or other material that is intended to have uniform character
and quality, within specified acceptance criteria, and is produced according to a single
manufacturing order during the same cycle of manufacture (21 CFR 210.3(b)(2)). See also “lot.”
Bare metal stent (BMS): An intravascular stent that is not coated with either a polymer or drug.
Traditional materials for BMSs include 316L stainless steel and cobalt chromium alloy.
Balloon expandable stent: A stent that is expanded by a balloon. The diameter of the stent
increases as the balloon diameter increases. The stent remains expanded after deflation of the
balloon.
(AOAC): Association of Official Analytical Chemists
Area under curve (AUC): PK parameter, area under the blood concentration-time curve
Adhesion: The degree of attachment between two different surfaces, such as a coating or film
and the underlying material.
Chronic refers to any time after assessment of the initial stent deployment in a simulated vessel
throughout the lifetime of the implant.
Acute: Refers to any time up through expansion and deployment of the DES
Acceptance criteria: Numerical limits, ranges, or other suitable measures for acceptance of
results of analytical procedures (see ICH guidance Q6A)
GLOSSARY OF TERMS
Draft — Not for Implementation
Draft — Not for Implementation
Below are examples of stability testing protocols.
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
3073
3074
3075
3076
3077
3078
3079
3080
3081
3082
3083
3084
3085
3086
3087
3088
3089
3090
3091
3092
3093
3094
3095
3096
3097
3098
3099
3100
3101
3102
3103
3104
3105
3106
3107
3108
3109
3110
3111
3112
3113
76
ICH Guidance E9 Statistical Principles for Clinical Trials
ICH Guidance E9 Statistical Principles for Clinical Trials
3/26/2008
54
53
Drug-eluting stent (DES): A combination product consisting of both drug and device
components. The device component consists of an intravascular stent platform that is used not
only for radial support, but also as a vehicle for the delivery of an active pharmaceutical agent or
drug. The drug component is commonly incorporated and released from a polymeric carrier,
either a single polymer or a combination of polymers, which is physically or chemically adherent
to the stent substrate. The purpose of the polymer carrier is to allow for adequate deposition of
the drug onto the stent surface as well as to influence the release kinetics of the drug from the
Blinding, or masking, is intended to limit the occurrence of conscious and unconscious bias in
the conduct and interpretation of a clinical trial arising from the influence that the knowledge of
treatment may have on the recruitment and allocation of subjects, their subsequent care, the
attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals,
the exclusion of data from analysis, and so on.54
Double-blinded: A double-blind trial is one in which neither the subject nor any of the
investigators or sponsor staff involved in the treatment or clinical evaluation of the subjects are
aware of the treatment received. This includes anyone determining subject eligibility, evaluating
endpoints, or assessing compliance with the protocol; blinding is maintained throughout the
conduct of the trial.53
Device history record: (DHR) a compilation of records containing the production history of a
finished device (21 CFR 820.3(i))
Degradation product: A molecule resulting from a chemical change in a drug or polymer
molecule brought about over time and/or by the action of light, temperature, pH, water, or by
reaction with an excipient and/or the immediate container/closure or packaging system. Also
called decomposition product (see ICH guidance Q6A).
Chronic: See Acute.
Component: For a device: any raw material, substance, piece, part, software, firmware,
labeling, or assembly which is intended to be included as part of the finished, packaged, and
labeled device (21 CFR 820.3(c)).
Component: For a drug: Any ingredient intended for use in the manufacture of a product,
including those that may not appear in such product (21 CFR 210.3(b)(3)).
3114
3115
3116
3117
3118
3119
3120
3121
3122
3123
3124
3125
3126
3127
3128
3129
3130
3131
3132
3133
3134
3135
3136
3137
3138
3139
3140
3141
3142
3143
3144
3145
3146
3147
3148
3149
3150
3151
3152
3153
3154
3155
3156
3157
77
ICH Guidance E9 Statistical Principles for Clinical Trials
3/26/2008
55
Independent data monitoring committee (IDMC) (data and safety monitoring board,
monitoring committee, data monitoring committee): An independent data monitoring
committee that may be established by the sponsor to assess at intervals the progress of a clinical
Glass transition temperature (Tg): The temperature at which a polymer changes from glassy
to elastomeric behavior.
Generalizability, generalization: The extent to which the findings of a clinical trial can be
reliably extrapolated from the subjects who participated in the trial to a broader patient
population and a broader range of clinical settings. 55
Functional excipient: An excipient that performs a role in maintaining product quality or in
achieving a desired in vivo performance.
Four corners: Refers to a 2 x 2 factorial of the largest and smallest diameters and
lengths for each stent design.
Formulation: The qualitative and quantitative composition of the finished product. This is
often called the composition statement.
Extended release: Products that are formulated to make the drug available over an extended
period after implantation.
Excipient: Any component other than the drug substance(s) present in the finished product.
Established name: The designated FDA official name, the compendial name, the USAN
Council name, or the common or usual name (section 502(e)(3) of the Act and 21 CFR 299.4).
Ordinarily, the established name of a drug will be the compendial name. However, FDA may
designate an established name in cases where a monograph does not exist (see the CDER Data
Standards Manual).
EP: European Pharmacopeia
Drug substance: An active ingredient that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to
affect the structure or any function of the human body, but does not include intermediates used in
the synthesis of such ingredient (21 CFR 314.3(b)).
Drug product: A finished dosage form, for example, tablet, capsule, or solution, that contains a
drug substance, generally, but not necessarily, in association with one or more other ingredients
(21 CFR 314.3(b)).
stent surface. The DES is mounted onto a stent delivery system to deliver the stent to its final
intended location in the vasculature.
Draft — Not for Implementation
Draft — Not for Implementation
Combination product: A product (defined in further detail in 21 CFR 3.2(e)) comprised of two
or more different types of regulated entities (i.e., drug-device, drug-biologic, device-biologic, or
drug-device-biologic products).
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
3158
3159
3160
3161
3162
3163
3164
3165
3166
3167
3168
3169
3170
3171
3172
3173
3174
3175
3176
3177
3178
3179
3180
3181
3182
3183
3184
3185
3186
3187
3188
3189
3190
3191
3192
3193
3194
3195
3196
3197
3198
78
ICH Guidance E9 Statistical Principles for Clinical Trials
57
3/26/2008
ICH Guidance E9 Statistical Principles for Clinical Trials
56
Master file: A reference source submitted to FDA, which may include drug master files (DMF),
device master files (MAF), etc. A master file may contain detailed information on a specific
manufacturing facility, process, methodology, or component used in the manufacture,
processing, or packaging of a drug (21 CFR 314.420) or a medical device (21 CFR 814).
Lot: Or batch means one or more components or finished devices that consist of a single type,
model, class, size, composition, or software version that are manufactured under essentially the
same conditions and that are intended to have uniform characteristics and quality within
specified limits (21 CFR 820.3(m)). (Note that a similar definition is provided within the CGMP
regulations: A batch, or a specific identified portion of a batch, having uniform character and
quality within specified acceptance criteria. In the case of a product produced by continuous
process, it is a specific identified amount produced in a unit of time or quantity in a manner that
ensures its having uniform character and quality within specified acceptance criteria (21 CFR
210.3(b)(10)).)
Letter of authorization (LOA): A written statement by the holder or designated agent or
representative (sponsor or applicant) permitting FDA the authority to access information
included within one regulatory submission (e.g., IDE, PMA, MAF or DMF) to support a separate
regulatory submission (e.g., IDE or PMA).
JP: Japanese Pharmacopeia
Intravascular stent: For this guidance, an intravascular stent is a synthetic tubular structure
intended for permanent implantation in the native coronary vasculature. The stent is designed to
provide mechanical radial support after deployment; this support is meant to enhance vessel
patency over the life of the stent. Once the stent reaches the intended location, it is expanded by a
balloon or self-expanding mechanism.
Intention-to-treat principle: The principle that asserts that the effect of a treatment policy can
be best assessed by evaluating on the basis of the intention to treat a subject (i.e., the planned
treatment regimen) rather than the actual treatment given (e.g., results from a patient who
discontinues a treatment are counted in the treatment group). It has the consequence that subjects
allocated to a treatment group should be followed up, assessed, and analyzed as members of that
group irrespective of their compliance with the planned course of treatment.57
In-process material: Any material fabricated, compounded, blended, or derived by chemical
reaction that is produced for, and used in, the preparation of a finished product.
3199
3200
3201
3202
3203
3204
3205
3206
3207
3208
3209
3210
3211
3212
3213
3214
3215
3216
3217
3218
3219
3220
3221
3222
3223
3224
3225
3226
3227
3228
3229
3230
3231
3232
3233
3234
3235
3236
3237
3238
3239
3/26/2008
79
58
In December 2002, the Agency issued a draft guidance for industry and reviewers Estimating the Safe Starting
Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers. Once finalized, it will represent the Agency's
current thinking on this topic.
Partition coefficient: The ratio of the concentration of a chemical species in one environment to
its concentration in another environment.
Packaging system: The sum of packaging components that together contain and protect the
product. This includes primary packaging components and secondary packaging components, if
the latter are intended to provide additional protection to a DES.
OUS: Outside the United States
Novel excipient: An ingredient used for the first time in a human drug or combination product
in the United States or in a new route of administration.
Noninferiority trial: A trial with the primary objective of showing that the response to the
investigational product is inferior to a comparative agent by more than a defined amount (the
noninferiority margin).
No Observed Adverse Effect Level (NOAELNOAEL means the highest dose level that does
not produce a significant increase in adverse effects. The NOAEL can serve as the starting point
for determining a reasonably safe starting dose of a new drug in healthy human volunteers.
Studies to determine the NOAEL by examining at least two different species are needed to
identify the starting dose for intravenous human studies (see guidance for industry Estimating the
Maximum Starting Dose in Initial Clinical Trials for Therapeutics in Adult Health Volunteers).
The duration of an animal study is determined by the duration of drug elution from the stent.
The minimum duration should be 2 weeks for a nonpolymerized drug, which is considered a
single dose. See the guidance for industry Single Dose Acute Toxicity Testing for
Pharmaceuticals and M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials
for Pharmaceuticals, for more information.58
Molecular weight (MW) (of a polymer): Weight of an average polymer molecule. The two
most popular expressions of molecular weight of polymers are number-average molecular
weight (Mn) and weight-average molecular weight (Mw). Mn is the total weight of all the
polymer molecules in a sample, divided by the total number of polymer molecules in a sample.
This number represents the average weight of a chain, Mi, weighted according to number
fraction of each component i. Mw is the average molecular weight of a chain, Mi, weighted
according to weight fractions of each component i.
Master production record: A record containing the method of manufacture of the product,
including, in part, the master formula of defined size, complete manufacturing and control
instructions, in-process tests and acceptance criteria, equipment and operating parameters, yield
and yield reconciliation calculations, and provisions for packaging and labeling (see 21 CFR
211.186(b)) See also “Device history record.”
Draft — Not for Implementation
Draft — Not for Implementation
trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor
whether to continue, modify, or stop a trial. 56
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
3240
3241
3242
3243
3244
3245
3246
3247
3248
3249
3250
3251
3252
3253
3254
3255
3256
3257
3258
3259
3260
3261
3262
3263
3264
3265
3266
3267
3268
3269
3270
3271
3272
3273
3274
3275
3276
3277
3278
3279
3280
3281
80
ICH Guidance E9 Statistical Principles for Clinical Trials
60
3/26/2008
ICH Guidance E9 Statistical Principles for Clinical Trials
59
Stent delivery system: A stent delivery system delivers a stent through the vasculature to its
intended target site and then deploys the stent. A stent delivery system for a balloon expandable
stent consists of a balloon catheter. Self-expanding stent delivery systems may or may not
include a balloon.
Stent platform: The component of the DES that provides mechanical structural support when
deployed in a vessel and is usually metallic and either balloon expandable or self-expanding.
Statistical analysis plan: A statistical analysis plan is a document that contains a more technical
and detailed elaboration of the principal features of the analysis described in the protocol, and
includes detailed procedures for executing the statistical analysis of the primary and secondary
variables and other data. 60
Specified degradation product: An identified or unidentified degradation product that is
selected for inclusion in the product specification and is individually listed and limited to ensure
the safety and quality of the product
Specification: The quality standard (i.e., tests, analytical procedures, and acceptance criteria)
provided in an application to confirm the quality of drug substances, products, intermediates, raw
materials, reagents and other components including packaging system, and in-process materials.
A specification sheet includes the list of tests, references to analytical procedures, and
acceptance criteria.
Quality: The suitability of a DES for its intended use. This term includes such attributes as the
identity, content, purity, and potency.
Primary stability data: Data on the finished product stored in the proposed package for
marketing under storage conditions that support the proposed shelf life
Pharmacodynamics: The study of the biochemical and physiological effects of drugs (and/or
metabolites) on the body and the mechanisms of drug action, including the characterization of
the relationship between the drug exposure and pharmacologic effects (efficacious and toxic),
and the factors influencing such relationships. Often, the time course of these effects is also
described.
3293
3294
3295
3296
3297
3298
3299
3290
3291
3292
3282
3283
3284
3285
3286
3287
3288
3289
81
ICH Guidance E9 Statistical Principles for Clinical Trials
3/26/2008
61
Unstudied drug: a molecular entity that has not been approved for use in humans, or that does
not have human clinical study information available
Unspecified degradation product: A degradation product that is not included in the list of
specified degradation products
United States Pharmacopeia (USP): The United States Pharmacopeia (USP) is the official
public standards-setting authority for all prescription and over-the-counter medicines, dietary
supplements, and other healthcare products manufactured and sold in the United States.
Tmax: PK parameter, time to maximum concentration
Superiority trial: A trial with the primary objective of showing that the response to the
investigational product is superior to a comparative agent (active or placebo control). 61
Studied drug: a molecular entity that has been previously approved or studied under IND (i.e.,
has an approved NDA or ANDA, or has undergone human clinical studies under IND)
Draft — Not for Implementation
Draft — Not for Implementation
Per protocol set (valid cases, efficacy sample, evaluable subjects sample): The set of data
generated by the subset of subjects who complied with the protocol sufficiently to ensure that
these data would be likely to exhibit the effects of treatment according to the underlying
scientific model. Compliance covers such considerations as exposure to treatment, availability
of measurements, and absence of major protocol violations.59
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
Food and Drug Administration Guidance Documents
Application User Fees for Combination Products
Assessing User Fees: PMA Supplement Definitions, Modular PMA Fees, BLA and Efficacy
Supplement Definitions, Bundling Multiple Devices in a Single Application, and Fees for
Combination Products
Combination Products: Submission and Resolution of Formal Disputes Regarding the
Timeliness of Premarket Review of a Combination Product (Dispute Resolution
Guidance)
Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of
Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products
Current Good Manufacturing Practice for Combination Products
Dissolution Testing of Immediate Release Solid Oral Dosage Forms
Drug Master Files
Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro
Environmental Assessment of Human Drug and Biologics Applications
Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy
Volunteers
Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In
Vivo Correlations
Format and Content of the Human Pharmacokinetics and Bioavailability Section of an
Application
Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application
Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data
Monitoring Committees
How to Write a Request for Designation
Immunotoxicology Evaluation of Investigational New Drugs
INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls Information
Master Files: Part III – Guidance on Scientific and Technical Information
Nonclinical Studies for Development of Pharmaceutical Excipients
3308
3309
3310
3311
3312
3313
3314
3315
3316
3317
3318
3319
3320
3321
3322
3323
3324
3325
3326
3327
3328
3329
3330
3331
3332
3333
3334
3335
3/26/2008
82
The following documents have either been referenced in this guidance or will be of interest to
DES applicants and sponsors. They are grouped by document type and listed in alphabetical
order.
BIBLIOGRAPHY
Single Dose Acute Toxicology Testing for Pharmaceuticals
Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug
Substances
3341
3342
3343
Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products
Q2B Validation of Analytical Procedures: Methodology
Q3A(R) Impurities in New Drug Substances
Q3B(R) Impurities in New Drug Products
Q3C Impurities: Residual Solvents, December
Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and
New Drug Products: Chemical Substances
S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals
S7A Safety Pharmacology Studies for Human Pharmaceuticals
3352
3353
3354
3355
3356
3357
3358
3359
3361
3362
3363
3364
3365
3366
3367
3368
3369
3370
3371
3372
3373
3/26/2008
83
11607 Packaging for terminally sterilized medical devices —Part 1: Requirements for materials,
sterile barrier systems and packaging systems
10993-1 Biological Evaluation of Medical Devices -- Part 1: Evaluation and Testing,
8318 Packaging — Complete, filled transport packages and unit loads — Sinusoidal vibration
tests using a variable frequency
2248 Packaging – Complete, filled transport packages – Vertical impact test by dropping
International Organization for Standardization (ISO)
S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals
Q1B Photostability Testing of New Drug Substances and Products
3350
3351
3360
Q1A(R2) Stability Testing of New Drug Substances and Products
3349
International Conference on Harmonisation (ICH) Guidances
3346
3347
3348
3345
Submitting Documentation for the Manufacturing of and Controls for Drug Products
Premarket Approval Application Modular Review
3340
3344
PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality
Assurance
Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery
Systems
3338
3339
3336
3337
Draft — Not for Implementation
Draft — Not for Implementation
3300
3301
3302
3303
3304
3305
3306
3307
Contains Nonbinding Recommendations
Contains Nonbinding Recommendations
3/26/2008
Susceptibility of Small Implant Devices
84
G71 Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes
3389
3390
3391
F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization
Measurements to Determine the Corrosion
<905> Content Uniformity
3387
3388
<724> Drug Release
3381
F746 Standard Test Method for Pitting or Crevice Corrosion of Metallic Surgical Implant
Materials
<71> Sterility
3380
American Standards for Testing Materials (ASTM)
<85> Bacterial Endotoxins
3379
3382
3383
3384
3385
3386
<788> Particulate Matter in Injections (Small Volume)
3378
United States Pharmacopeia (USP)
3374
3375
3376
3377
Draft — Not for Implementation
Contains Nonbinding Recommendations
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