平成 22 年度経済産業省委託事業

平成２２年度戦略的技術開発委託費
医療機器開発ガイドライン策定事業（医療機器に関する開発ガイドライン作成のための支援事業）

医療機器評価指標ガイドライン
画像診断分野（コンピュータ診断支援装置）
開発ＷＧ報告書

平成２３年３月

独立行政法人

産業技術総合研究所

平成２２年度

画像診断分野（コンピュータ診断支援装置）開発 WG 委員名簿
（敬称略、※座長）※小畑 秀文

東京農工大学 学長

安藤 裕

放射線医学総合研究所 重粒子医科学センター病院 病院長

鴛田 栄二㈳日本画像医療システム工業会 法規・安全部会ソフトウェア委員会 副委員長
富士フイルム㈱ メディカルシステム事業部 事業部長附椎名 毅

京都大学大学院 医学研究科 人間健康科学系専攻 教授

軸丸 幸彦㈳日本画像医療システム工業会 法規・安全部会副部会長 ソフトウェア委員会 委員長
コニカミノルタエムジー㈱ 品質保証センター シニア アドバイザー

清水 昭伸

東京農工大学大学院 工学部電気電子工学科 准教授

縄野 繁

国際医療福祉大学 三田病院 放射線医学センター 教授

仁木 登

徳島大学大学院 ソシオテクノサイエンス研究部 教授

藤田 広志

岐阜大学大学院 医学系研究科 知能イメージ情報分野 教授

古川 浩㈳日本画像医療システム工業会 法規・安全部会部会長 法規委員会 委員長
東芝メディカルシステムズ㈱ 社長附

森山 紀之

国立がんセンター がん予防・検診センター センター長

諸岡 直樹㈳日本画像医療システム工業会 法規・安全部会 副部会長（CAD-WG 主査）㈱島津製作所 医用機器事業部 品質保証部 規格・製造品質管理グループ 課長

横井 英人

香川大学医学部附属病院 医療情報部 教授

タスクフォース（ＴＦ）委員名簿
性能評価項目選定小委員会

評価用代替データ小委員会

CAD ソフトウェア品質管理
評価項目選定小委員会

藤田 広志

安藤

裕

横井 英人

仁木 登

縄野

繁

軸丸 幸彦

椎名 毅

清水

昭伸

古川 浩

清水 昭伸

藤田

広志

鴛田 栄二

縄野 繁

椎名

毅

諸岡 直樹

鴛田 栄二
軸丸 幸彦
古川 浩
諸岡 直樹
開発ＷＧ事務局
本間 一弘

産業技術総合研究所 ヒューマンライフテクノロジー研究部門

坂無 英徳

産業技術総合研究所 情報技術研究部門
センサーコミュニケーション研究グループ

画像診断分野（コンピュータ診断支援装置）開発 WG

第 1 回開発 WG 委員会
開催日

平成 22 年 10 月

5日

(火)

平成 22 年 11 月 10 日

(水)

第 2 回開発 WG 委員会
開催日

第 3 回開発 WG 委員会
開催日

平成 22 年 12 月 28 日

(火)

第 4 回開発 WG 委員会
開催日

平成 23 年 1 月 25 日

(火)

第 5 回開発 WG 委員会
開催日

平成 23 年 2 月 28 日

(月)委員会開催日目次

1. 当該技術分野の現状 ...............................................................................................................................1

2. 当該技術分野におけるガイドライン策定の意義 ..............................................................................2

3. ガイドラインの検討過程 .......................................................................................................................3
3.1 画像診断分野（コンピュータ診断支援装置）開発 WG 委員会概要
3.2 TF1（性能評価項目選定小委員会）の総括
3.3 TF2（評価用代替データ検討小委員会）の総括
3.4 TF3（CAD ソフトウェア品質管理評価項目選定小委員会）の総括

4. ガイドラインの検討結果 .................................................................................................................... 14
コンピュータ検出支援装置の性能評価項目開発ガイドライン 2010（案）コンピュータ検出支援装置におけるソフトウェア品質管理
開発ガイドライン 2010（案）5. 開発 WG 委員会からの提言 ............................................................................................................... 16
5.1 CAD の発展のために

6. 平成 22 年度の総括 .............................................................................................................................. 18

参考資料 .................................................................................................................................................... 20
参考資料 1： GHTF/SG1/N41R9:2005
GHTF FINAL DOCUMENT『Essential Principles of Safety and Performanceof Medical Devices』

参考資料 2： GHTF/SG1/N15:2006
GHTF FINAL DOCUMENT『Principles of Medical Devices Classification』

参考資料 3： GHTF/SG1/N011:2008
GHTF FINAL DOCUMENT『Summary Technical Documentation for Demonstrating
Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED)』

参考資料 4： Draft Guidance for Industry and FDA Staff
Clinical Performance Assessment: Considerations for Computer-Assisted Detection Devices
Applied to Radiology Images and Radiology Device Data - Premarket Approval (PMA) andPremarket Notification [510(k)] Submissions

参考資料 5： Draft Guidance for Industry and FDA Staff
Computer-Assisted Detection Devices Applied to Radiology Images and Radiology Device
Data - Premarket Notification [510(k)] Submissions

1. 当該技術分野の現状
コンピュータで画像診断を支援するという基礎研究は 1960 年代には始まっており、当時は“自動診断”と言うネーミングが使われていた。胸部単純 X 線写真や胃二重造影写真の分野を中心に、欧米に負けず本邦から世界をリードするすばらしい多くの学術的な研究成果が発信されてきた。
一方、実用化面では、世界最初のコンピュータ支援検出（computer-aided detection; CAD）装置
として、マンモグラフィ CAD 装置が米国の FDA（Food and Drug Administration, アメリカ食品医薬品局）の認可を得て 1998 年に発売されており、すでに 10 年以上の年月が経過している。現在の米国では、乳がん検診において年間 3800 万人の対象患者の半数以上は CAD 装置を用いて診断されると推定されている（販売台数は 1 万台規模）。マンモグラフィ CAD 装置に続いて、胸部単
純 X 線写真、
肺 CT (Computed Tomography)、大腸 CT コロノスコピー、乳房 MR (Magnetic Resonance)、
前立腺 MR、乳房超音波の領域で CAD もしくはそれに類する商品（後者の 3 例はどちらかというとコンピュータ支援診断の範疇になる）が商用化されている。
本邦では、残念ながら薬事承認された商品はいまだにマンモグラフィ CAD 装置のみという現状であり、販売総数はいまだに 100 台未満と推定される。そのため、商用の CAD 装置を使った臨床評価に関する論文も、皆無に近いと言っても過言ではない。世界をリードできる技術力を古くから有しているにも関わらず、産業面でも学術的な臨床評価の面でも世界に大きな遅れをとってしまったのは、誠に残念な限りである。その理由の一つとして、本邦には薬事承認のための定まったガイドラインがこれまでになく、承認までにはいたずらにかなりの時間を要していることが挙げられる。米国では 2009 年 10 月に、コンピュータ支援検出を行う CAD 装置の承認基準を、FDA の審査の基準の見直しにあわせて厳しく設定したために、それ以降 CAD 装置開発に対する企業の意欲を減退させ、その普及も大きく遅らせている悪因になっている。本邦ではそのようなことが起きないよう、CAD 装置の本質を見極めたガイドラインの策定が関連する工業界から渇望されており、本開発 WG 委員会で協議を重ねてきた次第である。
本ガイドラインにより多くの商用 CAD 装置が出現し、次の 10 年で CAD 装置の商用化が活況を呈するような状況になり、世界をリードするようになることを願ってやまない。

12. 当該技術分野におけるガイドライン策定の意義
1998 年、世界で最初に米国において医療機器として FDA に認可されたマンモグラフィ CAD（Computer-Aided Detection/Diagnosis）装置は、検診に保険適用が認められたことも加わって普及が目覚ましい。既に１万台を超える CAD 装置が臨床に使用され、医師の診断支援のツールとして高い評価が得られている。最近では乳房以外の部位に対応した CAD ソフトウェアの実用化が進むのに伴い、米国 FDA が CAD ソフトウェア用のガイドラインを策定し、CAD ソフトウェアを開発する大学や企業の研究機関へのサービスを提供している。
一方日本では、医療機器のイノベーションとしての代表的な技術の一環に位置づけられている
CAD 装置は、診断医から高い評価を得ていながら、米国に対して約 10 年も市場導入が遅れているとみられている。2010 年 12 月の時点で国内でのマンモグラフィ CAD 装置の導入施設が 100 に達しない状況である。
2000 年 1 月 31 日にフィルムマンモグラフィ CAD 装置が薬事承認されたが、画質・その他の要因であまり普及せず、2007 年 4 月 9 日にデジタルマンモグラフィ CAD 装置が、また 2007 年 12 月 4 日、2010 年 3 月 17 日及び、2010 年 5 月 21 日に国内企業がマンモグラフィ
CAD 装置の薬事認可を取得したのみである。このように、CAD 装置に関する薬事承認事例がまだ 5 件（2011 年 3 月現在）と非常に少なく、日本国内ではソフトウェアに関する薬事法での取扱いが不明確な状況の中、CAD 装置の定義が定まっていない実情が存在する。その上、これまで
CAD 装置の薬事承認申請期間が約 3 年と時間がかかっており、薬事認可を取得した段階ではソフ
トウェアが陳腐化してしまっているという問題と、ソフトウェアの開発費と薬事申請に多額の経費がかかる問題のために、中小企業はもちろんのこと大企業でも医療機器としての CAD 装置の商品化を躊躇している。
そのような厳しい状況下にあるにも関わらず、各大学の研究室や医療機器関連企業及びソフト
ウェアベンチャー企業等の研究開発部門では、将来性を見越して新たな CAD 装置の開発を試みている。装置も X 線撮影装置から X-CT、USI、MRI、PET/CT、眼底カメラ、及びカプセル内視鏡等と、また対象部位においても、これまでの乳房から肺、大腸、肝臓、膵臓、脳神経、前立腺、歯科パノラマ、及び病理等、多岐にわたった CAD 装置の研究・開発が進められている。
これらの実情を鑑み、日本の医療機器産業の活性化を考慮し、当開発ワーキンググループ(WG)
委員会では医療機器としての価値を認められている CAD 装置としての効果・効能を謳える「CAD
ソフトウェア＋ハードウェア」のシステム、並びに将来ソフトウェアの単独医療機器が設定された場合を想定し、「CAD ソフトウェア」も念頭において、各企業がそれらを医療機器市場に早急に導入できるよう製品開発と薬事申請を行ないやすくすることを目的として本ガイドラインを策定することとした。

2

3. ガイドラインの検討過程
CAD (Computer-Aided Detection/Diagnosis)装置を開発するために必要な項目に関するガイ
ドラインの策定、CAD 装置などで用いるソフトウェアの在るべき姿を検討することを目的に、開発ワーキンググループ委員会を設置し、本年度は、5 回 (10 月 5 日、11 月 10 日、12 月 28 日、
1 月 25 日、2 月 28 日)開催した。開発 WG の下に、3 つの TF：タスクフォース（TF１：性能評
価項目選定小委員会、TF2：評価用代替データ検討小委員会、TF3：CAD ソフトウェア品質管理
評価項目選定小委員会）を設け、各 TF で必要な項目を詳細に検討し、開発ＷＧ委員会で総括審議を行った。

3.1 画像診断分野（コンピュータ診断支援装置）開発 WG 委員会概要
3.1.1 第 1 回開発 WG 委員会(1) 開催日時: 平成 22 年 10 月 5 日 (火) 18:00～20:00(2) 配布資料
資料 1：開発 WG 委員名簿
資料 2：審査 WG 委員名簿
資料 3：Ｘ線による乳房の診断装置（既承品医療機器）
資料 4：基本要件適合性チェックリスト（据置型アナログ式乳房用Ｘ線診断装置等基準）
資料 5：医療機器の臨床試験の実施の基準の運用について（薬食機発 1224 第４号）
資料 6：COCIR（欧州放射線・医療電子機器産業連合会）のメモ
COCIR Internal Briefing Status in Canada, EU and US on Medical Software
資料 7：資料 6 にある欧州のドラフトガイドライン
Guidelines for the qualification and classification of software used in healthcare
environment within the regulatory framework of medical devices
資料 8：資料 6 にある米国のパブコメ募集文書
資料 9：資料 6 にあるカナダの NOTICEClassification of Medical Devices Class I or Class II patient management software
資料 10：米国の CAD に関するパブコメ募集文書１
Computer-Assisted Detection Devices Applied to Radiology Images and Radiology Device
Data - Premarket Notification [510(k)] Submissions
資料 11：米国の CAD に関するパブコメ募集文書 2
Clinical Performance Assessment: Considerations for Computer-Assisted Detection Devices
Applied to Radiology Images and Radiology Device Data - Premarket Approval (PMA) andPremarket Notification [510(k)] Submissions
資料 12：GHTF 最終文書
『医療機器の安全性及び性能の基本要件』
資料 13：GHTF 最終文書
『医療機器のクラス分類の原則』
3

資料 14：GHTF 最終文書
『医療機器の安全性及び性能に関する基本要件への適合を立証するためのサマリーテクニカルドキュメンテーション(STED)』
資料 15：討議事項（開発ガイドラインにおける技術的評価項目）
参考資料 1：医療機器ガイドライン事業における従来の成果
参考資料 2：過去に策定した開発ガイドラインの例（高機能人工心臓システム）(3) 出席者
委員： 小畑秀文、森山紀之、安藤裕、縄野繁、清水昭伸、藤田広志、仁木登、横井英人、
鴛田栄二、軸丸幸彦、古川浩
経済産業省：安達昌孝、吉野正人
国立医薬品食品衛生研究所：蓜島由二、植松美幸
事務局：赤松幹之、本間一弘、山根隆志、鷲尾利克（産業技術総合研究所）(4) 議事概要①今年度の検討方針
CAD 装置の開発において必要な評価項目に検討し、ガイドラインの策定を推進する。このために、下記の TF（タスクフォース）を設置し、詳細を検討する。各 TF における検討状況は開発
WG 委員会にて報告し、同委員会にて審議する。
TF1：性能評価項目選定小委員会（取り纏め：藤田委員）
コンピュータ診断支援装置の性能、有効性などに関する技術的評価項目を選定する。
共通する評価項目、部位・モダリティ特有の評価項目
TF2：評価用代替データ検討小委員会（取り纏め：安藤委員）
標準 DB の構築や疾患モデル、シミュレーションの可能性など
TF3：CAD ソフトウェア品質管理評価項目選定小委員会（取り纏め：横井委員）
医療機器のソフトウェアに対する品質管理、技術的に規定すべき項目など②対象とする医療機器の名称と定義
対象とする医療機器の名称と定義(使用目的・適用範囲)に関して審議した結果、以下を案とする。審査 WG 委員会の審議を踏まえ、今後、さらに審議するものとする。
1)

CADe：コンピュータ検出支援ソフトウェア

2)

CADx：コンピュータ診断支援ソフトウェア

3.1.2 第 2 回開発 WG 委員会(1) 開催日時: 平成 22 年 11 月 10 日 (金) 18:00～21:00(2) 配布資料
資料 2-1：第 1 回開発 WG 議事録
4

資料 2-2：開発 WG 委員名簿（10 月 1 日現在）
資料 2-3：TF1（性能評価項目選定小委員会）
1. 小委員会 議事録（性能評価項目に関する検討結果）
2. 関連資料（医用画像処理表示装置:MV-SR657 添付資料）
3. 関連資料（Small Pulmonary Nodules:Effect of 2 CAD Systems on Radiologist Performance）
資料 2-4：TF2（評価用代替データ検討小委員会）
評価用代替データの検討結果
資料 2-5：TF3（CAD ソフトウェア品質管理評価項目選定小委員会）
1. 小委員会 議事録
2. 品質管理に関する検討結果（CAD ソフトウェアの品質管理の考え方）
資料 2-6：コンピュータ診断支援装置 審査 WG の活動状況
資料 2-7：開発ガイドライン（項目案）(3)出席者
委員： 小畑秀文、森山紀之、縄野繁、清水昭伸、藤田広志、椎名毅、仁木登、横井英人、
鴛田栄二、軸丸幸彦、古川浩、諸岡直樹
医薬品医療機器総合機構：池田潔
国立医薬品食品衛生研究所：蓜島由二、植松美幸
事務局：本間一弘、鷲尾利克、坂無英徳、安佛尚志（産業技術総合研究所）(4) 議事概要①TF（タスクフォース）の検討状況の報告
1)TF1：性能評価項目選定小委員会報告（藤田委員）
過去のマンモグラフィ CAD システムの薬事申請時に係わる評価方法を踏まえて、CADe の評
価項目の選定に対する検討を行った。その結果、CADe の目的（検出対象）、適用範囲、機能、使用方法などの明確な記述、及び、評価対象の画像データベースの詳細の記述が必要である。
また、評価項目は、画像データベースを用いて、必ず統計的な有効性を示す。CAD 装置の使用目的・用途を検討し、それに対応した機器の仕様を明確にする。あわせて、評価用臨床用臨床データの要否、その理由などを検討する。
2)TF2：評価用代替データ検討小委員会報告（縄野委員）
代替案として「データベース用画像収集」、「CAD 評価用のファントムによる評価」「電子ファ
ントムによる評価」が考えられる。データベースの構築にかかる時間や、評価用ファントムを作成する費用等を考慮すると、「電子ファントムによる評価」がもっとも有望である。これらの使用に関して詳細を検討する。
3)TF3：CAD ソフトウェア品質管理評価項目選定小委員会報告（横井委員）
CAD ソフトウェアに関する品質管理についての検討方針を固め、IEC62304（JIST62304（仮称））を元に、その基準に必要な項目を CAD ソフトウェアに対応した形で表記した。関連する全ての基準などを洗い出し、あらたに加えるべき評価項目を検討する。

5

②コンピュータ診断支援装置 審査 WG の活動状況の報告（蓜島審査 WG 事務局）
審査 WG より今年の指針及び作業内容についての報告があった。
③開発ガイドライン（骨子案）について
現在までの議論の内容を踏まえての骨子案の提示を行った。さらに各 TF 内での審議を進め、次回 WG にて結果を取り纏めていくものとする。
④その他
審査 WG との資料・情報の共有化が了承された。

3.1.3 第 3 回開発 WG 委員会(1) 開催日時: 平成 22 年 12 月 28 日 (火) 10:00～12:00(2) 配布資料
資料 3-1：第 2 回開発 WG 議事録
資料 3-2：コンピュータ診断支援装置 審査 WG の活動状況 評価指標案
資料 3-3：CAD の定義
資料 3-4：TF1（性能評価項目選定小委員会）の活動状況報告
資料 3-5：TF2（評価用代替データ検討小委員会）の活動状況報告
資料 3-6：TF3（CAD ソフトウェア品質管理評価項目選定小委員会）の活動状況報告
資料 3-7：TF3 品質管理に関する検討結果（CAD の品質管理の考え方）2010.12.27 改訂(3)出席者
委員： 小畑秀文、安藤裕、縄野繁、清水昭伸、藤田広志、椎名毅、仁木登、横井英人、
鴛田栄二、軸丸幸彦、古川浩、諸岡直樹
経済産業省：加藤二子
医薬品医療機器総合機構：池田潔
国立医薬品食品衛生研究所：植松美幸
事務局：本間一弘、山根隆志、鷲尾利克、坂無英徳、安佛尚志（産業技術総合研究所）(4) 議事概要①コンピュータ診断支援装置 審査 WG の活動状況の報告（植松審査 WG 事務局）
審査 WG よりコンピュ－タ診断支援装置（画像情報処理の部分）に関する評価指針案についての報告があった。
②CAD の定義に関する討議
CAD の定義に関し、今までに出された案を討議した。審査 WG 委員会側の定義との整合を行い、事務局から次回の開発 WG にて提案し、再審議する。
6

③TF（タスクフォース）の検討状況の報告
1)TF1：性能評価項目選定小委員会報告（藤田委員）
CADe 及び CADx に対する評価項目に関して技術的側面から検討した。次回の開発 WG において、CADe の開発ガイドライン（案）を提案する。
2)TF2：評価用代替データ検討小委員会報告（安藤委員）
評価用の代替案のためのモダリティと部位の対応を検討した。評価用代替の画像 DB や電子フ
ァントムの仕様に関して検討し、次回の開発 WG において、開発ガイドライン（案）を提案する。
3)TF3：CAD ソフトウェア品質管理評価項目選定小委員会報告（横井委員）
ソフトウェア品質管理に対する評価項目を選定し、関連する基準の選定、新しく検討すべき項
目と内容を検討した。次回の開発 WG において、開発ガイドライン（案）を提案する。
④次回の WG にて、今年度において提案する開発ガイドラインの内容を審議する。

3.1.4 第 4 回開発 WG 委員会(1) 開催日時: 平成 23 年 1 月 25 日 (火) 18:00～21:00(2) 配布資料
資料 4-1：第 3 回開発 WG 議事録（案）資料 4-2：CAD の定義
資料 4-3：TF1（性能評価項目選定小委員会）
資料 4-4：TF2（評価用代替データ検討小委員会）
資料 4-5：TF3（CAD ソフトウェア品質管理評価項目選定小委員会）
資料 4-6：関連規格のリスト（案）
資料 4-7：平成 22 年度 CAD 開発 WG 報告書（骨子案）(3)出席者
委員： 小畑秀文、安藤裕、縄野繁、清水昭伸、藤田広志、椎名毅、仁木登、鴛田栄二、
軸丸幸彦、古川浩、諸岡直樹
経済産業省：安達昌孝、吉野正人、加藤二子
医薬品医療機器総合機構：池田潔
国立医薬品食品衛生研究所：蓜島由二、植松美幸
事務局：本間一弘、山根隆志、鷲尾利克、坂無英徳、大塚幸雄（産業技術総合研究所）(4) 議事概要①コンピュータ診断支援装置 審査 WG の活動状況の報告（蓜島審査 WG 事務局）
審査 WG より検討状況に関して報告がなされた。審査 WG は 3 回開催し、コンピュータ診断支
援装置に関する評価指標に関して検討した。今年度末には審査ガイドラインを提案する予定であ7

る。
②CAD 装置の定義に関する審議
資料 4-2 をもとに、本開発 WG としては CAD（コンピュータ診断支援）装置を CADe と CADxに分類し、各々、以下の定義とすることを決定した。

1)コンピュータ検出支援ソフトウェア CADe (Computer-Aided Detection)
画像を解析し、内蔵する基準に基づいて異常と想定される位置をコンピュータが自動的に抽出するソフトウェアあるいはそれを具備する装置。
用途：医師の診断を支援する。

2)コンピュータ診断支援ソフトウェア CADx

(Computer-Aided Diagnosis)

画像を解析し、内蔵する基準に基づいて病変の候補部位をコンピュータが自動的に分析し、疾患の候補やその進行度あるいはリスク評価に関する情報などを提供するソフトウェアあるいはそれを具備する装置。
用途：医師の診断を支援する。

③開発ガイドライン(案) に関する審議
性能評価項目選定小委員会（タスクフォース TF1）、評価用代替データ検討小委員会（TF2）、
CAD ソフトウェア品質管理評価項目選定小委員会（TF3）から、検討した開発ガイドライン(案)に関して報告がなされた（資料 4-3～5）。審議において以下の指摘があり、これに基づいて再検討し、次回の開発 WG にて報告する。また、各々の開発ガイドライン(案)には、欄外あるいは末尾に記載内容の解説を付記する。
〇コンピュータ検出支援装置の性能評価(案)・審査 WG で検討する内容との差別化が必要である。
・臨床データ収集不要の範囲あるいは代替案を科学的根拠をもって示すことを検討する。
・CADx に関する審議は未了と判断し、平成 22 年度に提案する開発ガイドラインは CADeの内容に限定する。これに起因して、資料 4-3 に記載される CADx に関する記載は削除する。
・開発 WG としては、CADx は来年度において検討することを希望することとする。
〇性能評価用データの代替法(案)・利用者が必要な内容の全てを規定する。
・電子ファントムに対する要求仕様を詳細に記載する。
・臨床データに対する要求仕様を詳細に記載する。
・DB を構築する場合に必要となる条件を記載する。
（GCP への対応の要否、必要な場合はその内容）
・上記に関する評価項目は科学的根拠をもって示す。
8

〇医療機器におけるソフトウェア品質管理(案)・ソフトウェアそのものを技術的に評価する際に必要な評価項目の全てを検討する。

④平成 22 年度の報告書
資料 4-7 に基づいて平成 22 年度報告書の目次案を審議し、執筆分担を定めた。

3.1.5 第 5 回開発 WG 委員会(1) 開催日時: 平成 23 年 2 月 28 日 (月) 18:00～20:10(2) 配布資料
資料 5-1：第 4 回開発ＷＧ議事録（案）資料 5-2：ガイドライン「コンピュ－タ検出支援装置の性能評価項目」（案）
資料 5-3：電子ファントムによる CAD の性能評価（案）Ver.1（案）資料 5-4：ガイドライン「医療機器におけるソフトウェア品質管理」（案）資料 5-5：平成 22 年度 CAD 開発 WG 報告書（骨子案）
資料 5-6：平成 22 年度開発ＷＧ報告書における「開発 WG からの提言」への記載案
参考資料 5-1：CAD の定義確定版
参考資料 5-2：第 10 回合同検討会 HP
参考資料 5-3：合同検討会資料（案）(3) 出席者
委員： 小畑秀文、安藤裕、縄野繁、清水昭伸、藤田広志、椎名毅、仁木登、横井英人、
鴛田栄二、軸丸幸彦、古川浩、諸岡直樹
経済産業省：安達昌孝
国立医薬品食品衛生研究所：植松美幸
内閣官房:廣瀬大也
事務局：本間一弘、山根隆志、鷲尾利克、坂無英徳、大塚幸雄(産業技術総合研究所）(4) 議事概要
・各タスクフォースにおける検討の結果として提示された 3 件の開発ガイドライン(案)「CADe（コンピュータ検出支援ソフトウェア）」、「医療機器におけるソフトウェアの品質管理」、「性能評価用データ収集の代替法」に関して審議を行った。
・CADe に関する開発ガイドライン(案)は、審査ガイドラインにおける記載内容との重複を避け、開発者の視点に立った評価項目を具体的かつ詳細に記載することとする。
・ソフトウェアの品質管理に関する開発ガイドライン(案)は、ソフトウェアを単独で評価するために必要不可欠な評価項目を選定し、加筆修正する。
・前 2 者に対して本日の審議内容を反映させ、開発ガイドライン案として提案する。また、性能評価用データ収集の代替法及び CADx
（コンピュータ診断支援ソフトウェア）に関しては、
詳細な検討と審議の継続が必要なことから、次年度において開発ガイドラインの策定を検討
9する。
・平成 22 年度の報告書は委員及び事務局の分担執筆とする。

3.2 TF1（性能評価項目選定小委員会）の総括
本ガイドライン策定のために，主に以下の点を中心に議論が行われた。
3.2.1. 過去の薬事申請時の性能項目に関する調査
国内企業 2 社から過去のマンモグラフィ CAD の薬事承認過程に関わる情報を収集し議論を行った。
3.2.2 評価項目選定に関して
1) CADe の目的（検出対象）、適用範囲、機能、使用方法などの記述について
2) 評価対象の画像データベースの詳細（症例数、病変の特徴など）の記述について
3) 1) の効能を実証する技術的な評価データを提示について
・評価項目は、画像データベースを用いて、CADe の検出率（真陽性率）と偽陽性数（あるいは偽陽性率）による定量的データ、あるいは ROC（Receiver Operative Characteristic）解析等の技術で評価を行い、必ず統計的な有効性を示す。
・過去に承認された事例がある場合には、システムの性能の呈示と承認事例の性能との差違を検討し、統計的に有効性を示す。
過去に認可された類似の CADe がない新規事例の場合には、医師の単独性能と医師が CADe を利用したときの性能との比較評価などで、CADe の有効性を示す。
4) CAD 装置の真の評価（有効性の実証）の難しさ
CAD 装置は「うっかりミス」を防ぐ目的で設計されていることが多く、そのような状況を模擬した臨床的な環境下でプロスペクティブ（前向き）に実証実験をすることが望ましい。しかし、集団検診のような状況下ではがん発生率が極めて少ないので（0.3%程度のオーダー）容易ではない。ROC 実験は、実験室における極めて特殊な環境下（データ数や読影環境など）における一つの評価実験に過ぎない。また、最近の国際学会でも議論があるが、クリニックにおける CAD 装置の有効性の評価例は、まだどこからも出ていない。
3.2.3 性能評価用の画像データの問題
1) 臨床画像の収集の難しさ
CAD 装置開発の生命線である臨床画像データの収集は、非常に困難であるのが一般的である。
その理由は、倫理委員会承認の問題もあるが（次項）、それが解決したとしても、特にがんなどの異常症例の収集作業については一般病院ではかなりの時間を要する。CAD アルゴリズムの学習やテスト（学習には使わないデータで実行する必要がある）に使うために十分な枚数の病変（特にがん病変）の出現頻度が小さいことが多いためである。
そのため、研究開発段階で収集したものでも、訓練データとして使用していことが担保でき、
薬事申請用にも十分な条件を満たしている場合には、問題なく利用できるような仕組みも採用す
10

べきと考える。
また、統計的な偏りのないことを示す十分な根拠があれば、一施設で収集されたデータの薬事申請用としての使用についても将来的に認められるべきと考える。
2) 倫理委員会
施設の倫理委員会承認のクリアも必ずしも容易ではない。同意書について個別同意が必要か、
包括的同意でよいか、あるいは不要かなどは、各施設の倫理委員会によっても方針が大きく異なり、特に検診施設では個別同意書はとれない（むしろ、CAD 装置の研究では画像を完全に匿名化処理して使うため、同意書は不要で承認すると倫理委員会から言われることさえある）のが現状である。
なお、CAD は医師による読影の診断の支援であり、薬の臨床試験（治験）のように患者に直接危害を加える可能性はゼロであることを根拠として、臨床試験を行う施設の倫理審査委員会の承認を得ている画像データであれば、必ずしもすべて GCP 準拠である必要はないのではないかとの意見もあった。
3) 代替画像データ
学術団体（学会）など公開している公共の画像データベースが使えるケースも希にあり得る。
例えば、肺癌 CT のケースを集めた LIDC (Lung Image Database Consortium)データベースや南フロリダ大学のマンモグラフィ用の画像データベースがある。ただし、一般的には小規模なものが多く、CAD 装置の評価用には十分ではない。医師の教育用の画像データベースの利用もあり得るが、現状では、CAD 装置の評価に利用できるものは非常に少ないと考えられる。
4) 電子ファントム
電子ファントムを代替に利用するという手段があるが、現状では、国内外の学会を見る限りでは、CAD 装置の評価に使えるような電子ファントムはまだ開発されていない状況である。電子ファントムが開発されれば、本 CAD の性能評価には有効に活用できる可能性があると考える。
5) 開発と薬事審査における画像データの扱い
開発時の画像データと薬事申請時の画像データは全く異なるデータを使う必要性があり、両者が混合されないように特に注意が必要である。

3.3 TF2（評価用代替データ検討小委員会）の総括
ガイドラインの検討を以下の項目において行った。
3.3.1 使用目的
本ガイドラインは、臨床データを用いた性能評価の代替法を科学的根拠に基づいて明確にする。
3.2.2 適応範囲
検出支援装置（CADe）、診断支援装置（CADx）の性能評価に適用する。

11

3.2.3 代替法
CADe に対する性能評価に活用できる臨床データの仕様及び新たなデータ収集を代替できる方策に関して検討を行った。
CADe の性能を評価するために利用できる臨床データは GCP を遵守することが不可欠である。
ただし、レトロスペクティブな評価が可能になると判断されることから、GCP を遵守した臨床データと同等の状態で確保されたデータであれば、評価に利用可能と判断する。現状の技術においては電子ファントムや評価用データベースがその候補となる。これらに関する詳細な仕様は今後において詳細を検討するものとする。

3.4 TF3（CAD ソフトウェア品質管理評価項目選定小委員会）の総括
本内容については、主として CAD ソフトウェアの開発に関連する業界団体の有識者を中心に検討を進めた。
CAD ソフトウェアに限らず、医療機器ソフトウェアの品質とは、通常の医療機器の品質とは大きく異なる性格を持つ。つまりソフトウェアは物質・物体として製造するものではないので、その生産から出荷に於ける品質管理の要素はごく僅かである。現実的な製造行為は、ソフトウェア
を記入したメディアの製造であり、これらはコンピュータ上でおよそ内部処理的に行われるので、通常の医療機器のような品質管理を必要としない。
ソフトウェアの品質としてはむしろ、開発時からソフトウェア流通の全てのフェイズに於ける設計管理をはじめとしたプロセス管理が寄与する割合が大きい。現在、このプロセス管理のために
IEC62304 (国内に於いては JIS T 2304) の適用が一般的になっている。欧米に於いては本規格に準拠した管理文書の提出が求められている。
CAD ソフトウェアの計算アルゴリズムにおける臨床的な性能の評価項目（性能評価項目）については、本 WG に於いては TF1 等で議論されているので、本 TF では、ソフトウェアの開発過程の技術的な部分に焦点を絞って、必要な項目を案出した。
IEC62304 に準拠する場合、ISO14971 にも準拠が必要になる。また、薬事上の QMS (Quality
Management System)としては ISO13485 への準拠も必要となる。したがって「JIS Q 13485 医療機
器－品質マネジメントシステム」「JIS T 14971 医療機器－リスクマネジメントの医療機器への適用」も視野に入れた上で、CAD 開発に関する具体的な各ステップについての必要条件を検討していった。
まず、CAD 装置の品質管理項目を、組み合わせるハードウェアとソフトウェアとして、その詳細の設計開発プロセスへの適用として、以下の各開発段階に於いての評価項目として挙げた。
①製品に関連する要求事項の明確化（意図する用途）②設計開発のインプット③ソフトウェア要求事項分析④アーキテクチャ設計⑤システム試験⑥リスクマネジメント
12

⑦構成管理プロセス⑧設計開発の検証⑨設計開発の妥当性確認（臨床評価）
本案では、論理の明確化のために対象のソフトウェアを「画像を解析し、内蔵する基準に基づいて異常と想定される位置をコンピュータが自動的に抽出するソフトウェア、あるいはそれを具備する装置」としたが、今後、質的診断に寄与するソフトウェアに関する内容も含め議論が必要になる。
本案は以上のような意図を持って開発に於ける基準の明確化を図ることを目的に作成されたも
のである。

13

4. ガイドラインの検討結果

コンピュータ検出支援装置の性能評価項目開発ガイドライン 2010（案）（確定作業中のため本文の掲載は省略）

14コンピュータ検出支援装置におけるソフトウェア品質管理
開発ガイドライン 2010（案）

本ガイドラインは、平成 23 年度 医療機器開発ガイドライン策定事業（医療機器に関する開発ガ
イドライン作成のための支援事業）画像診断分野開発 WG において改訂され、経済産業省より「コンピュータ診断支援装置におけるソフトウェア設計・開発管理 開発ガイドライン 2012」として平成 25 年 3 月に公開された。
経済産業省 医療機器開発ガイドライン策定事業
http://www.meti.go.jp/policy/mono_info_service/service/iryou_fukushi/index.html

15

5. 開発 WG 委員会からの提言
5. 1 CAD の発展のために産業界は、品質、有効性及び安全性が担保された医療機器としてのCADの普及と医療への貢献を切に願っている。しかしながら最近では、CADの使用目的や性能を持ちながらも、未承認のまま製造販売したり、単なる解析ソフトウェアとして認証取得し製造販売したりするケースが多々見られる。このままでは薬事規制を遵守した品質、有効性及び安全性が担保された医療機器としてのCAD
が日本の市場から消え去ってしまうことが強く懸念される。
以下にCADがこのような状況に陥っている理由や背景を考察し、この現状を改善するための提言を行う。
■CADの定義の周知とリスクに見合った審査基準の設定
この現状は、CADの定義や使用目的・使用方法の明確化及びその周知がなされていないということと、薬事承認取得のハードルがCADの使用時のリスクに比較してあまりに高いというところに起因しているものと考える。CADはあくまでも病変の見落とし防止の注意喚起など、医師等が読影や診断の際に補助的に利用するツールであって、最終的な読影や診断はオリジナル画像を見て医師等が行うため、CADを適正に使用した場合の実際のリスクは高くない。これまでの承認前例において申請時に必要とされた臨床データはCADが持つリスクに対してあまりにハードルが高く、臨床デー
タの収集と承認取得に莫大なコストと長期間を要した。
CADの定義や使用目的・使用方法の明確化と、薬事承認の審査基準をCADのリスクに見合った内容に見直し、かつその審査基準を周知し、申請者が投資回収や承認時期の見通しをもって申請することができるように改善願いたい。
■CAD等の医療用アプリケーションソフトウェアの医療機器化
現在、医療現場において IT 化が進んでおり、様々な情報機器が導入されている。CAD を臨床現場で利用する場合、すでに設置されている情報機器端末に CAD のソフトウェアだけを導入して、臨床に利用したいという要望が強い。しかし、現在の日本の薬事規制においては、CAD に代表される医療用アプリケーションソフトウェアを製造販売する場合は PC などの汎用ハードウェ
アに医療用アプリケーションソフトウェアを組み込んだ構成で薬事承認を取得し、同構成で製造販売しなければならない。そして、設置時及び導入後においても医療機器は厳格に構成品管理がなされるために、他の汎用 PC や他のソフトウェアとの組合せ変更が医療現場において実施できない。具体的には以下のような足かせ（デメリット）が医療現場で発生している。
・ 医療現場のワークフローや操作性に最適な PC に CAD をインストールできない・ 複数ソフトウェアの同居による PC の削減による低コスト・省スペース化が困難
・ 陳腐化した PC を最新鋭のものに交換することができない
一方、未承認の CAD は薬事規制を遵守する必要がないため、ソフトウェア単独で取り扱うことができ、これらの足かせ（デメリット）が一切ない。また、CAD は前述したように、最終的な読影や診断はオリジナル画像を見て医師等が行うので、実際の使用時のリスクはさほど高くないため、医師等も品質、有効性及び安全性が担保された医療機器としての CAD の必要性をさほど感じない。従って、同様な機能・性能を持った CAD であれば、足かせ（デメリット）のない安
価な未承認の CAD が使用者に好まれ、足かせ（デメリット）のあるハードウェア込みの高価な
16

医療機器としての CAD は敬遠される。
CAD等の医療用アプリケーションソフトウェアの医療機器化を行い、ソフトウェア単独製品として製造販売できるようにして、医療機関での設置時及び導入後における上記のような足かせ（デメリット）の解消を切望する。

CADは診断支援の医療機器として、医療への貢献の潜在能力は大きい。是非、規制当局には日本
におけるCADの発展の“行き詰まり感”を認識していただき、多くの企業がCADの研究開発に切磋琢
磨し、品質、有効性及び安全性に優れた多くのCADが医療現場で使用されるように規制環境面での見直しと整備をお願いしたい。

17

6. 平成 22 年度の総括
開発ガイドライン策定のために、「CAD に対する性能評価項目の選定」「評価用データの収集代替法の検討」及び「CAD におけるソフトウェアの品質管理に対する評価項目の選定」について検討することを目的に、3 つのタスクフォース（TF）を設置した。各々、性能評価項目選定小委員
会、評価用代替データ検討小委員会、CAD ソフトウェア品質管理評価項目選定小委員会とした。
各々ＴＦにおいて詳細に検討した結果を、開発 WG 委員会にて総括討論した。その結果、開発
WG 委員会として、CADe（コンピュータ検出支援ソフトウェア）とソフトウェアの品質管理に関する開発ガイドライン(案)を提案することとした。
また、「性能評価用データ収集の代替法」及び「CADx（コンピュータ診断支援ソフトウェア）」に関しては、さらに詳細な検討と審議が必要であり、今後、開発ガイドラインの策定を検討して
いきたい。

18

19

参考資料
参考資料１： GHTF/SG1/N41R9:2005
GHTF FINAL DOCUMENT『Essential Principles of Safety and Performanceof Medical Devices』
参考資料２：GHTF/SG1/N15:2006
GHTF FINAL DOCUMENT『Principles of Medical Devices Classification』
参考資料３：GHTF/SG1/N011:2008
GHTF FINAL DOCUMENT『Summary Technical Documentation for Demonstrating
Conformity to the Essential Principles of Safety and Performance of Medical Devices(STED)』
参考資料 4： Draft Guidance for Industry and FDA Staff
Clinical Performance Assessment: Considerations for Computer-Assisted Detection
Devices Applied to Radiology Images and Radiology Device Data - Premarket
Approval (PMA) and Premarket Notification [510(k)] Submissions
参考資料 5： Draft Guidance for Industry and FDA Staff
Computer-Assisted Detection Devices Applied to Radiology Images and Radiology
Device Data - Premarket Notification [510(k)] Submissions

20

参考資料１：GHTF/SG1/N41R9:2005
GHTF FINAL DOCUMENT『Essential Principles of Safety and Performanceof Medical Devices』

GHTF/SG1/N41R9:2005

FINAL DOCUMENT
Title:

Essential Principles of Safety and Performanceof Medical Devices

Authoring Group:

GHTF Study Group 1

Endorsed by:

The Global Harmonization Task Force

Date:

May 20, 2005

Abraao Carvalho, GHTF Chair
This document was produced by the Global Harmonization Task Force, a voluntary internationalgroup of representatives from medical device regulatory authorities and trade associations from
Europe, the United States of America (USA), Canada, Japan and Australia.
The document is intended to provide non-binding guidance to regulatory authorities for use in theregulation of medical devices, and has been subject to consultation throughout its development.
There are no restrictions on the reproduction, distribution or use of this document; however,incorporation of this document, in part or in whole, into any other document, or its translation into
languages other than English, does not convey or represent an endorsement of any kind by the Global
Harmonization Task Force.

Copyright © 2000 by the Global Harmonization Task ForceEssential Principles of Safety and Performance of Medical Devices
Study Group 1 Final Document GHTF/SG1/N41R9:2005

Table of Contents

1

Introduction ...................................................................................................................52

Rationale, Purpose and Scope ........................................................................................6

2.1

Rationale....................................................................................................................6

2.2

Purpose......................................................................................................................6

2.3

Scope.........................................................................................................................63

References .....................................................................................................................74

Definitions.....................................................................................................................7

5

Essential Principles of Safety and Performance of Medical Devices...............................8

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Preface
The document herein was produced by the Global Harmonization Task Force, avoluntary group of representatives from medical device regulatory authorities and theregulated industry. The document is intended to provide non-binding guidance for use in theregulation of medical devices, and has been subject to consultation throughout its
development.
There are no restrictions on the reproduction, distribution, translation or use of thisdocument however, incorporation of this document, in part or in whole, into any otherdocument does not convey or represent an endorsement of any kind by the Global
Harmonization Task Force.

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1

Introduction

The primary way in which the GHTF achieves its goals is through the production of aseries of guidance documents that together describe a global regulatory model for medical
devices. The purpose of such guidance is to harmonize the documentation and proceduresthat are used to assess whether a medical device conforms to the regulations that apply ineach jurisdiction. Eliminating differences between jurisdictions decreases the cost of gaining
regulatory compliance and allows patients earlier access to new technologies and treatments.
This document has been developed to encourage and support global convergence ofregulatory systems. It is intended for use by Regulatory Authorities, Conformity Assessment
Bodies and industry, and will provide benefits in establishing, in a consistent way, an
economic and effective approach to the control of medical devices in the interest of publichealth. It seeks to strike a balance between the responsibilities of Regulatory Authorities tosafeguard the health of their citizens and their obligations to avoid placing unnecessary
burdens upon the industry. Study Group 1 of the GHTF supports and encourages regulatory
harmonization but recognises that some Regulatory Authorities may have to reflect different
local needs when they introduce new regulations on conformity assessment. However,Regulatory Authorities that are developing conformity assessment schemes or amending
existing ones are encouraged to consider the adoption of the system described in thisdocument, as this will help to reduce the diversity of schemes worldwide and facilitate theprocess of harmonization.
The GHTF has identified as a priority the need to harmonize essential safety andperformance criteria for a medical device that allow the manufacturer to demonstrate its
product is suitable for its intended use. This goal was achieved through the publication of
guidance on the subject entitled Essential Principles of Safety and Performance of Medical
Devices (SG1/N020 of June 30, 1999) that applied to the majority of medical devices but not
to in vitro diagnostic devices. This current document supersedes that earlier one. The
major difference between them is the expanded scope; this document now includes medical
devices for the in vitro examination of specimens derived from the human body.
The regulatory requirements of some countries do not, at this time, align fully withthis guidance.
Study Group 1 of the Global Harmonization Task Force (GHTF) has prepared thisguidance document. Comments or questions about it should be directed to either the
Chairman or Secretary of GHTF Study Group 1 whose contact details may be found on the
GHTF web page1.

1

www.ghtf.org

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2

Rationale, Purpose and Scope

2.1

Rationale

Consistent identification, selection and application of safety and performance
principles to a medical device offers significant benefits to the manufacturer, user, patient or
consumer, and to Regulatory Authorities since it allows its manufacturer to design,
manufacture and demonstrate the device is suitable for its intended use. Moreover,eliminating differences between jurisdictions decreases the cost of gaining regulatorycompliance and allows patients earlier access to new technologies and treatments.
2.2

PurposeTo describe six general requirements of safety and performance that apply to all
medical devices.
To provide a comprehensive list of design and manufacturing requirements ofsafety and performance, some of which are relevant to each medical device. These aregrouped as:• Chemical, physical and biological properties.
• Infection and microbial contamination.
• Manufacturing and environmental properties.
• Devices with a diagnostic or measuring function.
• Protection against radiation.
• Requirements for medical devices connected to or equipped with an energy source.
• Protection against mechanical risks.
• Protection against the risks posed to the patient by supplied energy or substances.
• Protection against the risks posed to the patient for devices for self-testing or selfadministration.
• Information supplied by the manufacturer.
• Performance evaluation including, where appropriate, clinical evaluation.
Note: the manufacturer selects which of the design and manufacturing requirements
are relevant to a particular medical device, documenting the reasons for excluding the others.
The Regulatory Authority and/or Conformity Assessment Body may verify this decision
during the conformity assessment process.
2.3

Scope

This document applies to all products that fall within the definition of a medical
device that appears within the GHTF document Information Document Concerning theDefinition of the Term “Medical Device”, including those used for the in vitro examinationof specimens derived from the human body.

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3

References

GHTF final documents
SG1/N009 Labelling for Medical Devices
SG1/N012 Role of Standards in the Assessment of Medical Devices.
SG1/N020 Essential Principles of Safety and Performance of Medical Devices

GHTF documents available for public comment
SG1(PD)/N011 Summary Technical Documentation for Demonstrating Conformity to the
Essential Principles of Safety and Performance of Medical Devices.
SG1(PD)/N029 Information Document Concerning the Definition of the Term ‘Medical
Device’.
SG1(PD)/N043 Labelling for Medical Devices (revised).

GHTF document being prepared for public comment
SG1(PD)/N040 Principles of Conformity Assessment for Medical Devices.

International standard
ISO 14971:2001 Medical devices – Application of risk management to medical devices.
ISO/TR 16142:2004 Medical Devices – Guidance on the Selection of Standards in Supportof the Recognized Essential Principles of Safety and Performance of Medical

4

Definitions

Clinical evaluation: The review of relevant scientific literature and/or the review andassessment of data collected through clinical investigation.
Clinical investigation: Any designed and planned systematic study in human subjects
undertaken to verify the safety and/or performance of a specific device. (Source –ISO/DIS 14155-1)
Device for self-testing/self-administration: Any device intended by the manufacturer to beable to be used by lay persons in a non-clinical environment. (Source – based on
European Directive 98/79/EC)
Harm: Physical injury or damage to the health of people or damage to property or theenvironment. (Source – ISO/IEC Guide 51:1999)
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Hazard: Potential source of harm. (Source – ISO/IEC Guide 51:1999)
Intended use / purpose: The objective intent of the manufacturer regarding the use of a
product, process or service as reflected in the specifications, instructions andinformation provided by the manufacturer. (Source – 21 CFR 801.4)
Medical device: Refer to GHTF guidance document: Information Concerning the Definitionof the Term “Medical Device” (SG1/N029).
Performance evaluation: Review of the performance of a medical device based upon data
already available, scientific literature and, where appropriate, laboratory, animal or
clinical investigations.
Regulatory Authority (RA): A government agency or other entity that exercises a legal
right to control the use or sale of medical devices within its jurisdiction, and may takeenforcement action to ensure that medical products marketed within its jurisdiction
comply with legal requirements. (Source – EU-Canada MRA)
Risk: Combination of the probability of occurrence of harm and the severity of that harm.
(Source – ISO/IEC Guide 51:1999)
Specimen: The discrete portion of a body fluid or tissue or other sample associated with the
body taken for examination, study, or analysis of one or more quantity or
characteristic to determine the character of the whole.

5

Essential Principles of Safety and Performance of Medical Devices
General Requirements

5.1

Medical devices should be designed and manufactured in such a way that, when used
under the conditions and for the purposes intended and, where applicable, by virtue ofthe technical knowledge, experience, education or training of intended users, they will
not compromise the clinical condition or the safety of patients, or the safety and healthof users or, where applicable, other persons, provided that any risks which may be
associated with their use constitute acceptable risks when weighed against the benefits
to the patient and are compatible with a high level of protection of health and safety.

5.2

The solutions adopted by the manufacturer for the design and manufacture of thedevices should conform to safety principles, taking account of the generally
acknowledged state of the art. When risk reduction is required, the manufacturer
should control the risk(s) so that the residual risk(s) associated with each hazard isjudged acceptable. The manufacturer should apply the following principles in thepriority order listed:•
identify known or foreseeable hazards and estimate the associated risks
arising from the intended use and foreseeable misuse,

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eliminate risks as far as reasonably practicable through inherently safe
design and manufacture,
reduce as far as is reasonably practicable the remaining risks by taking
adequate protection measures, including alarms,
inform users of any residual risks.

5.3

Devices should achieve the performance intended by the manufacturer and be
designed, manufactured and packaged in such a way that they are suitable for one ormore of the functions within the scope of the definition of a medical device applicablein each jurisdiction.

5.4

The characteristics and performances referred to in Clauses 5.1, 5.2 and 5.3 should not
be adversely affected to such a degree that the health or safety of the patient or theuser and, where applicable, of other persons are compromised during the lifetime ofthe device, as indicated by the manufacturer, when the device is subjected to thestresses which can occur during normal conditions of use and has been properly
maintained in accordance with the manufacturer’s instructions.

5.5

The devices should be designed, manufactured and packed in such a way that theircharacteristics and performances during their intended use will not be adversely
affected under transport and storage conditions (for example, fluctuations oftemperature and humidity) taking account of the instructions and information
provided by the manufacturer.

5.6

The benefits must be determined to outweigh any undesirable side effects for the
performances intended.

Design and Manufacturing Requirements
5.7

Chemical, physical and biological properties

5.7.1 The devices should be designed and manufactured in such a way as to ensure thecharacteristics and performance referred to in Clauses 5.1 to 5.6 of the 'General
Requirements'. Particular attention should be paid to:•the choice of materials used, particularly as regards toxicity and, whereappropriate, flammability,•
the compatibility between the materials used and biological tissues,
cells, body fluids, and specimens, taking account of the intended purposeof the device.
•
the choice of materials used should reflect, where appropriate, matterssuch as hardness, wear and fatigue strength.
5.7.2 The devices should be designed, manufactured and packed in such a way as tominimize the risk posed by contaminants and residues to the persons involved in thetransport, storage and use of the devices and to patients, taking account of theintended purpose of the product. Particular attention should be paid to tissues
exposed and to the duration and frequency of exposure.
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5.7.3 The devices should be designed and manufactured in such a way that they can be usedsafely with the materials, substances and gases with which they enter into contact
during their normal use or during routine procedures; if the devices are intended toadminister medicinal products they should be designed and manufactured in such a
way as to be compatible with the medicinal products concerned according to theprovisions and restrictions governing these products and that their performance ismaintained in accordance with the intended use.
5.7.4 Where a device incorporates, as an integral part, a substance which, if used separately,
may be considered to be a medicinal product/drug as defined in the relevant
legislation that applies within that jurisdiction and which is liable to act upon the bodywith action ancillary to that of the device, the safety, quality and usefulness of thesubstance should be verified, taking account of the intended purpose of the device.
5.7.5 The devices should be designed and manufactured in such a way as to reduce as far as
reasonably practicable and appropriate the risks posed by substances that may leach orleak from the device.
5.7.6 Devices should be designed and manufactured in such a way as to reduce as far as
reasonably practicable and appropriate risks posed by the unintentional ingress oregress of substances into or from the device taking into account the device and thenature of the environment in which it is intended to be used.
5.8

Infection and microbial contamination

5.8.1 The devices and manufacturing processes should be designed in such a way as toeliminate or to reduce as far as reasonably practicable and appropriate the risk ofinfection to patients, users and, where applicable, other persons. The design should:• allow easy handling,
and, where necessary:• reduce as far as reasonably practicable and appropriate any microbial
leakage from the device and/or microbial exposure during use,
• prevent microbial contamination of the device, or specimen whereapplicable, by the patient, user or other person.
5.8.2 Where a device incorporates substances of biological origin, the risk of infection must
be reduced as far as reasonably practicable and appropriate by selecting appropriate
sources, donors and substances and by using, as appropriate, validated inactivation,conservation, test and control procedures.
5.8.3 In some jurisdictions products incorporating tissues, cells and substances of nonhuman origin may be considered medical devices. In this case, such tissues, cells andsubstances should originate from animals that have been subjected to veterinary
controls and surveillance adapted to the intended use of the tissues. National
regulations may require that the manufacturer and/or the Regulatory Authority retain
information on the geographical origin of the animals. Processing, preservation,
testing and handling of tissues, cells and substances of animal origin should be carriedout so as to provide optimal safety. In particular, safety with regard to viruses andMarch 1, 2005

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other transmissible agents should be addressed by implementation of validated
methods of elimination or inactivation in the course of the manufacturing process.
5.8.4 In some jurisdictions products incorporating human tissues, cells and substances may
be considered medical devices. In this case, the selection of sources, donors and/or
substances of human origin, the processing, preservation, testing and handling oftissues, cells and substances of such origin should be carried out so as to provide
optimal safety. In particular, safety with regard to viruses and other transmissible
agents should be addressed by implementation of validated methods of elimination or
inactivation in the course of the manufacturing process.
5.8.5 Devices labelled as having a special microbiological state should be designed,
manufactured and packed to ensure they remain so when placed on the market andremain so under the transport and storage conditions specified by the manufacturer.
5.8.6 Devices delivered in a sterile state should be designed, manufactured and packed in a
non-reusable pack, and/or according to appropriate procedures, to ensure that they aresterile when placed on the market and remain sterile, under the transport and storage
conditions indicated by the manufacturer, until the protective packaging is damaged or
opened.
5.8.7 Devices labelled either as sterile or as having a special microbiological state shouldhave been processed, manufactured and, if applicable, sterilized by appropriate,validated methods.
5.8.8 Devices intended to be sterilized should be manufactured in appropriately controlled(e.g. environmental) conditions.
5.8.9 Packaging systems for non-sterile devices should keep the product without
deterioration at the level of cleanliness stipulated and, if the devices are to besterilized prior to use, minimize the risk of microbial contamination; the packaging
system should be suitable taking account of the method of sterilization indicated by
the manufacturer.
5.8.10 The packaging and/or label of the device should distinguish between identical orsimilar products placed on the market in both sterile and non-sterile condition.
5.9

Manufacturing and environmental properties

5.9.1 If the device is intended for use in combination with other devices or equipment, thewhole combination, including the connection system should be safe and should not
impair the specified performance of the devices. Any restrictions on use applying tosuch combinations should be indicated on the label and/or in the instructions for use.
5.9.2 Devices should be designed and manufactured in such a way as to remove or reduce
as far as reasonably practicable and appropriate:•
the risk of injury, in connection with their physical features, including
the volume/pressure ratio, dimensional and where appropriate ergonomic
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•
•
•
•
•

environmental conditions, such as magnetic fields, external electrical andelectromagnetic effects, electrostatic discharge, pressure, humidity,
temperature or variations in pressure and acceleration;
the risks connected to their use in conjunction with materials, substancesand gases with which they may come into contact during normal
conditions of use;
the risks of accidental penetration of substances into the device;
the risk of incorrect identification of specimens;
the risks of reciprocal interference with other devices normally used in
the investigations or for the treatment given;risks arising where maintenance or calibration are not possible (as withimplants), from ageing of materials used or loss of accuracy of any
measuring or control mechanism.

5.9.3 Devices should be designed and manufactured in such a way as to minimize the risksof fire or explosion during normal use and in single fault condition. Particularattention should be paid to devices whose intended use includes exposure to or use inassociation with flammable substances or substances which could cause combustion.
5.9.4 Devices must be designed and manufactured in such a way as to facilitate the safe
disposal of any waste substances.
5.10

Devices with a diagnostic or measuring function

5.10.1 Devices with a measuring function, where inaccuracy could have a significant adverse
effect on the patient, should be designed and manufactured in such a way as toprovide sufficient accuracy, precision and stability for their intended purpose of thedevice. The limits of accuracy should be indicated by the manufacturer.
5.10.2 Diagnostic devices should be designed and manufactured in such a way as to provide
sufficient accuracy, precision and stability for their intended use, based on appropriatescientific and technical methods. In particular the design should address sensitivity,
specificity, trueness, repeatability, reproducibility, control of known relevantinterference and limits of detection, as appropriate.
5.10.3 Where the performance of devices depends on the use of calibrators and/or control
materials, the traceability of values assigned to such calibrators and/or control
materials should be assured through a quality management system.
5.10.4 Any measurement, monitoring or display scale should be designed in line withergonomic principles, taking account of the intended purpose of the device.
5.10.5 Wherever possible values expressed numerically should be in commonly accepted,
standardised units, and understood by the users of the device.
Note: While SG1 generally supports convergence on the global use of internationallystandardised measurement units, considerations of safety, user familiarity, andestablished clinical practice may justify the use of other recognised measurement
units.
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5.11

Protection against radiation

5.11.1 General
5.11.1.1

Devices should be designed and manufactured and packaged in such a way that
exposure of patients, users and other persons to any emitted radiation should be
reduced as far as practicable and appropriate, compatible with the intended
purpose, whilst not restricting the application of appropriate specified levels fortherapeutic and diagnostic purposes.

5.11.2 Intended radiation
5.11.2.1

Where devices are designed to emit hazardous, or potentially hazardous, levels ofvisible and/or invisible radiation necessary for a specific medical purpose thebenefit of which is considered to outweigh the risks inherent in the emission, it
should be possible for the user to control the emissions. Such devices should bedesigned and manufactured to ensure reproducibility of relevant variable
parameters within an acceptable tolerance.

5.11.2.2

Where devices are intended to emit potentially hazardous, visible and/or invisible
radiation, they should be fitted, where practicable, with visual displays and/or
audible warnings of such emissions.

5.11.3 Unintended radiation
5.11.3.1

Devices should be designed and manufactured in such a way that exposure ofpatients, users and other persons to the emission of unintended, stray or scatteredradiation is reduced as far as practicable and appropriate.

5.11.4 Instructions for use
5.11.4.1

The operating instructions for devices emitting radiation should give detailed
information as to the nature of the emitted radiation, means of protecting thepatient and the user and on ways of avoiding misuse and of eliminating the risks
inherent in installation.

5.11.5 Ionizing radiation
5.11.5.1

Devices intended to emit ionizing radiation should be designed and manufactured
in such a way as to ensure that, where practicable, the quantity, geometry andenergy distribution (or quality) of radiation emitted can be varied and controlled
taking into account the intended use.

5.11.5.2

Devices emitting ionizing radiation intended for diagnostic radiology should bedesigned and manufactured in such a way as to achieve appropriate image and/or
output quality for the intended medical purpose whilst minimising radiation
exposure of the patient and user.

5.11.5.3

Devices emitting ionizing radiation, intended for therapeutic radiology should bedesigned and manufactured in such a way as to enable reliable monitoring andMarch 1, 2005

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control of the delivered dose, the beam type and energy and where appropriate theenergy distribution of the radiation beam.
5.12

Requirements for medical devices connected to or equipped with an energy
source5.12.1 Devices incorporating electronic programmable systems, including software, should
be designed to ensure the repeatability, reliability and performance of these systems
according to the intended use. In the event of a single fault condition in the system,
appropriate means should be adopted to eliminate or reduce as far as practicable andappropriate consequent risks.
5.12.2 Devices where the safety of the patients depends on an internal power supply shouldbe equipped with a means of determining the state of the power supply.
5.12.3 Devices where the safety of the patients depends on an external power supply should
include an alarm system to signal any power failure.
5.12.4 Devices intended to monitor one or more clinical parameters of a patient should beequipped with appropriate alarm systems to alert the user of situations which could
lead to death or severe deterioration of the patient's state of health
5.12.5 Devices should be designed and manufactured in such a way as to reduce as far aspracticable and appropriate the risks of creating electromagnetic interference which
could impair the operation of this or other devices or equipment in the usualenvironment.
5.12.6 Devices should be designed and manufactured in such a way as to provide anadequate level of intrinsic immunity to electromagnetic disturbance to enable them tooperate as intended.
5.12.7 Protection against electrical risks
Devices should be designed and manufactured in such a way as to avoid, as far as
possible, the risk of accidental electric shocks during normal use and in single fault
condition, provided the devices are installed and maintained as indicated by the
manufacturer.
5.13

Protection against mechanical risks

5.13.1 Devices should be designed and manufactured in such a way as to protect the patientand user against mechanical risks connected with, for example, resistance tomovement, instability and moving parts.
5.13.2 Devices should be designed and manufactured in such a way as to reduce to thelowest practicable level the risks arising from vibration generated by the devices,taking account of technical progress and of the means available for limiting
vibrations, particularly at source, unless the vibrations are part of the specified
performance.

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5.13.3 Devices should be designed and manufactured in such a way as to reduce to thelowest practicable level the risks arising from the noise emitted, taking account oftechnical progress and of the means available to reduce noise, particularly at source,
unless the noise emitted is part of the specified performance.
5.13.4 Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy
supplies which the user has to handle should be designed and constructed in such a
way as to minimize all possible risks.
5.13.5 Accessible parts of the devices (excluding the parts or areas intended to supply heator reach given temperatures) and their surroundings should not attain potentially
dangerous temperatures under normal use.
5.14

Protection against the risks posed to the patient by supplied energy or substances

5.14.1 Devices for supplying the patient with energy or substances should be designed andconstructed in such a way that the delivered amount can be set and maintained
accurately enough to guarantee the safety of the patient and of the user.
5.14.2 Devices should be fitted with the means of preventing and/or indicating any
inadequacies in the delivered amount which could pose a danger. Devices shouldincorporate suitable means to prevent, as far as possible, the accidental release of
dangerous levels of energy from an energy and/or substance source.
5.14.3 The function of the controls and indicators should be clearly specified on the devices.
Where a device bears instructions required for its operation or indicates operating or
adjustment parameters by means of a visual system, such information should beunderstandable to the user and, as appropriate, the patient.
5.15

Protection against the risks posed to the patient for devices for self-testing or
self-administration

5.15.1 Such devices should be designed and manufactured in such a way that they perform
appropriately for their intended purpose taking into account the skills and the means
available to users and the influence resulting from variation that can reasonably be
anticipated in user’s technique and environment. The information and instructions
provided by the manufacturer should be easy for the user to understand and apply.
5.15.2 Such devices should be designed and manufactured in such a way as to reduce as far
as practicable the risk of use error in the handling of the device and, if applicable, thespecimen, and also in the interpretation of results.
5.15.3 Such devices should, where reasonably possible, include a procedure by which theuser can verify that, at the time of use, that the product will perform as intended by
the manufacturer.
5.16

Information supplied by the manufacturer

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5.16.1 Users should be provided with the information needed to identify the manufacturer, to
use the device safely and to ensure the intended performance, taking account of theirtraining and knowledge. This information should be easily understood.
Note: Further information is provided in SG1/N009 Labelling for Medical Devices
and in SG1/N043 Labelling for Medical Devices (revised).
5.17

Performance evaluation including, where appropriate, clinical evaluation

5.17.1 All data generated in support of performance evaluation should be obtained inaccordance with the relevant requirements applicable in each jurisdiction.
5.17.2 Clinical investigations on human subjects should be carried out in accordance withthe spirit of the Helsinki Declaration. This includes every step in the clinicalinvestigation from first consideration of the need and justification of the study to
publication of the results. In addition, some countries may have specific regulatory
requirements for pre-study protocol review or informed consent.
Note: Refer to SG1(PD)/N040 Principles of Conformity Assessment for Medical
Devices and the work of GHTF Study Group 5 for further information on the use ofclinical evaluation to demonstrate compliance with these Essential Principles.

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参考資料２：GHTF/SG1/N15:2006
GHTF FINAL DOCUMENT『Principles of Medical Devices Classification』

GHTF/SG1/N15:2006

FINAL DOCUMENT
Title: Principles of Medical Devices Classification
Authoring Group: Study Group 1
Endorsed by: The Global Harmonization Task Force
Date: June 27, 2006

Georgette Lalis, GHTF Chair
The document herein was produced by the Global Harmonization Task Force, which is comprised ofrepresentatives from medical device regulatory agencies and the regulated industry. The document isintended to provide non-binding guidance for use in the regulation of medical devices, and has been
subject to consultation throughout its development.
There are no restrictions on the reproduction, distribution or use of this document; however,incorporation of this document, in part or in whole, into any other document, or its translation into
languages other than English, does not convey or represent an endorsement of any kind by the Global
Harmonization Task Force.
Copyright © 2000 by the Global Harmonization Task ForcePrinciples of Medical Devices Classification
Study Group 1 Final Document GHTF/SG1/N15

Table of Contents
1.0
Introduction ................................................................................................................... 4
2.0
Scope............................................................................................................................... 5
3.0
References ...................................................................................................................... 5
4.0
Definitions ...................................................................................................................... 5
5.0
General Principles ......................................................................................................... 7
6.0
Recommendations ......................................................................................................... 8
6.1 Primary Recommendations ............................................................................................. 8
6.2 Factors Influencing Device Classification ...................................................................... 8
6.3 Proposed General Classification System for Medical Devices ..................................... 10
7.0
The Determination of Device Class using this Rules-based System .......................... 11
8.0
Initial Classification Rules ......................................................................................... 12
8.1 Rationale for the inclusion of the Additional Rules into this document ....................... 19
Appendix A: Decision trees to demonstrate how the rules may be used to classify specificdevices………..………………………………………………………………………21

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Preface
The document herein was produced by the Global Harmonization Task Force, avoluntary group of representatives from medical device Regulatory Authorities and theregulated industry. The document is intended to provide non-binding guidance for use in theregulation of medical devices, and has been subject to consultation throughout its development.
There are no restrictions on the reproduction, distribution, translation or use of thisdocument. However, incorporation of this document, in part or in whole, into any otherdocument does not convey or represent an endorsement of any kind by the Global
Harmonization Task Force.

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1.0 Introduction
The objective of the Global Harmonization Task Force (GHTF) is to encourage
convergence at the global level in the evolution of regulatory systems for medical devices inorder to facilitate trade whilst preserving the right of participating members to address theprotection of public health by those regulatory means considered the most suitable.
The primary way in which the Global Harmonization Task Force (GHTF) achieves its
goals is through the production of harmonized guidance documents suitable for implementation
or adoption by member Regulatory Authorities, as appropriate taking into account their
existing legal framework, or by nations with developing regulatory programmes. Eliminating
differences between jurisdictions decreases the cost of gaining regulatory compliance andallows patients earlier access to new technologies and treatments.
This guidance document is one of a series that together describe a global regulatorymodel for medical devices. Its purpose is to assist a manufacturer to allocate its medical device
to an appropriate risk class using a set of harmonized principles. Regulatory Authorities havethe responsibility of ruling upon matters of interpretation for a particular medical device. Onceassigned, such classification will prescribe how the manufacturer will demonstrate that its
device complies with other documents in the series and, in particular, with those entitledEssential Principles of Safety and Performance of Medical Devices and Labelling for Medical
Devices should it be required or requested so to do by a Regulatory Authority, Conformity
Assessment Body, user or third party. It seeks to strike a balance between the responsibilities
of Regulatory Authorities to safeguard the health of their citizens and their obligations to avoid
placing unnecessary burdens upon the industry.
This document should be read in conjunction with the GHTF document on Principles ofConformity Assessment for Medical Devices that recommends conformity assessment
requirements appropriate to each of the four risk classes proposed herein. This link between
documents on classification and conformity assessment is important to ensure a consistent
approach across all countries/regions adopting the global regulatory model recommended by
the GHTF, so that premarket approval for a particular device may become acceptable globally.
Regulatory Authorities who have different classification procedures are encouraged to adopt
this GHTF guidance as the opportunity permits.
This document is intended for use by Regulatory Authorities, Conformity Assessment
Bodies and industry, and will provide benefits in establishing, in a consistent way, an economicand effective approach to the control of medical devices in the interest of public health.
Regulatory Authorities that are developing classification schemes or amending existingones are encouraged to consider the adoption of the system described in this document, as thiswill help to reduce the diversity of schemes worldwide and facilitate the process ofharmonization.
At this time, classification requirements and other regulatory controls assigned to a
medical device by different Regulatory Authorities have yet to be harmonized and may varyfrom the guidance provided in this document.
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This guidance document has been prepared by Study Group 1 of the Global
Harmonization Task Force (GHTF). Comments or questions about it should be directed toeither the Chairman or Secretary of GHTF Study Group 1 whose contact details may be foundon the GHTF web page.

2.0 ScopeThis document applies to all products that fall within the definition of a medical device
that appears within the GHTF document Information Document Concerning the Definition of
the Term ‘Medical Device’, other than those used for the in vitro examination of specimens
derived from the human body for which a separate document is being developed.
.

3.0 References
GHTF final documents
GHTF/SG1/N12:2000 Role of Standards in the Assessment of Medical Devices.
GHTF/SG1/N29:2005 Information Document Concerning the Definition of the Term ‘Medical
Device’.
GHTF/SG1/N40:2006 Principles of Conformity Assessment for Medical Devices.
GHTF/SG1/N41:2005 Essential Principles of Safety and Performance of Medical Devices.
GHTF/SG1/N43:2005 Labelling for Medical Devices.

4.0 Definitions
Active medical device: Any medical device, operation of which depends on a source of electricalenergy or any source of power other than that directly generated by the human body or
gravity and which acts by converting this energy. Medical devices intended to transmit
energy, substances or other elements between an active medical device and the patient,
without any significant change, are not considered to be active medical devices. (Source European Directive 93/42/EEC)
Active therapeutic device: Any active medical device, whether used alone or in combination
with other medical devices, to support, modify, replace or restore biological functions or
structures with a view to treatment or alleviation of an illness, injury or handicap. (Source- European Directive 93/42/EEC)
Active device intended for diagnosis: Any active medical device, whether used alone or in
combination with other medical devices, to supply information for detecting, diagnosing,monitoring or to support in treating physiological conditions, states of health, illnesses orcongenital deformities. (Source – based on European Directive 93/42/EEC)
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Central circulatory system: For the purpose of this document, central circulatory systemmeans the major internal blood vessels including the following: pulmonary veins,
pulmonary arteries, cardiac veins, coronary arteries, carotid arteries (common, internaland external), cerebral arteries, brachiocephalic artery, aorta (includes all segments of
the aorta), inferior and superior vena cava and common iliac arteries.
Central nervous system: For the purpose of this document, central nervous system means brain,
meninges and spinal cord. (Source - European Directive 93/42/EEC)
Duration of use
Transient: Normally intended for continuous use for less than 60 minutes.
Short term: Normally intended for continuous use for between 60 minutes and 30 days.
Long term: Normally intended for continuous use for more than 30 days.
NOTE: For the purpose of this document, continuous use means:a) The entire duration of use of the device without regard to temporary interruption of use
during a procedure or, temporary removal for purposes such as cleaning or disinfection of
the device.
b) The accumulated use of a device that is intended by the manufacturer to be replaced
immediately with another of the same type.
(Source - European Directive 93/42/EEC - modified)
Harm: Physical injury or damage to the health of people or damage to property or theenvironment. (Source – ISO/IEC Guide 51:1999)
Hazard: Potential source of harm. (Source – ISO/IEC Guide 51:1999)
Immediate danger: A situation where the patient is at risk of either losing life or an important
physiological function if no immediate preventative measure is taken.
Intended use / purpose: The objective intent of the manufacturer regarding the use of a
product, process or service as reflected in the specifications, instructions andinformation provided by the manufacturer.
Invasive devices
Invasive device: A device, which, in whole or in part, penetrates inside the body, either
through a body orifice or through the surface of the body.
Body orifice: Any natural opening in the body, as well as the external surface of theeyeball, or any permanent artificial opening, such as a stoma or permanent tracheotomy.
Surgically invasive device: An invasive device which penetrates inside the body throughthe surface of the body, with the aid or in the context of a surgical operation.
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NOTE: Devices other than those referred to in the previous subparagraph andwhich produce penetration other than through an established body orifice, should betreated as surgically invasive devices.
Implantable device: Any device, including those that are partially or wholly absorbed,
which is intended:  to be totally introduced into the human body or, to replace an epithelial surface or the surface of the eye,by surgical intervention which is intended to remain in place after the procedure.
Any device intended to be partially introduced into the human body through surgicalintervention and intended to remain in place after the procedure for at least 30 days is also
considered an implantable device.
(Source - European Directive 93/42/EEC)Life supporting or life sustaining: A device that is essential to, or that yields information thatis essential to, the restoration or continuation of a bodily function important to thecontinuation of human life.
Medical device: See GHTF guidance document: Information Document Concerning theDefinition of the Term ‘Medical Device’ (GHTF/SG1/N29:2005).
Reusable surgical instrument: Instrument intended for surgical use by cutting, drilling, sawing,scratching, scraping, clamping, retracting, clipping or other surgical procedures, without
connection to any active medical device and which are intended by the manufacturer to bereused after appropriate procedures for cleaning and/or sterilisation have been carried out.
(Source - European Directive 93/42/EEC – modified)
Risk: Combination of the probability of occurrence of harm and the severity of that harm.
(Source – ISO/IEC Guide 51:1999)

5.0 General Principles
Regulatory controls are intended to safeguard the health and safety of patients, users
and other persons by ensuring that manufacturers of medical devices follow specified
procedures during design, manufacture and marketing.
The GHTF guidance documents Essential Principles of Safety and Performance ofMedical Devices and Labelling for Medical Devices apply to all devices whatever their risk
class.
Regulatory controls should be proportional to the level of risk associated with a medical
device. The level of regulatory control should increase with increasing degree of risk, taking
account of the benefits offered by use of the device. At the same time, the imposition ofregulatory controls should not place an unnecessary burden on regulators or manufacturers.

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Therefore:
 there is a need to classify medical devices based on their risk to patients, users andother persons; and there is benefit for manufacturers and Regulatory Authorities if a globally
harmonized classification system is developed.
The risk presented by a particular device depends substantially on its intended purpose
and the effectiveness of the risk management techniques applied during design, manufacture
and use.
The risk presented by a device also depends, in part, on its intended user(s), its mode ofoperation, and/or technologies. In general, the classification rules are intended toaccommodate new technologies. Without prejudice to these rules, Regulatory Authorities may
wish to require the notification of new devices being placed on the market in their jurisdictions.
Such notification may be used in assessing the evidence requirements for use in the conformity
assessment process. It may also be used to consider the need, if any, for possible reclassification and/or changes in these harmonized classification rules.

6.0 Recommendations
6.1

Primary Recommendations








6.2

Regulatory Authorities should work towards the establishment of a globalclassification system.
This system should consist of four risk classes. Based on experience of GHTF
Founding Members, this is sufficient to accommodate all medical devices and allows
an efficient and graduated system of conformity assessment controls.
The initial determination of class should be based on a set of rules derived from thosefeatures of devices that create risk. In most cases the initial rules based classification
will also be the final classification.
These rules should be sufficiently clear that manufacturers may readily identify theclass of their medical devices, subject, as required, to final classification by theRegulatory Authority.
The rules should be capable of accommodating future technological developments.
The manufacturer should document its justification for placing its product into aparticular risk class, including the resolution of any matters of interpretation where it
has asked a Regulatory Authority and/or Conformity Assessment Body for a ruling.
Decisions on final classifications, which deviate from the initial rules-basedclassification, should be weighed against the disadvantages of disharmonizedinternational classification.

Factors Influencing Device Classification

A number of factors, including for example the duration of device contact with the body,the degree of invasiveness, whether the device delivers medicinal products or energy to theJune 27, 2006

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patient, whether they are intended to have a biological affect on the patient and local versus
systemic effects (e.g. conventional versus absorbable sutures) may, alone or in combination,affect device classification.
If, based on the manufacturer’s intended purpose, two or more classification rules apply
to the device, the device is allocated the highest level of classification indicated.
Where one medical device is intended to be used together with another medical device,that may or may not be from the same manufacturer, (e.g. a physiological monitor and aseparate recorder, or a general purpose syringe and a syringe driver), the classification rules
should apply separately to each of the devices.
Classification of an assemblage of medical devices that individually comply with all
regulatory requirements depends on the manufacturer’s purpose in packaging and marketingsuch a combination of separate devices. For example:
 If the combination results in a product that is intended by the manufacturer to meet a
purpose different from that of the individual medical devices that make it up, thecombination is a new medical device in its own right and should be classified according to
the new intended use.
 If the combination is for the convenience of the user but does not change the intended usesof the individual medical devices that make it up (e.g. a customised kit that provides all thedevices necessary to carry out a particular surgical procedure), the classification allocatedto the assemblage for the purpose of a Declaration of Conformity is at the level of thehighest classified device included within it.
If one or more of the medical devices that is in the assemblage has yet to comply withall the relevant regulatory requirements, the combination should be classified as a wholeaccording to its intended use.
Accessories intended specifically by manufacturers to be used together with a ‘parent’
medical device to enable that medical device to achieve its intended purpose, should be subject toall the GHTF guidance documents as apply to the medical device itself (e.g. Essential
principles for Safety and Performance, post-market surveillance etc.). For classification
purposes an accessory may be classified as though it is a medical device in its own right.
While most software is incorporated into the medical device itself, some is not.
Provided such standalone software falls within the scope of the definition for a ‘medical
device’, it should be classified as follows: Where it drives or influences the use of a separate medical device, it should beclassified according to the intended use of the combination.
 Where it is independent of any other medical device, it is classified in its own rightusing the rules in Section 8.0 of this document.
 Standalone software (to the extent it falls within the definition of a medical device) isdeemed to be an active device.
Experience gained from the clinical use of a particular type of medical device may
suggest that the rules appearing in Section 8.0 of this document are inappropriate. Current
GHTF procedures require that all GHTF documents be reviewed at regular intervals. Such a
review of this document will provide any participant with an opportunity to suggest a changeof text that, in his/her opinion, will address any shortcoming.
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The purpose of risk classification is to make sure that the regulatory controls applied toa medical device are proportionate to risk. Statutory conformity assessment authority provides
Regulatory Authorities methods to assure compliance with regulatory controls. At this time,
conformity assessment requirements and other regulatory controls assigned to each class ofdevice by different Regulatory Authorities have yet to be harmonized and may vary. While
Study Group 1 of GHTF continues to support and encourage regulatory harmonization, it
recognises that some Regulatory Authorities may have to reflect different local needs or social
considerations when they introduce new regulations on classification, for example, in theapplication of devices covered by the Additional Rules 13 to 16. Study Group 1 hopes any
such differences will disappear in the course of time.
6.3

Proposed General Classification System for Medical Devices

Figure 1 indicates the four risk classes of devices. The examples given are forillustration only and the manufacturer must apply the classification rules to each medical
device according to its intended purpose.

Figure 1: Proposed general classification system for medical devices
CLASS

RISK LEVELDEVICE EXAMPLES

A
B
C

Low Risk
Low-moderate Risk
Moderate-high
Risk
High Risk

Surgical retractors / tongue depressors
Hypodermic Needles / suction equipment
Lung ventilator / bone fixation plate

DHeart valves / implantable defibrillator

Figure 2 shows a conceptual illustration of increasing levels of regulatory requirements
as the device risk class increases. These regulatory controls may include, for example: 






operation of a quality system (recommended for all devices);
technical data;
product testing using in-house or independent resources;
documentation of clinical evidence to support the manufacturer’s claims;
the need for and frequency of independent external audit of the manufacturer’squality system; andindependent external review of the manufacturer’s technical data.

The concept is expanded in the GHTF guidance document entitled Principles ofConformity Assessment for Medical Devices.

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Figure 2: Conceptual illustration of regulatory controls increasing with device risk class

Regulatory
requirements
HIGHERLOWER

Device Class:

A

B

C

D

7.0 The Determination of Device Class using this Rules-based System
The manufacturer should:
1. Decide if the product concerned is a medical device, using the appropriate definition.
NOTE: Medical devices that are used for the in vitro examination of specimens derived
from the human body are not covered by the classification rules within this document(see Scope).
2. Document the intended use of the medical device.
3. Take into consideration all the rules that follow in order to establish the properclassification for the device, noting that where a medical device has features thatplace it into more than one class, classification and conformity assessment should
be based on the highest class indicated.
4. Determine if the device is subject to special national rules that apply within a particularjurisdiction..
NOTES:
 Once a rules-based system has been adopted, modifications may occasionally berequired. For example, where through post-market experience, a level of risk for a
type of medical device, classified using the criteria found in this guidance document isJune 27, 2006

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no longer appropriate, consideration should be given to re-classification of the device
type by a change to the rules.


Similarly, the historical knowledge of a device may necessitate a different class than the
one assigned by the initial classification. Unlike the principle of reclassification after
post-market experience with a device, this principle of historical knowledge should beapplied immediately when the initial classification yields an inappropriate result.

Where special national rules are applied, resulting in a device class other than thatsuggested by the present rules, then a different conformity assessment procedure may
be indicated. This may have an effect on the acceptability of such devices for freemovement in countries where these present rules have been adopted unless other, or
additional, conformity assessment procedures are carried out.

8.0 Initial Classification Rules
The actual classification of each device depends on the claims made by the
manufacturer and on its intended use. While the provision of illustrative examples in the tablethat follows is helpful when interpreting the purpose of each rule, it must be emphasised thatthe actual classification of a particular device must be considered individually, taking accountof its design and intended use.

RULE

ILLUSTRATIVE EXAMPLES OF DEVICES
THAT MAY CONFORM WITH A RULE NON-INVASIVE DEVICES
Rule 1. All non-invasive devices which Devices covered by this rule are extremely claim
sensitive.
come into contact with injured skin:
Examples: simple wound dressings; cotton wool.
- are in Class A if they are intended to
be used as a mechanical barrier, forcompression or for absorption of
exudates only, i.e. they heal by primary
intent;- are in Class B if they are intended to
Examples: non-medicated impregnated gauze
be used principally with wounds which dressings.
have breached the dermis, including
devices principally intended to manage
the microenvironment of a wound.
Devices used to treat wounds where theunless they are intended to be usedsubcutaneous tissue is as least partially exposed
principally with wounds which haveand the edges of the wound are not sufficiently
breached the dermis and can only healby secondary intent, in which case they close to be pulled together. To close the wound,new tissue must be formed within the wound
are in Class C.
prior to external closure. The device
manufacturer claims that they promote healing
through physical methods other than ‘primary
intent’.
Examples: dressings for chronic ulcerated
wounds; dressings for severe burns.
June 27, 2006

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Rule 2. All non-invasive devices
intended for channelling or storing body liquids or tissues,
 liquids or gases
for the purpose of eventual infusion,
administration or introduction into thebody are in Class A,
unless they may be connected to an
active medical device in Class B or ahigher class, in which case they areClass B;

unless they are intended for use of channeling blood, or storing or channeling other bodyliquids, or for storing organs, parts oforgans or body tissues,
in which case they are Class B.
unless they are blood bags, in whichcase they are Class C.

Rule 3. All non-invasive devices
intended for modifying the biological orchemical composition of blood, other body liquids, or other liquids
intended for infusion into the body are
in Class C,

unless the treatment consists offiltration, centrifuging or exchanges ofgas or of heat, in which case they are inClass B.
Rule 4. All other non-invasive devices
are in Class A.

Such devices are ‘indirectly invasive’ in thatthey channel or store liquids that will eventually
be delivered into the body (see comment forRule 4).
Examples: administration sets for gravity
infusion; syringes without needles.

Examples: syringes and administration sets forinfusion pumps; anaesthesia breathing circuits.
NOTE: “Connection” to an active device covers
those circumstances where the safety andperformance of the active device is influenced by
the non-active device and vice versa.
Examples: tubes used for blood transfusion,organ storage containers.

Example: Blood bags that do not incorporate ananti-coagulant.
NOTE: in some jurisdictions, blood bags have a
special rule that places them within a different
risk class.
Such devices are indirectly invasive in that theytreat or modify substances that will eventually bedelivered into the body (see note to comment forRule 4). They are normally used in conjunction
with an active device within the scope of either
Rule 9 or 11.
Examples: haemodializers; devices to remove
white blood cells from whole blood.
NOTE: for the purpose of this part of the rule,‘modification’ does not include simple,
mechanical filtration or centrifuging which arecovered below.
Examples: devices to remove carbon dioxide;
particulate filters in an extracorporial circulation
system.

These devices either do not touch the patient or
contact intact skin only.
Examples: urine collection bottles; compression
hosiery; non-invasive electrodes, hospital beds.
 INVASIVE DEVICES
Rule 5. All invasive devices with
Such devices are invasive in body orifices andrespect to body orifices (other thanare not surgically invasive (refer to definition inJune 27, 2006

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those which are surgically invasive) andwhich:
 are not intended for connection to an
active medical device, or are intended for connection to a
Class A medical device only.
- are in Class A if they are intended fortransient use;
- are in Class B if they are intended forshort-term use;
unless they are intended for short-term
use in the oral cavity as far as thepharynx, in an ear canal up to the ear
drum or in a nasal cavity, in which casethey are in Class A,- are in Class C if they are intended forlong-term use;

unless they are intended for long-term
use in the oral cavity as far as thepharynx, in an ear canal up to the eardrum or in a nasal cavity and are notliable to be absorbed by the mucous
membrane, in which case they are inClass B.
All invasive devices with respect tobody orifices (other than those which
are surgically invasive) that are
intended to be connected to an active
medical device in Class B or a higher
class, are in Class B.
Rule 6. All surgically invasive devices
intended for transient use are in Class B,

unless they are reusable surgicalinstruments, in which case they are inClass A; orunless intended to supply energy in theJune 27, 2006

Section 4). Devices tend to be diagnostic andtherapeutic instruments used in ENT,
ophthalmology, dentistry, proctology, urology
and gynaecology. Classification depends on the
duration of use and the sensitivity (orvulnerability) of the orifice to such invasion.
Examples: examination gloves; enema devices.
Examples: urinary catheters, tracheal tubes.
Examples: dentures intended to be removed by
the patient; dressings for nose bleeds.

Example: urethral stent; contact lenses for longterm continuous use (for this device, removal of
the lens for cleaning or maintenance isconsidered as part of the continuous use).
Examples: orthodontic wire, fixed dental
prosthesis.

Examples: tracheal tubes connected to aventilator; suction catheters for stomach
drainage; dental aspirator tips.
NOTE: independent of the time for which they
are invasive.
A majority of such devices fall into several
major groups: those that create a conduit throughthe skin (e.g. syringe needles; lancets), surgicalinstruments (e.g. single-use scalpels; surgicalstaplers; single-use aortic punch); surgicalgloves; and various types of catheter/sucker etc.
NOTE: a surgical instrument (other than thosein Class D) is in Class A if reusable and in Class
B if supplied sterile and intended for single use.
Also, a surgical instrument connected to an
active device is in a higher class than A.
NOTE: if the device incorporates a medicinal
substance in a secondary role refer to Rule 13.
Examples: Manually operated surgical drill bits
and saws.
Example: catheter incorporating/containing
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form of ionizing radiation, in whichcase they are in Class C; orunless intended to have a biologicaleffect or be wholly or mainly absorbed,
in which case they are in Class C; orunless intended to administer medicinal
products by means of a delivery system,
if this is done in a manner that is
potentially hazardous taking account of
the mode of application, in which they
are in Class C; orunless they are intended specifically foruse in direct contact with the central
nervous system, in which case they are
in Class D; orunless intended specifically todiagnose, monitor or correct a defect of
the heart or of the central circulatory
system through direct contact with theseparts of the body, in which case they are
in Class D.
Rule 7. All surgically invasive devices
intended for short-term use are in Class
B,

unless they are intended to administer
medicinal products, in which case they
are in Class C; orunless they are intended to undergochemical change in the body (except if
the devices are placed in the teeth), in
which case they are in Class C; orunless they are intended to supply
June 27, 2006

sealed radioisotopes.
NOTES: (a) the ‘biological effect’ referred to is
an intended one rather than unintentional. The
term ‘absorption’ refers to the degradation of amaterial within the body and the metabolic
elimination of the resulting degradation products
from the body.
(b) This part of the rule does not apply to those
substances that are excreted without
modification from the body.
Example: Insufflation gases for the abdominal
cavity.
Example: insulin pen for self-administration.
NOTE: the term ‘administration of medicines’
implies storage and/or influencing therate/volume of medicine delivered not justchannelling. The term ‘potentially hazardous
manner’ refers to the characteristics of the device
and not the competence of the user.

Examples: angioplasty balloon catheters andrelated guide wires; dedicated disposablecardiovascular surgical instruments.

Such devices are mostly used in the context ofsurgery or post-operative care, or are infusion
devices, or are catheters of various types.
Examples: infusion cannulae; temporary fillingmaterials; non-absorbable skin closure devices;
tissue stabilisers used in cardiac surgery.
NOTE: includes devices that are used during
cardiac surgery but do not monitor or correct a
defect.
NOTE: if the device incorporates a medicinal
substance in a secondary role refer to Rule 13.
NOTE: the term ‘administration of medicines’
implies storage and/or influencing therate/volume of medicine delivered not justchannelling.
Example: surgical adhesive.

Example: brachytherapy device.
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energy in the form or ionizing radiation,in which case they are in Class C; orunless they are intended to have abiological effect or to be wholly or
mainly absorbed, in which case they are
in Class D; orunless they are intended specifically foruse in direct contact with the central
nervous system, in which case they are
in Class D;
unless they are intended specifically todiagnose, monitor or correct a defect of
the heart or of the central circulatory
system through direct contact with theseparts of the body, in which case they are
in Class D.
Rule 8. All implantable devices, andlong-term surgically invasive devices, arein Class C,

unless they are intended to be placed
into the teeth, in which case they are inClass B; orunless they are intended to be used indirect contact with the heart, the central
circulatory system or the central
nervous system, in which case they are
in Class D; orunless they are intended to be life
supporting or life sustaining, in whichcase they are in Class D; orunless they are intended to be active
implantable medical devices, in whichcase they are Class D; orunless they are intended to have abiological effect or to be wholly or
mainly absorbed, in which case they are
in Class D; orunless they are intended to administer
medicinal products, in which case they
are in Class D; orJune 27, 2006

Example: absorbable suture; biological adhesive.
NOTE: the ‘biological effect’ referred to is anintended one rather than unintentional. The term
‘absorption’ refers to the degradation of amaterial within the body and the metabolic
elimination of the resulting degradation products
from the body.
Example: neurological catheter.

Examples: cardiovascular catheters; temporary
pacemaker leads; carotid artery shunts.

Most of the devices covered by this rule are
implants used in the orthopaedic, dental,
ophthalmic and cardiovascular fields.
Example: maxilla-facial implants; prosthetic
joint replacements; bone cement; non-absorbableinternal sutures; posts to secure teeth to themandibula bone (without a bioactive coating).
NOTE: if the device incorporates a medicinal
substance in a secondary role refer to Rule 13.
Examples: bridges; crowns; dental fillingmaterials.
Examples: prosthetic heart valves; spinal andvascular stents.

Example: pacemakers, their electrodes and theirleads; implantable defibrillators.
Example: implants claimed to be bioactive.
NOTE: hydroxy-apatite is considered as having
biological effect only if so claimed anddemonstrated by the manufacturer.
Example: rechargeable non-active drug delivery
system.

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NOTE: bone cement is not within the scope ofunless they are intended to undergo
the term ‘chemical change in the body’ since any
chemical change in the body (except ifchange takes place in the short rather than longthe devices are placed in the teeth), in
term.
which case they are in Class D; orunless they are breast implants, in whichcase they are in Class D.
 ACTIVE DEVICES
Rule 9(i). All active therapeutic devices Such devices are mostly electrically powered
equipment used in surgery; devices forintended to administer or exchange
specialised treatment and some stimulators.
energy are in Class B,
Examples: muscle stimulators; TENS devices;
powered dental hand pieces; hearing aids;
neonatal phototherapy equipment; ultrasoundequipment for physiotherapy.
Examples: lung ventilators; baby incubators;
unless their characteristics are such thatthey may administer or exchange energy electrosurgical generators; external pacemakers
and defibrillators; surgical lasers; lithotriptors;
to or from the human body in atherapeutic X-ray and other sources of ionizing
potentially hazardous way, including
ionizing radiation, taking account of the radiation.
nature, the density and site of application NOTE: the term ‘potentially hazardous’ refers
to the type of technology involved and theof the energy, in which case they are inintended application.
Class C.
Rule 9(ii). All active devices intended
Examples: external feedback systems for active
to control or monitor the performance of therapeutic devices.
active therapeutic devices in Class C, orintended directly to influence theperformance of such devices, are inClass C.
Such devices include equipment for ultrasonic
Rule 10(i). Active devices intended for
diagnosis/imaging, capture of physiologicaldiagnosis are in Class B:
signals, interventional radiology and diagnostic
radiology.
Examples: magnetic resonance equipment;- if they are intended to supply energy
diagnostic ultrasound in non-criticalwhich will be absorbed by the humanapplications; evoked response stimulators.
body (except for devices used solely toilluminate the patient's body, with lightin the visible or near infra-red spectrum,in which case they are Class A), or
Example: gamma/nuclear cameras.
- if they are intended to image in vivo
distribution of radiopharmaceuticals, orExample: electronic thermometers, stethoscopes- if they are intended to allow direct
and blood pressure monitors;
diagnosis or monitoring of vital
electrocardiographs.
physiological processes,
unless they are specifically intendedfor:
Example: monitors/alarms for intensive care;a) monitoring of vital physiologicalbiological sensors; oxygen saturation monitors;
parameters, where the nature of
apnoea monitors.
variations is such that it could result in
immediate danger to the patient, for
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instance variations in cardiac
performance, respiration, activity ofcentral nervous system, orb) diagnosing in clinical situations
where the patient is in immediate
danger,in which case they are in Class C.
Rule 10(ii). Active devices intended toemit ionizing radiation and intended for
diagnostic and/or interventional
radiology, including devices which
control or monitor such devices, or thosewhich directly influence theirperformance, are in Class C.
Rule 11. All active devices intended toadminister and/or remove medicinal
products, body liquids or othersubstances to or from the body are inClass B,

unless this is done in a manner that is
potentially hazardous, taking account of
the nature of the substances involved, ofthe part of the body concerned and of themode and route of administration, in
which case they are in Class C.
Rule 12. All other active devices are inClass A.

Example: ultrasound equipment for use ininterventional cardiac procedures.

Example: these include devices for the control,
monitoring or influencing of the emission ofionizing radiation.

Such devices are mostly drug delivery systems
or anaesthesia equipment.
Examples of Class B devices: suction
equipment; feeding pumps; jet injectors for
vaccination; nebuliser to be used on consciousand spontaneously breathing patients where
failure to deliver the appropriate dosage
characteristics is not potentially hazardous.
Examples: infusion pumps; anaesthesia
equipment; dialysis equipment; hyperbaric
chambers; nebuliser where the failure to deliver
the appropriate dosage characteristics could be
hazardous.

Examples: examination lamps; surgicalmicroscopes; powered hospital beds &wheelchairs; powered equipment for therecording, processing, viewing of diagnostic
images; dental curing lights.
 ADDITIONAL RULES
Rule 13. All devices incorporating, as an These medical devices incorporate medicinal
integral part, a substance which, if used
substances in an ancillary role.
separately, can be considered to be a
Examples: antibiotic bone cements; heparinmedicinal product, and which is liable to coated catheters; wound dressings incorporating
act on the human body with action
antimicrobial agents to provide ancillary action
ancillary to that of the devices, are inon the wound; blood bags incorporating an antiClass D.
coagulant.
NOTE: Such medical devices may be subject toadditional conformity assessment procedures
according to the regional or national
requirements of medicinal product Regulatory
Authorities.
Rule 14. All devices manufactured fromor incorporating animal or humanJune 27, 2006

NOTE: In some jurisdictions such products:- are considered to be outside the scope of the
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cells/tissues/derivatives thereof,
whether viable or non-viable,
are Class D,

unless such devices are manufactured
from or incorporate non-viable animal
tissues or their derivatives that come incontact with intact skin only, where they
are in Class A.

-

medical device definition;
may be subject to different controls.

It is likely the regulations controlling thesedevices will be the subject of future
harmonization efforts.
Examples: porcine heart valves; catgut sutures.
Examples: leather components of orthopaedic
appliances.

Examples: devices for disinfecting or sterilisingendoscopes; disinfectants intended to be used withmedical devices.
NOTE: This rule does not apply to products thatare intended to clean medical devices by means ofphysical action e.g. washing machines.
unless they are intended for disinfecting Example: washer disinfectors.
medical devices prior to end pointsterilisation or higher level disinfection,in which case they are in Class B; or
In some jurisdictions solutions for use with
unless they are intended specifically to
be used for disinfecting, cleaning, rinsing contact lenses:- are considered to be outside the scope of theor, when appropriate, hydrating contact
medical devices definition;lenses, in which case they are in Class C.
- may be subject to different controls.
Examples: condoms; contraceptive diaphragms.
Rule 16. All devices used forcontraception or the prevention of thetransmission of sexually transmitted
diseases are in Class C,
unless they are implantable or long-term Example: intrauterine contraceptive device.
invasive devices, in which case they are
in Class D.
Rule 15. All devices intended
specifically to be used for sterilising
medical devices, or disinfecting as theend point of processing, are in Class C.

Decision trees illustrating how these rules may be used to classify specific devices areshown in Appendix A.
8.1

Rationale for the inclusion of the Additional Rules into this document

There are a small number of products that fall within the scope of the definition of a
medical device and which may need to be classified to take account of factors other than those
covered by the general rules (Rules 1 to 12). For the understanding of those countries that are
not Founding Members of GHTF, it is felt important to offer guidance on the classification ofsuch devices (see Clause 6.2, above). Therefore, four Additional Rules are provided (Rules 13
to 16).
Matters that may need to be considered are: June 27, 2006

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Rule 13:Rule 14:

Rule 15

Rule 16

June 27, 2006

Devices incorporating a medicinal product The regulations applying to medicinal products requiredifferent acceptance procedures to those for medical devices.
 The behavior of a medicinal product used in conjunction with a
medical device may differ from that covered by its approved
use as a medicinal product alone.
Devices incorporating animal or human tissues
 There is an absence of global regulatory controls for suchdevices.
 Classification needs to acknowledge the diversity of opinions
on such devices, globally.
 The possible risks associated with the transmission of
infectious agents through materials used in such devices, e.g.
Bovine Spongiform Encephalopathies (BSE) and CreutzfeldtJacob disease (CJD), demand classification at a higher risk
level.
Disinfectants
 The particular concerns relating to those disinfectants that areused with contact lenses, due to sensitivity and vulnerability ofthe eye.
Contraceptive devices
 The risks associated with unwanted pregnancy if caused bymechanical failure of the device.
 The need to safeguard public health through the use of condoms
to reduce the prevalence of sexually transmitted diseases.
 User expectation that contraceptive devices are perfectly
reliable and safe despite published data to the contrary.

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Appendix A: Decision trees to demonstrate how the rules
may be used to classify specific devices.

June 27, 2006

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NOTE: This diagram and those that follow are for illustrative purposes only and thedetermination of risk class for a particular device should be made by referring to therules themselves and not the decision trees. Where a medical device has features thatplace it into more than one class, conformity assessment should be based on the highest
class indicated.
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参考資料３：GHTF/SG1/N011:2008
GHTF FINAL DOCUMENT『Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of
Safety and Performance of Medical Devices (STED)』

GHTF/SG1/N011:2008

FINAL DOCUMENT
Global Harmonization Task Force

Title: Summary Technical Documentation for Demonstrating Conformity to
the Essential Principles of Safety and Performance of Medical Devices(STED)
Authoring Group: Study Group 1 of the Global Harmonization Task Force
Date: February 21, 2008

Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and
Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008

Table of Contents
1.0
Introduction ................................................................................................................... 4
2.0
Rationale, Purpose and Scope ...................................................................................... 4
2.1 Rationale ....................................................................................................................... 4
2.2 Purpose ......................................................................................................................... 5
2.3 Scope............................................................................................................................. 5
3.0
References ...................................................................................................................... 5
4.0
Definitions ...................................................................................................................... 6

PART 1 – PURPOSE OF THE STED
5.0
Preparation and Use of the STED ............................................................................... 6
5.1 Preparation .................................................................................................................... 6
5.2 The Use of the STED in the Premarket Phase .............................................................. 7
5.3 The Use of the STED in the Post-market Phase ........................................................... 8
5.4 The Use of the STED to Notify Changes to the RA/CAB ........................................... 9PART 2 – CONTENTS OF THE STED
6.0
Device Description and Product Specification, Including Variants andAccessories ................................................................................................................................. 9
6.1 Device Description ....................................................................................................... 9
6.2 Product Specification .................................................................................................. 10
6.3 Reference to similar and previous generations of the device ..................................... 10
7.0
Labelling ...................................................................................................................... 10
8.0
Design and Manufacturing Information ................................................................... 11
8.1 Device Design ............................................................................................................. 11
8.2 Manufacturing Processes ............................................................................................ 11
8.3 Design and Manufacturing Sites ................................................................................. 11
9.0
Essential Principles (EP) Checklist ........................................................................... 11
10.0 Risk Analysis and Control Summary ........................................................................ 1211.0 Product Verification and Validation ......................................................................... 1211.1 General ........................................................................................................................ 1211.2 Biocompatibility ......................................................................................................... 13
11.3 Medicinal Substances ................................................................................................. 13
11.4 Biological Safety ........................................................................................................ 13
11.5 Sterilisation ................................................................................................................. 14
11.6 Software Verification and Validation ......................................................................... 14
11.7 Animal Studies............................................................................................................ 14
11.8 Clinical Evidence ........................................................................................................ 14
12.0 Format of the STED.................................................................................................... 15
13.0 Declaration of Conformity ......................................................................................... 15
Appendix A .......................................................................................................................... 16

February 21, 2008

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Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008

Preface
The document herein was produced by the Global Harmonization Task Force, avoluntary group of representatives from medical device regulatory authorities and theregulated industry. The document is intended to provide non-binding guidance for use in theregulation of medical devices, and has been subject to consultation throughout its
development.
There are no restrictions on the reproduction, distribution, translation or use of thisdocument. However, incorporation of this document, in part or in whole, into any otherdocument does not convey or represent an endorsement of any kind by the Global
Harmonization Task Force.

February 21, 2008

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Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and
Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008

1.0 Introduction
The primary way in which the GHTF achieves its goals is through the production of aseries of guidance documents that together describe a global regulatory model for medical
devices. The purpose of such guidance is to harmonize the documentation and proceduresthat are used to assess whether a medical device conforms to the regulations that apply ineach jurisdiction. Eliminating differences between jurisdictions decreases the cost of gaining
regulatory compliance and allows patients earlier access to new technologies and treatments.
This document has been developed to encourage and support global convergence ofregulatory systems. It is intended for use by Regulatory Authorities (RAs), Conformity
Assessment Bodies (CABs) and industry, and will provide benefits in establishing, in aconsistent way, an economic and effective approach to the control of medical devices in theinterest of public health. It seeks to strike a balance between the responsibilities ofRegulatory Authorities to safeguard the health of their citizens and their obligations to avoid
placing unnecessary burdens upon the industry.
The GHTF has identified as a priority the need to harmonize the documentation ofevidence of conformity to the essential principles of safety and performance. This guideline
provides recommendations on the content of summary technical documentation (STED) to beassembled and submitted to a Regulatory Authority or Conformity Assessment Body. Itshould enable a manufacturer to prepare a STED and provide different Regulatory
Authorities or Conformity Assessment Bodies with the same body of documentary evidence
that its medical device conforms to the essential principles. The use of the STED should
reduce costs for the manufacturer and reviewer, remove barriers to trade and facilitate timely
international access to medical devices.
Where other guidance documents within the series are referenced within this text,
their titles are italicised for clarity.
The regulatory requirements of some countries do not, at this time, align fully withthis guidance.
Study Group 1 of the Global Harmonization Task Force (GHTF) has prepared thisguidance document. Comments or questions should be directed to either the Chairman or
Secretary of GHTF Study Group 1 whose contact details may be found on the GHTF web
page1.

2.0 Rationale, Purpose and Scope
2.1

Rationale

Manufacturers are expected to prepare, and either hold or provide timely access to,technical documentation that shows how each medical device was developed, designed andmanufactured. This technical documentation, typically controlled in the manufacturer’s
1

www.ghtf.org

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Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008

quality management system (QMS), is often extensive and sections of it may be held in
different locations. The documentation is updated to reflect any changes made during thelifecycle of the device.
It is advantageous to both RAs/CABs and the regulated industry if a subset of thistechnical documentation is used for selected premarket and postmarket conformity
assessment activities. This documentation subset is intended to be in a consistent,summarised or abridged form, with sufficient detail to allow the RA/CAB to fulfil its
obligations. In the main, the documents contained within this subset are derived from thetechnical documentation held by the manufacturer and allow the manufacturer to demonstratethat the medical device to which it applies conforms to the Essential Principles of Safety and
Performance of Medical Devices.
The availability of such Summary Technical Documentation (STED) should help
eliminate differences in documentation requirements between jurisdictions, thus decreasing
the cost of gaining regulatory compliance and allowing patients earlier access to newtechnologies and treatments.
2.2

PurposeThis document is intended to provide guidance on the content of the STED to beassembled and submitted to a RA or CAB for premarket review, and for use post-market toassess continuing conformity to the Essential Principles of Safety and Performance.
2.3

Scope

This document applies to all products that fall within the definition of a medical
device that appears within the GHTF document Information Document Concerning theDefinition of the Term “Medical Device”, excluding those used for the in vitro diagnostic
examination of specimens derived from the human body.

3.0 References
GHTF/SG1/N044:2008 Role of Standards in the Assessment of Medical Devices.
GHTF/SG1/N15:2006 Principles of Medical Devices Classification.
GHTF/SG1/N29:2005 Information Document Concerning the Definition of the Term
‘Medical Device’.
GHTF/SG1/N40:2006 Principles of Conformity Assessment for Medical Devices.
GHTF/SG1/N41:2005 Essential Principles of Safety and Performance of Medical Devices.
GHTF/SG1/N43:2005 Labelling for Medical Devices.

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4.0 Definitions
4.1

Recognised standard: standard deemed to offer the presumption of conformity to
specific Essential Principles of Safety and Performance.

4.2

Technical documentation: the documented evidence, normally an output of thequality management system that demonstrates conformity of a device to the Essential
Principles of Safety and Performance of Medical Devices.

PART 1 – PURPOSE OF THE STED
5.0 Preparation and Use of the STED
5.1

Preparation

Manufacturers of all classes of device are expected to demonstrate conformity of thedevice to the Essential Principles of Safety and Performance of Medical Devices (hereafterreferred to as Essential Principles) through the preparation and holding of technicaldocumentation that shows how each medical device was developed, designed andmanufactured together with the descriptions and explanations necessary to understand the
manufacturer’s determination with respect to such conformity. This technical documentation
is updated as necessary to reflect the current status, specification and configuration of thedevice.
For the purpose of conformity assessment, the manufacturer creates the STED fromexisting technical documentation to provide evidence to the RA/CAB that the subject medical
device is in conformity with the Essential Principles. The STED reflects the status of the
medical device at a particular moment in time (e.g. at the moment of premarket submission orwhen requested by a RA for post-market purposes) and is prepared in order to meet
regulatory requirements. The flow of information from the technical documentation to the
STED is illustrated in Figures 1 and 2.
The STED should be in a language acceptable to the RA/CAB.
The depth and detail of the information contained in the STED will depend on: the classification of the subject device; the complexity of the subject device.
It also depends upon whether the device has the following characteristics:
 it incorporates novel technology;
 it is an already marketed device type that is now being offered for an intended
use different from the original one; it is new to the manufacturer;

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the device type has been associated with a significant number of adverse
events, including use errors2;
it incorporates novel or potentially hazardous materials;
the device type raises specific public health concerns.

The STED should contain summary information on selected topics, detailed
information on certain specific topics (as indicated below) and an Essential Principles
checklist (EP checklist). The information provided may include, for example, abstracts, highlevel summaries, or existing controlled documents, as appropriate, sufficient to communicate
key relevant information and allow a reviewer to understand the subject. The EP checklist is
created as part of the manufacturer’s technical documentation and should be a controlled
document within the manufacturer’s QMS. It provides a tabular overview of the Essential
Principles and identifies those that are applicable to the device, the chosen method of
demonstrating that the device conforms to each relevant Essential Principle and the referenceof the controlled document/s that is/are relevant to a specific Essential Principle. While many
controlled documents are referenced in the EP checklist, only some are contained within the
STED. The cited references to the controlled documents facilitate requests from a RA/CAB
to provide additional information.
5.2

The Use of the STED in the Premarket Phase

In the premarket phase, the STED will be prepared and submitted to the RA/CAB forClass C and D devices. For Class A and B devices the STED will be prepared and submitted
only at the request of a RA/CAB. (See Figure 1)
NOTES:
 For Class A and B devices where the STED is prepared on request, themanufacturer should be able to assemble and submit it in the timeframe
indicated by the RA/CAB. This may be short.
 A copy of any submitted STED should be held by the manufacturer for futurereference.

2

See GHTF/SG2 guidance documents.

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TECHNICALDOCUMENTATION (Controlled
Documents e.g. Under a QMS)
Device description and productspecification, including variants andaccessories

Documentation subset

Documentation subset

SUMMARY TECHNICALDOCUMENTATION (STED)
General description and list of
specified features

Documentation subset
Set of labels and list of language
variants

LabellingComplete design and manufacturing
information

Relevant Essential Principles andproof of conformity

Device risk management fileUpon request, prepare
STED for Class A & B
devices & make available
for review by RA/CABFor Class C & D devices
prepare and submit
STED to RA / CAB forreview
E.P. Checklist

Summary of the technicaldocumentation concerning design
and manufacturing

E.P. Checklist

Risk analysis and control summary

Documentation subset
Complete product verification andvalidation documentation

Clinical evidence

Documentation subset

Summary of verification andvalidation studies

Documentation subset

Clinical evaluation report

FIGURE 1: PREMARKET USE OF THE STED

5.3

The Use of the STED in the Post-market Phase

In the post-market phase, the RA/CAB may request submission of a STED for thedevice in question either to investigate conformity of a Class A or B medical device or thecontinued conformity of a Class C or D medical device (see Figure 2).
The STED would not typically be used to aid the postmarket investigation of adverse
events, or the reporting of data from postmarket registries or studies, where different types of
information are likely to be called for.
NOTES:
 The manufacturer should be able to prepare and submit the STED in thetimeframe indicated by the RA/CAB. This may be short.
 A copy of any submitted STED should be held by the manufacturer for futurereference.

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TECHNICALDOCUMENTATION (Controlled
Documents e.g. Under a QMS)
Device description and productspecification, including variants andaccessories

Documentation subset

Documentation subset

SUMMARY TECHNICALDOCUMENTATION (STED)
General description and list of
specified features

Documentation subset
Set of labels and list of language
variants

LabellingComplete design and manufacturing
information

Relevant Essential Principles andproof of conformity

Device risk management fileUpon request, prepare
STED & make available
for review by RA/CAB

Summary of the technicaldocumentation concerning design
and manufacturing

E.P. Checklist

E.P. Checklist

Risk analysis and control summary

Documentation subset
Complete product verification andvalidation documentation

Clinical evidence

Documentation subset
Documentation subset

Summary of verification andvalidation studies
Clinical evaluation report

FIGURE 2: POST-MARKET USE OF THE STED

5.4

The Use of the STED to Notify Changes to the RA/CAB

Where prior approval of a proposed change to a medical device is required, the STED
may be used in support of this process. Guidance on this case will be provided in the future

PART 2 – CONTENTS OF THE STED
6.0 Device Description and Product Specification, Including Variants andAccessories
6.1

Device Description
The STED should contain the following descriptive information for the device:a) a general description including its intended use/purpose;b) the intended patient population and medical condition to be diagnosed
and/or treated and other considerations such as patient selection criteria;c) principles of operation;d) risk class and the applicable classification rule according to Principles ofMedical Devices Classification;

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Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and
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Study Group 1 Final Document GHTF/SG1/N011:2008e) an explanation of any novel features;f) a description of the accessories, other medical devices and other productsthat are not medical devices, which are intended to be used in
combination with it;g) a description or complete list of the various configurations/variants of thedevice that will be made available;h) a general description of the key functional elements, e.g. its
parts/components (including software if appropriate), its formulation, its
composition, its functionality. Where appropriate, this will include:
labelled pictorial representations (e.g. diagrams, photographs, anddrawings), clearly indicating key parts/components, including sufficient
explanation to understand the drawings and diagrams.
i) a description of the materials incorporated into key functional elements
and those making either direct contact with a human body or indirectcontact with the body, e.g., during extracorporial circulation of body
fluids.
6.2

Product Specification

The STED should contain a list of the features, dimensions and performance attributesof the medical device, its variants and accessories (if such are within the scope of the STED),
that would typically appear in the product specification made available to the end user, e.g. inbrochures, catalogues and the like.
6.3

Reference to similar and previous generations of the device

Where relevant to demonstrating conformity to the Essential Principles, and to theprovision of general background information, the STED should contain an overview of:a) the manufacturer’s previous generation(s) of the device, if such exist;
and/orb) similar devices available on the local and international markets.

7.0 Labelling
The STED should typically contain a complete set of labelling associated with thedevice as described in GHTF guideline Labelling for Medical Devices and a list of language
variants for the countries where the device will be marketed. Information on labelling should
include the following: labels on the device and its packaging; instructions for use; and promotional material.
The labelling set should be in a language acceptable to the reviewing RA or CAB.

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8.0 Design and Manufacturing Information
8.1

Device Design

The STED should contain information to allow a reviewer to obtain a general
understanding of the design stages applied to the device. It is not intended to take the placeof the more detailed information required for a QMS audit or other conformity assessment
activity. The information may take the form of a flow chart.
8.2

Manufacturing Processes

The STED should contain information to allow a reviewer to obtain a general
understanding of the manufacturing processes. It is not intended to take the place of the moredetailed information required for a QMS audit or other conformity assessment activity. The
information may take the form of a process flow chart showing, for example, an overview of
production, assembly, any final product testing, and packaging of the finished medical device.
8.3

Design and Manufacturing Sites

For the activities in 8.1 and 8.2, the STED should identify the sites where these
activities are performed. If QMS certificates, or the equivalent, exist for these sites, theyshould be annexed to the STED.

9.0 Essential Principles (EP) Checklist
The STED should contain an EP checklist that identifies:a) the Essential Principles;b) whether each Essential Principle applies to the device and if not, why not;c) the method(s) used to demonstrate conformity with each Essential
Principle that applies;d) a reference for the method(s) employed (e.g., standard), ande) the precise identity of the controlled document(s) that offers evidence ofconformity with each method used.
Methods used to demonstrate conformity may include one or more of the following:a) conformity with recognised or other standards3;b) conformity with a commonly accepted industry test method(s);c) conformity with an in-house test method(s);d) the evaluation of pre-clinical and clinical evidence4.
e) comparison to a similar device already available on the market.
The EP checklist should incorporate a cross-reference to the location of such evidence
both within the full technical documentation held by the manufacturer and within the STED
3
4

See GHTF/SG1/N044:2008 Role of Standards in the Assessment of Medical Devices
See GHTF/SG5 guidance documents

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Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008(when such documentation is specifically required for inclusion in the Summary TechnicalDocumentation as outlined in this guidance).
A template for a checklist is shown in Appendix A.

10.0 Risk Analysis and Control Summary
The STED should contain a summary of the risks identified during the risk analysis
process and how these risks have been controlled to an acceptable level. Preferably, this risk
analysis should be based on recognised standards and be part of the manufacturer’s risk
management plan.

11.0 Product Verification and Validation
11.1 General
The STED should contain product verification and validation documentation. The
level of detail will vary (see Section 5.1).
As a general rule, the STED should summarise the results of verification andvalidation studies undertaken to demonstrate conformity of the device with the Essential
Principles that apply to it. Such information would typically cover:a) engineering tests;b) laboratory tests;c) simulated use testing;d) any animal tests for demonstrating feasibility or proof of concept of thefinished device;e) any published literature regarding the device or substantially similar
devices.
Such summary information may include:a) declaration/certificate of conformity to a recognised standard(s) andsummary of the data if no acceptance criteria are specified in the standard;b) declaration/certificate of conformity to a published standard(s) that has
not been recognised, supported by a rationale for its use, and summary ofthe data if no acceptance criteria are specified in the standard;c) declaration/certificate of conformity to a professional guideline(s),industry method(s), or in-house test method(s), supported by a rationale
for its use, a description of the method used, and summary of the data in
sufficient detail to allow assessment of its adequacy;d) a review of published literature regarding the device or substantiallysimilar devices.
In addition, where applicable to the device, the STED should contain detailed
information on:a) biocompatibility;
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Study Group 1 Final Document GHTF/SG1/N011:2008b) medicinal substances incorporated into the device, including compatibilityof the device with the medicinal substance;c) biological safety of devices incorporating animal or human cells, tissues
or their derivatives;d) sterilisation;e) software verification and validation;f) animal studies that provide direct evidence of safety and performance ofthe device, especially when no clinical investigation of the device wasconducted;g) clinical evidence.
Detailed information will describe test design, complete test or study protocols,
methods of data analysis, in addition to data summaries and test conclusions. Where no new
testing has been undertaken, the STED should incorporate a rationale for that decision, e.g.
biocompatibility testing on the identical materials was conducted when these wereincorporated in a previous, legally marketed version of the device. The rationale may beincorporated into the EP checklist.
11.2 Biocompatibility
The STED should contain a list of all materials in direct or indirect contact with thepatient or user.
Where biocompatibility testing has been undertaken to characterize the physical,
chemical, toxicological and biological response of a material, detailed information should be
included on the tests conducted, standards applied, test protocols, the analysis of data and thesummary of results. At a minimum, tests should be conducted on samples from the finished,sterilised (when supplied sterile) device.
11.3 Medicinal Substances
Where the medical device incorporates a medicinal substance(s), the STED should
provide detailed information concerning that medicinal substance, its identity and source, theintended reason for its presence, and its safety and performance in the intended application.
11.4 Biological Safety
The STED should contain a list of all materials of animal or human origin used in thedevice. For these materials, detailed information should be provided concerning the selectionof sources/donors; the harvesting, processing, preservation, testing and handling of tissues,
cells and substances of such origin should also be provided.
Process validation results should be included to substantiate that manufacturing
procedures are in place to minimize biological risks, in particular, with regard to viruses andother transmissible agents.

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The system for record-keeping to allow traceability from sources to the finisheddevice should be fully described.
11.5 Sterilisation
Where the device is supplied sterile, the STED should contain the detailed
information of the initial sterilisation validation including bioburden testing, pyrogen testing,testing for sterilant residues (if applicable) and packaging validation.
Typically, the detailed validation information should include the method used,sterility assurance level attained, standards applied, the sterilisation protocol developed inaccordance with those standards, and a summary of results.
Evidence of the ongoing revalidation of the process should also be provided.
Typically this would consist of arrangements for, or evidence of, revalidation of the
packaging and sterilisation processes.
11.6 Software Verification and Validation
The STED should contain information on the software design and development
process and evidence of the validation of the software, as used in the finished device. This
information should typically include the summary results of all verification, validation andtesting performed both in-house and in a simulated or actual user environment prior to final
release. It should also address all of the different hardware configurations and, whereapplicable, operating systems identified in the labelling.
11.7 Animal Studies
Where studies in an animal model have been undertaken to provide evidence ofconformity with the Essential Principles related to functional safety and performance,
detailed information should be contained in the STED.
The STED should describe the study objectives, methodology, results, analysis andconclusions and document conformity with Good Laboratory Practices. The rationale (andlimitations) of selecting the particular animal model should be discussed.
11.8 Clinical Evidence
The STED should contain the clinical evidence that demonstrates conformity of thedevice with the Essential Principles that apply to it. It needs to address the elements
contained in the Clinical Evaluation Report described in guidance GHTF/SG5/N2.

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12.0

Format of the STED

While this guidance document makes no specific recommendation for the format of
the STED, it would be helpful to both manufacturers and reviewers if the STED wasorganized such that it incorporates the same sections as described in this guidance document
e.g. device description, product specification etc..

13.0 Declaration of Conformity
The Declaration of Conformity is not part of the STED. However, it may be annexedto the STED once the conformity assessment process has been completed. The content of the
Declaration of Conformity is described in GHTF/SG1/N40:2006 Principles of Conformity
Assessment for Medical Devices.

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Appendix A

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Essential Principles (EP) Checklist
The EP checklist can be used by RAs, CABs and manufacturers to readily understandhow the manufacturer demonstrates conformity to the essential principles for a particulardevice. The EP checklist also allows easy identification of relevant documents and data for
conformity assessment purposes.
The contents of the checklist will vary from device to device. Complex devices arelikely to reference a large number of standards, test reports and documents. The EP checklist
in such cases may be many pages long. Very simple devices are more likely to have shorter
EP checklists as many of the Essential Principles may not be applicable. In these cases, thesupporting references to be incorporated into the checklist may be minimal.
The following is a recommended template for the EP checklist. Preparation of the EP
checklist as outlined below will provide a useful overview of the device’s conformity with the
Essential Principles. The consistent use of this template will support harmonization acrossjurisdictions.
How to Complete the Checklista) Identity of the device
The manufacturer should identify the device, and where applicable the various
configurations / variants covered by the checklist.
b) Applicable to the device?
Is the listed Essential Principle applicable to the device? Here the answer is either‘YES’ or ‘NO’. If the answer is ‘NO’ this should be explained briefly in the ‘method used todemonstrate conformity’ column.
Example: For a device that does not incorporate biological substances, the answer toEssential Principle 5.8.2 would be ‘NO’ and, in the ‘method used to demonstrate
conformity’ column, would include an explanation such as ‘The device does notincorporate biological substances.’c) Method used to demonstrate conformity
In this column the manufacturer should state the type(s) of method(s) that they havechosen to use to demonstrate conformity e.g. the recognised standard(s), industry or in-house
test method(s), comparison study(ies) or other method used.
d) Method reference
After having stated the method in the previous column, here the manufacturer should
now name the title and reference of the recognised standard(s), industry or in-house test
method(s), comparison study(ies) or other method used to demonstrate conformity. For
standards, this should include the date of the standard and where appropriate, the clause(s)that demonstrates conformity with the relevant EP.
e) Reference to supporting controlled documents
This column should contain the reference to the actual technical documentation that
demonstrates conformity to the essential principle, i.e. the certificates, test reports, validation
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reports, study reports or other documents that resulted from the method used to demonstrate
conformity and its location within the STED.
NOTE: the Table that follows is for illustrative purposes only. The Essential Principles
listed in the first column should be extracted from the latest version of GHTF’s
guidance document Essential Principles of Safety and Performance of Medical
Devices. Those incorporated into this document are extracted from
GHTF/SG1/N41:2005.

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Essential Principle Checklist
Device:Essential Principle

Applicable to
the Device?

Method Used
to Demonstrate
Conformity

General Requirements
5.1
Medical devices should be designed and manufactured in such a way that, whenused under the conditions and for the purposes intended and, where applicable, by virtueof the technical knowledge, experience, education or training of intended users, they will
not compromise the clinical condition or the safety of patients, or the safety and health ofusers or, where applicable, other persons, provided that any risks which may be associatedwith their use constitute acceptable risks when weighed against the benefits to the patientand are compatible with a high level of protection of health and safety.
5.2
The solutions adopted by the manufacturer for the design and manufacture of thedevices should conform to safety principles, taking account of the generally acknowledged
state of the art. When risk reduction is required, the manufacturer should control therisk(s) so that the residual risk(s) associated with each hazard is judged acceptable. The
manufacturer should apply the following principles in the priority order listed:

identify known or foreseeable hazards and estimate the associated risks arisingfrom the intended use and foreseeable misuse,

eliminate risks as far as reasonably practicable through inherently safe design
and manufacture,

reduce as far as is reasonably practicable the remaining risks by taking adequate
protection measures, including alarms,

inform users of any residual risks.

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MethodReference

Reference to Supporting
Controlled Documents

Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008

Essential Principle

Applicable to
the Device?

Method Used
to Demonstrate
Conformity

5.3
Devices should achieve the performance intended by the manufacturer and be
designed, manufactured and packaged in such a way that they are suitable for one or moreof the functions within the scope of the definition of a medical device applicable in eachjurisdiction.
5.4
The characteristics and performances referred to in Clauses 5.1, 5.2 and 5.3
should not be adversely affected to such a degree that the health or safety of the patient or
the user and, where applicable, of other persons are compromised during the lifetime ofthe device, as indicated by the manufacturer, when the device is subjected to the stresses
which can occur during normal conditions of use and has been properly maintained inaccordance with the manufacturer’s instructions.
5.5
The devices should be designed, manufactured and packed in such a way that
their characteristics and performances during their intended use will not be adversely
affected under transport and storage conditions (for example, fluctuations of temperatureand humidity) taking account of the instructions and information provided by the
manufacturer.
5.6
The benefits must be determined to outweigh any undesirable side effects for the
performances intended.

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MethodReference

Reference to Supporting
Controlled Documents

Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED)
Study Group 1 Final Document GHTF/SG1/N011:2008

Design and Manufacturing Requirements
5.7

Chemical, physical and biological properties

5.7.1
The devices should be designed and manufactured in such a way as to ensure thecharacteristics and performance referred to in Clauses 5.1 to 5.6 of the 'General
Requirements'. Particular attention should be paid to:the choice of materials used, particularly as regards toxicity and, where appropriate,
flammability,the compatibility between the materials used and biological tissues, cells, body fluids,
and specimens, taking account of the intended purpose of the device,the choice of materials used should reflect, where appropriate, matters such as
hardness, wear and fatigue strength.

5.7.2
The devices should be designed, manufactured and packed in such a way as tominimize the risk posed by contaminants and residues to the persons involved in thetransport, storage and use of the devices and to patients, taking account of the intended
purpose of the product. Particular attention should be paid to tissues exposed and to theduration and frequency of exposure.
5.7.3------------------------------- etc. --------------------------------------------

5.7.4------------------------------- etc. --------------------------------------------

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参考資料４：
Draft Guidance for Industry and FDA Staff
Clinical Performance Assessment: Considerations for Computer-Assisted Detection
Devices Applied to Radiology Images and Radiology Device Data –Premarket Approval (PMA) and Premarket Notification [510(k)] Submissions

Draft Guidance forIndustry and FDA Staff
Clinical Performance Assessment:
Considerations for ComputerAssisted Detection Devices Applied toRadiology Images and Radiology
Device Data - Premarket Approval(PMA) and Premarket Notification[510(k)] Submissions
DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.
Document issued on: October 21, 2009
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 written comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Alternatively, electroniccomments may be submitted to http://www.regulations.gov. All comments should be identified
with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft guidance document, contact Nicholas Petrick (OSEL) at 301-7962563, or by e-mail at Nicholas.Petrick@fda.hhs.gov; or Joyce Whang (ODE) at, 301-796-6516 orby e-mail at Joyce.Whang@fda.hhs.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Division of Imaging and Applied Mathematics
Office of Science and Engineering Laboratories

Contains Nonbinding Recommendations
Draft - Not for Implementation
Radiological Devices Branch
Division of Reproductive, Abdominal, and Radiological Devices
Office of Device Evaluation

2

Contains Nonbinding Recommendations
Draft - Not for Implementation

Preface
Additional Copies
Additional copies are available from the Internet at:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm18
7277.htm. You may also send an e-mail request to dsmica@fda.hhs.gov to receive an electronic
copy of the guidance or send a fax request to 240-276-3151 to receive a hard copy. Please use thedocument number (1698) to identify the guidance you are requesting.

3

Contains Nonbinding Recommendations
Draft - Not for Implementation

Table of Contents
1.

INTRODUCTION.................................................................................................................5
The Least Burdensome Approach...........................................................................................................6

2.

SCOPE ...................................................................................................................................63.

RATIONALE ........................................................................................................................7

4.

CLINICAL STUDY DESIGN..............................................................................................8
Evaluation Paradigm and Study Endpoints.........................................................................................10Control Arm............................................................................................................................................12
Reading Scenarios and Randomization................................................................................................13
Rating Scale.............................................................................................................................................14
Scoring .....................................................................................................................................................14
Training of Study Participants..............................................................................................................15

5.

STUDY POPULATION .....................................................................................................15
Data Poolability ......................................................................................................................................17

6.

REFERENCE STANDARD...............................................................................................17

7.

REPORTING ......................................................................................................................18

8.

POSTMARKET PLANNING FOR PMAS ......................................................................19

4

Contains Nonbinding Recommendations
Draft - Not for Implementation

Draft Guidance for Industry and FDA Staff

1
2

Clinical Performance Assessment:
Considerations for Computer-Assisted
Detection Devices Applied to Radiology
Images and Radiology Device Data Premarket Approval (PMA) and Premarket
Notification [510(k)] Submissions

3
4
5
6
7
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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. 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 thisguidance. If you cannot identify the appropriate FDA staff, call the appropriate number listedon the title page of this guidance.

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Introduction

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This draft guidance document provides recommendations to industry, systems and service
providers, consultants, FDA staff, and others regarding clinical performance assessment ofcomputer-assisted detection (CADe 1 ) devices applied to radiology images and radiology device
data (often referred to as “radiological data” in this document). CADe devices are computerized
systems that incorporate pattern recognition and data analysis capabilities (i.e., combine values,
measurements, or features extracted from the patient radiological data) intended to identify, mark,highlight, or in any other manner direct attention to portions of an image, or aspects of radiology
device data, that may reveal abnormalities during interpretation of patient radiology images or
patient radiology device data by the intended user (i.e., a physician or other health care
professional), referred to as the “clinician” in this document. In drafting this document, weconsidered the recommendations on documentation and performance testing for CADe devices
made during the public meeting of the Radiological Devices Advisory Panel on March 4-5,
2008. 2 This draft guidance is issued for comment purposes only.
1

The use of the acronym CADe for computer-assisted detection may not be a generally
recognized acronym in the community at large. It is used here to identify the specific type ofdevices discussed in this document.
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http://www.fda.gov/ohrms/dockets/ac/cdrh08.html#radiology
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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 arecited. The use of the word should in Agency guidances means that something is suggested orrecommended, but not required.

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The Least Burdensome ApproachThis draft guidance document reflects our careful review of what we believe are the relevant
issues related to clinical performance studies for CADe devices applied to radiological data
and what we believe would be the least burdensome way of addressing these issues. If you
have comments on whether there is a less burdensome approach, however, please submit yourcomments as indicated on the cover of this document.

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This document provides guidance regarding clinical performance assessment studies for CADe
devices applied to radiology images and radiology device data. Radiological data include thosethat are produced during patient examination with ultrasound, radiography, magnetic resonanceimaging (MRI), computed tomography (CT), positron emission tomography (PET), etc. 3 As
stated above, CADe devices are computerized systems intended to identify, mark, highlight, or in
any other manner direct attention to portions of an image, or aspects of radiology device data, that
may reveal abnormalities during interpretation of patient radiology images or patient radiology
device data, by the clinician.

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Scope

By design, a CADe device can be a unique detection scheme specific to only one type of potential
abnormality, or a combination or bundle of multiple parallel detection schemes, each one
specifically designed to detect one type of potential abnormality revealed in the patientradiological data. Examples of CADe devices that fall within the scope of this draft guidance
include:• a CADe algorithm designed to identify and prompt microcalcification clusters and masses
on digital mammograms,• a CADe device designed to identify and prompt colonic polyps on CT colonography
studies,••a CADe designed to identify and prompt filling defects on thoracic CT examination and,a CADe designed to identify and prompt brain lesions on head MRI studies.

This draft guidance does not cover clinical performance assessment studies for CADe devices thatare intended for use during intra-operative procedures or for computer-assisted diagnostic devices
3

For any use of a contrast imaging agent, we recommend that you verify that such comports withthe regulation, labeling, and indications of the imaging drugs and devices. You may wish to
consult the draft guidance New Contrast Imaging Indication Considerations for Devices andApproved Drug and Biological Products (DRAFT)(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126051.pdf) for new
contrast imaging drugs and devices indications.
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(CADx) and computer-triage devices, whether marketed as unique devices or bundled with a
CADe device that, by itself, may be subject to this draft guidance. Below is further explanationof the CADx and computer-triage devices not covered by this draft guidance:

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For any of these types of devices, we recommend that you contact the Agency to inquire about
regulatory pathways, regulatory requirements, and recommendations about nonclinical andclinical data.

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This draft guidance makes recommendations as to how you should design and conduct yourclinical performance assessment studies (i.e., well-controlled clinical investigations) for your
CADe device. These studies may be part of your premarket submission to FDA. 4 The
recommendations in this document are meant to guide you as you develop and test your CADe
device; they are not meant to specify the full content or type of premarket submission that may be
applicable to your device. 5 If you would like the Agency's advice about the classification and the•

CADx devices are computerized systems intended to provide information beyond
identifying, marking, highlighting, or in any other manner directing attention to portionsof an image, or aspects of radiology data, that may reveal abnormalities during
interpretation of patient radiology images or patient radiology device data by the clinician.
CADx devices include those devices intended to provide an assessment of disease or otherconditions in terms of the likelihood of the presence or absence of disease, or devices
intended to specify disease type (i.e., specific diagnosis or differential diagnosis), severity,
stage, or intervention recommended. An example of such a device would be a computer
algorithm designed both to identify and prompt potential microcalcification clusters andmasses on digital mammograms and also to provide a probability score to the clinician foreach potential lesion as additional information.

•

Computer-triage devices are computerized systems intended to in any way reduce or
eliminate any aspect of clinical care currently provided by a clinician, such as a device forwhich the output indicates that a subset of patients (i.e., one or more patients in the target
population) are normal and therefore do not require interpretation of their radiological
data by a clinician. An example of this device is a prescreening computer scheme that
identifies patients with normal MRI scans that do not require any review or diagnostic
interpretation by a clinician.

Rationale

4This submission may be a premarket notification (510(k)), an application for premarket approval(PMA), an application for a product development protocol (PDP), an application for ahumanitarian device exemption (HDE), or an application for an investigational device exemption(IDE).
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A 510(k) submission and a PMA application are the most common submission types for the
CADe devices addressed in this draft guidance. As described in the draft guidance ComputerAssisted Detection Devices Applied to Radiology Images and Radiology Device Data Premarket Notification [510(k)] Submissions(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm1
87249.htm ), some CADe devices are Class II regulated under 21 CFR 892.2050 and require a
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regulatory requirements that may be applicable to your device, you may submit a request under
Section 513(g) of the Federal Food, Drug, and Cosmetic Act (the Act). 6

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The clinical performance assessment of a CADe device is intended to demonstrate the clinicalsafety and effectiveness of your device for its intended use, when used by the intended user and inaccordance with its proposed labeling and instructions.

Regardless of the type of premarket submission you are required to submit for your device, we
recommend that you request the Agency’s review of your protocols prior to initiating yourstandalone performance assessment and clinical performance assessment studies for your CADe
device. To request the Agency’s review of your protocols, you may submit a pre-submission to
the Agency.

Clinical Study Design

As described above in the scope, a CADe device, by design, is intended to identify data that may
reveal abnormalities during interpretation of patient images or data by the clinician. There is acomplex relationship between the CADe output and the clinician such that clinical performance
may depend on a variety of factors that should be considered in any study design including:19•

timing of CADe application in the interpretive process;

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physical characteristics of the CADe mark, i.e., size and shape, type of boundary (e.g.,solid, dashed, circle, isocontour), and proximity of the CADe mark to the abnormality;

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user’s knowledge of the type of abnormalities that the CADe is designed to mark; and23•

number of CADe marks.

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Your clinical performance assessment should be well-controlled especially if performed in alaboratory setting (i.e., off site of the clinical arena) to preclude or limit various biases that might
impact conclusions on the device safety or effectiveness. Some various types of study designs
that may be utilized to assess your CADe device include:••

A field test or prospective reader study (e.g., randomized controlled trial) that evaluates adevice in actual clinical conditions. A field test may not be practical in situations, forexample, where there is very low disease prevalence that may necessitate enrollment of anexcessively large number of patients.
A retrospective reader study consisting of a retrospective case collection enriched withdiseased/abnormal cases is a possible surrogate for a field test.

510(k) while others are Class III and require a PMA. For more information on the various deviceclasses, see Section 513(a)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C.
360c(a)(1)).
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Section 513(g) of the Act (21 U.S.C. 360c(g)) provides a means for obtaining the Agency's
views about the classification and the regulatory requirements that may be applicable to yourdevice.
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A stress test is another option for the clinical performance assessment of some CADe
devices. A stress test is a retrospective study enriched with patient cases that containmore challenging imaging findings (or other image data) than normally seen in routine
clinical practice but that still fall within the device’s intended use population (see Section
5. Study Population). Note that the use of sample enrichment will likely alter reader
performance in the trial compared with clinical practice because of the differences indisease prevalence (and case difficulty for stress testing) between the trial and clinicalpractice.

The clinical performance assessment of CADe devices is typically performed by utilizing a
multiple reader multiple case (MRMC) study design, where a set of readers evaluate image data
under multiple reading conditions or modalities (e.g., readers unaided versus readers aided byCADe). The MRMC design can be “fully-crossed” whereby all readers independently read all of
the cases. This design offers the greatest statistical power for a given number of cases. However,
non-fully crossed study designs may be acceptable, for example in prospective studies whereinterpretations of the same patient data by multiple clinicians may not be feasible.
Whether you decide on a fully-crossed study design or not, we recommend the use of an MRMC
evaluation paradigm to assess the clinical performance of a CADe device using one of the study
designs described above. A complete clinical study design protocol should be included in yoursubmission. Pre-specification of the statistical analysis is a key factor for obtaining consistentand convincing scientific evidence. We recommend you provide: 7

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a description of the study design;a description of how the imaging data are to be collected (e.g., make and model of theimaging device imaging protocol) and the expertise of the person collecting the data (e.g.,
x-ray technician)27•

a copy of the protocol, including the following:28

o hypothesis to be tested and study endpoints,

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o plans for checking any assumptions required to validate the tests,

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o alternative procedures/tests to be used if the required assumptions are not met,

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o study success criteria that indicate which hypotheses should be met in order for theclinical study to be considered a success,33

o statistical and clinical justification of the selected case sample size,

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o statistical and clinical justification of the selected number of readers,35o image interpretation methodology and relationship to clinical practice,36

o randomization methods, and37o reader task including rating scale used (see Section 4, subsection Rating Scale);38•

the reader qualifications and experience;39•

a description of the reader training;

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Precisely what information you should provide to FDA will depend largely on the type ofpremarket submission required for your device.
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a statistical analysis plan (i.e., endpoints, statistical methods) with description of:2o the process for defining truth (see Section 6. Reference Standard),3o the details of the scoring technique used (see Section 4, subsection Scoring), and

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o any results from a pilot study supporting the proposed design.
Valid estimation of clinical performance for CADe devices is dependent upon sound study
design. Aspects of sound clinical study design should include the following:

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study populations (both diseased and normal cases) are appropriately representative of theintended use population;

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study design avoids confounding of the CADe effect, e.g., reading session effects

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sample size is sufficient to demonstrate performance claims;

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truth definition is appropriate for assessment of performance, and uncertainty in thereference standard is correctly accounted for in the study analysis, if applicable;

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appropriate data cohorts are represented in the data set;

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readers are selected such that they are representative of the intended population of clinicalusers; and17•

imaging hardware are selected such that they are consistent with current clinical practice.

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Evaluation Paradigm and Study Endpoints
Study endpoints should be selected to demonstrate that your CADe device is effective (i.e.,that in a significant portion of the target population, the use of the device for its intended uses
and conditions of use, when accompanied by adequate directions for use and warnings against
unsafe use, will provide clinically significant results). 8 Selection of the primary andsecondary endpoints will depend on the intended use of your device and should be fixed prior
to initiating your evaluation. Performance metrics based on the receiver operating
characteristic (ROC) curve or variant of ROC (e.g., free-response receiver operating
characteristic (FROC) curve or location-specific receiver operating characteristic (LROC)
curve), in addition to sensitivity (Se) and specificity (Sp) at a clinical action point will belikely candidates as endpoints. Considering Se/Sp and an ROC based endpoint allows
evaluation of the device over the entire range of operating points as well as at the usual cut
point a reader would act on in practice. Data collection for both sets of endpoints can be done
simultaneously within a single reader study. Sensitivity (Se) is defined as the probability thata test is positive for a population of patients with the disease/condition/abnormality while
Specificity (Sp) is defined as the probability that the test is negative for a population of
normal patients (i.e., patients without the disease/condition/abnormality). An ROC curve is aplot of all sensitivities at all possible specificities. It is a summary of diagnostic performanceof a device or a clinician. An FROC curve is a plot of sensitivity versus the number of false
positive marks. FROC metrics summarize diagnostic performance when multiple disease8

See 21 CFR 860.7(e).
10Contains Nonbinding Recommendations
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79 10 for additional details on these assessment paradigms.

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Various summary performance metrics to assess the effectiveness of the use of your CADe
device by readers may be employed (and may vary based on the specific device and clinicalindication). Examples of these include:

7•

area, partial area, or any other measures, under ROC curve,

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area, partial area, or any other measures, under the FROC curve,

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area, partial area, or any other measures, under the LROC curve,

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reader Se/Sp (or recall rate 11 ) pair, and

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reader localization accuracy.

We recommend the inclusion of lesion-based, patient-based, and any other relevant
anatomical or image unit-based measures of performance in the assessment. The selection oflesion-based, patient-based or another unit-based measure of performance as a primary or
secondary endpoint will depend on the intended use and the expected impact of the device on
clinical practice.
For study endpoints based on the area under the ROC/FROC/LROC curve or partial area
under the ROC/FROC/LROC curve, we recommend that you provide plots of the actual
curves along with summary performance information for both parametric and non-parametricanalysis approaches when possible. See Gur et al. 12 for potential limitations of relying on
only one type of ROC analyses. As mentioned above, we also recommend that you include asensitivity/specificity (or recall rate) endpoint in your analysis when an area-based endpoint isused because it is not always straightforward to translate the magnitude of an area under the
curve (AUC) change into the magnitude of change expected in clinical practice. Reporting
sensitivity/specificity (or recall rate) may provide additional information for understanding
the expected impact of a device on clinical practice.
We recommend that you describe your statistical evaluation methodology, and provide results
including:•32

overall reader performance;

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Wagner, R. F., Metz, C. E., and Campbell, G., “Assessment of medical imaging systems andcomputer aids: A tutorial review,” Acad. Radiol. 14:723–48, 2007.
10
ICRU Report 79, “Receiver Operating Characteristic Analysis in Medical Imaging,” Vol.8
No.1 (2008), Oxford University Press (ISSN 1473-6691).
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Recall rate refers to the percentage of patients (including diseased and non-diseased patients)that are called back or recalled for additional medical assessment.
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Gur, D., Bandos, A.I., and Rockette, H.E., “Comparing Areas under Receiver Operating
Characteristic Curves: Potential Impact of the Last Experimentally Measured Operating Point,”
Radiology 247:12–15, 2008.
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stratified performance by relevant confounders or effect modifiers (e.g., lesion type,lesion size, lesion location, scanning protocol, imaging hardware, concomitantdiseases) (see Section 5, Study Population); and

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confidence intervals (CIs) that account for reader variability, case variability, and truth
variability or other sources of variability when appropriate.

We recommend that you identify and validate your analysis software. 13 You should provide areference to the analysis approach used, clarify the software implementation, and specify aversion number if appropriate. Certain validated MRMC analysis approaches, examples ofwhich can be found in the literature or obtained online, may be appropriate for your device
evaluation depending on its intended use and conditions of use. 14,15 If you plan to write
your own analysis software we recommend you submit a copy of the code developed alongwith your validation data.
The definitions of a true positive, true negative, false positive, and false negative CADe markshould be consistent with the intended use of the device and the characterization of thereference standard (see Section 6, Reference Standard).

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Control Arm
We recommend you assess the clinical performance of your CADe device relative to a control
modality. For PMA submissions, a study control arm that uses conventional clinicalinterpretation (i.e., interpretation without the CADe device) should generally be the most
relevant comparator in CADe performance assessment. For CADe devices intended as
second readers, another possible control is double reading by two clinicians. For 510(k)submissions, direct comparison with the predicate CADe device may be useful forestablishing substantial equivalence. Other control arms can be valid. We recommend you
contact the Agency to discuss your choice of a control arm prior to conducting your clinicalstudy.
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For more information on MRMC analysis software, see, for example, Obuchowski, N. A.,
Beiden, S. V., Berbaum, K. S., Hillis, S. L., Ishwaran, H., Song, H. H., and Wagner, R. F.,“Multi-reader, multi-case ROC analysis: An empirical comparison of five methods,” Acad.
Radiol. 11: 980–995, 2004.
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For MRMC literature references, see, for example: Metz, C. E., “Fundamental ROC analysis,”
Handbook of Medical Imaging. Vol. 1. Physics and Psychophysics. Beutel J, Kundel HL, and
VanMetter RL (Eds.) SPIE Press, 751–769, 2000; Wagner, R. F., Metz, C. E., and Campbell, G.,“Assessment of medical imaging systems and computer aids: A tutorial review,” Acad. Radiol.
14:723–48, 2007; Obuchowski, N. A., Beiden, S. V., Berbaum, K. S., Hillis, S. L., Ishwaran, H.,
Song, H. H., and Wagner, R. F., “Multi-reader, multi-case ROC analysis: An empiricalcomparison of five methods,” Acad. Radiol. 11: 980–995, 2004.
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For online access to software that analyzes MRMC data based on validated techniques, see, forexample: LABMRMC software and general ROC software, The University of Chicago:
http://xray.bsd.uchicago.edu/krl/roc_soft6.htm (for either quasi-continuous or categorical data);
University of Iowa MRMC software: ftp://perception.radiology.uiowa.edu/PUBLIC (forcategorical data); OBUMRM software: http://www.bio.ri.ccf.org/html/obumrm.html.
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The study control arm should utilize the same reading methodology as the device arm and beconsistent with clinical practice. The same population of cases, if not the same cases
themselves, should be in all study arms to minimize potential bias. For designs that include
distinct cases in each study arm, we recommend you provide a description and flow chart
demonstrating how patients and readers were randomized into the different arms.

Reading Scenarios and Randomization
Reading scenarios should be consistent with the intended use of the device. We suggest thefollowing as possible reading scenarios for inclusion as part of the clinical testing:11•

a conventional reading without the CADe device (i.e., reader alone);

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a second-read in which the CADe output is displayed immediately after conducting a
conventional interpretation; and

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a concurrent or simultaneous read in which the CADe output is available at any time
during the interpretation process.

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You should randomize readers, cases, and reading scenarios to reduce bias in performancemeasures. We recommend you describe your randomization methodology and provide an
associated flowchart. One approach to randomization is to make use of the principle of Latin
squares. For example, when evaluating both concurrent and second-reader modes with a setof 450 cases, a possible study design may consist of first dividing the cases into three groupsof 150 cases, A, B and C. Each group is further divided into subsets of fifty cases, which areread with the same reading scenario. If α, β and γ are the index for the conventional reading,the second-read mode and the concurrent reading mode respectively, then reading scenariosand cases can be assigned as follows:
Image
Group
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(50)
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B(150) (50)
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C(150) (50)
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If the study enrolled four readers, the example above would result in 600=150x4 readings pergroup per reading session. The order in which the 150 cases are read should be randomized
within each group and reading session. Note that the sample sizes used here are forillustrative purposes only. Generally, the sample sizes needed for clinical studies should be
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representative of the intended use population. Likewise, this example study design illustrated
above is not the only one that could be used to validate the effectiveness of your CADe
device.

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Rating Scale

In case of multiple reading sessions where the same cases are read multiple times, werecommend that each reading session be separated in time by at least four weeks to avoid
memory bias. However, longer time gaps may be advisable. For shorter or longer time gaps
between reading sessions, we recommend you provide data supporting your proposed time
gaps.

You should use conventional medical interpretation and reporting for lesion location, extent,
and patient management. ROC-based endpoints (see Section 4, subsection Evaluation
Paradigm and Study Endpoints) may support collecting data with a finer rating scale (e.g., a
7-point or 100-point scale) when readers rate the lesion and/or disease status in a patient. We
recommend providing training to the readers on the use of the rating scale (see Section 4,
subsection Training of Study Participants).

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Scoring
We refer to the procedure for determining the correspondence between the reader’sinterpretation and the truth (e.g., disease status) as the scoring process. The scoring process
and the scoring definition are important components in the clinical assessment of a CADe
device and should be described. We recommend you describe the process (i.e., rationale,definition, and criteria) for determining whether a reader’s interpretation corresponds to thetruth status established during the truthing process (see Section 6. Reference Standard for
information on the truthing process).
In this document, we describe scoring in terms of the clinical performance assessment. A
different type of scoring is used to evaluate device standalone performance which is describedin the draft guidance entitled Computer-Assisted Detection Devices Applied to Radiology
Images and Radiology Device Data - Premarket Notification [510(k)] Submissions. 16
The scoring process for the clinical studies should be consistent with the abnormalities
marked by the CADe and the intended use of your device. The scoring process should be
described and fixed prior to initiating your evaluation. In your description of the scoringprocess, we recommend you indicate whether the scoring is based on:

35•electronic or non-electronic means;

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physical overlap of the boundary, area, or volume of a reader mark in relation to theboundary, area, or volume of reference standard;16

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relationship of the centroid of a reader mark to the boundary or spatial location ofreference standard;

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relationship of the centroid of the reference standard to the boundary or spatial
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interpretation by reviewing reader(s); or

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other methods.

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For scoring that relies on interpretations by reviewing readers, we recommend you provide
the number of readers involved, their qualifications, their levels of experience and expertise,
the specific instructions conveyed to them prior to their participation in the scoring process,and any specific criteria used as part of the scoring process. When multiple readers are
involved in scoring, you should describe the process by which their interpretations are
combined to make an overall scoring determination or how their interpretations areincorporated in the performance evaluation, including how any inconsistencies are addressed.

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Training of Study Participants
We recommend you specify instructions and provide training to study participants on the useof the CADe device and the details on how to participate in the clinical study. Training
should include a description of the device and instructions for how to use the device. For
specialized reading instructions or rules (e.g., rules for changing initial without-CADeinterpretation when reviewing the CADe marks), we recommend you justify their clinicalrelevance according to reading task, clinical workflow, and medical practice.
We also recommend that training be provided to the readers on the use of the rating scale (seeSection 4, subsection Rating Scale), especially if such a rating scale is not generally utilized
in clinical practice. Such training helps avoid incorrect or un-interpretable results. We
recommend that reader training include rating a representative set of normal and abnormalcases according to the study design methodology, and making use of cases that are not part of
the testing database.

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Study Population

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Patient data (i.e., cases) may be collected prospectively or retrospectively based on well-defined
inclusion and exclusion criteria. We recommend that you provide the protocol for your casecollections. Note that cases collected for your clinical trial should be independent of the cases
used during your device development and should be new to the readers participating in theclinical assessment of the device. An acceptable approach for acquiring data is the collection ofconsecutive cases that are within the inclusion and outside of the exclusion criteria from eachparticipating collection site.
Enrichment with diseased/abnormal cases is permissible for an efficient and less burdensome
representative case dataset. You may also enrich the study population with patient cases that
contain imaging findings (or other image data) that are challenging to clinicians but that still fallwithin the device’s intended use population. This enrichment is often referred to as stress testing.
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For example, if assessing a CADe device designed to assist in detecting colon polyps, the study
population may be enriched with cases containing small polyps. Enrichment may affect reader
performance so the extent of enrichment should be weighed against the introduction of biases into
the study design.
The sample size of the study should be large enough such that the study has adequate power todetect with statistical significance your proposed performance claims. If performance claims areproposed for individual subsets, then the sample sizes for these subsets should be determinedaccordingly to detect these claims with statistical significance. For formal subset analysis, a prespecified statistical adjustment for the testing of multiple subsets would be statistically necessary.
The study population should be representative of the intended use population for your device.
Your study dataset should include the full range of diseased/abnormal and normal cases. The
study should also contain a sufficient number of cases from important cohorts (e.g., subsets
defined by clinically relevant confounders, effect modifiers, and concomitant diseases) such thatclinical performance estimates can be obtained for these individual subsets. As stated above,
powering these subsets for statistical significance may not be recommended unless specific subset
performance claims are being included.
When describing your study population, we recommend you provide specific information, whereappropriate, including:22•

the patient demographic data (e.g., age, ethnicity, race);23•

the patient medical history relevant to the CADe application;24•

the patient disease state and indications for the radiologic test

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the conditions of radiologic testing, e.g. technique (including whether the test was
performed with/without contrast, contrast type and dose per patient, patient body massindex, radiation exposure, T-weighting for MRI images) and views taken

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a description of how the imaging data were collected (e.g., make and model of imaging
devices and the imaging protocol) and the expertise of the person collecting the data (e.g.,
x-ray technician)31•

the collection sites;32•

the processing sites if applicable (e.g., patient data digitization);33•

the number of cases:

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o the number of diseased cases

35o the number of normal cases

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o methods used to determine disease status, location and extent (see Section 6.
Reference Standard);

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the case distributions stratified by relevant confounders or effect modifiers, such as lesion
type (e.g., hyperplastic vs. adenomatous colonic polyps), lesion size, lesion location,disease stage, organ characteristics (e.g., breast composition), concomitant diseases,
imaging hardware (e.g., makes and models), imaging or scanning protocols, collection
sites, and processing sites (if applicable); and16

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Data Poolability

a comparison of the clinical, imaging, and pathologic characteristics of the patient datacompared to the target population.

Premarket approval applications based solely on foreign data and otherwise meeting thecriteria for approval may be approved if, among other requirements, the foreign data areapplicable to the United States (U.S.) population and U.S. medical practice and the studies
have been performed by clinical investigators of recognized competence (21 CFR 814.15).
You should justify why non-U.S. data reflects what is expected for a U.S. population withrespect to disease occurrence, characteristics, practice of medicine, and clinician competency.
In accordance with good clinical study design, you should justify, both statistically andclinically, the poolability of data from multiple sites. We recommend that premarket
notification applications follow similar quality data practices with regard to foreign data anddata poolability. You are encouraged to contact the Agency if you intend to make use offoreign data as the basis of your premarket submission.

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Reference Standard

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For purposes of this document, the reference standard (also often called the “gold standard” or“ground truth” in the imaging community) for patient data indicates whether the
disease/condition/abnormality is present and may include such attributes as the extent or locationof the disease/condition/abnormality. We refer to the characterization of the reference standard
for the patient, e.g., disease status, as the truthing process.
We recommend that you provide the rationale for your truthing process and indicate if it is based
on:

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the output from another device;26•

an established clinical determination (e.g., biopsy, specific laboratory test);

27•

a follow-up clinical imaging examination;28•

a follow-up medical examination other than imaging; or

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an interpretation by a reviewing clinician(s) (i.e., truther(s)).

We also recommend that you describe the methodology utilized to make this reference standard
determination (e.g., based on pathology or based on a standard of care determination). For
truthing that relies on the interpretation by a reviewing clinician(s), we recommend you provide:34•

the number of truthers involved;

35•

their qualifications;36•

their levels of experience and expertise;37•

the instructions conveyed to them prior to participating in the truthing process;

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all available clinical information from the patient utilized by the truthers in theidentification of disease/condition/abnormality and in the marking of the location andextent of the disease/condition/abnormality; and17

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any specific criteria used as part of the truthing process.

When multiple truthers are involved, you should describe the process by which theirinterpretations are combined to make an overall reference standard determination and how yourprocess accounts for inconsistencies between clinicians participating in the truthing process (truth
variability) (see Section 4, subsection Evaluation Paradigm and Study Endpoints). Note thatclinicians participating in the truthing process should not be the same as those who participate in
the core clinical performance assessment of the CADe device.

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Reporting

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Reporting of performance results may be guided by the FDA Guidance entitled Statistical
Guidance on Reporting Results from Studies Evaluating Diagnostic Tests; Guidance forIndustry and FDA Reviewers. 17 We recommend submitting electronically the data used in any
statistical analysis in your study including the following:

15•

patient information,16•

disease or normal status,

17•

concomitant diseases,

18•

lesion size,

19•

lesion type,20•

lesion location,21•

disease stage,

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organ characteristics.

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imaging hardware,24•

imaging or scanning protocol,

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imaging and data characteristics (e.g., characteristics associated with differences indigitization architectures for a CADe using scanned films),

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and statistical analysis.

For more information on submitting data electronically, please see the FDA white paper entitled
Clinical Data for Premarket Submissions. 18

17

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071148.htm
18
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
PremarketSubmissions/ucm136377.htm
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Postmarket Planning for PMAs

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FDA applies the “Total Product Life Cycle (TPLC)” model to promote and protect the publichealth. Premarket approval (PMA) applications should include a postmarket plan to assess thecontinued safety, effectiveness, and reliability of an approved device for its intended use.
One potential piece of a postmarket plan is a post-approval study (PAS). FDA may require you to
conduct a post-approval study as a condition of approval in a PMA approval order (21 CFR
814.82(a)(2)). A post-approval study is not always necessary as a condition of approval. FDA
determines whether one is necessary on a case-by-case basis.
In the event your PMA approval order does require a post-approval study, we suggest that the
study population characterization include race, age and target population baselines. FDA
recommends that the target population include baselines for prevalence of the abnormality to be
detected, as well as current screening method sensitivity, positive predictive value (PPV),
specificity, negative predictive value (NPV), biopsy rate, and recall rate. FDA further
recommends that you include in your study protocol, at a minimum, the following:
•
•
•
•
•
•
•
•

Radiologist training and experience for those participating in the PAS
User training with the CADe device
Adjustments to CADe systems that may occur during the study period
Types of abnormalities detected
Type of imaging center
Consecutive enrollment of subjects
Study sensitivity, PPV, specificity, NPV, biopsy rate, recall rate, false-negative rate,
number of missed abnormalities (may consider evaluation of readings at next exam forcomparison of missed abnormalities)
Area under of curve and/or ROC analysis

FDA will work interactively with you to finalize the postmarket plan and/or any post-approval
study protocol prior to approval decisions so that they are ready to implement if the device isapproved.
For additional information, please refer to the FDA Guidance entitled Procedures for Handling
Post-Approval Studies Imposed by PMA Order; Guidance for Industry and FDA Staff. 1919

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070974.htm
19参考資料５：
Draft Guidance for Industry and FDA Staff
Computer-Assisted Detection Devices Applied to Radiology Images
and Radiology Device Data - Premarket Notification [510(k)] Submissions

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Draft Guidance for Industry and FDA
Staff

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Computer-Assisted Detection
Devices Applied to Radiology
Images and Radiology Device Data Premarket Notification [510(k)]Submissions

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DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.
Document issued on: October 21, 2009
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 written comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Alternatively, electroniccomments may be submitted to http://www.regulations.gov. All comments should be identified
with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft guidance document contact Nicholas Petrick (OSEL) at 301-7962563, or by e-mail at Nicholas.Petrick@fda.hhs.gov; or Joyce Whang (ODE) at 301-796-6516, orby e-mail at Joyce.Whang@fda.hhs.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Division of Imaging and Applied Mathematics
Office of Science and Engineering Laboratories
Radiological Devices Branch
Division of Reproductive, Abdominal, and Radiological Devices
Office of Device Evaluation

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Preface

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Additional Copies
Additional copies are available from the Internet at:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm18
7249.htm. You may also send an e-mail request to dsmica@fda.hhs.gov to receive an electronic
copy of the guidance or send a fax request to 301-847-8149 to receive a hard copy. Please use thedocument number (1697) to identify the guidance you are requesting.

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Table of Contents

1
2

1.

3

INTRODUCTION...................................................................................................................1
The Least Burdensome Approach...........................................................................................................24

2.

BACKGROUND .....................................................................................................................2

5

3.

SCOPE .....................................................................................................................................3

6

4.

DESCRIBING THE DEVICE IN A 510(K) PREMARKET NOTIFICATION...............5

7

General Information.................................................................................................................................5

8

Algorithm Design and Function ..............................................................................................................6

9

Processing ..................................................................................................................................................7

10

Features and Feature Selection ...............................................................................................................7

11

Models and Classifiers..............................................................................................................................8

12

Algorithm Training ..................................................................................................................................813

Databases...................................................................................................................................................914

Reference Standard ................................................................................................................................10

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Scoring .....................................................................................................................................................11

16

Other Information ..................................................................................................................................12

17

5.

STANDALONE PERFORMANCE ASSESSMENT.........................................................1318

Study Population.....................................................................................................................................14

19

Detection Accuracy.................................................................................................................................15

20

Localization Accuracy ............................................................................................................................16

21

Reproducibility Testing..........................................................................................................................17

22

Algorithm Stability Testing ...................................................................................................................18

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Algorithm Training Performance .........................................................................................................18

24

Other Information ..................................................................................................................................18

25

6.

CLINICAL PERFORMANCE ASSESSMENT.................................................................1926

7.

USER TRAINING ................................................................................................................2127

8.

LABELING ...........................................................................................................................21

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Indications for use ..................................................................................................................................22

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Directions for use ....................................................................................................................................22

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Warnings .................................................................................................................................................22

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Precautions ..............................................................................................................................................22

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Device Description ..................................................................................................................................23

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Clinical Performance Assessment .........................................................................................................23

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Standalone Performance Assessment ...................................................................................................23

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Guidance for Industry and FDA Staff

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Computer-Assisted Detection Devices Applied
to Radiology Images and Radiology Device
Data - Premarket Notification [510(k)]Submissions

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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. 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 thisguidance. If you cannot identify the appropriate FDA staff, call the appropriate number listedon the title page of this guidance.

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1.

Introduction

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This draft guidance document provides recommendations to industry, systems and service
providers, consultants, FDA staff, and others regarding premarket notification (510(k))
submissions for computer-assisted detection (CADe 1 ) devices applied to radiology images andradiology device data (often referred to as “radiological data” in this document). CADe devices
are computerized systems that incorporate pattern recognition and data analysis capabilities (i.e.,
combine values, measurements, or features extracted from the patient radiological data) and areintended to identify, mark, highlight, or in any other manner direct attention to portions of animage, or aspects of radiology device data, that may reveal abnormalities during interpretation ofpatient radiology images or patient radiology device data by the intended user (i.e., a physician orother health care professional), referred to as the “clinician” in this document. In drafting thisdocument, we considered the recommendations on documentation and performance testing for
CADe devices made during the Radiology Advisory Public Panel on March 4-5, 2008. 2 This
draft guidance is issued for comment purposes only.

1

The use of the acronym CADe for computer-assisted detection may not be a generally
recognized acronym in the community at large. It is used here to identify the specific type ofdevices discussed in this document.
2
http://www.fda.gov/ohrms/dockets/ac/cdrh08.html#radiology

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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 arecited. The use of the word should in Agency guidances means that something is suggested orrecommended, but not required.

The Least Burdensome Approach

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This draft guidance document reflects our careful review of what we believe are the relevant
issues related to computer-assisted detection on radiological data and what we believe would
be the least burdensome way of addressing these issues. If you have comments on whether
there is a less burdensome approach, however, please submit your comments as indicated on
the cover of this document.

13

2.

Background

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This draft guidance applies to the CADe devices identified in Section 3. Scope by theirclassification regulation (21 CFR 892.2050) and product codes (NWE, OEB, OMJ). A
manufacturer who intends to market one of these devices must:

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conform to the general controls of the Federal Food, Drug, and Cosmetic Act (the Act),
including the premarket notification requirements described in 21 CFR 807 Subpart E;

19•

conform to the special controls designated for this device (see 21 CFR 892.2050(b)); and

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obtain a substantial equivalence determination from FDA prior to marketing the device.
(See also 21 CFR 807.81 and 807.87.)

This document provides recommendations regarding premarket notifications (510(k)s) for thesedevices. It supplements the requirements in 21 CFR 807.87 and other FDA documents
concerning the specific content of a premarket notification submission, including the guidance,
Format for Traditional and Abbreviated 510(k)s. 3
Under “The New 510(k) Paradigm - Alternate Approaches to Demonstrating Substantial
Equivalence in Premarket Notifications,” 4 a manufacturer may submit a Traditional 510(k) or
has the option of submitting either an Abbreviated 510(k) or a Special 510(k). FDA believes an
Abbreviated 510(k) provides the least burdensome means of demonstrating substantial
equivalence for a new device, particularly once FDA has issued a guidance document addressing

3

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm084365.htm
4
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080187.htm

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that device. Manufacturers considering certain modifications to their own cleared devices may
lessen the regulatory burden by submitting a Special 510(k).

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3.

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This document provides guidance regarding premarket notification (510(k)) submissions for
CADe devices applied to radiology images and radiology device data. Radiological data include
those that are produced during patient examination with ultrasound, radiography, magnetic
resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET),
etc. 5 As stated above, CADe devices are computerized systems intended to identify, mark,highlight, or in any other manner direct attention to portions of an image, or aspects of radiology
device data, that may reveal abnormalities during interpretation of patient radiology images or
patient radiology device data by the clinician. This draft guidance covers CADe devices
marketed as a complete package with a review workstation, or as an add-on software to beembedded within imaging equipment, an image review platform (for example, a PACS (picturearchiving and communications system)), or other imaging accessory equipment.

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This draft guidance does not address non-CADe device components or capabilities, including themany non-CADe devices that are covered by 21 CFR 892.2050, i.e. product codes LLZ (System,
Image Processing, Radiological) and NFJ (System, Image Management, Ophthalmic).

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(a) Identification. A picture archiving and communications system is a device that provides
one or more capabilities relating to the acceptance, transfer, display, storage, and digitalprocessing of medical images. Its hardware components may include workstations, digitizers,
communications devices, computers, video monitors, magnetic, optical disk, or other digital
data storage devices, and hardcopy devices. The software components may provide functions
for performing operations related to image manipulation, enhancement, compression orquantification.

Scope

This draft guidance document applies to the CADe devices under 21 CFR 892.2050 Picturearchiving and communications systems, and the following current product codes:• NWE (Colon computed tomography system, computer-aided detection),• OEB (Lung computed tomography system, computer-aided detection), and• OMJ (Chest x-ray, computer-aided detection).

21 CFR 892.2050 Picture archiving and communications system.

5

For any use of a contrast imaging agent, we recommend that you verify that such comports withthe regulation, labeling, and indications of the imaging drugs and devices. You may wish to
consult the draft guidance New Contrast Imaging Indication Considerations for Devices andApproved Drug and Biological Products (DRAFT)(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126051.pdf) for new
contrast imaging drugs and devices indications.

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(b) Classification. Class II (special controls; voluntary standards--Digital Imaging andCommunications in Medicine (DICOM) Std., Joint Photographic Experts Group (JPEG) Std.,
Society of Motion Picture and Television Engineers (SMPTE) Test Pattern).
By design, a CADe device can be a unique detection scheme specific to only one type of potential
abnormality or a combination or bundle of multiple parallel detection schemes, each specificallydesigned to detect one type of potential abnormality that is revealed in the patient radiological
data. Examples of CADe devices that fall within the scope of this draft guidance include:• a CADe device designed to identify and prompt colonic polyps on CT colonography
studies,• a CADe designed to identify and prompt filling defects on thoracic CT examination, and• a CADe designed to identify lung nodules on MRI studies.
This draft guidance does not cover devices in the Class III product code MYN (Analyzer, Medical
Image), any CADe devices that are intended for use during intra-operative procedures, or any
computer-assisted diagnostic devices (CADx) or computer-triage devices, whether marketed as
unique devices or bundled with a computer-assisted detection device that, by itself, may besubject to this draft guidance. Below is further explanation of the CADx and computer-triage
devices not covered by this draft guidance:•

CADx devices are computerized systems intended to provide information beyond
identifying, marking, highlighting, or in any other manner directing attention to portionsof an image, or aspects of radiology device data, that may reveal abnormalities during
interpretation of patient radiology images or patient radiology device data by the clinician.
CADx devices include those devices that are intended to provide an assessment of diseaseor other conditions in terms of the likelihood of the presence or absence of disease, or are
intended to specify disease type (i.e., specific diagnosis or differential diagnosis), severity,
stage, or intervention recommended. An example of such a device would be a computer
algorithm designed both to identify and prompt lung nodules on CT exams and also toprovide a probability score to the clinician for each potential lesion as additional
information.

•

Computer-triage devices are computerized systems intended to in any way reduce or
eliminate any aspect of clinical care currently provided by a clinician, such as a device forwhich the output indicates that a subset of patients (i.e., one or more patients in the target
population) are normal and therefore do not require interpretation of their radiological databy a clinician. An example of this device is a prescreening computer scheme that
identifies patients with normal MRI scans that do not require any review or diagnostic
interpretation by a clinician.

For any of these types of devices, we recommend that you contact the Agency to inquire about
premarket pathways, regulatory requirements, and recommendations about nonclinical andclinical data.

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4.

Describing the Device in a 510(k) Premarket
Notification

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We recommend you identify your device by the regulation and product code described in Section
3. Scope, and provide an overview of your CADe algorithm and a detailed description of thefollowing:7•

the algorithm design and function,

8•

processing steps,

9•

features,10•

models and classifiers,

11•

training paradigm,

12•

databases,

13•

reference standard, and14•

scoring methodology.

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General Information
In accordance with 21 CFR 807.87, provide proposed labels, labeling, and advertisements
sufficient to describe the device, the intended use, directions for use, a complete description of
the operational principles for your device, and a 510(k) summary or a 510(k) statement (see21 CFR 807.87(e), (f) & (h) and Section 8. Labeling). In providing a description of yourdevice, we recommend you include the following information:

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target population information including patient population, organs of interest,
diseases/conditions/abnormalities of interest, and appropriate clinician intended to use
the device (e.g., radiologist, family practice physician, nurse);

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radiological data used as input and compatible with your CADe design, including
imaging modalities (e.g., computed tomography, magnetic resonance), make, modeland specific trade name for each modality/system if applicable, specific image
acquisition parameter ranges (e.g., kVp range, slice thickness), and specific clinicalimaging protocol(s) (e.g., oral contrast studies, magnetic resonance imaging (MRI)
sequence);

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current clinical practice relevant to the diseases/conditions/abnormalities of interest;

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proposed clinical workflow (as compared to the predicate device) including adescription of:o how your device is labeled for use in clinical practice,o when your device should be utilized within the proposed workflow,o effects on interpretation time as it relates to specific claims;

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device impact (as compared to the predicate device), including:o the impact on patient health from additional medical procedures resulting from an
unnecessary patient recommendation or follow-up by the clinician based on theinformation provided by the device (e.g., an incorrect follow-up determination
would likely result in short term surveillance imaging for the patient or an
incorrect follow-up determination would likely result in a biopsy),o the impact on the patient associated with device performance for true positive andtrue negative marks, separately, ando the impact on the patient associated with device performance for false positive andfalse negative marks, separately;

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device limitations (as compared to the predicate device) including
diseases/conditions/abnormalities for which the device has been found ineffective andshould not be used; and14•

supporting data from the scientific literature.

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Algorithm Design and Function
We recommend you provide information on the algorithm design and function including
details on the following:•algorithm implementation:o a description of the format of all CADe marks available, including all relevantgeometric and other properties such as shape, size, intended location in relation toregion of interest (e.g., overlap, adjacent), border (e.g., solid, dashed), and color.

We recommend you provide a detailed flowchart identifying the processing, features, models,and classifiers utilized by your algorithm. We suggest your flowchart include the following:

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all manual operations and associated predefined default settings (e.g., selection ofrules or thresholds by the physician);

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all semi-automatic operations and associated predefined default settings (e.g., selectionof seed points for region segmentation); and

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all automatic operations that do not involve direct interaction with the clinician.

You should include other algorithm information including:

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name,

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version and important characteristics of the software platform,

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operating system, and

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programming language.

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We also recommend you describe the design and function for each stage of your algorithm,
where a stage is an independent or well-defined functional unit within the CADe algorithm.
Your description may likely include a discussion of the following:

4•

purpose of the stage,

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processing steps,

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features,7•classifiers and their estimated complexity,

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training paradigm,

9•development and training databases utilized, and10•reference standard.

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Processing

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Features and Feature Selection

Processing refers to any image or signal normalization, filtering, and segmentation of areas or
structures of interest. Examples of filtering and segmentation processes are the use of asmoothing filter for noise reduction or the delineation of an organ of interest from its
surroundings, respectively. We recommend that you provide a description of all processing aswell as relevant algorithm flowcharts, equations, and references.
Normalization processing refers to calibration or transformation of image or signal
characteristics to that of a reference image or signal. We recommend you provide a
description of the technique used to establish the proper calibration or transformation, as wellas the characteristics of the reference.

Features are computer or human estimated quantities characterizing images, regions, or pixels
within radiological data, including any specific patient characteristics (e.g., age, sex,ethnicity). Feature selection includes any processes used to cull a set of candidate features.
Feature selection or dimensional reduction may be accomplished by manual selection ofimportant features by a user or by an automated selection algorithm (e.g., through the use of agenetic algorithm). For each stage of your algorithm, we recommend you provide:

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the total number of features computed and evaluated during algorithm development,
and

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the number of features retained after feature selection, if appropriate.

For each feature, we recommend you provide:34•

a description of how the feature is determined (e.g., mathematical expression),

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the feature class (e.g., demographic, biological, morphological and geometricalfeatures), and7

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the feature type (i.e., computer estimated feature value or reader estimated feature
value).

Models and Classifiers
We define a model as any method or rule used to rate or categorize information within animage. A classifier is a human- or statistically-defined model used to rate or categorize
regions within an image with respect to disease, condition, or abnormality. This model is an
assumed relationship between image features and the rating or categorization of disease,condition, or abnormality, and depends on a specific set of parameters that are determined inprocessing steps either manually or automatically. Models and classifiers typically perform
some type of pattern recognition procedure. They can vary from a single threshold on auniquely extracted feature to a complex classifier (i.e., a weighted combination of feature
values). For each stage of your algorithm, we recommend you provide the following:13•

the number of different models and classifiers utilized; and

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the types of models and classifiers used (e.g., simple threshold, decision tree, linear
discriminant, neural network, support vector machine), including specific parametersand values being utilized.

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Algorithm Training
Algorithm training is a procedure used to set algorithm parameters and thresholds. This
procedure includes the adjustment of filter parameters, the selection of the most discriminantfeatures, and the adjustment of classifier weights and model parameters. Training may bedone manually by humans (e.g., the programmer or a medical professional), automaticallyusing a specialized training algorithm, or by a combination of both. For the individual stages
as well as the overall algorithm, we recommend you describe your algorithm training
paradigm, including the technique employed for feature selection, and indicate if it isperformed:

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manually by humans;

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automatically using a computerized training method; or

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by a combination of manual and computerized techniques.

If algorithm training is performed manually, we recommend you provide the number andqualifications of the individuals performing the training. Whether the training is performed
manually, automatically, or by a combination of techniques, we recommend you describe thecriteria and performance metrics used to determine the settings (i.e., thresholds, weights, orparameters) of each individual stage and provide a summary of the resulting observed
performance.
We further recommend you provide history of the accrual and use of data in the training andevaluation of the CADe device.

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Databases
Databases refer to the sets of radiology images or radiology device data used in training andtesting your device. These databases may contain computer simulated data, phantom data, or
patient data depending on the nature of the evaluation.
For a database of computer simulated or phantom data (i.e., training and testing cases), we
recommend you provide:8•

a description of the phantom or simulation methodology; and

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any data characterizing the relationship between the simulated or phantom data andactual patient data for the imaging technique, organ, and disease of interest.

For each database of patient data (i.e., training and testing cases), we recommend you provide
specific information including:14•

the patient demographic data (e.g., age, ethnicity, race);15•

the patient medical history relevant to the CADe application;16•

the patient disease state and indications for the radiologic test;

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the conditions of radiologic testing, for example technique (including whether the test
was performed with/without contrast, contrast type and dose per patient, patient bodymass index, radiation exposure, T1-weighting for MRI images) and views taken;

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a description of how the imaging data were collected (e.g., make and model ofimaging devices and the imaging protocol) and the expertise of the person collecting
the data (e.g., x-ray technician);23•

the collection sites;24•

the processing sites, if applicable (e.g., patient data digitization);

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the number of cases:o the number of diseased cases,o the number of normal cases,o any methods used to determine disease status, location and extent (see Section 4,
subsection Reference Standard);

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the case distributions stratified by relevant confounders or effect modifiers, such aslesion type (e.g., hyperplastic vs. adenomatous colonic polyps), lesion size, lesion
location, disease stage, organ characteristics, concomitant diseases, imaging hardware(e.g., makes and models), imaging or scanning protocols, collection sites, andprocessing sites (if applicable);

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a comparison of the clinical, imaging, and pathologic characteristics of the patient datacompared to the target population; and

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a history of the accrual and use of both training and test databases.

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For CADe devices intended to be used with proprietary imaging devices, we recommend you
provide the trade names, regulatory status, and physical characteristics of these proprietaryimaging devices.

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Reference Standard
For purposes of this document, the reference standard (also often called the “gold standard” or“ground truth” in the imaging community) for patient data indicates whether or not thedisease/condition/abnormality is present and may include such attributes as the extent or
location of the disease/condition/abnormality CADe device development and evaluation often
relies on databases of a radiology images or radiology device data with a reference standard
addressing whether or not the disease/condition/abnormality is present within an individual
patient and if so, its location and extent. We refer to this characterization of the reference
standard for the patient, e.g., disease status, as the truthing process.
The methodology utilized to establish the reference standard can impact reported
performance. The types and nature of the abnormalities marked or not marked by your CADe
device should be consistent with the intended use of your device. You should provide therationale and describe the procedure for defining if a disease/condition/abnormality is present
and the location and extent of the disease/condition/abnormality (e.g., based on pathology orbased on a standard of care determination). You should also indicate if the reference standard
is based on:22•

the output from another device;23•

an established clinical determination (e.g., biopsy, specific laboratory test);

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a follow-up clinical imaging examination;25•

a follow-up medical examination other than imaging; or

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an interpretation by reviewing clinician(s) (i.e., truther(s)).

The methodology utilized to make this reference standard determination should be describedand should be fixed prior to initiating your evaluation. For truthing that relies on theinterpretation by reviewing clinician (i.e., truther), we recommend you provide:31•

the number of truthers involved;

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their qualifications;33•

their levels of experience and expertise;34•

the instructions conveyed to them prior to participating in the truthing process;

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all available clinical information from the patient utilized by them in the identification of
disease/condition/abnormality and in the marking of the location and extent of thedisease/condition/abnormality; and

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any specific criteria used as part of the truthing process.

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When multiple truthers are involved, you should describe the process by which theirinterpretations are combined to make an overall reference standard determination and how
your process accounts for any inconsistencies between clinicians participating in the truthing
process (truth variability). Clinicians participating in the truthing process should not be thesame as those who participate in the core clinical performance assessment of the CADe device
because doing so would introduce bias into the study results.

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Scoring
In addition to determining the reference standard for the location and extent of thedisease/condition/abnormality, CADe device development and evaluation often rely on
determining whether the spatial location and extent of a CADe mark correspond to thelocation and extent of the disease/condition/abnormality. We define the procedure fordetermining the correspondence between the CADe output and the reference standard (e.g.,disease location) as the scoring process. The scoring procedure and the scoring definition areimportant components for interpreting standalone device performance and for appropriately
labeling the device.
In this document we describe the scoring used to evaluate device standalone performance. A
different type of scoring is used in the clinical performance assessment which is described in
the draft guidance entitled Clinical Performance Assessment: Considerations for
Computer-Assisted Detection Devices Applied to Radiology Images and Radiology
Device Data - Premarket Approval (PMA) and Premarket Notification [510(k)]Submissions. 6
The scoring process should be consistent with the abnormalities being marked by the CADeand the intended use of your device. The scoring process should be described and primaryand secondary endpoints should be fixed prior to initiating your evaluation. In yourdescription of the scoring process, we recommend you indicate whether the scoring is based
on:

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electronic or non-electronic means;

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physical overlap of the boundary, area, or volume of the mark in relation to theboundary, area, or volume of the reference standard;

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relationship of the centroid of the mark to the boundary or spatial location of thereference standard;

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relationship of the centroid of the reference standard to the boundary or spatial
location of the mark;36•

interpretation by reviewing readers; or6

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm18
7277.htm

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other methods.

For scoring that relies on interpretations by reviewing readers, we recommend you provide thenumber of readers involved, their qualifications, their level of experience and expertise, thespecific instructions conveyed to them prior to participating in the scoring process, and any
specific criteria used as part of the scoring process. When multiple readers are involved inscoring, you should describe the process by which their interpretations are combined to makean overall scoring determination or how their interpretations are incorporated in theperformance evaluation, including how any inconsistencies are addressed.

Other Information

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We recommend that you include information for software-controlled devices described in
Guidance for the Content of Premarket Submissions for Software Contained in Medical
Devices 7 and in Guidance for Off-the-Shelf Software Use in Medical Devices. 8 The kindof information we recommend is determined by the “level of concern,” which is related to therisks associated with a software failure. The level of concern for a device may be minor,
moderate, or major. Based on prior CADe device submissions, the level of concern for a
CADe system is generally moderate or major.
If the CADe system is an add-on software to be installed within a third party image review
platform, we recommend you also provide the names, version/model numbers, andcharacteristics of these third party platforms as well as a description of the file format of the
CADe output that is generated by your device. If applicable, we recommend you refer to
Guidance for the Submission of Premarket Notifications for Medical ImageManagement Devices. 9
We recommend submitting electronically the data used in any statistical analysis in yourstudy. For more information on submitting data electronically, please see the FDA white
paper entitled Clinical Data for Premarket Submissions. 107

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089543.htm
8
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0
73778.htm
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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0
73720.htm
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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
PremarketSubmissions/ucm136377.htm

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5.

Standalone Performance Assessment

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Because each new CADe device represents a new implementation of software, FDA expects thateach new CADe device (as well as software and other design, technology, or performancechanges to an already cleared CADe device) will have different technological characteristics fromthe legally marketed predicate device even while sharing the same intended use. Accordingly,
under section 513(i)(1)(A) of the Act, determinations of substantial equivalence will rest onwhether the information submitted, including appropriate clinical or scientific data, demonstratethat the new or changed device is as safe and effective as the legally marketed predicate device
and does not raise different questions of safety and effectiveness than the predicate device.
To support a substantial equivalence determination for a new CADe device, or for changes to an
already cleared CADe device that could significantly affect safety or effectiveness, werecommend you measure and report the performance of your CADe device by itself, in theabsence of any interaction with a clinician (i.e., standalone performance assessment). These
measurements estimate how well the CADe device, by itself, marks regions of known
abnormalities and how well the CADe device avoids marking regions other than the abnormalities(e.g., normal organ and structures). Study endpoints should be selected to establish meaningful
and statistically significant performance for the device.
To support substantial equivalence, we recommend comparing the standalone performance ofyour CADe device to the standalone performance of the predicate device on the same dataset, if
possible. Otherwise, the characteristics or makeup of the database used to assess standalone
performance should be comparable to the characteristics or makeup of the database used inassessing the predicate device.
The types and nature of the abnormalities marked or not marked by your CADe device should beconsistent with the intended use of your device. To measure standalone performance, the true
location of abnormalities should be determined through some well-described truthing process (seeSection 4, subsection Reference Standard). The location and extent of a CADe mark should becompared to the truthed location and extent of an abnormality using the established scoringprocess (see Section 4, subsection Scoring). The reference standard definition, scoring process,and analysis methodology, including primary and secondary performance endpoints, should beestablished prior to the collection of the standalone performance assessment data and analysis ofthese data. Any performance claims based on a covariate analysis should be demonstrated
through a prespecified analysis plan.
We recommend that you perform standalone testing in a way that will provide good estimates of
performance stratified by important covariates, such as lesion type, size or shape. This stratified
standalone performance is useful in labeling by providing the end users with additional
information to better interpret the meanings of the CADe marks.

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Study Population
We recommend you assess and report your device standalone performance on testing data thatis independent and sequestered from the data on which the CADe was developed and trained.
Reusing test data (i.e., conducting multiple tests on the same data) is problematic forinterpreting the results. Test data, used once before, does not constitute independent data for
testing a CADe device because the CADe algorithm may have become trained to that data,
either implicitly or explicitly. If you intend to reuse test data, we recommend that you contact
the Agency to discuss the scientific validity of your proposed methodology and seek advice
on the reuse of test data.
Your testing database should be representative of the target population and the target disease,condition, or abnormality for which your device is intended. We recommend that you provide
the protocol for your case collections. An acceptable approach for acquiring data that isrepresentative of the intended use population is the collection of consecutive cases from eachparticipating collection site that fall within the inclusion and outside the exclusion criteria.
The full range of diseased/abnormal and normal cases should be sufficiently represented in thetesting database.
Enrichment with diseased/abnormal cases is permissible for an efficient and least burdensome
representative case dataset but may affect standalone performance estimates (e.g., theperformance estimates may not generalize to the intended use population). You may choose
to enrich the study population with patient cases that contain imaging findings (or other imagedata) that are known to challenge clinicians but that still fall within the device’s intended use
population (i.e., stress testing). For example, if assessing a CADe device designed to detectcolon polyps, the study population may be enriched with cases containing smaller polyps.
The study should contain a sufficient number of cases from important cohorts (e.g., subsets
defined by clinically relevant confounders, effect modifiers, and concomitant diseases) suchthat standalone performance estimates can be obtained for these individual subsets (e.g.,
performance estimates for different nodule size categories when evaluating a lung CADe
device). Powering these subsets for statistical significance may not be necessary unlessspecific subset performance claims are being included. A good study design might include
and report results for both an enriched data set containing relevant confounders as well as aset of consecutive cases from each participating collection site where the consecutive cases
may better represent the standalone performance in clinical practice.
The sample size of the study should be large enough such that the study has adequate power todetect with statistical significance your proposed performance claims. If performance claims
are proposed for individual subsets, then the sample sizes for these subsets should bedetermined accordingly to detect these claims with statistical significance. For formal subset
analysis, a pre-specified statistical adjustment for the testing of multiple subsets would bestatistically necessary.

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As part of the device standalone performance assessment, you should describe the testing
database (see Section 4, subsection Databases). We recommend your performance testing
include:

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detection accuracy testing,5•

localization accuracy testing,6•

reproducibility testing,7•

stability analysis, and8•

algorithm training performance.

Detection Accuracy

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We recommend you estimate and report the CADe standalone performance following thescoring process (see Section 4, subsection Scoring). The definition of a true positive, true
negative, false positive, and false negative CADe mark should be consistent with the intended
use of the device. For example, if the device is intended to detect all abnormalities (e.g.,benign and malignant), then a true positive CADe mark should be defined as “marking” any
abnormalities. On the other hand, if a device is intended to detect only a subset ofabnormalities (e.g., only those lesions with certain imaging features), then a true or false
CADe mark should be defined accordingly.
For truthing (e.g., disease type, location, and extent) that relies on the interpretation byreviewing readers, we recommend that you account for reader variability in the truthing
process and for various consensus or agreement rules between expert readers, in the CADestandalone performance estimates. One method of accounting for variability in the reference
standard is to resample the expert truthing panel. See Miller et al. 11 for details on one
approach.
We recommend you report the overall lesion-based, patient-based, and any other relevant
anatomical or image unit-based sensitivities, and average number of false positives per case
(FPs/case) or other relevant measure of specificity, at each device operating point as well as
stratified analysis per relevant confounder or effect modifier as appropriate (e.g., lesion size,
lesion type, imaging or scanning protocols, imaging or data characteristics). FPs/case or otherrelevant measure of specificity should be derived from normal and abnormal patient data
separately. If your device allows the clinician to select or manipulate the device operating
point, we recommend you provide the device performance for each selectable operating point
or for the range of possible operating points. The detection accuracy assessment
methodology, including the selection of primary and secondary performance endpoints,should be determined and fixed prior to initiating your evaluation.

11

Miller, D. P., O’Shaughnessy, K. F., Wood, S. A., and Castellino, R. A., “Gold standards andexpert panels: A pulmonary nodule case study with challenges and solutions,” Proc. of the SPIE,
Medical Imaging; 5372: 173–184, 2004.

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All performance measures should be reported with associated confidence intervals (CIs). We
recommend you provide a description of your methodology for estimating these CIs and theclinical significance associated with these CIs.
We also recommend you provide graphs of the free-response receiver operating characteristic(FROC) curves (i.e., a plot of patient-based sensitivity vs. average number of FPs/case as afunction of operating point) when reporting detection accuracy and the clinical interpretationof this analysis. Associated FROC CIs should be reported when appropriate. Resamplingtechniques, such as bootstrapping, 12 are potential methodologies for estimating these CIs.

Localization Accuracy

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Localization accuracy depends upon the scoring criteria used to determine the nature of each
CADe detection, i.e., true positive (TP) or false positive (FP). Using only one scoring
criterion, i.e., the criterion used for the device performance reported in the labeling (seeSection 4, subsection Scoring), may not be sufficient to evaluate localization accuracy. We
recommend you report the CADe localization accuracy by reporting the overall lesion-based,patient-based, and any other relevant anatomical or image unit-based sensitivities, and theaverage number of FPs/case or other relevant measure of specificity, using multiple scoring
criteria. Common scoring criteria used to determine the nature of each CADe detection
include:21
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centroid of the CADe detection area or volume falling in the reference standard area orvolume;23•

distance between centroids of the CADe detection and the reference standard;

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ratio of the distance between centroids of the CADe detection and the reference
standard, relative to the maximum width of the reference standard region;

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ratio of the area (A) or volume (V) intersection between the CADe detection and thereference standard, with the total area or volume of the reference standard defined asfollows:

A(CAD) ∩ A( Ref )A( Ref )

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V(CAD) ∩ V( Ref )V( Ref )ratio of the area (A) or volume (V) intersection between the CADe detection and thereference standard, with the total area or volume of the CADe detection, defined asfollows:
A(CAD) ∩ A( Ref )A(CAD)

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oror

V(CAD) ∩ V( Ref )V(CAD)

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Efron, B., and Tibshirani, R., “Bootstrap methods for standard errors, confidence intervals andother measures of statistical accuracy,” Statistical Science 1, 54–77, 1986.

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ratio of the area (A) or volume (V) intersection between the CADe detection and thereference standard with the total area or volume union of the reference standard andthe CADe detection, defined as follows:
A(CAD) ∩ A( Ref )A(CAD) ∪ A( Ref )

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or

V(CAD) ∩ V( Ref )V(CAD) ∪ V( Ref )We recommend you estimate and report location accuracy performance of your device using
various values of the distance and ratio criteria and, if applicable, plots showing theperformance change as a function of overlap criteria. The location accuracy assessment
methodology, including the selection of primary and secondary performance endpoints,should be determined and fixed prior to initiating your evaluation.
We also recommend you supplement this evaluation by examining the impact of relevant
confounders or effect modifiers, such as:

14•lesion size,

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lesion type,16•

lesion location,17•

disease stage,18•

organ characteristics,

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imaging hardware,

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imaging or scanning protocol, and

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image or data characteristics (e.g., characteristics associated with differences indigitization architectures for a CADe using scanned films).

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We recommend you report all performance measures with associated CIs.

Reproducibility Testing
We recommend you report device reproducibility testing. These testing processes provide
insight into the stability of the algorithm and its dependency on parameters usually related tothe image acquisition protocol. For example, for digitized image data, the placement of thefilm in the scanner or the time when the scanning occurs could produce data differences that
may affect how the algorithm performs. Providing standalone performance from the same
patient and from multiple scans acquired using the same (or a different) acquisition protocol
will provide information regarding the reproducibility and stability of the algorithm, withrespect to the expected variation in data collection methods. We recommend you provide thefollowing:

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description of the reproducibility study;

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parameters expected to introduce variability in the results (e.g., scanningcharacteristics, make and model of the imaging devices, acquisition protocol
parameters such as contrast agent or probe positioning);

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effects to be monitored (e.g., effect on the segmentation accuracy, feature extraction,
overall CADe performance accuracy); and

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results and statistical analysis.

Algorithm Stability Testing6

We further recommend you conduct algorithm stability testing including:

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algorithm stability with respect to training set changes (i.e., invariance of the CADealgorithm with respect to the datasets used in its design and training) (e.g., see Yousef
et al. 13 ),

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algorithm stability over time (e.g., invariance to changes in the imaging system,
acquisition conditions, operator settings), and

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algorithm stability with respect to other relevant covariates.

For assessment of the stability of your CADe algorithm, we recommend that you describe
your methodology and provide results. Such evaluation may be performed, for example, by
resampling using multiple bootstrap sets of the training database.

Algorithm Training Performance

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We recommend you measure and report standalone performance of your CADe device on thedataset used to train the algorithm. Assessment of the algorithm training performance may
include measures such as lesion-based, patient-based, and other relevant anatomical or image
unit-based sensitivities, and the average number of false positives per case (FPs/case) or otherrelevant measure of specificity, at each device operating point. If your device allows
clinicians to select or manipulate the device’s operating point, we recommend you provide thedevice performance for individual selectable operating points or the range in performance forcontinuously varying parameters.

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In addition to all device performance assessment testing described above, we reiterate ourrecommendation that you provide a comparison of the performance testing results to thecorresponding performances testing results of the legally marketed predicate device to which
you are claiming substantial equivalence (e.g., a previously released version of the device), if
applicable. Valid comparison of device performance is dependent upon sound study design inthe collection of your testing database. We recommend that you describe your comparison
analysis, hypothesis to be tested, sample size estimation, and endpoints, and that you provide

Other Information

13

Yousef, W. A., Wagner, R. F., and Loew, M. H., “Estimating the uncertainty in the estimatedmean area under the ROC curve of a classifier,” Pattern Recognition Letters, 2005
(http://www.sciencedirect.com/science/article/B6V15-4GTW8JJ1/2/58c02b75531e668fbcbcd7810c7034b7).

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Draft - Not for Implementationcomparison results. For example, when using a common database sequestered from thedevelopment and training of both your device and the predicate device, a comparison of the
CADe standalone performance may include a measure of the:

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difference in area under the FROC curves with associated statistical analysis (e.g., see
Samuelson et al. 14 ), and

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difference in detection sensitivity and number of FPs/case at the device operating
points.

Reporting of standalone performance results may be guided by the FDA Guidance entitled
Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests;
Guidance for Industry and FDA Reviewers. 15
We again recommend submitting electronically 16 the data used in any statistical analysis inyour study including patient information, disease or normal status, lesion size, lesion type,imaging and scanning setting, and imaging and data characteristics.
We also recommend you provide all data on a CD-ROM.

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Clinical Performance Assessment

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As described above, because each new CADe device represents a new implementation ofsoftware, FDA expects that each new CADe device (as well as software and other design,technology, or performance changes to an already cleared CADe device) will have different
technological characteristics from the legally marketed predicate device even while sharing thesame intended use. Accordingly, under section 513(i)(1)(A) of the Act, determinations of
substantial equivalence will rest on whether the information submitted, including appropriate
clinical or scientific data, demonstrate that the new or changed device is as safe and effective as
the legally marketed predicate device and does not raise different questions of safety andeffectiveness than the predicate device.
Because the reader is an integral part of the diagnostic process for CADe devices, we believe thata standalone performance assessment without a clinical performance assessment (i.e., a reader
study) will usually not be adequate to demonstrate that the diagnostic performance of the CADe
device is as safe and effective as the legally marketed predicate. Therefore, you should assume
that a clinical assessment will be necessary to demonstrate substantial equivalence between your

14

Samuelson, F. W., and Petrick, N., “Comparing image detection algorithms using resampling,”
in Proceedings of the IEEE International Symposium on Biomedical Imaging. IEEE, pp. 1312–
1315, 2006.
15
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071148.htm
16
See footnote 10.

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CADe device and its predicate for its intended use, when used by the intended user and inaccordance with its proposed labeling and instructions. This clinical performance assessment
should provide an estimate of the clinical effect of the CADe device on clinician performance. If
you believe a clinical assessment may not be necessary for demonstrating substantial equivalenceof your device with the predicate, we recommend that you contact the Agency to seek advice
prior to conducting your studies.
For clinical assessment, various control arms can be employed, including reading aided by thepredicate device and unaided reading. The use of the predicate device as the control, with bothdevices evaluated on the same data set, allows for direct comparison of your device with thepredicate for assessing substantial equivalence. The use of unaided reading as the control provides
an assessment of the clinical effectiveness of your device, which, in 510(k) studies, should becompared with the clinical effectiveness of the predicate device, as estimated in a prior study. For
this comparison to be unbiased, the two studies would ordinarily have to be calibrated on the
distributions of important covariates, which can require that the data be available at the patientlevel in both studies. In addition, the comparison can be problematic to make if different sets ofreaders, different reference standards, or different scoring methods are used in the two studies.
For further detail on potential clinical assessment methodologies, we recommend that you consult
the draft guidance entitled Clinical Performance Assessment: Considerations for ComputerAssisted Detection Devices Applied to Radiology Images and Radiology Device Data Premarket Approval (PMA) and Premarket Notification [510(k)] Submissions. 17
Examples of changes to an already cleared CADe device for which we recommend submitting aclinical performance assessment include:

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•

characteristics or makeup of the database used to assess standalone performance (seeSection 5) cannot be demonstrated to be comparable to the characteristics or makeup of
the database used in assessing the predicate device and these difference raises clinicalconcerns (i.e., could significantly affect safety or effectiveness);

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•

the results of the standalone performance assessment (see Section 5) are different fromthose of the predicate device, and the significance and effect on the clinician or patient forthese different levels of performance are not well-known or well-described in theliterature;

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•

the reference standard definition, scoring process, analysis methodology, or performance
endpoints are different from those of the predicate device, and the significance and effecton the clinician or patient of these differences are not well-known or well-described in theliterature;17

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm18
7277.htm

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12•

the algorithm design is different from that of the predicate device and this difference raises
clinical concerns (i.e., could significantly affect safety or effectiveness);34•

the device design has different human factors from those of the predicate device (e.g.,clinician’s interaction with a different CADe output display); or

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•

a new precursor technology or acquisition protocol is employed, changing the nature of
the inputs to the CADe (e.g., the current CADe device is applied to digital radiographs
whereas the predicate device was applied to film-based radiographs).

There may be situations where a standalone performance assessment without a clinicalperformance assessment (i.e., a reader study) may be sufficient to demonstrate substantial
equivalence. If you believe that a standalone performance assessment without a clinicalperformance assessment (i.e., a reader study) may suffice to show substantial equivalence, we
recommend you contact the Agency to discuss your proposed approach.

15

7.

User Training

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We recommend you provide a summary of the procedure that will be used to train the intended
users of your device when marketed. The goal of this training should be to help clinicians use the
CADe device in an appropriate manner and to provide training so that they can achieve theexpected device effectiveness. Training should include both the expected advantages and known
limitations of the device (e.g., the CADe does not identify calcified nodules). An aspect of the
training may be provided in the form of a self-test for the clinician. This self-test should provide
feedback to the clinician on how well he/she performs before and after the integration of the
CADe device and guidance on how to improve his/her performance. Training should be based ona broad set of patient data including normal cases. This training data should include typical true
positives (TPs) and false positive (FPs) that the device tends to output, as well as typical true
negatives (TNs) and false negatives (FNs).
For CADe devices allowing multiple thresholds or operating points, the training should help
clinicians identify the most appropriate device setting for their practices. In addition, the training
should help allow clinicians to identify suitable CADe reading scenarios.

32

8.

Labeling

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The premarket notification must include labeling in sufficient detail to satisfy the requirements of
21 CFR 807.87(e). The following suggestions are aimed at assisting you in preparing labelingthat satisfies the requirements of 21 CFR Part 801. 18

18

Although final labeling is not required for 510(k) clearance, final labeling must comply withthe requirements of 21 CFR Part 801 before a medical device is introduced or delivered for
introduction into interstate commerce. In addition, final labeling for prescription medical devices

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Your user manual should include the information described below.

Indications for use

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We recommend that the indications for use (IFU) address how the device will be used, forexample:

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There must be adequate directions for use as described in 21 CFR 801.5; the requirements
applicable to prescription devices are described in 21 CFR 801.109. You should submit clear
and concise instructions that delineate the technological features of the specific device andhow the device is to be used on patient images/data. Instructions should encourage
local/institutional training programs designed to familiarize clinicians with the features of thedevice and how to use it in a safe and effective manner. The direction should also clearly
define the intended user of the device.

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Warnings

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Precautions

The device is intended to assist [target users] in their review of [patient/datacharacteristics] in the detection of [target disease/condition/abnormality] using [image
type/technique and conditions of imaging].

Directions for use

The warnings should address limitations of the device. For example:[target user] should not rely solely on the output identified by [device trade name], butshould perform a full systematic review and interpretation of the entire patient dataset.
Another example may be:
This CADe device has been found to be ineffective for patients with [disease/condition/
abnormality]. This CADe should not be utilized with patients presenting with this
[disease/condition/abnormality].

The precautions should discuss the potential for adverse events associated with the use of thedevice and recommend mitigation measures. The adverse event discussion should at least
include a discussion of potential adverse events associated with an increased workup rate (i.e.,
events from false-positives) and missed disease/condition/abnormality.

must comply with 21 CFR 801.109. Labeling recommendations in this guidance are consistent
with the requirements of 21 CFR Part 801.

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2

Device Description3

We recommend you include the following in your device description:

4•

an overview of the algorithm design and features,

5•

an overview of the training paradigm and the training or development database, and

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a description of the reference standard used for patient data utilized in the development
and adjustment of the algorithm.

Clinical Performance Assessment

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When appropriate, we recommend you include a summary of the clinical performanceassessment including:

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study objectives,

13•

study design,

14•

patient population, e.g., age, ethnicity, race,15•

number of clinicians and their qualification,

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description of the methodology used in gathering clinical information,

17•

description of the statistical methods used to analyze the data, and

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study results.

Additional information on reporting clinical performance results can be found in the draft
guidance entitled Clinical Performance Assessment: Considerations for ComputerAssisted Detection Devices Applied to Radiology Images and Radiology Device Data Premarket Approval (PMA) and Premarket Notification [510(k)] Submissions. 19

Standalone Performance Assessment

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We recommend you provide a summary of the device standalone performance andreproducibility testing including:
•

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the scoring criteria used to determine the nature of each region marked by your CADe
device;19

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm18
7277.htm

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•

the overall lesion-based, patient-based, and any other relevant anatomical or image
unit-based sensitivities, and the average number of FPs/case or other relevant measureof specificity, at each available device operating point;4
5•

the stratified analysis per lesion size, per lesion type, per imaging or scanning
protocols, per imaging or data characteristics, as appropriate;6•

the confidence intervals (CIs) on each measure; and

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•

the free-response receiver operating characteristic (FROC) performance, as
appropriate.

24この報告書は、平成２２年度に独立行政法人

産業技術総合研究所が、経済産業省からの委託を受けて実施した成果を取りまとめたものです。

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医療機器開発ガイドライン策定事業（医療機器に関する開発ガイドライン作成のための支援事業）
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開発ＷＧ報告書
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TEL：03-3501-1562
FAX：03-3501-6613
URL：http://www.meti.go.jp/

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