ER/ES実践について研究するページです。
＊万が一文中に解釈の間違い等がありましても、当社では責任をとりかねます。
本文書の改訂は予告なく行われることがあります。
ERESガイドライン対応のための課題と問題点（その2）
1. はじめに
前回に引き続き、ERESガイドライン対応のための課題と問題点を整理してみたい。
ERESガイドラインは、言うまでもなく日本国内における指針である。しかしながらグローバル化が進む製薬業界において、ERESガイドラインを遵守するのみではすまされない。グローバルな企業にとって、ERESガイドラインとPart11などの諸外国の規制要件が整合しない場合、いわゆるダブルスタンダードの問題がおきる。
今回はPart11や、その他関連ガイダンスも引用し、検討を行ってみたい。
2. コンピュータ・システム・バリデーション
ERESガイドラインを遵守する前提として、コンピュータ・システム・バリデーション（以下、CSV）を実施しなければならない。（図1参照）
| 3.1. 電磁的記録の管理方法 電磁的記録利用システムとそのシステムの運用方法により、次に掲げる事項が確立されていること。この場合、電磁的記録利用システムはコンピュータ・システム・バリデーションによりシステムの信頼性が確保されている事を前提とする。 |
図1 コンピュータ・システム・バリデーション
しかしながら厚生労働省では、拠り所とするべき具体的なCSVに関する指針などの規制要件を発行していない。
当局から指針等が出されない場合、製薬各社がCSVに関するSOP等を作成したとしても、それらの「適合性の確認」が行えない。これは品質保証活動（以下、QA）上の大きな問題である。
「適合性の確認」は、規制要件と自社のSOPを照し合せて、それらに差異がないことを確認する。この適合性をもったSOPによって、品質管理システム（Quality Management System：QMS）が成り立つのである。
ちなみにFDAでは、2003年9月に発行した「Part 11, Electronic Records; Electronic Signatures ? Scope and Application」において「コンピュータ・システムのバリデーションに関する詳しいガイダンスについては、FDAによる業界およびFDAスタッフ向けのガイダンスである、FDA staff General Principles of Software Validation およびGAMP 4 Guideといった業界向けのガイダンスを参照のこと。」と述べている。
2008年2月には、ISPEからGAMP 5が発行された。今後欧米の多くの製薬会社はGAMP 5に準拠したCSV SOPを作成し、CSVを実施することになると思われる。
おそらく日本の製薬企業も同様にGAMP 5等を参考にしてCSV SOPを作成しCSVを実施することになると思われるが、前述の通り規制当局が拠り所とする指針等を発行し、FDAのようにGAMP 5等を参照することと明記することが望まれる。
ちなみにPart11でもCSVは前提条件であり、§11.10 (a)に次のように記載されている。
「Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.（正確性、信頼性、意図した性能の一貫した確保、ならびに無効となったり変更されたりした記録を識別する能力が保証されるようにするためのシステムのバリデーション）」
意外と知られていないことであるが、FDAはPart11の発行をもってバリデーションの定義を変更した。この条文にあるように従来のバリデーションに加えて「無効となったり変更されたりした記録を識別する能力」すなわち「修正証跡（監査証跡）」を要求している。修正証跡（監査証跡）機能がないシステムは、Non-Validateである。
3. ハイブリッドシステム
電子の記録を利用するが、電子署名は使用せず、記録を紙媒体に印刷したものに手書きの署名を付す方法をハイブリッドシステムと呼ぶ。
考えてみれば、製薬企業の記録の大部分はハイブリッドシステムで成り立っている。逆の言い方をすれば、ペーパーレス（すなわち電子署名を利用しているシステム）は、EDCシステムや安全性電子報告システム等に過ぎない。eCTDも現在のところ署名ページをスキャンニングし提出している。
FDAは、Part11のSub Part B「Electronic Records」とSub Part C「Electronic Signature」は別々の要件としてとらえて良いと述べている。Part11では、電子記録は使用するが電子署名を利用しないといったハイブリッドシステムの利用を想定し、手書き署名に関しても言及している。
しかしながらERESガイドラインでは、ハイブリッドシステムに関する記述は見当たらない。つまり電子記録を利用し、記録を紙媒体に印刷したものに記名・捺印または手書きの署名を付す場合の要件である。
ただし通知文の「3. 適用範囲」には、
「資料、原資料、その他薬事法及び関連法令により保存が義務づけられている資料を紙媒体で作成する際に電磁的記録及び電子署名を利用する場合にあっても、可能な限り本指針に基づくことが望ましいこと。」とある。
4. 電磁的記録媒体への出力
ERESガイドラインでは、見読性の要件のひとつとして、電磁的記録媒体へのコピーをあげている。（図2参照）
この条文はPart11を参考にしているものと思われる。
すでに本シリーズで解説した通り、電磁的記録媒体へのコピーとは、書面に印刷する代わりに、書面と同様の形式でpdf等でCD-R等の電磁的記録媒体に出力することを指している。したがって、ここでは「コピー」ではなく「出力」と読み替えた方が理解しやすい。
| 3.1.2.電磁的記録の見読性 電磁的記録の内容を人が読める形式で出力（ディスプレイ装置への表示、紙への印刷、電磁的記録媒体へのコピー等）ができること。 |
図2 電磁的記録媒体へのコピー
5. 電子署名
電子署名に関しては、本シリーズで幾度となく取り上げてきた。
解説の繰り返しは避けるが、ERESガイドラインにおける電子署名の問題点は、電子署名法に従うこととしたことである。
電子署名法による電子署名（つまり認証局により認証を受けたデジタル署名）は、FDAをはじめグローバルの標準と整合しない。
このままでは、EDCシステムを利用したグローバル治験等に影響が出てしまうのである。
はたして製薬各社は、治験責任医師等がEDCにより電子的にCRFを作成または変更する際に、電子署名法に基づいた電子署名を利用させることができるのであろうか。
また外国製のEDCシステムは、電子署名法に基づいた電子署名の機能を搭載するであろうか。
しかしながら、ERESガイドラインのみではなく、厚生労働省令第44号にも電子署名法に基づいた電子署名の使用が明記されている。
例えば、GCPに従い必須文書として電子CRFを医療機関が保存する場合、電子署名法に基づいた電子署名が付されていなければ、厚生労働省令第44号に違反することとなる。
厚生労働省令第44号およびERESガイドラインが改定されない限り、電子署名（ペーパーレス）は利用を控えた方が無難であるかも知れない。
6. クローズド・システムとオープン・システム
ERESガイドラインでは、Part11と同様にクローズド･システムとオープン・システムに関する記載がある。
「3.2. クローズド・システムの利用」（図3参照）は、条文が意図する事柄が筆者には不明である。特別にクローズド･システムに特化した要件が記載されているとは思えない。
| 3.2. クローズド・システムの利用 電磁的記録を作成、変更、維持、保管、取出または配信をするためにクローズド・システムを利用する場合は、3.1 に記載された要件を満たしていること。また、電子署名を使用する場合には、4. に記載された要件を満たしていること。 |
図3 ERESガイドラインにおけるクローズド・システムの利用
さらに「3.3. オープン・システムの利用」（図4参照）は、筆者には難解である。
「デジタル署名」の使用は、オープン・システムの利用時に特化した追加手段の一例であるとしている。しかしながら電子署名を使用する場合には、4. に記載された要件を満たすことを求めている。
つまりERESガイドラインでは、電子署名とデジタル署名を区別しているように読み取れる。しかしながら「デジタル署名」は「電子署名」という行為を実現するための技術であることから、本来区別することはできないはずである。
| 3.3. オープン・システムの利用 電磁的記録を作成、変更、維持、保管、取出または配信をするためにオープン・システムを利用する場合は、3.1 に記載された要件に加え、電磁的記録が作成されてから受け取られるまでの間の真正性、機密性を確保するために必要な手段を適切に実施すること。追加手段には、電磁的記録の暗号化やデジタル署名の技術の採用などが含まれる。さらに、電子署名を使用する場合には、4. に記載された要件を満たしていること。 |
図4 オープン・システムの利用
余談であるが、Part11は現在改定作業中であるが、改定後はクローズド･システムとオープン・システムを特に区別しないことになると聞いている。
7. 21 CFR Part 11との相違
7.1 国際的な整合性
ERESガイドラインとPart11の関連性及び国際的な整合性に関して、パブリックコメントの回答に記載がある。（図5参照）
| #142 本指針とPart 11は、両者ともに電磁的記録と電子署名に関する要件を規定している点で関連があります。 #144 国際的な整合性については、海外における規制動向等もふまえ、随時対応していく予定です。 #145、#147 （電子記録・電子署名について日・米・欧3極で）基本的な概念は同じであると考えます。現行の内容は、欧米の方向性を十分に考慮されているものと考えています。 |
図5 国際的な整合性に関するパブリックコメントの回答
ERESガイドラインとPart11が完全に整合しない限り、日本の製薬企業ではいわゆる「ダブルスタンダード」の問題が出てくる。
当該電磁的記録が日本国内のみの適用であれば問題がないのであるが、米国へ申請・報告等を行う場合や、EDCを利用してグローバル治験を実施する際などに問題が起きる可能性がある。
7.2 スコープの違い
ERESガイドラインでは、適用範囲を以下のように定めている。
- 薬事法及び関連法令に基づいて、医薬品、医薬部外品、化粧品及び医療機器の承認又は許可等並びに適合性認証機関の登録等に係る申請、届出又は報告等にあたって提出する資料として電磁的記録又は電子署名を利用する場合
- 原資料、その他薬事法及び関連法令により保存が義務づけられている資料として電磁的記録及び電子署名を利用する場合
一方Part11では、図6のように記載されている。
| §11.10(b) 「This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations. This part also applies to electronic records submitted to the agency under requirements of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, even if such records are not specifically identified in agency regulations.」 （この条項はFDAの規則で記録が要求されていることに伴い、作成されたり変更されたり、保持されたり、保管されたり、検索されたり、配信されたりする電子形式の記録に適用される。この条項はまた、Federal Food, Drug, and Cosmetic ActおよびPublic Health Service Actに規定された要件にもとづきFDAに提出する電子記録にも、そのような記録についてFDAの規則に明確な指定がない場合においても適用される。） |
図6 Part11におけるスコープ
前回も述べたとおりERESガイドラインは、資料を電磁的記録により提出する場合と、原資料等を電磁的記録により保存する際に適用される。これはもともとeCTDを対象に検討された経緯があるからであると思われる。
これに対してPart11は、もともとGMPにおける製造記録のペーパーレス化（つまり手書き署名を割愛し、電子署名の使用を認める）を目指したものであったことから、記録全般に適用されているものと思われる。
7.3 アプローチ
FDAは2002年8月21日のFDA NEWSで、GMPを改定し21世紀のcGMPのイニシャティブのひとつとしてリスクベースアプローチを採用することを発表した。
これを受けてFDAが2003年9月に発行した「Guidance for Industry － Part 11, Electronic Records; Electronic Signatures ? Scope and Application」では、Part11においてもすべての電子記録に一様に対応するのではなく、リスクベースアプローチをとることを推奨し、次のように記述している。
「FDA が推奨するアプローチは、リスク・アセスメントの正当化および文書化、そして製品の品質と安全性、記録の完全性に影響を及ぼす可能性をもつシステム判断することに重点をおいたアプローチである。」
またGAMP 5もFDAおよびICH Q9との整合を図るため、リスクベースアプローチを採用している。そのため副題を「 A Risk-Based Approach to Compliant GxP Computerized Systems」とした。ちなみにGAMP 5では、データの完全性、製品の品質、患者の安全に大きく影響するコンピュータ化されたシステムにフォーカスしている。
ERESガイドラインでは、リスクベースアプローチに関しての記載はない。これは対象範囲を資料及び原資料等としており、電子記録全般に及ばないことからであると理解する。
7.4 電子記録に対する要件
ERESガイドラインでは「3.1. 電磁的記録の管理方法」において「真正性」「見読性」「保存性」の3つの要件を求めており、また加えて「3.3. オープン・システムの利用」において「機密性」を要求している。
これに対してPart11では、§11.10 Controls for closed systemsにおいて「真正性および完全性、さらに該当する場合には機密性」を要求している。（図7参照）
さらに§11.10 (b)では「見読性」、§11.10 (c)では「検索性」を求めている。
上記を比較した場合、ERESガイドラインでは、クローズ・システムにおける「機密性」の要求がない。
また「検索性」に関しては記述が見当たらない。
| §11.10 Controls for closed systems 「Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and to ensure that the signer cannot readily repudiate the signed record as not genuine. （電子記録を作成し、変更し、保存し、伝達するためにクローズド・システムを使用する者は、電子記録の真正性および完全性、さらに該当する場合には機密性も含めてこれらが保証されるように、また署名者が署名した記録が真正のものでないと否認することが容易にできないようにするために考案された手続きと管理方法を併用しなければならない。） |
図7 Part11におけるクローズド・システムの利用
7.5 治験における詳細な要件
FDAは、2007年5月に「Guidance for Industry － Computerized Systems Used in Clinical Investigations」と題したガイダンスを発行した。これは1999 年 4 月に発表した「Guidance for Industry － Computerized Systems Used in Clinical Trials」を置き換えるものである。
またこのガイダンスにおいてFDAは「Guidance for Industry － Part11, Electronic Records; Electronic Signatures Scope and Applicationを補足し、臨床試験の現場において発生するソース・データに適用する際の規制当局の国際的調和への貢献の補足となる。」としている。
またEMEAにおいても、2007年11月にGCP IWG（査察検討グループ）が「Draft Reflection Paper on Expectations for Electronic Source Documents used in Clinical Trials（治験で使用する電子的ソース・ドキュメントに関する期待についてのリフレクション・ペーパ（案））」を発表した。
ちなみにリフレクション・ペーパとは、関連する文献等を研究・集積し、自らの考えを述べた文献のことである。
日本の当局は、これら欧米のガイダンスに相当し、ERESガイドラインを補足する治験におけるコンピュータシステムの利用に関する指針を発行していない。
8. 電磁的記録利用システムの2つのタイプ
厚生労働省令第44号の第6条（電磁的記録による作成）には、以下のように記載されている。
「当該書面に係る電磁的記録の作成を行う場合は、民間事業者等の使用に係る電子計算機に備えられたファイルに記録する方法又は磁気ディスク等をもって調製する方法により作成を行わなければならない。」
厚生労働省令第44号が記述している「ファイルに記録する方法」と「磁気ディスク等をもって調製する方法」の区別は、ERESガイドラインには見当たらない。
この電磁的記録の作成の2つの方法は、それぞれ真正性を確保する方法が異なる。
詳しくは本シリーズ第4回を参照されたい。
9. 本格的な査察実施のタイミングと内容
FDAは、1999年5月にCompliance Policy Guide 7153.17（以下、CPG 7153.17）を発表した。
CPG 7153.17は、Part 11に対するFDAの考え方を示し、査察や是正措置執行に際する手引きとなるものである。
このようにFDAでは具体的に査察の考え方を明らかにしている。
日本において規制当局がいつ本格的な査察を行うのか、またその内容がどんなものになるのかは多くの製薬企業の関心のあるところであろう。
なお現在CPG 7153.17は、Part11の改定作業に伴い取り下げられている。
10. おわりに
米国ではPart11発行後、コンプライアンスコストが問題となった。日本においても過剰な投資は避けなければならない。しかしながら電磁的記録および電子署名の信頼性の確保を行うための最低限の対応は必要である。
紙媒体での記録や記名・捺印または手書き署名にかえて、電磁的記録および電子署名を利用したことによって、社会的な混乱を起こしてはならない。
製薬業界に限らず、ずさんな管理による品質の問題により世間を騒がせる事件は後を絶たない。
また規制当局も不作為では困る。IT化の波が押し寄せる現代にあって、業界の電磁的記録および電子署名に関する品質水準を向上させるためのより具体的な指針が望まれる。
参考
- 「PHARMSTAGE Vol.8, No.1 2008 ER/ES実践講座 (第4回)」技術情報協会 2008.4
- 「電子署名及び認証業務に関する法律」平成12年5月31日 法律第102号
- 「医薬品等の承認又は許可等に係る申請等における電磁的記録及び電子署名の利用について」平成17年4月1日 薬食発第0401022号
- 「医薬品等の承認又は許可に係る申請に関する電磁的記録・電子署名利用のための指針（案）」に関する意見・情報の募集結果について」 平成17年5月9日 厚生労働省医薬食品局審査管理課
- 「Title 21 of the Code of Federal Regulations Part 11,“Electronic Records; Electronic Signatures”」 FDA 1997.3.20
- 「Enforcement Policy: 21 CFR Part 11; Electronic Records; Electronic Signatures (CPG 7153.17) 」 FDA, Office of Regulatory Affairs 1999.5.13 COMPLIANCE POLICY GUIDE Section 160.850
- 「Guidance for Industry: Part 11, Electronic Records; Electronic Signatures – Scope and Application」 FDA 2003.9
- 「GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems」 ISPE 2008.2
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