Requirements for Computer Systems in the clinical practice

1. Requirements for Computer Systems in the clinical practice Danilo Neri, PhD Pomezia, 13 Settembre 2005

2. Requirements for Computer Systems in the clinical practice • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario

3. Fundamental Requirements for clinical data attributable legible contemporaneous (timeliness) original Accurate Integrity Security Traceability Data shall be (regardless the format !)

4. Integrity Integrity Security Security Traceability Traceability Different implications for different environments CLOSED Records are fully under Responsibility of the Firm OPEN Responsibility of Records is shared with Third Parts

5. Requirements for Computer Systems in the clinical practice • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario

6. Case History Evolution of Computer System in GCP: the old Scenario Paper CRF Clinical DB (eCRF) w/o eSignature • Data are registered in the paper Case History • Data are reported in the CRF Paper Form • Data are migrated in the Clinical DB (option: Electronic Signature)

7. Paper CRF Case History ICH E6 for Computer Systems 21 CFR Part 11 Requirements (Closed System) Protection of Privacy (21 CFR Part 21, EU 95/46/EC) Compliance Requriments for Computer Systems Source Data Verification Clinical DB (eCRF) w/o eSignature Regulations

8. ICH E6 Requirements for Computer Systems (1.2) 5.5.3.a Ensure and document that the electronic data processing system(s) conforms to the Sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH Harmonised Tripartite Guideline – Guideline For Good Clinical Practice

9. ICH E6 Requirements for Computer Systems (2.2) Par. 5.8: Integrity of Data and Computer Software The credibility of the numerical results of the analysis depends on the quality and VALIDITY of the method and software used both for data management (data entry, storage, verification,correction and retrieval) and also for processing the data statistically. The computer software used for data management and statistical analysis should be reliable and documentation of appropriate software testing procedures should be available. International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use – ICH Harmonised Tripartite Guideline – Guideline Guideline for statistical principle on Clinical trial

10. Electronic Records Code of Federal Regulations 21 CFR Part 11; Eletronic Records; Electronic Signature August, 1997 Criteria set forth for 21 CFR Part 11 • RECORD LIFE CYCLE • creation • modifying • maintenance • archiving • retrieving • transmission Electronic Signature Electronic Record Electronic Signature Criteria set forth for EQUIVALENCE Paper Record Handwritten Signature

11. 21 CFR Part 11 Requirements for Electronic Records • Control for Closed Systems [ref. §11.10] - • The use of closed systems to manage electronic records implies: • (a) Validation of computer system • (b) Accurate and complete copies of records • (c) Protection of the data • (d) Limiting access • (e) Audit trails • (f) Operational system checks • (g) Authority checks • (h) Control on validity of input actions • (i) Adequate education and training • (l) Control on documentation distribution and change • control procedure application

12. What is Computer System Validation? Documented evidence High degree of assurance intended functions accurately and reliably CSV is the documented evidence, to a high degree of assurance, that a computer system performs its intended functions accurately and reliably.

13. ISO equivalent Requirements (The Quality is) The totality of characteristics of an entity that bear on its ability to satisfy stated and implied need. [ISO 8402: 1994] Note: In ISO/IEC 14598 the relevant entity is a software product An entity is a product, process, person, activity, machine, service, system, department, company, institution, or organization.

14. GAMP Validation Lifecycle related to User Requirements Specification Risk Assessment Process Performance Qualification related to Risk Assessment Function Operational Qualification Functional Specification Configuration related to Installation Qualification Design Specification Testing System Build Design Review

15. Validation Deliverables User Requirements Specifications Decommissioning Plan/Report Audit Report De commissioning Functional Specifications SOPs Design Specifications Test Plan Installation Operational Performance Qualification Protocol & Reports Unit Testing System Acceptance Testing

16. Part 11 vs ICH E6 Requirements (1/2)

17. Part 11 vs ICH E6 Requirements (2/2)

18. Requirements for Computer Systems in the clinical practice • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario

19. Case History Evolution of Computer System in GCP: the current Scenario Clinical DB (eCRF) + eSignature Network • Data are registered in the Case History • Data are directly recorded in the Clinical DB through remote access and electronically signed

20. Case History ICH E6 for Computer Systems 21 CFR Part 11 Requirements (Open System + eSig Reqs) Protection of Privacy (21 CFR Part 21, EU 95/46/EC) Compliance Requriments for Computer Systems Source Data Verification Clinical DB (eCRF) + eSignature Network Regulations

21. 21 CFR Part 11: Requirements for Open Systems • Control for Open Systems [ref. §11.30] - • The use of open systems to manage electronic records implies: • Controls for Closed System (see previous slide); several requirements (I.e. Device Checks) might be enforced • Document encryption • Digital signatures standards

22. 21 CFR Part 11: Requirements for Electronic Signatures • [ref. §11.50; 11.70; 11.100] - • The use of Electronic Signature (ES) for signing Electronic Records (ER) implies: • Using ES when required by the predicate rule(s) • ES manifestation • ES / ER linking • Procedure for managing attribution and use of ES

23. 21 CFR PART 11 Electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic records to ensure that the signatures cannot be excised, copied, or otherwise transferred to falsify an electronic record by ordinary means. Ref. §11.70. Preamble 15,53,107,108,109,110,11,112,113 Fundamental requirement: Signature-Record Linking Signed Record Signature IMMUTABLE BY ORDINARY MEANS

24. Requirements for Computer Systems in the clinical practice • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario • Requirements for Computer Systems in GCP • The old scenario • The current scenario • The next scenario

25. Evolution of Computer System in GCP: the near next Scenario Electronic Case History Paper CRF Network Clinical DB (eCRF) + eSignature Printed Case History • Data are registered directly in the electronic Case History (ECH) • Case History are printed based upon ECH • Data are reported in paper CRF and then migrated to the clinical DB or directly entered in the Clinical DB

26. Current use of Computer System for Electronic History Case

27. Electronic Case History + eSignature Paper CRF Network ICH E6 for Computer Systems 21 CFR Part 11 Requirements (Open System + eSig Reqs) Printed Case History Protection of Privacy (21 CFR Part 21, EU 95/46/EC) Requirements for Computer Systems Regulations Regulations Ministry of Health Rules Quality ISO requirements Privacy related local laws (DL675/196, DL196/2003) Clinical DB (eCRF) + eSignature ? Source Data Verification

28. Requirements for Privacy Protection Legal “trigger” Directive 95/46/EC, 24 October 1995 Member States shall protect the fundamental rights and freedoms of natural persons, and in particular their right to privacy with respect to the processing of personal data

29. Any operation or set of operations which is performed upon personal data, whether or not by automatic means, such as: • collection • recording • organization • storage • adaptation or alteration, • retrieval • Consultation • use • disclosure by transmission • dissemination or otherwise making available • alignment or combination • blocking, erasure or destruction Directive 95/46/EC: Processing of Personal Data Directive 95/46/EC, 24 October 1995 Chapter I, Art. 2

30. Directive 95/46/EC: Application Field Processing of personal data wholly or partly by automatic means Processing of personal data which form part of a filing system or are intended to form part of a filing system Directive 95/46/EC, 24 October 1995 Chapter I, Art. 3

31. Directive 95/46/EC: Data Quality • Controller has to ensure that data are: • Processed fairly and lawfully • Collected for specified, explicit and legitimate purposes • Adequate, relevant and not excessive in relation to the purposes • Accurate and, where necessary, kept up to date • Kept in a form which permits identification of data subjects for no longer than is necessary Directive 95/46/EC, 24 October 1995 Chapter II, Art. 6

32. Directive 95/46/EC: Data Subject’s Rights • Information • Access to Data • Right to object

33. Directive 95/46/EC: Data Subject’s Information • Data subject has to know: • Identity of the Controller (or Representative) • Purpose of the Data Processing • Recipient of the Data • Own rights Directive 95/46/EC, 24 October 1995 Chapter II, Art. 10

34. Directive 95/46/EC: Data Subject’s Access to Data • Data Subject has to obtain from the Controller: • Information about subject’s personal data effective use, data undergoing process, logic involved in any automatic processing of data, own rights • Erasure or blocking of data not compliant to 95/46/EC • Notification about data disclosure to third parties Directive 95/46/EC, 24 October 1995 Chapter II, Art. 12

35. Directive 95/46/EC: Confidentiality of Processing “Any person acting under the authority of the controller or of the processor, including the processor himself, who has access to personal data must not process them except on instructions from the controller, unless he is required to do so by law.” “ Directive 95/46/EC, 24 October 1995 Chapter II, Art. 16

36. Directive 95/46/EC: Security of Processing • Safely processing • Protection against accidental or malicious • loss • alteration • unauthorized disclosure or access • Security measures implementation Directive 95/46/EC, 24 October 1995 Chapter II, Art. 17

37. Local Laws application • Italian laws DL675/196, DL196/2003 include the statements of EU directive • The Technical attachment B dedicated to Electronic data management. • The law and the Technical attachment B address nearly the same requirements set forth by pharmaceutical regulations, such as 21 CFR Part 11

38. Requirements set forth by the Technical Attachment for data management (1.2) (2) Le credenziali di autenticazione consistono in un codice per l'identificazione dell'incaricato associato a una parola chiave riservata conosciuta solamente dal medesimo oppure in un dispositivo di autenticazione in possesso e uso esclusivo dell'incaricato, eventualmente associato a un codice identificativo o a una parola chiave, oppure in una caratteristica biometrica dell'incaricato, eventualmente associata a un codice identificativo o a una parola chiave. Security Management (5) La parola chiave, quando è prevista dal sistema di autenticazione, è composta da almeno otto caratteri oppure, nel caso in cui lo strumento elettronico non lo permetta, da un numero di caratteri pari al massimo consentito; essa non contiene riferimenti agevolmente riconducibili all'incaricato ed è modificata da quest'ultimo al primo utilizzo e, successivamente, almeno ogni sei mesi. In caso di trattamento di dati sensibili e di dati giudiziari la parola chiave è modificata almeno ogni tre mesi. Password Management

39. Requirements set forth by the Technical Attachment for data management (2.2) (13) I profili di autorizzazione, per ciascun incaricato o per classi omogenee di incaricati, sono individuati e configurati anteriormente all'inizio del trattamento, in modo da limitare l'accesso ai soli dati necessari per effettuare le operazioni di trattamento. ; User Profiles (19.3) (Il documento programmatico sulla Sicurezza (DPS) deve contenere) l'analisi dei rischi che incombono sui dati; Risk Analysis (19.4) (Il documento programmatico sulla Sicurezza (DPS) deve contenere) le misure da adottare per garantire l'integrità e la disponibilità dei dati, nonchè la protezione delle aree e dei locali, rilevanti ai fini della loro custodia e accessibilità Backup (19.5) (Il documento programmatico sulla Sicurezza (DPS) deve contenere) la descrizione dei criteri e delle modalità per il ripristino della disponibilità dei dati in seguito a distruzione o danneggiamento Restore

40. ISO Requirements • Implementation of ISO Quality System in hospital management has been recommended by the Ministry of Health • The Electronic Case History may be a powerful and fundamental key point of the Quality System provided that following requirements are met: • Traceability • Clarity • Accuracy • Trustworthiness • Completeness • Implied requirements almost equal to the ones set forth by pharmaceutical regulations

41. Electronic Case History + eSignature Paper CRF Network Printed Case History Only if these requirements are met, Electronic Case History can be used for Source Data Verification Electronic Data for Source Data Verification Ministry of Health Rules Quality ISO requirements Privacy related local laws (DL675/196, DL196/2003) Clinical DB (eCRF) + eSignature Source Data Verification

42. Conclusions • Requirements for data managed by Computer System are increasing due to the increment of Computer System in the product life cycle • Electronic Case History might be used provided that they verify the provisions set for Regulated Records • The checklist for Computer System Compliance may be used in order to justify the use of Electronic Case History within the Source Data Verification

43. Thanks for your attention Should you have any question, feel free to contact me