Nilvad GCP Overview Susan Lennon Clinical Research Manager ICRIN/MMI

1. Nilvad GCP OverviewSusan LennonClinical Research ManagerICRIN/MMI 1

2. WARNING This Presentation is NOT a substitute for GCP training • Need to source this locally • Need to have documentary evidence of having received training • WILL BE AUDITED

3. European Legislation for Clinical Trials

4. Clinical Research Rules & Regulations Directive 2001/20/EC Aimed to harmonise rules within EU and improve the conduct of trials within EU Implemented nationally: 1 May 2004

5. Clinical Trials Regulatory Background: What did the Clinical Trials Directive change? Defined a Clinical Trial Defined GCP Defined Rules for Informed Consent Established a Single Opinion by Ethics Committees Defined Rules/Timelines for CA Authorisation Defined Rules/Timelines for Protocol Amendments

6. Clinical Trials Regulatory Background: What did the Clinical Trials Directive change? Established Information Sharing across Member States Established GMP for IMPs Established Labelling requirements Provided for GCP Inspection Provided for Safety Reporting/Clinical Trials Vigilance

7. Clinical Trials Regulatory Background: Directive 2005/28/EC or “GCP Directive” Arose from CT Directive – Article 1 Defines principles and guidelines for GCP…

8. Clinical Research Rules & Regulations

9. Clinical Research Rules & Regulations Volume 10 of Eudralex ‘The rules governing medicinal products in the European Union’ contains guidance documents applying to clinical trials

10. Useful EU Guidance Documents: Annex 13 What is an IMP Guidance TMF and Archiving ICH GCP

11. What is the purpose of ICH GCP? Provides public assurance that Rights Safety Well-being Of subjects are protected Assurance that data are credible Came into force: January 1997 (Otherwise known as CPMP/ICH/135/95/Step 5 or ICH E6)

12. Recap – The principles of GCP

13. Principles of ICH GCP “Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s)” 13

14. Principles of ICH GCP 1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and the applicable regulatory requirements. 14

15. Principles of ICH GCP 2. “Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks” Declaration of Helsinki (B8) 15

16. Principles of ICH GCP 3. “The rights, safety, and well-being of the trial subject are the most important considerations and should prevail over interests of science and society” Declaration of Helsinki (A6) 4.“The available non clinical and clinical information on an investigational product should be adequate to support the proposed trial” Declaration of Helsinki (B2)

17. Principles of ICH GCP 5. “Clinical trials should be scientifically sound, and described in a clear and detailed protocol” Declaration of Helsinki (B4) 6. “A trial should be conducted in compliance with the protocol that has received prior independent ethics committee approval/favourable opinion” Declaration of Helsinki (B5)

18. Principles of ICH GCP 7. “The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician, or when appropriate, of a qualified dentist” 8. “Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s)” Declaration of Helsinki (B6)

19. Principles of ICH GCP 9. “Freely given informed consent should be obtained from every subject prior to clinical trial participation” Declaration of Helsinki (B14) 10. “All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification”

20. Principles of ICH GCP 11. The confidentiality of records that could identify subjects should be protected , respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements 12. Investigational products should be manufactured, handled and stored in accordance with Good Manufacturing Practice(GMP). They should be used in accordance with the approved protocol.

21. Principles of ICH GCP 13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

22. Essential Documents

23. Essential Documents Section 8 of ICH GCP Lists required documents to be maintained Investigator trial file Sponsor trial file Before start of study During conduct of study At end of study

24. Essential Documents- why? Permit evaluation of the conduct of the trial Permit evaluation of the quality of data produced Demonstrates compliance of investigator, sponsor and monitor with GCP and regulatory requirements Assists in successful management of the trial Used as part of audit/inspection process Confirm the validity of the trial Confirm the integrity of the data collected

25. Essential Documents Should be established at beginning of trial both at the investigative site and the sponsor’s office Documents should be filed in a timely manner Final close-out only when monitor has confirmed all necessary documents are in appropriate files Investigator should take measures to prevent accidental or premature destruction Refer to EU Guidance document on trial master file and archiving

26. Where should it be filed and when? • Investigator Brochure • Both Sponsor and investigator files • Before the clinical phase of the trial commences • Signed protocol and amendments, if any and sample CRF • Both Sponsor and investigator files • Before the clinical phase of the trial commences

27. Where should it be filed and when? • Monitoring visit reports • Sponsor files only • During the clinical conduct of the trial • Documentation of CRF corrections • Both Sponsor (original) and investigator (copy) files • During the clinical conduct of the trial

28. Where should it be filed and when? • Clinical study report • Both Sponsor and investigator (if applicable) files • After completion or termination of the trial • Final Trial close out monitoring report • Sponsor files only • After completion or termination of the trial

29. CRF Completion 29

30. CRF Completion Clinical trial is intended to find answers to the research question by means of generating data for proving or disproving a hypothesis. The quality of data generated plays an important role in the integrity of the clinical trial. • Complete all sections of CRF • Majority of queries • Missing data not indicated as such not available, not done, unknown • Inconsistent data with previous entries • Abbreviations • Implausible data • Concomitant meds and AEs • Spurious lab data

31. CRF Completion • Ensure that delegation log indicates who is completing the CRF • Ensure that training record reflects training on completion of CRF • Information must be identical to information in patients records • If data is unavailable then indicate this, follow instructions on eCRF • 777 for not available data • 888 for not done • 999 for unknown • All Dates are in MM-DD-YYYY format • Missing/Unknown dates.. Follow instructions on eCRF • Enter 01/01/1900 • All data should be entered verbatim, do not abbreviate CRF entries.

32. CRF Completion • All text entries MUST be made in English • Do not use subscript or superscript when entering data. • Text exceeding field length will be flagged automatically by the EDC system. • Symbols should not be entered in the EDC system. • Quotes should not be used when entering data on the eCRF. • Check spellings of AEs, medications etc. • If a brand name concomitant medication was taken use that name, if a generic concomitant medication was taken, use the generic name • Ensure you complete the causality assessment for SAEs • Think about other data dependencies e.g. metformin on concomitant medication page, is there an AE of Diabetes or it is reflected in the medical history.

33. GCP Audits 33

34. Qualifications & Agreements “The Investigator(s) should be qualified by education, training and experience to assume responsibility for proper conduct of trial, … and should provide evidence of such qualifications through up-to-date CV and/or other relevant documentation requested by the sponsor, EC or regulatory authority” CV Updated regularly, e.g. review annually Signed & dated, and after each review Include CT experience and training? Consider training records Standard department procedure and template?

35. Qualifications & Agreements “The Investigator should be thoroughly familiar with the appropriate use of the IP as described in the protocol, current IB, product Information and other information sources provided by sponsor” Evidence of signature on the protocol with appropriate dates Evidence that received by investigator in timely manner signature of receipt Also applies to updates to these documents

36. Qualifications & Agreements “The Investigator should be aware of, and comply with GCP and the applicable regulatory requirements” Evidence of training in these areas: Consider Training SOP Training Plan Training Records

37. Qualifications & Agreements “The Investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties” Delegation Log Update with any changes to staff Revise with any change to delegation of duties Ideally include start and stop dates Should be signed by PI Must reflect actual delegation Very common deficiency during inspection

38. Adequate Resources “The investigator should be able to demonstrate (e.g. based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period” Will look for evidence of this

39. Adequate Resources “The Investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period” Monitors, should check this Auditors and inspectors will check this Very important for patient safety and data integrity

40. Adequate Resources “The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.” Staff Qualifications/Experience evidenced in: CV’s – qualifications/experience Training Records Resource evidenced in: Delegation Log – start/stop dates Facilities Appropriate storage areas Calibration and servicing of equipment

41. Adequate Resources “The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the IP and their trial-related duties and functions” Investigator – not sponsor – responsibility If all staff not available for initiation/investigator meeting – investigator responsible for training Staff changes – investigator responsibility Maintain training records Consider SOP to cover these situations Another common inspection deficiency

42. Medical Care of Trial Subjects “A qualified physician, who is an investigator, or sub-investigator for the trial, should be responsible for all trial-related medical decisions” Documentary evidence of this

43. Communication with Ethics Committee “Before initiating a trial, the investigator should have written and dated approval from the ethics committee for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g. advertisements) and any other written information to be provided to subjects” Approval letters should include version numbers and dates Must be in investigator trial file Should have copy of approval prior to FPFV

44. Communication with Ethics Committee “As part of the application to the ethics committee, the investigator should provide the ethics committee with a copy of the IB. If the IB is updated during the trial, the investigator should supply a copy of this to the ethics committee.” Responsibility of chief investigator to supply original IB Responsibility of sponsor for any updates/amendments

45. Compliance with Protocol “The investigator should conduct the trial in compliance with the protocol agreed to by the sponsor, and, if required, by the regulatory authorities and which was given approval by the ethics committee. The investigator and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.” Must be familiar with protocol-signature of investigator Date of signature before FPFV Documentation of any protocol violations along with the reason for them

46. Compliance with Protocol “The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and approval from the ethics committee, except where necessary to eliminate an immediate hazard to trial subjects, or when changes are administrative, e.g. change of monitor, telephone numbers etc.” No exceptions No protocol waivers

47. Compliance with Protocol “The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.” Do not cover up deviations NB for integrity of data Important to implement corrective/preventative action

48. Compliance with Protocol “The investigator may implement a deviation, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior EC approval. As soon as possible, the implemented deviation or change, the reasons for it, and if, appropriate, the proposed protocol amendments should be submitted to the EC, sponsor, and IMB.” Urgent Safety Measure only Report with regulatory timeframes Sponsor Responsibility

49. Investigational Products “Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.”

50. Investigational Products “Where allowed/required, the investigator may/should assign some or all of the investigator’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator” Can delegate task to pharmacy – delegation log Responsibility still rests with investigator Investigator responsible for keeping pharmacy department updated on all amendments Investigator responsible for training pharmacist