Clinical trials with reference to GCP Guidelines

1. Clinical trials with reference to GCP Guidelines Certificate course in Research Ethics Review (CCRER) 25th April 2008 Priyadarshani Galappatthy MD,MRCP Department of Pharmacology

2. Overview • Definition and phases of clinical trials • Principles of GCP guidelines • Responsibilities, functions, procedures for ERC/IRB in GCP guidelines • Monitoring and auditing • Documents for clinical trials • Approvals for a clinical trial in SL

3. Clinical Research • Broad definition: • Medical research in human subjects • Narrow definition: • The gamut of activities related to testing and development of diagnostic, prophylactic, therapeutic and cosmetic modalities in human subjects

4. Clinical Research in Drug Development • Defines efficacy, safety, PK, PD, PE – hence transforms a chemical substance to a drug • Involves multiple stakeholders • Every aspect is subject to regulatory review • Governed by specific laws, rights, & legal implications • Involves risks and benefits for patients • Holds ethical implications and penalties • Has liabilities for investigators and ethics committees

5. Phases of Clinical Research (1) • Phase 0 • Very early human dosing • Helps determine critical pharmacokinetic factors • Increasingly used for early decision-making • Phase 1 • Series of healthy volunteer studies • Terminology often used for all volunteer studies • Establishes safety, PK, and healthy PD in humans • Conducted in specialized units

6. Phases of Clinical Research (2) • Phase 2 • Proof of concept (PoC) and dose range finding (DRF) studies in patients • Successful PoC transforms value • Phase 3 • Definitive studies to confirm efficacy & safety • Establishes level of less frequent side-effects • Often unaffordable for smaller companies • Phase 4 • Post marketing surveillance (PMS) • Establishes long-term benefit risk ratio • Establishes place in therapy

7. How to ensure clinical trials are conducted ethically and according to regulatory requirements ? • Guidelines • Benchmarks

9. GCP: The Code of Conduct • Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. • Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles in the Declaration of Helsinki, and that the clinical trial data are credible. • Guideline was developed with consideration of the current good clinical practices of the European Union, Japan, United States, Australia, Canada, the Nordic countries and the WHO.

10. ICH GCP Organization • Glossary and Principles • Responsibilities • ERC/IRB • Investigators • Sponsor • Trial protocol and protocol amendments • Investigators’ brochure • Document inventory and location

12. Essential Elements of GCP • Autonomy and informed consent • Ethical oversight • Benefit-risk evaluation • Documentation and monitoring • Drug product integrity & accountability • Fidelity of data • Qualified and trained staff • Audits & Inspections

13. Autonomy & Informed Consent • Enshrined as Respect for Persons - One of the 3 Basic Ethical Principles in the Belmont Report of 1979 and in the Basic Principles of the Declaration of Helsinki. • Requires the documentation of consent: • Involves a consent procedure, materials, discussion • Written where possible, else witnessed • Includes autonomy to refuse and withdraw • A healthy refusal rate is expected

14. Ethical Oversight Aspects pertaining to the Ethical Review committee/ Institutional review Board (ERC/IRB) in GCP guidelines • Responsibilities • Composition, functions and operations • Procedures

15. Responsibilities of IRB/IEC (1) • Safeguard the rights, safety, and well-being of all trial subjects. • Special attention paid to vulnerable subjects. • The IRB/IEC should obtain the following documents: • trial protocol/amendments, • written informed consent forms consent form updates, • subject recruitment procedures (e.g. advertisements), • written information to be provided to subjects, • Investigator's Brochure (IB), • available safety information, • information about payments and compensation to subjects, • the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, • any other documents that the IRB/IEC may need to fulfil its responsibilities.

16. Responsibilities of ERC/IRB (2) • Consider the qualifications of the investigator/s • Conduct continuing review of each ongoing trial, at least once per year. • If the protocol indicates that prior consent of the trial subject is not possible, the IRB/IEC should determine that the protocol addresses ethical concerns and meets regulatory requirements • Review amount and method of payment to subjects to assure that coercion or undue influence on the subjects is prevented. • Ensure that information regarding payment to subjects, is in the informed consent form

17. Responsibilities of ERC/IRB- (3) • The IRB/IEC should review a proposed clinical trial within a reasonable time • Document IRB/ERC views in writing, identifying the trial, the documents reviewed and the dates for the following • approval/favourable opinion • modifications required prior to its approval/favourable opinion • disapproval / negative opinion • termination/suspension of any prior approval/favourable opinion.

18. Composition, Functions and Operations of ERC (1) • Consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. • It is recommended that the IRB/IEC should include: • At least five members. • At least one member whose primary area of interest is in a non-scientific area. • At least one member who is independent of the institution/trial site. • A list of IRB/IEC members and their qualifications should be maintained. • An IRB/IEC may invite non-members with expertise in special areas for assistance

19. Composition, Functions and Operations of ERC (2) • The IRB/IEC should function according to written operating procedures • Maintain written records of its activities and minutes • Comply with GCP and regulatory requirements. • Make decisions at meetings at which a quorum, as stipulated in operating procedures, is present. • Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise. • The investigator may provide information on the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.

20. Procedures in ERC/IRB (1) • Document in writing, and follow its procedures, including • composition and the authority under which it is established. • Schedule, notify conducting its meetings. • Conduct initial and continuing review of trials. • Provide expedited review and approval of amendments/revisions in ongoing trials that have the approval of the IRB/IEC. • Specify that no subject should be admitted to a trial before the IRB/IEC issues its written approval of the trial.

21. Procedures in ERC/IRB- (2) • Specify that the investigator should promptly report to the IRB/IEC: • Deviations from, or changes of, the protocol. • Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial • All adverse drug reactions (ADRs) that are both serious and unexpected. • New information that may affect adversely the safety of the subjects or the conduct of the trial. • Ensure that the IRB/IEC promptly notify in writing the investigator/institution concerning: • Its trial-related decisions/opinions. • The reasons for its decisions/opinions. • Procedures for appeal of its decisions/opinions.

22. Qualified & Trained Staff • Applies to: • Investigators and other site staff • Monitors, auditors, and sponsor’s administrative staff • Statisticians and data managers • Independent data monitoring committee • CVs of investigators, co-investigators, and sponsor’s staff must be on file • Investigators & site staff should be trained on protocol & procedures through investigators’ meetings and site initiation meetings • Training files of sponsors’ staff to be maintained

23. Benefit-risk Evaluation • Applies to: Sponsor, regulatory authority, investigators, ethics committees • Based on: Prior information available to sponsor, data submitted to regulatory authority, investigators brochure, emerging safety reports • Currently a qualitative exercise – outcome may vary based on the evaluator’s perspective and individual sensitivities

24. Safety Reporting • All serious adverse events (SAEs) should be reported immediately to the sponsor • The investigator should also comply with the applicable regulatory requirements related to the reporting of unexpected serious adverse drug reactions to the regulatory authorities and the IRB/IEC. • Adverse events and/or laboratory abnormalities identified should be reported within the time periods specified in the protocol.

25. Documentation and Monitoring • The long-term nature of clinical development • Sponsor’s responsibilities: • Securing direct access for sponsor and regulators • Monitoring and audits to verify protection of subjects’ rights, data accuracy, and compliance to protocol, GCP, & regulations • Direct access monitoring • Source data verification, consent verification,drug accountability, training & information, communication of deviations through monitoring reports

26. Monitoring The purposes of trial monitoring are to verify that: • The rights and well-being of human subjects are protected. • The reported trial data are accurate, complete, and verifiable from source documents. • The conduct of the trial is in compliance with the currently approved protocol /amendments, with GCP, and with the applicable regulatory requirements.

27. Product Integrity & Accountability • Manufacturing & packaging under GMP • Appropriate labeling • Transport under appropriate conditions • Secure and appropriate storage • Accountability of dispensing and returns • Compliance monitoring

28. Audits & Inspections • Definition • Auditors and inspectors • The audit/inspection process • Notification • Presentation of credentials • Hospitality and access • Audit report, observations, & corrective action plan • Termination and notification of termination • Regulatory access to audit reports

29. Audit • A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirements. • If or when sponsors perform audits, as part of implementing quality assurance, they should consider: • Purpose • Selection and Qualification of Auditors • The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits. • The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.

30. Quality Assurance and Quality Control • The sponsor is responsible for implementing and maintaining quality assurance with written SOPs to ensure that trials are conducted, data are generated, documented and reported in compliance with the protocol, GCP, and regulatory requirements. • A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor.

31. Contract Research Organization (CRO) • The CRO should implement quality assurance and quality control. • Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing. • All references to a sponsor in GCP guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions

32. Essential documents for conduct of a clinical trial –(1) • Before starting trial - 20 • During clinical conduct - 25 • After completion/termination - 8

33. Essential documents for conduct of a clinical trial –(2)

34. Essential documents for conduct of a clinical trial – (3)

35. Essential documents for conduct of a clinical trial – (4)

36. GCP: The Code of Conduct • A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

37. Approvals for a clinical trial in SL • ERC/IRB • Hospital authorities/ERC • Drug regulatory authority – for registration and import of trial drug • Sri Lanka Clinical trials registry

38. Thank You