Research Ethics & Governance Claire Daffern Quality Assurance Manager Clinical Trials Unit

1. Research Ethics & Governance Claire Daffern Quality Assurance Manager Clinical Trials Unit

2. NHS research governance Ethical & legal frameworks for research Principles of Good Clinical Practice How to obtain approvals to commence a research project In this session:

3. Declaration of Helsinkiwidely regarded as the cornerstone document of human research ethics • KEY principles: • Respect for the individual • Informed consent • Risks and benefits • Ethics review 5 updates

4. 1964 Declaration of Helsinki 1981 FDA regulations 1986 ABPI regulations 1989 Nordic guidelines 1989 MHW Japan guidelines 1990/1 EU guidelines/directives 1992 WHO guidelines 1996 ICH GCP guidelines 1998 MRC GCP guidelines Development of Good Clinical Practice

5. UK Regulations 2004 EU Directive 2001/20/EU Amendment 2006

6. Key changes • Compliance with the principles of GCP is now a legal requirement for all IMP trials • New regulatory approval system – via MHRA (UK Competent Authority) • Mandatory GCP and GMP inspections • National REC with specific timescales for review • Regulatory approval for phase I trials • Additional constraints for trials involving vulnerable subjects • IMP trials to be registered on EUDRACT database • Manufacturing of IMP only at licensed sites under GMP conditions

7. Which Guidelines? If yes = EU Directive = ICH GCP If no = MRC GCP

8. NHS Research Governance Framework 2005 • Sets out the broad principle of good research governance for health and social care • brings together general principles of good practice • refers to the law on clinical trials involving medicines • seeks to promote improvements in research quality

9. Health and social care research is not the province of a • single discipline, professionor organisation and no • single document adequately captures the full range of legislation, standards and good practice guidelines that apply to this body of work. • The framework covers five domains: • • ethics; • • science; • • information; • • health, safety and employment; • • finance and intellectual property. • For each domain the framework stipulates: • requirements in legislation and regulations; • standards required by the Department of Health; • • other established principles of good practice from recognised international and national authorities and professional organisations.

10. Good Clinical Practice is … • “international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects” • “assurance that therights, safety and well-beingof trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data is credible.”

11. 13 Principles of Good Practice Definition of Responsibilities (Ethics Committees, Investigators & Sponsors) Protocol – what should be included Investigator Brochure – information relating to the IMP in use Essential Documents – how trial data should be managed GCP Guidelines include:

12. 13 Principles of GCP

13. Principle 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 requirement(s). 

14. RISK ASSESSMENT Principle 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 risk. Sponsor MREC DMEC TSC MHRA RISK BENEFIT SOP 18

15. Principle 3 The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. 1 2 3 SOP 17

16. Principle 4 The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

17. Principle 5 Clinical trials should be scientifically sound and described in a clear, detailed protocol. SOPs 4, 8 & 9 TEMPLATE

18. Principle 6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB) / independent ethics committee (IEC) approval / favourable opinion. SOPs 5, 6 & 29

19. Curriculum Vitae JBrown 07/04/07 Principle 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. MRC-GCP: situations where it would be appropriate for other healthcare professionals, such as midwives etc. to be responsible for patient care.

20. Personal Development Folder Principle 8 Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective task(s). • Induction documentation • Job description • Full CV – signed and dated • Internal training (incl SOPs) records • External training records • Publications SOP 24

21. Principle 9 Freely given informed consent should be obtained from every subject prior to clinical trial participation. “taken freely after being duly informed of its nature, significance, implications and risks” 20 Elements listed in GCP SOP 7 Minors Incapacitated MRC-GCP: situations do exist in which fully informed consent may not be possible. In these cases, procedures agreed in existing guidelines should be followed, provided favourable EC opinion given.

22. X SOP 11 Age (yrs) Age (yrs) Age (yrs) Trial Master File Site Master File Principle 10 All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification.

23. Principle 11 The confidentiality of records that could identify subjects should be protected by privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). SOP 15

24. Sponsor Investigator Investigator Subject Principle 12 Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. SOP 27

25. Principle 13 Systems with procedures that assure the quality of every aspect of the trial should be implemented. SOPs Monitoring Audits SOPs 18, 19 & 25

26. Applications Agreements Approvals

27. Sponsorship ICH GCP defines a Sponsor as: An individual, company institution or organisation which takes responsibility for the initiation, management, and/or financing of a clinical trial  Educational Research Laboratory Non-clinical intervention Sponsor Clinical Interventions NHS patients SOP 3 University involvement Clinical Intervention Commercially Funded For the University of Warwick to act as your sponsor, apply via WMS research Ethics & Governance Office wmssponsorship@warwick.ac.uk

28. Insurance Invasive? Insurance Non-negligent cover? • The University of Warwick has Clinical Trials Insurance cover in place, • provided by HDI Gerling • The policy covers most trialsat Warwick, but there are multiple criteria where • a referral to the insurers is required. Including (but not limited to): • Studies where blood-products will be tested • Studies with a planned duration of more than 8 years • Studies in which pregnant women are involved • Any trial to be conducted outside of the UK • Studies involving children under the age of 5 SOP 10

29. APPROVALS Apply for ISRCTN Yes ££ Randomised Controlled? Apply for EUDRACT Yes Is it a drug trial? Submit via IRAS Yes Approvals

30. IRASIntegrated Research Application System 1 Form Ethics ARSAC MHRA NIGB GTAC R&D NOMS https://www.myresearchproject.org.uk/

31. APPROVALS Apply for ISRCTN Yes ££ Randomised Controlled? Apply for EUDRACT Yes Is it a drug trial? 60 days Approvals via IRAS Yes SOP 6 Main Ethics Site Approvals R&D Submit to MHRA ££ SOP 5 45 days ARSAC CAG NOMS GTAC

32. CONTRACTS } Funder University Research Support Services Co-Sponsor Subcontracts Sites Staff via HR Honorary Contracts

33. Letter of Sponsorship agreement Insurance Certificate Written Ethics Approval Written R&D / PCT Approval Written Regulatory Approval (for CTIMPs) ARSAC Certificate/other approvals Signed agreement by all parties CV of CI/PI at sites Before First Subject enters

34. Warwick CTU web site • For further information, go to: • http://www2.warwick.ac.uk/fac/med/research/hscience/ctu/ • Section entitled ‘Conducting a Clinical trial’ includes: • Current SOPs • Links to UoW Research Code of Practice • Links to legislation • And a step by step guide to running a trial, split into sections: • Initial Planning • Set-up • During the Trial • After the Trial

35. Thanks for your attention • Any questions