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

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

3. Declaration of Helsinki widely regarded as the cornerstone document of human research ethics
KEY principles:
Respect for the individual
Informed consent
Risks and benefits
Ethics review
Produced by the World Medical Association (WMA) – not legally binding but considered to be the ‘cornerstone document in relation to human research ethics.
Declaration of Helsinki 1st published in 1964 – developed from the Nuremburg Code which came about after the Nuremburg war trials
Major points;
Respect for the individual
The right to make informed decisions (consent; both initially and during the course of the trial)
The subject's welfare must always take precedence over the interests of science and society
Ethical considerations must always take precedence over laws and regulations
5 updates

4. Development of Good Clinical Practice
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

5. Amendment 2006 UK Regulations 2004 EU Directive 2001/20/EU
ICH GCP – basis of EU Directive – each member state obliged to transpose the Directive into law – so a few discrepancies between member states – Directive is currently under revision and will eventually be re-issued as a Regulation i.e. will be the same across whole of Europe.
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. If yes = EU Directive = ICH GCP
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, profession or 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.
54 pages

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 the rights, safety and well-being of 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.”
All work undertaken within CTU is based on the principles of Good Clinical Practice.
Good Clinical Practice is defined as "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“ (ICH GCP).
SUBJECT PROTECTION MOST IMPORTANT
QUALITY STANDARD
Applicable to the whole of the clinical trial/clinical research process - affects everyone involved: subjects, investigators and AZ employees.

11. GCP Guidelines include:
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

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. 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
RISK ASSESSMENT
MHRA
TSC
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.
i.e. get as much background information as possible to justify the need for the trial

17. Principle 5 SOPs 4, 8 & 9 TEMPLATE
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. 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.
Curriculum
Vitae
JBrown
07/04/07
MRC-GCP: situations where it would be appropriate for other healthcare professionals, such as midwives etc. to be responsible for patient care.

20. 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).
Personal
Development
Folder
Induction documentation
Job description
Full CV – signed and dated
Internal training (incl SOPs) records
External training records
Publications
Name
Responsibilities
Initals
Sign
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. Principle 10
All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification. X
Trial Master File
Site Master File
SOP 11
Age (yrs)

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. 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.
Investigator
Subject
Sponsor
SOP 27

25. SOPs Monitoring Principle 13 Audits SOPs 18, 19 & 25
Systems with procedures that assure the quality of every aspect of the trial should be implemented.
SOPs
Monitoring
Audits
SOP 19 – Quality Control
Procedures to ensure the trial is being conducted as intended i.e. to protocol
Especially important during recruitment and data collection phases
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
A sponsor is a company, institution, organisation or individual which takes responsibility for the quality and delivery of the research.
A sponsor is required for all research within the NHS and all trial involving IMPs.
If your trial requires a sponsor, you must have a formal letter from your sponsor before any work can commence. The ethics committee will require proof of sponsorship – so it’s a good idea to start this process as early as possible.
The CI is responsible for ensuring sponsorship arrangements are in place – for UoW CI’s, contact REGM in WMS in first instance.
For the University of Warwick to act as your sponsor, apply via WMS research Ethics & Governance Office

28. Insurance SOP 10 Invasive? Insurance Non-negligent cover?
The University of Warwick has Clinical Trials Insurance cover in place,
provided by HDI Gerling
The policy covers most trials at 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
Other referral criteria are stated – check SOP 10 for full details
List on slide is not all of the criteria – need to check the SOP

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

30. IRAS Integrated Research Application System
1 Form
Ethics
ARSAC
MHRA
NIGB
GTAC
NOMS
R&D
An integrated system that brings together the information requirements for a range of permissions and approvals. It streamlines the application process by allowing you to enter study information in one place without duplication in separate application forms for each type of account.

31. Randomised Controlled?
APPROVALS
Yes
Apply for
ISRCTN
Randomised Controlled? ££
Yes
Apply for
EUDRACT
Is it a drug trial?
60 days
Approvals via IRAS
Yes
Main Ethics
SOP 6
Site Approvals
R&D
Submit to
MHRA
MHRA – 45 days for type B + C trials. 14 days for type A (low risk trials) – see SOP 5
SOP 5 ££
45 days
ARSAC
CAG
NOMS
GTAC

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

33. Before First Subject enters
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

34. Warwick CTU web site For further information, go to:
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