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

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

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

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

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

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

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

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

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

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.

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

13 Principles of GCP

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). 

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

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

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

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

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

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.

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

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.

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)

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

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

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

Applications Agreements Approvals

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 wmssponsorship@warwick.ac.uk

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

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

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. https://www.myresearchproject.org.uk/

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

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

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

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

Thanks for your attention Any questions