Research Ethics & GovernanceClaire Daffern

Quality Assurance ManagerClinical 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 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

Development of Good Clinical Practice

1964 Declaration of Helsinki1981 FDA regulations1986 ABPI regulations1989 Nordic guidelines1989 MHW Japan guidelines1990/1 EU guidelines/directives1992 WHO guidelines1996 ICH GCP guidelines1998 MRC GCP guidelines

EU Directive2001/20/EU

UK Regulations 2004

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

Which Guidelines?

If yes = EU Directive = ICH GCPIf 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.

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.”

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 1Clinical 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).

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.

RISK ASSESSMENT

DMECMREC

MHRA TSC

Principle 2

Sponsor

RISK BENEFIT

The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

Principle 3

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

Principle 4

Clinical trials should be scientifically sound and described in a clear, detailed protocol.

Principle 5

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.

Principle 6

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.

Principle 7

Curriculum

VitaeCurriculum

Vitae

JBrow

n

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.

Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective task(s).

Principle 8

PersonalDevelopmentFolder

1. Induction documentation2. Job description3. Full CV – signed and dated4. Internal training (incl SOPs) records5. External training records6. Publications

Name Responsibilities Initals Sign

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”

20Elements

listed in GCP

Principle 9

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.

X

All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification.

Trial Master FileSite Master File

Principle 10

Age (yrs)

Age (yrs)

Age (yrs)

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

Principle 11

Principle 12Investigational 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.

InvestigatorInvestigator

Subject

Sponsor

Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Principle 13

MonitoringSOP

s

Applications Agreements

Approvals

Educational ResearchLaboratoryNon-clinical intervention

Clinical InterventionsNHS patients

University involvementClinical Intervention

Commercially Funded

Sponsor

SponsorshipICH 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

For the University of Warwick to act as your sponsor, apply via WMS research Ethics & Governance Officewmssponsorship@warwick.ac.uk

Invasive?

Non-negligent cover?Insurance

Insurance

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 yearsStudies in which pregnant women are involvedAny trial to be conducted outside of the UKStudies involving children under the age of 5

Randomised Controlled?Apply forISRCTN

Yes

APPROVALS

££

Is it a drug trial?Apply for

EUDRACTYes

ApprovalsSubmit via

IRASYes

IRASIntegrated Research Application System

ARSAC

Ethics

NOMSR&D

MHRA

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

NIGB

Randomised Controlled?Apply forISRCTN

Yes

APPROVALS

££

Is it a drug trial?Apply for

EUDRACTYes

Submit toMHRA45 days

££

ARSAC

Approvals via IRASMain Ethics

Yes60 days

Site Approvals R&D

GTACNOMSCAG

CONTRACTS

Funder

Sites

Staff

} University ResearchSupport Services

Co-Sponsor

HonoraryContracts

Subcontracts

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 siteFor further information, go to:http://www2.warwick.ac.uk/fac/med/research/hscience/ctu/Section entitled ‘Conducting a Clinical trial’ includes:o Current SOPso Links to UoW Research Code of Practiceo Links to legislationo 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