What a supervisor should know about research ethics

1. What a supervisor should know about research ethics Margaret Rees Chair elect UK Association for Research Ethics (AfRE) Reader Emeritus in Reproductive Medicine, University of Oxford Visiting Professor, University of Glasgow, Karolinska Institute and University of Turku Adjunct Associate ProfessorRobert Wood Johnson Medical School, at Rutgers University. Editor in Chief Maturitas President European Menopause and Andropause Society (EMAS)

2. Background: who am I • Researcher and supervisor: basic science • Researcher: clinical trials and PI • Chair National Health Service Research Ethics Committee (NRES)2006-2013 • Member Open University Human Research Ethics Committee • Council member University of Oxford Research Ethics Committee (CUREC) • Chair elect UK Association for Research Ethics (AfRE) • Secretary of the Committee on Publication Ethics (COPE) • Member Elsevier ethics committee • Editor in Chief J Br Menopause Soc/ Menopause International 1998-2008 • Editor in Chief Maturitas, Elsevier 2008- present • President European Menopause and Andropause Society (EMAS)

3. The principles and challenges • An integral process: a necessity not a burden • Ethically conducted research leads to more attention to good publications • Challenges with students (Masters, PhD, MDs, professional doctorates) and post docs from different countries and cultural backgrounds

4. Research ethics • Why • What • How • Specific issues

5. Medical experiments were undertaken upon concentration camp inmates and other living human subjects, without their consent, in the course of which experiments the defendants committed the murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts 23 physicians and scientists Crimes against humanity A) High-Altitude ExperimentsB) Freezing ExperimentsC) Malaria ExperimentsD) Lost (Mustard) Gas ExperimentsE) Sulfanilamide ExperimentsF) Bone, Muscle, and Nerve Regeneration and Bone Transplantation ExperimentsG) Sea-Water ExperimentsH) Epidemic Jaundice ExperimentsI) Sterilization ExperimentsJ) Spotted Fever (Fleckfieber) ExperimentsK) Experiments with PoisonL) Incendiary Bomb Experiments Why: Nuremberg trial

6. World Medical Association • Formed in 1945 • Represents physicians world wide • Non political • Non governmental • Addresses non clinical medical issues such as ethics and education

7. Declaration of Helsinki • First written in 1964 it is: • ‘ a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects’ • Both clinical trials and non-therapeutic research • Most recently updated version 2013

8. Declaration of Helsinki: key elements • Protection of patient rights • Informed consent • Independent approval • Scientific/medical basis • Appropriate risk benefit • Subject well being takes precedence over other considerations

9. Why: publication • Fabrication and falsification • Lack of ethical approval • Authorship • Conflict of interest • Plagiarism • Duplicate/ salami slice submission

11. What: REC/IRB/ethics committee • A REC is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects. • HRA REC members are expected to undergo regular training and RECs are appraised annually

12. https://www.gov.uk/government/publications/health-research-ethics-committees-governance-arrangementshttps://www.gov.uk/government/publications/health-research-ethics-committees-governance-arrangements • 4.2.3 A REC should contain a mixture of people who reflect the currency of public opinion (‘lay’ members), as well as people who have relevant formal qualifications or • professional experience that can help the REC understand particular aspects of research proposals (‘expert’ members). • i.e. societal representation

13. Composition of an ethics committee • Expert members • Lay members • Lay plus • Number maximum 18 • Quorum 7 • For RECs recognised for clinical trials at least one third membership must be lay and definitions are: • Expert is currently a registered “health care professional”/ has professional qualifications or experience relating to the conduct of, or use of statistics in clinical research, • A lay member is a person who does not qualify as an expert member and is eligible for appointment as a lay member but may have been previously eligible to be an expert member except for doctors and dentists • A Lay+ member is therefore a person who is not and never has been any of the following: (i) a health care professional; (ii) a person involved in the conduct of clinical research other than as a research subject;

14. Referees 4.2.20 RECs may seek advice from specialist referees on any aspects of a research proposal that fall beyond the members’ expertise. RECs may seek referees’ advice at their discretion or because the law requires them to do so. Referees’ advice should only be sought on issues material to the REC’s review of the research proposal, i.e. issues of research ethics. 4.2.21 Terms of reference for referees should be established. Referees do not count towards the quorum or vote on decisions. They are not involved in any REC business apart from advising on the issues put to them. Their advice is recorded in the minutes of the relevant REC meeting

15. Observers • 4.2.22 REC meetings are not public meetings. External observers may attend following a written invitation which states the terms and conditions of their attendance. Attendance will be agreed by the REC and minuted accordingly. Representatives of the relevant Research Ethics Service head office may attend and observe meetings at any time, with prior notification. • 4.2.23 Observers play no part in the deliberations of the REC.

16. How: the process • Does the study need REC approval? • Preparation of the application: IRAS, protocol, CV, PIS, consent form, peer review • Full REC review or proportionate review • The meeting and decisions • After approval: annual and end if study reports, minor and substantial amendments • Specific issues

17. Ethical approval for studies in humans • Research requires ethical approval and informed consent either through NHS or University RECs • BUT DOES NOT REQUIRE NHS REC REVIEW IN UK for • Service evaluation • Audit • Surveillance • Usual practice (in public health)

18. Types of research requiring ethical approval through the NHS • Clinical trials of medicinal products or devices • Studies administering questionnaires/ interviews • Studies human or other biological samples or data • Research tissue bank • Research database

19. Proportionate review http://www.nres.nhs.uk/applications/proportionate-review/ • The aim of proportionate review is for studies which present minimal risk or burden for participants to be reviewed by a proportionate review sub-committee within 14 days of receipt of a valid application. • I Research using data or tissue that is anonymous TO THE RESEARCHER • II Research using existing tissue samples already taken with consent for research • III Research using “extra tissue” (e.g. further blood taken at time of routine sampling or tissue taken at “clinically directed” operation) • IV Questionnaire research that does NOT include highly sensitive areas or where accidental disclosure would NOT have serious consequence • V Research interview / focus group that does NOT include highly sensitive areas or where accidental disclosure would NOT have serious consequences • VI Research surveying the safety or efficacy of established non drug treatments, involving limited intervention and NO change to the patients’ treatment

20. The following types of application always require review at a full REC meeting: • Clinical trials of investigational medicinal products (CTIMP’s) • Clinical investigations of medical devices prior to CE marking • Research involving adults lacking capacity and subject to the Mental Capacity Act 2005 • Invasive basic science studies involving healthy volunteers • Research involving exposure to ionising radiation which could be additional to that received in routine clinical care for any participant • Research tissue banks • Research databases • Prison research • Studies funded by the US department for Health and Human Sciences

21. How: the application • One application will provide a decision for the whole of the UK • IRAS form filter questions • All elements of the application need to be consistent eg number of participants, timing and types of intervention • PIS and consent forms need to be clear and follow the recommended guidance • Peer/ statistical review: supervisor, R and D, the grant giving body • The research must be justified

22. Who is the chief investigator? • Supervisor: MSc and professional doctorates • Researcher: PhD, MD or postdoc

23. Participant information sheets • Standard formats of information sheets • Language must be easily comprehensible and avoid use technical language • Why approached • Must not be coercive • Clinical trials should not be presented too enthusiastically • Side effects of interventions clearly stated • Patient support groups

24. Participant information sheets • What interventions are study specific • Travel expenses • Confidentiality • Use of samples and data • Publication : images and quotations and anonymity • Publication plan: hot topic at present for clinical trials • Who to complain to

25. Consent • Standard formats • Have those taking consent been trained? • Written if possible • Adequate time

26. Advertising • Concerns were raised with regard to the wording of the advertisement, as ‘.........................’ was felt to send a subliminal message and may suggest unreasonable expectations to participants.

27. Trial registration • Now a requirement From 30 September 2013 registration of clinical trials in a publicly accessible database will be a condition of the favourable ethical opinion. Failure to register will therefore be a breach of good research practice - See more at: http://www.hra.nhs.uk/news/2013/09/10/trial-registration-to-be-condition-of-the-favourable-rec-opinion-from-30-september/#sthash.m0Nto1rz.dpuf • Needed for publication • Clinical trials of medicines or devices need to be submitted for approval to regulatory bodies

28. How: the meeting and decisions • Supervisor should attend as will have more background knowledge/ expertise than the student • The REC is concerned as to whether the research is feasible, the researchers suitably qualified and participants are adequately informed • RECs try and help research • Opinion: • Favourable opinion with standard conditions • Favourable opinion with standard and additional conditions • Unfavourable opinion • Provisional opinion with request for further information, clarification or revision • Provisional opinion pending consultation with a referee – a written request for information may be made following receipt of the referee?s advice • No opinion – refer to full meeting for further review of significant ethical issues (proportionate review only).

29. How: after approval • Annual reports • Amendments • Safety reports • End of study report

30. Specific issues • Safety • Loss of capacity • Mental capacity • Research in children • Internet research, cluster RCTs, cell based therapies etc see AfRE web site Guidelines and downloads

31. Safety • Side effects of the intervention eg drugs/surgery • How many people have received the drug so far • Radiation: cancer induction no threshold dose of radiation but larger doses increase risk/ damage to a system eg skin burn where there is a threshold dose • 40-year-old male who underwent coronary angiography, coronary angioplasty and a second angiography procedure due to complications, followed by a coronary artery by-pass graft.

32. Loss of capacity during the study A35 IRAS form • Participant, identifiable data/ tissue withdrawn • Participant withdrawn, identifiable data/ tissue retained but study stops for that person • Participant would continue to be included in the study • N/A as informed consent not obtained • N/A not practicable as research cannot monitor capacity so continued capacity assumed

33. Mental capacity • The research is connected with an impairing condition which can affect capacity. • The research cannot be carried out as effectively if it was confined to participants able to give consent as they would not have the relevant clinical condition. • The research has the potential to benefit participants lacking capacity without imposing a disproportionate burden on them. • Reasonable arrangements were in place for identifying personal consultees, and for appointing nominated consultees independent of the project where no person can be identified to act as a personal consultee. • Information is adequate to enable consultees to give informed advice about the participation of persons lacking capacity. • Reasonable arrangements are in place for withdrawal from the project

34. Research in children • Parental/ legal guardian consent/ assent depending on the age of the child using the recommended age brackets, <5, 6-10, 11-15 and 16 and above. The PIS needs to be targeted to the appropriate audience ie the participant or the parent. • Potential coercion by the parent/ legal guardian for the child to participate and how has this been addressed as an ongoing process throughout the study. • Confidentiality for the child such as for sexual activity, orientation and contraception that they do not wish the parent/ legal guardian to be aware of.

35. Conclusion • Research ethics is a necessity and not a burden • Essential premise is to protect participants • Research ethics is an integral part of the process