Ethics of statistical research

1. Ethics of statistical research Chris Foy 8 July 2008 Gloucestershire R&D Support Unit South West Research Ethics Committee Chris.Foy@glos.nhs.uk

2. Research on human subjects • Research funder balances costs of research against benefits • But what about the inconvenience and risks to human subjects (participants)? • There is a well-developed system for research in the health field (not only for trials of medicines) • Other fields: education, criminal justice …

3. Ethical principles for research • Non-maleficence • Beneficence • Justice • Autonomy • Dignity • Welfare • Rights

4. A trial that went wrong • Eight healthy volunteers recruited for first human use of a monoclonal antibody • Two randomly assigned to placebo • The other six suffered serious adverse reactions; some were life-threatening • Investigation found poor practice • MHRA now has special precautions for Phase I trials

5. A study that couldn’t go wrong? • A student wishes to interview four cardiac rehabilitation patients about their experiences • Relatively harmless • But what about the pressure to take part? • And if poor care is revealed? • And the safety of the student?

6. Both need ethical review • But the depth of the review should be proportionate to the risks and inconvenience to participants • The National Research Ethics Service (formerly COREC) is moving towards this

7. Research Ethics Committees in UK • Started in 1960s • By 1980s, there were over 200, each with their own application form and working practices • Next to impossible for those conducting UK-wide research; people took short cuts • 1991 to 2001 – DH moves towards standardising and simplifying the system

8. What is the REC for? A REC “should safeguard the rights, safety and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.” (ICH GCP)

9. How does the REC do this in practice? • Committee has to judge the benefit that could arise from the research against the risks and inconvenience to participants • There’s no fixed rule for striking this balance, hence a committee weighs it up, not an individual • For student studies, the benefit may be educational

10. What is the REC looking for? • No-one is obliged to participate in research – it’s a favour, so … • How are participants identified, approached and recruited? • Is there a clear explanation of what will happen to them? • Do they give genuinely informed consent? • Do they know they can withdraw at any time without disapproval?

11. What is the REC looking for? • What about the risks (side effects) and inconvenience (time and travel)? • What about their study data? Who will see it? How long will it be kept? • What about tissue samples (including body fluids)? How long will they be kept? Could they be used in other studies? Will DNA be extracted? • Will GPs be informed?

12. What is the REC looking for? • What will happen at the end of the study (will study drug continue to be available)? • What about complaints? Does NHS indemnity apply? Is insurance needed? • Has the scientific review job been done, to show that the research is capable of delivering benefit? • Where will the study be published? Will participants get to know the results?

13. Special care for vulnerable participants • Children (Gillick guidelines may apply) • Adults without capacity to consent to study (mental illness, learning difficulty, or unconscious) • Those with a terminal illness • Prisoners • Dependent on the investigator (e.g. nursing home residents, students) • Those whose English isn’t up to informed consent

14. Who are the members? • Maximum of 18 members • One-third of these are “lay” • The rest are “expert” – doctors, nurses, allied professionals, statisticians and pharmacists • Open recruitment process

15. The Committee’s options • Favourable opinion • Provisional opinion with a set of written questions • No opinion, while the Committee consults a specialist referee (rare) • Unfavourable opinion • All to be done in 60 days

16. Randomised controlled trials • First reported trial 1948 • Tuberculosis: streptomycin and bed-rest vs. bed-rest only • RCTs called “clinical trials” when therapy is tested • Don’t have to be of therapy: e.g. housing improvements and health

17. Randomised controlled trial new treatment group 1 Outcome population Outcome group 2 control treatment

18. Why a control group? • Optimistic about new treatment • But need to be sure that benefits wouldn’t have happened anyway • What is additional benefit of new treatment against best existing treatment? • So compare some subjects who get new with some who get existing

19. Why randomise? • Want to compare the effect of the treatment and control • Need to remove other influences • These include patient and clinician preference • So don’t let patient or clinician choose • Choose by predetermined rule - “random”

20. Ethics of random allocation • To a patient unused to the idea, having treatment chosen by tossing a coin sounds unnerving, even callous • Careful explanation is called for

21. Sample wording for information sheet Sometimes because we do not know which way of treating patients is best, we need to make comparisons. Patients will be put into groups and compared. The groups are selected by a computer which has no information about the individual, i.e. by chance. Patients in each group then have a different treatment and these are compared. In this study, you will have a 50:50 chance of receiving X or Y.

22. Blinding • In a drug trial, clinician or subject report may be biased by knowledge of allocation • Can avoid this if subject does not know the allocation (single-blind) • If clinician does not know either, this is called double-blind • Requires identical-looking placebos

23. Ethics of blinding • Needs explanation • Need a mechanism for prompt breaking of the blind in case of an adverse event • “This is a double blind trial which means that neither you nor your doctor will know which group you are in (although if your doctor needs to find out they can do so).”

24. A modern proposal to experiment without randomising • Change standard treatment protocol every six months • Compare one cohort with the next • Avoids explaining about randomisation • But imports other problems: is the protocol change an undeclared experiment?

25. Quasi-experiment • Subjects fall into two or more groups • Not allocated by investigator • Take advantage of changing conditions • Also called “natural experiment” or “experiment of opportunity”

26. John Snow’s quasi-experiment • “The Great Experiment” 1850s • London supplied by two water companies • One intake in Central London • Other intake at Thames Ditton • Compared cholera mortality by source • Water-borne hypothesis confirmed • Organism not discovered for 30 years

27. Surveys • To gain a broad picture of health, lifestyle, satisfaction with services etc. • Usually postal • Looking for response rate 60%+ • Layout and content are important • Need reminders

28. Postal survey problems • Burden on respondents • One, two or more reminders? • Should replies be confidential (numbered, for reminders and data linkage)? • Or should they be anonymous (especially where subject is sensitive)?

29. Interview survey problems • Time taken – payments may be offered • Possibility for upset • For home interview, safety of researcher • Stigma – “I saw the bedwetting interview man on your doorstep”

30. Cohort study • Recruit a group and follow them through time • Looking for association between factors at baseline and disease later • Follow-up period may be years or even decades • Needs lots of contact to keep cohort together

31. Case-control study • Looking for association between disease and factor • Used where disease is rare: survey wouldn’t find enough cases • Choose one or more controls per case • Typically controls are matched on age and sex

32. Case-control study • Compare factors between cases and matched controls to estimate relative risk • Can be difficult to explain to controls why they are in study • Example: survey of parents of children who had meningitis, and control parents

33. Sample size in quantitative studies • A sample size calculation should be done, with reasonable estimates of the benefit sought • Too small a study – unethical because it exposes participants to burden and hazard for no scientific benefit • Too large a study – unethical because wasteful of participants

34. Qualitative studies • Used to gather a lot of information from relatively few respondents • Don’t use random sampling • Therefore no claim to be representative • Doesn’t limit respondents to investigator’s agenda • Not the “soft option” - analysis is hard work

35. Publication ethics • Ethical duty to publish, or the study might as well not have been done • Publication needs as much care as lab or field procedure • There has been little training for authors, editors, peer reviewers • www.equator-network.org

36. Finally • Research involves a degree of risk • Jenner wouldn’t have discovered smallpox vaccination without risk • RECs ensure that risks are reasonable and subjects are aware of them - not that risks are nil • Plenty still to discover