Informed Consent Practical Considerations

1. Yusuf Yazıcı, MD Assistant Professor of Medicine, NYU School of Medicine Director, Seligman Center for Advanced Therapeutics NYU Hospital for Joint Diseases Informed ConsentPractical Considerations

2. Conflicts of interest • Consultant / Speaker / Research Support • Bristol-Myers Squibb • Celgene • Centocor • Genentech • Roche • UCB

3. Topics • Declaration of Helsinki • ‘Seeding’ trials • Safety trials • Early termination • Equipoise • Routine care registries/trials • ‘opt in v opt out’

4. Declaration of Helsinki • Declaration of Geneva • International code of ethics (WMA) • All based on • No unnecessary risk to the participants • Unnecessary studies • Scientifically unsound studies • Poor planning

5. Declaration of Helsinki • In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests. • The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act in the patient's best interest when providing medical care." • Details of the protocol • IRB • Special cases • Volunteering • Disclosure of study results, negative or positive • Not only safety but also societal benefits?1 1-Goodyear MDE et al, BMJ 2008

6. Physicians should consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration.

7. Medical research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects.

8. History of Declaration of Helsinki Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008

9. Informed consent • Not only relevant at the beginning but has to be kept in mind at all times • University based vs central IRBs • Scrunity of private IRBs1 • Fake protocol sent to 3 IRBs • Rejected by two • Last one over the last 5 years approved 355/356 protocols sent • “If one accepted second one is free” • Different site specific IC • IC can change during trial depending on AEs and other consideretions • Lack of patients • Local norm changes in treatment options • 6th grade reading level 1-Lancet 2009

10. Informed consent vs exploitation Voluntary Understanding Drowning man AZT trials in Africa Surfactant in Bolivia RDS

11. Protocol • Does the study need to be done? • ‘Equipoise’ • Past studies in the same area • BMJ • ‘seeding’ trials • ADVANTAGE 1 • RADIUS • Placebo concerns • Trial duration • What happens post trial • Early termination of the study 1-Hill KP et al. Ann Intern Med 2008

12. Equipoise • Why is the study done? • If nothing new, interesting or different is being asked, why is it being done in the first place? • Most important question in any protocol • Equipoise • Placebo trials are hard to justify but can be if there is real equipoise • Active controlled trials • Especially when there are other options • Bolivia surfactant trial

14. Vioxx vs Celebrex • Vioxx - Celebrex • ADAPT1 • Stopped because NIH asked for it • No predetermined plan to stop the trial • Data published two years later • 17 vs 23 vs 22 • HR naproxen v placebo 1.57 (CI 0.87-2.81, p=0.13) • Unless there is very strong evidence trials should not be terminated early, neither for benefit or harm outcomes2 • Boundaries for early termination should be sufficiently stringent 1-Nissen S. PLoS Clin Trials 2006 2-Pocock S. JAMA 2005

15. Early termination • Scientific validity • Median relative risk 0.53 • Overestimation of benefit about 28 times greater • Incomplete data on outcomes that don’t affect trial truncation but are still important • disease free survival • AE • Vit e in premature newborns, stopped early because of decrease in intracranial bleed, but missed late sepsis seen in other studies • Early benefit or harm detected • Different exposure times, both treatment and control arms • Usually initial size of benefit is not reproducible • Neither are the harms • Social or scientific value and favorable risk-benefit ratio • Inflated results affect recommendations and have wider implications • B blockers for noncardiac surgery

16. Early termination 2 • Participant consent and respect of participants • Promise made to the patients • Patients may be expecting certain benefits • Volunteering to help advance science • Help to over all society • Independent review • Investigators, journals, sponsors all have incentives to stop early • Trials with large effects get published in prestigious journals….

17. Safety trials

19. Safety trials • Celebrex vs naproxen • 20,000 OA patients, followed for 18m • Patient with preexisting cardiac risk factors • Primary outcome • MI, death, nonfatal stroke • What were the patients told exactly? • What was the reason to the study in the first place? • How detailed were the studies already available examined?

31. TEMPO • Etanercept vs MTX vs etanercept+MTX • 1 vs. 2 years • Why enroll patient who have used MTX in the past? • What were the patients told at 1 year? • Were they offered “best available” treatment? Klareskog L, et al. Lancet 2004

32. A proposal All informed consents and version should be part of the public databases Informed consent is publics consent to RCT And their source of information

33. Baseline differences in cohorts • Differences in epileptic attack counts1 • General internal medicine clinics • Opt in is followed less frequently2 • Obtaining informed consent in routine care leads to different types of cohorts when compared to the whole population of patients • Opt in • Patient actively has to decide to be contacted for studies • Opt out • It is assumed patients are interested in research and can opt out and not participate after they are contacted • When clinical data that is used in routine care is collected, possibly no need for informed consent at the data collection phase • May obtain for data analysis 1-Al-Shahi R. et al. BMJ 2005 2-Junghans C. et al. BMJ 2005

34. ‘opt in v opt out’ • NYU ARMD • Every patient, every time, as part of routine care • The only way to collect consecutive patient data • Limits on what can be collected • An advantage over collecting nothing • Learned helplessness • Retrospective analysis of prospectively collected data • DNA, blood • MDHAQ collected in all patients each visit for a consecutive patient data base, much preferable to haphazard, selected patient database/registries • Loss of some data • 80% of data in 100% patients vs 100% of data in 10% of patients?

35. Do patients have to participate in clinical trials? • Autonomy over all • Taxes • Mandatory • Refusal leads to whole system collapse • Shared risk for shared benefits • Taxes can be left to only volunteers but not the ideal system Evans HM. J Med Ethics 2004

36. Considerations • Best treatment option made available in the shortest amount of time? • In specific circumstances mandatory participation can happen • Childhood cancers and parental decision making • Not everything can be forced how beneficial they may be but • Energy use • Helping the poor

37. A proposal Patients may (maybe) not refuse to be part of a clinical trial when: No known differences exist between treatment options Every patient gets active therapy Especially in government insurance /payment for treatment Not the doctor but random assignment decides which patient gets what Then the patient cannot refuse to be part of an observational protocol Evans HM. J Med Ethics 2004

38. A proposal 2 • Research is risky • We all benefit from previous trials • Other patients volunteered and provided us with the benefit • Any obligation on our part? • If there are two active treatment options and no differences among them as far as the doctor is aware and the need for additional treatment is set, then? • TNF vs TNF? • Comparative efficacy • Any comparative study? Evans HM. J Med Ethics 2004

39. What can be learned from routine care databases • Comparative studies • Rare disease • Small differences among treatment where large numbers are needed • Adverse event monitoring • No “other” incentives in picking one drug over another

40. Conclusions • Informed consent – needs to be part of clinical trial registries • Not every study need to be approached the same way • Not every study frankly needs to be done • Patient autonomy vs societal good