Etiquette

1. Etiquette • Press * 6 to mute; • Press # 6 to unmute • Keep your phone on mute unless you are dialoging with the presenter • Never place phone on hold

2. Issues in Trial Design and Data Management July 17th, 2008 Alan Sanders, Ph.D. Director, Center for Ethics Saint Joseph’s Health System System Ethicist, Catholic Health East

3. Why Ethics in Trial Design and Data Interpretation? • Relation between scientific quality and ethics • Bad design and analysis may expose human research subjects to unnecessary risks, also future patients • On the other hand, ethical considerations may interfere with quality design

4. Ethics and Trial Design • Purpose of Study • Design of Study • Analysis and Interpretation of Data

5. Case 1 – Purpose of Study • Study to test whether giving homeless people with inadequate footwear new and correct fitting footwear will improve their overall health of their feet and associated effects. Homeless people chosen based upon the inadequacy of their footwear. Those chosen were given new footwear. Required for follow-up visits.

6. Case 2 – Purpose of Study • Study to investigate the effects of a drug combination on human research subjects with high cholesterol levels. Human subjects will be assigned to one of three arms: drug combination, or an arm with just one of the drugs. Recent evidence questions the effectiveness of cholesterol drugs on heart disease.

7. Case 3 – Purpose of Study • A study to test a new drug combination on human research subjects with a particular type of stage IV breast cancer. Patients will either receive the new drug combination, a placebo, or standard of care (which is currently a drug with little effectiveness).

8. Purpose of Study – Equipoise • A genuine state of indifference or true uncertainty between 2 procedures, drugs, etc. • Many claim that it is unethical to assign human research subjects to different arms of a research trial if the investigator is not in a true state of equipoise.

9. Equipoise • Case 1 – Footwear for homeless • One Arm • Case 2 – Cholesterol drug combination • Active Control – Three arms • Case 3 – Chemotherapy for stage IV cancer • Placebo Control – Three arms

10. Clinical Equipoise • Genuine uncertainty within the expert medical community--not necessarily on the part of the individual investigator--about the preferred treatment. • Some have proposed an even broader social context for equipoise.

11. IRB Responsibilities? • Proper representation of appropriate clinical community • Proper representation of the public • How much/what kind of authority should the IRB have over the purpose of a study?

12. Design of Study • Placebo versus Active Controlled Trials • Argument for Placebo: • Provides a baseline for psychological effects or error in trial design • Some argue ethics requires placebo • However, others argue placebo should be used only when there is not an already accepted standard of care

13. Case 1 – Placebo vs. Active • Study to test why patients report relief after undergoing arthroscopy of the knee for osteoarthritis. Patients randomized to either receive arthroscopic lavage, arthroscopic debridement, or placebo surgery. In previous studies only half of human subjects reported symptomatic relief with arthroscopic surgery.

14. Middle Ground proposal • Some argue that placebos ethical if: • Not cause death • Not cause irreversible disability • Substantial harm • Also some say there must be compelling methodologic reasons to conduct placebo trial if a treatment exists • Example: Chronic stable angina

15. Case 2 – Placebo vs. Active • Trial of treatment for pain in patients with cancer. Capsule inserted into the base of the spine by a lumbar puncture. Capsules either contained an inert substance or an analgesic. Patients randomly assigned to one of these two arms.

16. Informed Consent and Paternalism • For placebos: • The informed consent argument • The minimal risk argument (number of human subjects) • The scientific quality-ethical protection argument • Against placebos: • The equipoise argument • The standard of care argument • The therapeutic misconception argument

17. Case 1 – Data Analysis and Interpretation • News story • When it comes to treatment for stroke, study after study has shown that drugs called “clot busters” can limit, sometimes even reverse the crippling effects and brain damage, but only if they’re given in time. So why are the vast majority of stroke patients not being treated with them? • Rather (1997)

18. Whose Interpretation? • Majority of acute stroke patients were not eligible to receive thrombolytics according to NINDS and AHA • At the time of remark, only 1 of 5 studies yielded positive results • Good reasons not to use thrombolytics for acute stroke even in ‘eligible’ patients

19. Ethical Interpretation of Data • Which scientific data warrant our attention? • Who should we trust to analyze this data? • How should data be interpreted to clinicians, other professionals, and regulators? • How should data be interpreted to the general public?

20. Case 2 – Analysis and Interpretation of Data • COX2 Inhibitors • One report stated that human research subjects in a Celebrex and Vioxx trial had similar heart attack rates: 8 out of 1,000 and 7.4 out of 1,000 respectively. In heart disease prevention studies, the authors wrote, the annual heart attack rate of those on a placebo was only 5 per 1,000.

21. Questions to Ask • Does the study design enable the investigator to address the aims of the study? • Are the outcomes and purpose clearly defined? • What are the sources of bias and how are they addressed? • Are there plans for adequate monitoring and analysis of safe and efficacy of data?

22. Questions to Consider • Is a trial always the necessary means? • What gives priority to certain diseases and/or trials? • What role might/should an IRB have in data analysis and interpretation? • What authority should an IRB have over the overall purpose or goal of a study?

23. References • Griffin Trotter. “Interpreting scientific data ethically.” In Research Ethics, Ana Iltis (Ed). Routledge, New York: 2006. • Janice Weinberg & Ken Kleinman. “Good study design and analysis plans as features of ethical research with humans.” IRB: Ethics and Human Research, 25, no. 5, 2003: 11-14.