The Placebo Orthodoxy and the Double Standard of Care in Multinational Clinical Research

1. The Placebo Orthodoxy and the Double Standard of Care in Multinational Clinical Research Maya J. Goldenberg Department of Philosophy University of Guelph

2. Outline • Perinatal HIV Transmission Trials in Developing Countries • Bioethics Response • Methodological Debate: Placebo vs. Active Controlled Trials • Inference from Historical Data • Where are we Now?

4. I. Perinatal HIV Trials • 076 regimen: the standard of care Connor EM, et al. “Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment.” Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-80. • Translational research for simpler AZT regimen in developing world • OBJECTIONS to placebo control trials • unethical in 2nd generation therapeutics research (Declaration of Helsinki, CIOMS) • Exploitative double-standard of care in developing world • Not methodologically superior to active-controlled equivalency trials

5. Trial Designs • Superiority Trials (usually placebo control) Determine clinically relevant difference between two interventions • Equivalence Trials (usually active control) Determine whether a (new) intervention is neither better nor worse than established intervention • Non-inferiority Trials (usually active control) Determine whether a (new) intervention is not inferior to another established intervention

6. Reply by:

7. II. Bioethics Response • Dissecting the vagaries of current codes governing research using human subjects (Macklin 2001; Lie et al. 2004) • Governing principles of “reasonable availability” and “fair benefits” for outsourcing clinical trails (Glantz et al 1998; Arras 2004; Emmanuel 2004; Grady 2005) 3. Are ethical norms universal or contextual? (Levine 1999) • Voluntary informed consent by desperately poor people? (Resnik 2001; Shuklenk 2001; Macklin 2003) • Social justice and global inequality (Benatar& Singer 2000; London 2005; Pratt & Loff 2013)

8. a. Accept the majority view on placebo controlled trials • The ethics of placebo controls debate framed as a trade-off between science and ethics: • PCTs are “scientifically sound but [often] ethically unacceptable” • ACEs are “ethically sound but scientifically not reliable” (Splawinski & Kuzniar 2004)

9. b. Acknowledge the methodological debate “Two epidemiologists who have opposed placebo-controlled trials contend that ‘most of the scientific arguments are either wrong or distorted.’ Of course opponents disagree” (Macklin 2004, p. 30)

10. c. Refuse to engage the methodological debate • Annas G, Grodin M (1998). Human Rights and Maternal-Fetal HIV Transmission Prevention Trials in Africa. Am J Pub Health 88: 560-563.

11. Declaration of Helsinki (rev. 2008) “Where for compelling and scientifically sound methodological reasons, the use of placebo is necessary to determine the efficacy or safety of an intervention” (Par. 33)

12. Perinatal HIV Transmission Trials Bioethics Response III. Methodological Debate: Placebo vs. Active Controlled trials IV. Inferences from the Historical Data V. Where are we Now?

13. Prior challenges to superiority of placebo-controlled trials • Rothman K, Michels K (1994). “The Continuing Unethical Use of Placebo-Controlled Trials.” New Engl J Med 331 (6): 394-398. • Rothman K (1996). “Placebo Mania.” [letter]. Brit Med J 313 (6 July): 3-4. • Freedman, Weijer C, Glass KC. (1996).” Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths.” J Law Med Ethics 24: 243-251.

14. Placebo Orthodoxy Placebo controlled trials “render a unique and irreplaceable service, in their ability to test whether a treatment has a specific biological effect on the disease under study. Influenced by that belief, many government regulators—prominently among them, the US Federal Drug Administration—have required repeated positive placebo-controlled trials before licensing new drugs, whether or not a trial involves withholding from the placebo group a standard therapy for the condition in question….

15. Placebo Orthodoxy “…It is recognized that, in some cases, it is impossible for ethical reasons to perform placebo controlled studies; in those cases, reluctantly, other forms of investigation might be permitted. Despite these exceptions, the randomized, placebo controlled trial is the gold standard in clinical research” Freedman B, Weijer C, Glass KC (1996). Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths. J Law Med Ethics 24, p. 243.

16. Why are PCTs methodologically superior for determining treatment efficacy? • Baseline measure • Simpler, more efficient (Varmus & Satcher1997) • Less participants to establish statistical significance (Temple 1982) • Active controlled equivalency trials lack assay sensitivity* (Temple & Ellenberg 2000) *Def.: A trial’s ability to distinguish effective treatment from ineffective treatment

17. A contextual argument for PCTs in the maternal-infant transmission trials? • Asking the right research question • Reviewing the total evidence

18. Asking the question that patients and providers want to know

19. A contextual argument for PCTs in the maternal-infant transmission trials? • Asking the right research question • Reviewing the total evidence

20. Perinatal HIV Transmission Trials Bioethics Response Methodological Debate: Placebo vs. Active Controlled Trials IV. Can we make legitimate inferences from the historical data? V. Where are we Now?

21. 076 subgroup analysis of pre-partum administration of AZT

22. Is 076 historical data applicable to new research context? • Oral dose and intravenous infusion have the same results • HIV transmission rates among women provided the 076 regimen in developing countries rivals that observed in the treatment arm of 076 • Increased risk of vertical transmission through breastfeeding insufficient to render 076 ineffective

23. Total evidence “on the basis of the ACTG 076 data…and pharmacokinetic data, the researchers should have had every reason to believe that well-designed shorter regimens would be more effective than placebo” (Lurie and Wolfe 1997, 855)

25. V. Where are we now? • Subsequent trials on short-course AZT • Still employed placebo-controls ii. Multinational research ethics • HIV-preventative microbicides and vaccines (1st generation)

26. “This guidance point is controversial from a methodological perspective. A clinical trial comparing an experimental preventive method with a proven method takes longer to complete and is more costly, and the results may be much more difficult to interpret than a placebo-controlled trial.” Macklin R (2010) “Intertwining Biomedical Research and Public Health in HIV Microbicide Research.“ Public Health Ethics 3 (3):199-209 , pp. 200-201.

27. In Conclusion • Review of maternal-infant HIV transmission trials reveals widespread acceptance of placebo orthodoxy among researchers, regulators, bioethicists • Placebo orthodoxy is unfounded. So are the ethical arguments in favour of PCT for the HIV trials. • Sufficient historical data available to preclude placebo controls in those HIV trials. • Ethics of HIV research in the developing world should acknowledge these findings.

28. Results from CDC-sponsored equivalency study