“Is the Developing World the Answer?”

1. “Is the Developing World the Answer?” Unethical clinical trials in the Third World Sammy Almashat, MD, MPH Sidney Wolfe, MD Public Citizen’s Health Research Group

2. Outline • History and structure of human experimentation • The commercialization of human experimentation: conflicts of interest abound • A story of self-regulation and the honor code • Globalization of clinical trials: “Is the developing world the answer?” • Case studies of double-standards for the Third World and efforts to stop unethical trials

3. Clinical Trials • Thousands of trials of pharmaceuticals and medical devices conducted on tens of thousands of people every year • Human testing necessary to ensure safe and effective products prior to marketing • The question is: who’s doing the testing on whom, and who’s watching them?

4. The Birth of a Drug Test tube (in vitro) testing Animal testing Human testing Phase 1 • Few healthy patients, testing safety Phase 2 • First study with sick patients, testing safety and efficacy Phase 3 • Largest trials with sick patients, testing safety and efficacy

5. Time is Money • Drug development is risky, expensive, and time-consuming • Average drug reaches market 7-10 years after first tests at a cost of anywhere from $55 million to $800 million per drug • Incentive is high to cut costs (and corners) and speed up the process

6. The Economics of Drug Development • Human Experimentation Corporations (HECs) • Started in the 1970s as small companies specializing in biopharmaceutical (bench) testing • Grew dramatically in the past few decades and moved into clinical (human) research, growing to a $20 billion industry by 2008, with annual growth rates of 15-17% • The IRB industry • Paralleled growth of HECs • Increasingly for-profit • “IRB-shopping”

8. Birth of Research Ethics • Atrocities of human experimentation in the 20th century prompted the development of universal ethical principles to govern all such research in the future

9. Universal Principles in Human Subjects Research • What do we mean by “unethical”? • Nuremburg Code • Declaration of Helsinki • Belmont Report and Common Rule (U.S.) • FDA (abandoned Helsinki in 2008)

10. Universal Principles in Human Subjects Research • Informed consent • Truly voluntary (not coerced) participation • Beneficence • Equity and justice

11. Clinical trial oversight U.S./Host Govt.IRBs Drug Company/HECs X X X

12. 2009 – GAO goes undercover • Fake IRB • Fake medical device company with fake device • Real medical device and IRB companies – and the Feds – all took the bait

13. “Globalization” of the Clinical Trial Industry

14. Clinical Trials in the Developing World

17. Globalization of Clinical Trials • 80% of drugs are now approved based on data from foreign clinical trials • Over half of clinical trial subjects and sites are located outside the United States • One-third of trial investigators are now from foreign sites

18. Why are companies moving abroad? • Cost • Speed • The “patient advantage” • Escaping regulatory “burdens”

22. Special considerations with vulnerable populations Exploitation is almost inherent in these trials • Lack of informed consent • Direct and indirect coercion • Lack of Equity • Lack of Recourse • Companies are not liable for intentional let alone unintentional harm caused by experimental drugs (certainly not liable for NOT giving effective treatment to a placebo group).

23. Case Studies: Double standards for the Third World

24. Case Study: Unethical HIV trials • 1997: Nine U.S. government-funded studies of pregnant women in Africa, Asia, and the Caribbean • Half the women in these trials received AZT, a therapy proven to help prevent HIV transmission to the fetus • The other half received ineffectual placebos

26. Provision of Antiretroviral Drugs in Perinatal Trials

31. Case Study: The Surfaxin trial Title of internal FDA meeting: “Use of placebo-controls in life threatening diseases: is the developing world the answer?” Location: Mexico, Peru, Bolivia, Ecuador Design: Surfaxin vs. placebo (vs. approved surfactant)

32. Case Study: The Surfaxin trial • Discovery Laboratories (Johnson & Johnson), Doylestown, PA • Synthetic surfactant (Surfaxin) • 4 surfactants on the market (1st in 1990) • Associated with 34% relative reduction in neonatal mortality (Cochrane meta-analysis)“Without doubt the most thoroughly studied new therapy in neonatal care” (NEJM review)

33. Case Study: The Surfaxin trial • “Further placebo controlled trials of synthetic surfactant are no longer warranted.” (Cochrane) • FDA: “Conduct of a placebo controlled surfactant trial for premature infants with RDS is considered unethical in the USA.” • European trial: Surfaxin vs. approved surfactant

35. Case Study: The Surfaxin trial • February 2001: Public Citizen writes to HHS Secretary Tommy Thompson • March 2001: Bolivian health ministry says the study is “totally prohibited” for legal, ethical and social reasons • April 2001: Discovery announces study changed to compare to known effective surfactant

36. Advertisement by Human Experimentation Corporation (HEC) Quintiles to the Pharmaceutical Industry: January, 1998

38. What needs to be done • More oversight • Addressing conflicts of interest • Tying in with more high-profile Third World health justice causes (e.g. access to medicines)

39. www.citizen.org/hrg www.citizen.org/hrgpublications