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Is the Developing World the Answer?

• Unethical clinical trials in the Third World
• Sammy Almashat, MD, MPH
• Sidney Wolfe, MD
• Public Citizens Health Research Group

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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

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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 whos doing the testing on whom,
  and whos watching them?

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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

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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

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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

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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

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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)

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Universal Principles in Human Subjects Research

• Informed consent
• Truly voluntary (not coerced) participation
• Beneficence
• Equity and justice

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Clinical trial oversight

• U.S./Host Govt. IRBs
• Drug Company/HECs

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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

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Globalization of the Clinical Trial Industry
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Clinical Trials in the Developing World
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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

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Why are companies moving abroad?

• Cost
• Speed
• The patient advantage
• Escaping regulatory burdens

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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).

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• Case Studies
• Double standards for the Third World

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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

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Provision of Antiretroviral Drugs in Perinatal
Trials
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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)

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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)Witho
  ut doubt the most thoroughly studied new therapy
  in neonatal care (NEJM review)

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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

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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

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

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• www.citizen.org/hrg
• www.citizen.org/hrgpublications