Some Considerations of Conducting
Drug Trials in the Developing World
Robert Scott Stewart, Ph.D.
Case Study
• Vertical transmission of HIV/AIDS from
pregnant woman to fetus
• Regimen 076: 1994 US study
– HIV+ pregnant women on zidovudine (ZDV,
previously AZT) reduced vertical transmission by
66% (from 25% in untreated HIV+ pregnant
women to 8%)
– ZDV for last 12 weeks of pregnancy; intravenous
dose during delivery; newborns given ZDV for 6
weeks post birth
Regimen 076
• Problems applying the regimen in developing
countries
– $1000 cost
– Lack of health care infrastructure to administer
regimen
– Breastfeeding
– Formula & Unclean drinking water
Other options for the Developing
World
• WHO, UN, NIH and CDC met in Geneva in
1994 to design clinical trials for a short term
oral dose of ZDV.
• Determining success: Placebo vs. standard
care (Regimen 076)
Context: Tuskegee
• Tuskegee Syphilis Case: 1930-1972
• Study in Nature of 399 African American Men
with Untreated Syphilis in Tuskegee, Alabama to
determine disease course carried out by US
Public Health Service
• No information or misinformation
• “Bad blood”
• Penicillin, the army and WWII
• Story breaks in AP report (Peter Buxton, a PHS
venereal disease investigator)
Context: Willowbrook
• Willowbrook State School in Staten Island, NY
for “mentally retarded” children
• Capacity of 4000 but 6000 living there
• Rampant Hepatitis
• Introduce a ‘mild’ form of hepatitis to new
students to track the disease and test
effectiveness of gamma globulin as an agent
for inoculating against hepatitis.
Big Pharma
(A Lustgarten et al. 2005. Drug Testing Goes Offshore,” Fortune 152 (3) 66-72)
• 40% of all clinical trials are now conducted in
developing countries 2008 up from 10 % in 1999
• It’s cheaper: $30,000/patient in USA vs.
$3000/patient in Romania
• Laxer regulations: “Ethics Review Committees in
developing countries were less likely to raise
either procedural or substantive issues compared
to U.S. boards.” (US National Bioethics
Committee, 2002)
Research Ethics: Background
• History of Medicine and the Germ Theory of
Medicine (19’th century)
• Pharmaceuticals and the 20’th Century
• World War II and Nazi (and Japanese)
experiments
• Nuremberg Code, 1947. Nazi doctors defense:
no law or regulations: little difference
between their experiments and ones
conducted prior to the war.
Nuremberg Code
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The ten points are, (all from United States National Institutes of Health)
1. The voluntary consent of the human subject is absolutely essential. This means that the person
involved should have legal capacity to give consent; should be so situated as to be able to exercise
free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge
and comprehension of the elements of the subject matter involved as to enable him/her to make
an understanding and enlightened decision. This latter element requires that before the acceptance
of an affirmative decision by the experimental subject there should be made known to him the
nature, duration, and purpose of the experiment; the method and means by which it is to be
conducted; all inconveniences and hazards reasonable to be expected; and the effects upon his
health or person which may possibly come from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests upon each individual
who initiates, directs or engages in the experiment. It is a personal duty and responsibility which
may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by
other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a
knowledge of the natural history of the disease or other problem under study that the anticipated
results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering
and injury.
Nuremberg Code
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5. No experiment should be conducted where there is a prior reason to believe that death or
disabling injury will occur; except, perhaps, in those experiments where the experimental
physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian
importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the
experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree
of skill and care should be required through all stages of the experiment of those who conduct or
engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the
experiment to an end if he has reached the physical or mental state where continuation of the
experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to terminate the
experiment at any stage, if he has probably cause to believe, in the exercise of the good faith,
superior skill and careful judgment required of him that a continuation of the experiment is likely to
result in injury, disability, or death to the experimental subject.
Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp.
181-182. Washington, D.C.: U.S. Government Printing Office, 1949.
Declaration of Helsinki
• June, 1964 – World Health Organization (WHO)
developed the 10 points of the Nuremberg Code
• Six revisions (October 2008 is the most recent)
and two clarifications, growing considerably in
length from 11 to 32 paragraphs.
• Individual countries have their own codes which
are more or less consistent with the WHO’s. (E.g.,
Canada – Tri- Council Policy Statement; USA –
Belmont Report; Egypt -- ???
Council for International Organizations
of Medical Sciences (CIOMS)
• Guideline 8: “Before undertaking research
involving subjects in underdeveloped
communities, whether in developed or
developing countries, the investigator must
ensure that persons in underdeveloped
communities will not ordinarily be involved in
research that could be carried out reasonably
in developed communities.”
CIOMS commentary of Guideline 8
• Phase I drug studies and Phase I and II vaccine
studies should be conducted only in developed
communities of the country of the sponsor. In
general, phase III vaccine trials and phase II and III
drug trials should be conducted simultaneously in
the host community and the sponsoring country;
they may be omitted in the sponsoring country
on condition only that the drug or vaccine is
designed to treat or prevent a disease or other
condition that rarely or never occurs in the
sponsoring country.
CIOMS Guideline and commentary
• “the research is responsive to the health needs and the
priorities of the community in which it is to be carried
out.”
• “As a general rule, the sponsoring agent should ensure
that, at the completion of successful testing, any
product developed will be made reasonably available
to inhabitants of the underdeveloped community in
which the research is carried out; exceptions to this
general requirement should be justified and agreed to
by all concerned parties before the research is begun.”
Helsinki declaration (1996)
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I.5. Concern for the interests of the subjects must always prevail over the interests of science
and society
II.3 In any medical study, every patient - including those of a control group, if any - should be
assured of the best proven diagnostic and therapeutic method. This does not exclude the use
of inert placebo in studies where no proven diagnostic or therapeutic method exits.
II.6 The physician can combine medical research with professional care, the objective being
the acquisition of new medical knowledge, only to the extent that medical research is
justified by its potential diagnostic or therapeutic value to the patient.
“if there is already an approved and accepted drug for the condition
that a candidate drug is designed to treat, placebo for controls usually cannot be justified”.
“no other interventions must be known to be superior to those being compared in the
clinical trial, unless eligibility to participate is limited to persons who have been
unsuccessfully
treated with the other superior intervention or to persons who are aware of the other
intervention
and its superiority and have chosen not to accept it”.