1. Some Considerations of Conducting Drug Trials in the Developing World Robert Scott Stewart, Ph.D.

2. 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

3. Regimen 076 Problems applying the regimen in developing countries – $1000 cost – Lack of health care infrastructure to administer regimen – Breastfeeding – Formula & Unclean drinking water

4. 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)

5. 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)

6. 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.

7. 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)

8. 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.

9. Nuremberg Code 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, over- reaching, 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.

10. Nuremberg Code 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.

11. 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 -- ???

12. 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.”

13. 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.

14. 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.”

15. Helsinki declaration (1996) 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”.