The Ethical Permissibility and Necessity of Phase One Clinical Trials

1. The Ethical Permissibility and Necessity of Phase One Clinical Trials William S. Aronstein PhD MD FACP Senior Medical Director CTI Clinical Trial and Consulting Services, Inc. Cincinnati, Ohio

2. Phase One Trials • Normal, healthy volunteer subjects • No therapeutic benefit to subjects • Drug characteristics • Metabolism • Specific pharmacological effects

3. Joseph AlpertAmerican Journal of MedicineJune 2008 Five Statements and a Conclusion Editorial: Dealing with Ethical Conflicts in Clinical Research American Journal of Medicine 121 (6): 457

4. Joseph AlpertAmerican Journal of MedicineJune 2008 “ Experimental pharmaceutical studies in human beings which were formerly carried out at teaching and research hospitals and medical schools are now largely performed by for-profit clinical research entities in the community.”

5. Joseph AlpertAmerican Journal of MedicineJune 2008 “ Many of the test subjects employed by these for-profit testing entities are ‘professional patients’ for whom the honoraria paid to participate in the research project are an important part of their income. Even more sinister is the use of homeless individuals, prisoners, and illegal immigrants in drug trials for whom the income derived is essential for their well-being.”

6. Joseph AlpertAmerican Journal of MedicineJune 2008 “The substantial sums of money paid to the human ‘guinea pigs’ clearly obfuscate any volunteerism on the part of the individuals involved in these clinical experiments.”

7. Joseph AlpertAmerican Journal of MedicineJune 2008 “Unfortunately, the overworked and under-funded Food and Drug Administration of our federal government has been unable to develop a system for satisfactory oversight of the for-profit research test centers.”

8. Joseph AlpertAmerican Journal of MedicineJune 2008 “Although some of these entities are owned and operated by non-physicians, many of them are, unfortunately, the property of practicing and non-practicing physicians who profit handsomely from this activity.”

9. Joseph AlpertAmerican Journal of MedicineJune 2008 “The potential conflict of interest for these doctors, and the possibility of the exploitation of the research subjects involved raises, at least, the specter of the horrible misdeeds carried out in the name of research by Nazi physicians.”

10. Conflicts and Contradictions • Town vs. gown • Paid vs. volunteer • Non-profit vs. profit • Governmental oversight vs. professional oversight • Physician vs. investigator

11. The Source Exploiting a Research Underclass in Phase 1 Clinical Trials Carl Elliott MD PHD and Roberto Abadie PhD NEJM 358: 2316-2317 (2008) “Guinea-pigging” Carl Elliott, the New Yorker, January 7, 2008

12. Elliott’s Technique “Even though the purpose of phase 1 trials is to test whether new drugs are safe, most sponsors apparently do not provide free care or treatment for subjects who are injured in these trials. . . . A recent study commissioned by the Department of Health and Human Services showed that only 16% of academic health centers provide injured subjects with free care.”

13. The Safety of Nontherapeutic Research Cardon, Dommel, Trumble (1976) NEJM 295:650-654 331 investigators 133,000 human subjects 4957 injuries: 3926 trivial, 974 temporarily disabling 57 permanent injuries including death, resulting from studies expected to benefit patients (eg cancer therapy) “The data suggest that the risks of participation in nontherapeutic research may be no greater than those of everyday life, and in therapeutic research, no greater than those of treatment in other settings.”

14. The safety of Phase 1 Research Zarafonetis et al. (1978) ClinPharmacolTher24:127-132. 805 protocol studies 29,162 participants 614,534 subject days 64 significant medical events (58 ADRs, 6 complications) One death (placebo; CVA) One subject with residual hip changes due to infection

15. Town versus Gown

16. Joseph AlpertAmerican Journal of MedicineJune 2008 “ Experimental pharmaceutical studies in human beings which were formerly carried out at teaching and research hospitals and medical schools are now largely performed by for-profit clinical research entities in the community.”

17. “Guinea-pigging”Carl Elliott, the New Yorker, January 7, 2008 “Rockwell had enrolled in many previous studies at corporate sites at places like Wyeth and GlaxoSmithKline. But the atmosphere there felt professional, bureaucratic, and cold. This unit was in a university hospital, not a corporate lab, and the staff had a casual attitude toward regulations and procedures. ‘The Animal House of research units’ is what Rockwell calls it. ‘I’m standing in the hallway juggling,’ he says. ‘I’m up at five in the morning watching movies.’ Although study guidelines called for stringent dietary restrictions, the subjects got so hungry that one of them picked the lock on the food closet. ‘We got giant boxes of cookies and ran into the lounge and put them in the couch,’ Rockwell says. ‘This one guy was putting them in the ceiling tiles.’ Rockwell has little confidence in the data that the study produced. ‘The most integral part of the study was the diet restriction,’ he says, ‘and we were just gorging ourselves at 2 A.M. on Cheez Doodles.’”

18. Two recent deaths of healthy volunteers “Traci Johnson, a previously healthy nineteen-year-old student, committed suicide in a safety study of Eli Lilly’s antidepressant Cymbalta in January of 2004. (Lilly denies that its product was to blame.)” In June 2001, Ms. Ellen Roche, a healthy volunteer research subject in a study intended to shed light on airway relaxation in asthma, died of pulmonary toxicity after being administered inhaled hexamethoniumbromide at the Johns Hopkins Asthma Center.

19. Lilly Case Ms. Johnson was a normal, healthy subject who was enrolled in a pharmacokinetics study. This was a crossover study, and at the time of her death, she was randomized to and receiving not duloxetine, but placebo. A careful search of the websites of the FDA and the Office of Human Research Protection shows that there was no regulatory action taken after the event.

20. FDA Findings in the Hopkins case • The Hopkins IRB did not follow the established guidelines for initial review of the research. The composition of the IRB was improper, and its standard procedures were inadequate. • The informed consent did not adequately describe the procedures to be followed in the study, and did not identify which procedures were experimental. • Subjects were not informed that hexamethonium bromide had never been approved to be administered by inhalation. • The IRB failed to obtain and review published toxicological literature regarding hexamethonium bromide. • There was no current IND for hexamethonium bromide. • The hexamethonium bromide administered was clearly labeled as for laboratory use only, not human or animal use. • The route of administration was changed without proper amendment of the protocol and notification of the IRB and regulatory authorities. • The investigators did not recognize that the syndrome which killed their subject (and which had affected a previous subject to a lesser degree of severity) was more or less identical to what had been, during its era of use, a well-described toxicity of hexamethonium. • The subject was an employee of the pulmonary center.

21. FDA Findings – Violations of the Act • The delivery of an unapproved new drug in interstate commerce. • Failure to submit an IND for the clinical investigation of a new drug. • Failure to maintain an effective IND, including the failure to submit supporting data regarding chemistry and manufacturing information, animal toxicity data, a summary of previous human dosing, a description of the dosing plan, and a description of “other measures critical to subject safety.” • Failure to notify and obtain IRB approval for changes in research activity, including the change in dosing conditions, the addition of sodium bicarbonate to hexamethonium bromide, the change in the hexamethonium bromide formulation. • Failure to promptly report to the IRB unanticipated problems involving risk to human subjects. • Failure to conduct the investigation in accordance with the protocol. • Failure to obtain proper informed consent. • Failure to obtain adequate and accurate records.

22. Non-profit vs. profit

23. Joseph AlpertAmerican Journal of MedicineJune 2008 “Although some of these entities are owned and operated by non-physicians, many of them are, unfortunately, the property of practicing and non-practicing physicians who profit handsomely from this activity.”

24. Paid versus Volunteer

25. Joseph AlpertAmerican Journal of MedicineJune 2008 “The substantial sums of money paid to the human ‘guinea pigs’ clearly obfuscate any volunteerism on the part of the individuals involved in these clinical experiments.”

26. Richard TitmussThe Gift Relationship (1970) BMJ: “With the eclipse of the politics of state socialism, Richard Titmuss has ceased to be a household name. But, for the postwar generation, he was one of the intellectual pillars of the welfare state, combining mastery of the statistics of poverty, inequality, and ill health with an impassioned philosophy of social justice. The Gift Relationship (1970), his last major work and now available once more in a welcome updated reprint, is vintage Titmuss: the model of the British National Blood Transfusion Service is commended . . .”

27. Elliott & Abadie, NEJM 358:2316-2317Exploiting a Research Underclass in Phase 1 Clinical Trials “Is it ethically problematic to pay poor people to test the safety of new drugs? “Paying study subjects is not a new practice, but neither is it uncontroversial. According to regulators, payment should not be so high as to become an ‘undue inducement,’ lest subjects enroll in risky, unpleasant, or degrading trials against their better judgment. But this standard gives IRBs little practical guidance: a sum of money that the wealthy can easily resist may be very tempting for poorer people. Keeping payments low, however, seems unfair to the poor, who submit to trials precisely because they need the money. And whether or not such people are being unduly induced, the larger question is whether they are being exploited.”

28. Elliott & Abadie, NEJM 358:2316-2317Exploiting a Research Underclass in Phase 1 Clinical Trials “Sponsors call subjects' payments ‘compensation’ to suggest that they are merely reimbursing participants for expenses and inconvenience, even as they fill studies with unemployed people who depend on trial income to make ends meet. They refer to paid subjects as ‘volunteers,’ implying that participation is a freely chosen act of altruism, whereas most subjects indicate that they take part in trials for the money. Regulators allow sponsors to use money to attract subjects but do not require them to provide the kinds of benefits that subjects would demand if they had more power. The result is what one Philadelphia trial subject describes as ‘a mild torture economy.’ ‘You are not being paid to do something,’ he explains. “You are being paid to endure.’”

29. Risk Benefit Ratio When there is no benefit to the subject, the risk benefit ratio approaches infinity.

30. Governmental oversight vs. professional oversight

31. Clinical research directed by theUnited States Public Health Service

32. Physician vs. investigator

33. A distinction that must be made in therapeutic clinical research The physician seeks the optimal individualized care for a particular patient The investigator seeks to standardize conditions to permit generalization of results Steven Grunberg & William Cefalu, NEJM 2003;348 914:1386-1388

34. A distinction that must be made in therapeutic clinical research A patient may mistake enrollment in a rigidly controlled trial for individualized care Physicians may confuse themselves as to the nature of protocol-driven treatments Medical therapy must always be distinguished from research

35. From the Declaration of Helsinki 1964: The doctor can combine clinical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that clinical research is justified by its therapeutic value for the patient. 2008: The physician may combine medical research with medical care only to the extent that the research is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.

36. Concluding Thoughts

37. The Conclusion?Carl Elliott, the New Yorker, January 7, 2008 “A professional guinea pig who does a dozen drug-safety trials a year is not exactly representative of the population that will be taking the drugs once they have been approved.” “The safety of new drugs has always depended on the willingness of someone to test them, and it seems inevitable that the job will fall to people who have no better options. Guinea-pigging requires no training or skill, and in a thoroughly commercial environment, where there can be no pretense of humanitarian motivation, it is hard to think of it as meaningful work.”

38. What is to be done? • Almost nobody who has not worked in the industry has any real idea of how drugs are developed and approved. • Somebody is going to be the first human being to try a new compound. • Since there is no benefit in a nontherapeutic trial, the risk must be offset in some way. • The usual way we compensate people for time, effort, inconvenience, and risk is cash. • Any other system would ultimately be coercive. • Professional oversight, by knowledgeable and experienced people, is preferable to ideological oversight. • The most dangerous quality in an investigator is arrogance.

39. Recommendations • It would be a good idea to disseminate knowledge of how drugs are actually developed, tested, and approved. • The promulgation of a simple, plain-language code of ethics by an association of Phase 1 units might be helpful.