the changing clinical trials scene: the role of the irb

The Changing Clinical Trials Scene: The Role of the IRBAuthor(s): Shiela C. Mitchell and Jay SteingrubSource: IRB: Ethics and Human Research, Vol. 10, No. 4 (Jul. - Aug., 1988), pp. 1-5Published by: The Hastings CenterStable URL: http://www.jstor.org/stable/3564623 .

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Volume 10 Number 4 July/August 1988

The Changing Clinical Trials Scene: The Role of the IRB by Shiela C. Mitchell and Jay Steingrub 1

The Role of Community Advisory Committees in Clinical Trials of Anti-HIV Agents by Ronald O. Valdiserri, Geraldine Maiatico Tama, and Monto Ho 5

CASE STUDY University Policy on Experimental Use of Aborted Fetal Tissue by James Tunstead Burtchaell 7

ANNOTATIONS 12

The Changing Clinical Trials Scene: The Role of the IRB by Shiela C. Mitchell and Jay Steingrub

The poliomyelitis vaccine trial of 1954 can be said to have established the modern American clinical trial. To be sure, a controlled clinical trial of streptomycin in tuberculosis had been published in 1948,1 and in 1950 there was a placebo arm, single-blind trial of antihistamines in the common cold,2 along with a double-blind study of deoxycorticosterone in rheumatoid arthritis.3 However, all these trials were done in Britain, the numbers in the first

Shiela C. Mitchell is a physician in Wilbraham, MA. Jay Steingrub is Associate Director, Critical Care Services, Baystate Medical Center, Springfield, MA.

and third studies were small-107 and 86 patients respectively-and in the second the participants were only informed that they were about to enter a controlled clinical trial because one could not "keep half as guinea-pigs and then hope for cooperation and good records."4 This suggests an entirely different mindset from the one that governed the polio vaccine trial.

This American trial, ultimately involving 1,829,916 children, literally put clinical trials on the map. 5,6 It encom- passed all the key elements of good clinical trials. It addressed an important question precisely and accurately. It utilized the newest technology, was

July/August 1988

based upon good but limited animal data, and had an adequate sample size. It was scientifically valid, having two control groups, one observational and one placebo (injected). While written informed consent was not required, the trial was firmly rooted in the ethical considerations that have been the hallmark of controlled clinical trials for three decades. Its findings were conclu- sive.7 They have altered both the practice of medicine and the face of disease.

Dating the birth of IRBs is more difficult since they were put in place gradually, in various forms around the country over a decade. However, by 1966 IRBs had been institutionalized and written, informed consent and ethical review had become required of all federally funded controlled clinical trials. Their design, conduct, and analysis has become a specialty in its own right with its own society, journal, and textbooks.8 The validity of these tech- niques is established and the risks inherent in tampering with them ought to be well known, especially to those engaged in, or charged with, monitoring clinical trials. But circumstances alter cases. This article looks at those circumstances, the alterations that have been made, and the possible outcomes to those changes.

The Problems

Some of the problems lie within clinical trials themselves, others do not. Inherent in a clinical trial, whether of a new preventive measure or a new therapy, is a valid control group, predetermined end points, provision for appropriate ongoing statistical analysis, all of which are preceded by informed consent and IRB approval. All this takes time. Yet increasingly new therapies and new clinical trials involve patients with life-threatening diseases. And patients with life-threatening diseases do not have time. They feel, and often with good reason, that they cannot wait for the outcome of controlled clinical trials.

In the past such patients have been accommodated by "compassionate" INDs and "emergency" INDs where research was involved, and by the conventional wisdom that physicians would know what was best for their patients and would be able to treat them accordingly where research was not involved. But with the frontiers of medicine and of clinical research increasingly involving patients who are critically or desperately ill, and with rapidly evolving new drugs for these diseases, physicians, as well as patients, often run out of time.

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A publication of The Hastings Center, 255 Elm Road Briarcliff Manor, NY 10510 o 1988



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This time-compression factor is clearly reflected in the new stance of the regulators and their recent revision of the federal regulations governing investigational new drugs and clinical research. Some of the effects these are having, or may have, on clinical trials will be dealt with in a later section.

IRBs have also felt the impact of changes in clinical trials and treatment with investigational drugs. Some lauda- ble coping strategies have been developed but they are not without cost. Any exception, modification, alteration, or constriction of study populations and study designs has a potential impact on the fairness doctrine, which is one of the cornerstones of IRB decisions. Such changes are also likely to complicate informed consent. Since understanding varies inversely with complexity, these developments make it increasingly hard for the IRB to ensure that consent is truly informed.

It is important to recognize that clinical trials continue to be affected by investigator/physicians who are eager to bypass controlled clinical trials and, one patient at a time, build up sufficient experience to convince themselves and subsequently others that the treatment in question is the treatment of choice. This saves the effort that valid research requires but its cost in real knowledge and true medical progress can be unacceptably high.

The Regulators

The regulators set forth their present views of when a controlled clinical trial is necessary and when exemptions from previous controls are permissible in the Federal Register on May 22, 1987.9 One of the best clarifications of these new regulations appeared last summer in this journal.'" But despite this article, and much discussion since, two very confusing terms remain-"treatment use" and "treatment IND." As the regulations stand, one or both of these require either an ongoing controlled clinical trial or a completed one. Then, if "the drug is intended to treat a serious or immediately life-threatening disease, and if there is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population," an investigational drug or therapy may be prescribed and sold for treatment use to the patient suffering from such a disease.9

Without a completed controlled clinical trial it would, on the face of it, seem difficult to know if there is a comparable drug or other therapy. It would also seem likely that only the

wealthy might be able to obtain new drugs. The writers of these regulations feel that this latter issue is outside their scope of expertise. This scarcely absolves them from the responsibility of perpetuating an inherently unfair situation. That aside, there is another and, ultimately, more serious difficulty inherent in the new regulations.

The second objective of the new FDA rule is "to obtain additional data on the drug's safety and effectiveness." (?312.34)9 Some of these data are clearly going to come from those who obtain the drug for treatment use. In effect, treatment use will become a treatment trial. And a treatment use trial is an uncontrolled trial. These are adven- tures, not scientific endeavors. Unfor- tunately, they almost always show beneficial results,1" results that may not be borne out by controlled clinical trials but that may govern therapy for years. These results may be difficult if not impossible to refute because they make controlled trials difficult if not impossible to conduct.

The need for completed, controlled, clinical trials and the fallacy of deter- mining treatment prior to their conduct has been shown in every branch of medicine for the last three decades. Prior to 1959 internal mammary artery ligation was the treatment of choice for coronary heart disease. Then a controlled clinical trial showed that it was no better than a sham operation.12 In retrospect the hypothesis seems tenu- ous but the epidemic of coronary heart disease was terrifying and no effective, alternative treatment was available. Similarly the use of urea to treat sickle cell disease crises is no longer favored. But prior to 1974 it was widely heralded as the optimal treatment for this painful and crippling event. Only a controlled clinical trial put this hypothesis firmly to rest.'" Radical mastectomies for some types of breast cancers finally yielded to lumpectomies,14 high oxygen concentration for premature infants to regulated gaseous environments,'5 and glomectomies for asthma'6 have faded from memory because controlled clinical trials were performed that dis- proved what clinicians "knew."

Even at the time, the late '50s and into the early '70s, there was contro- versy about these trials, principally, it seemed, because they called into question accepted, conventional therapeutic wisdom. It seems likely that some of them, particularly the trial requiring a sham operation for the patients who were assigned as "controls," could not have been done even 10 years later and certainly could not have been started in the '80s. All of this re-emphasizes the

need for controlled clinical trials to begin with the first patient to receive a new drug or therapy.

The passage of time has not only brought new therapies for threatening diseases, it has brought new voices to the medical decision making process. Consider AZT (azidothymidine) and TPA (tissue plasminogen activator). While AZT could be purchased for use by patients with AIDS prior to any controlled clinical trial being done, TPA could not be purchased for treatment use by patients with myocardial infarction until well after adequate clinical data of effectiveness and safety were at hand. Yet acute myocardial infarction is often a lethal disease. Prior to TPA 3096 of patients with acute myocardial infarction died within 30 days of their attack." No comparable or alternative drug or other therapy was available. Early on, the drug "comparable" to TPA in the controlled, multi- centered, clinical trial sponsored by the NHLBI was deemed to be so less efficacious as to be unethical and it was eliminated. What remained in the trial was fine tuning of ancillary treatments and procedures.

Apparently the decisive difference between AZT and TPA was the amount of public outcry with regard to AIDS and the public acceptance of the natural history of heart attacks.'" To determine medical care this way seems, at the very least, to be irresponsible on the part of physicians and those who regulate medical practice. But more is at stake here than "Who's in charge?"-the patient, the physician, the bureaucracy, or the press. What is at risk is an essential investigative tool, the controlled clinical trial.

Consider the situation we now face under the new regulations. Persuading patients with life-threatening disease to enroll in controlled clinical trials has never been easy, especially when one of the treatment regimens was a placebo. But those of us with long experience with clinical trials of new drugs have come to see that one of the things that makes a trial ethical is a valid control group. For many new drugs developed for diseases for which there is no acceptable standard therapy, this means a placebo arm. Not all new drugs prove to be safe and effective. Some, indeed, are worse than the disease. So every patient deserves the chance to get the placebo. Persuading him or her that this is so is not always easy. It is harder if the physician/investigator has not been persuaded that it is true. The miracles of modern medicine have, on occasion, been oversold to the profes- sion as well as to the public.



July/August 1988

In the past, one of the immediately apparent benefits to the patient of enrolling in a controlled clinical trial was the chance of receiving the investigational drug free of charge. But the new regulations may have eliminated that benefit, at least for certain drugs. What we then have are some studies for the rich, some for the poor and some, as Levine has pointed out, that may have an economic cross-over design.'0 To ask an IRB to approve as ethical a controlled clinical trial that enrolls only the poor and the ill-informed, or the well- to-do and the well-informed, is to ask them to abandon the bedrock of the fairness doctrine.

The newly introduced "treatment use" term presents another problem. These two words used together have a precise meaning to the FDA but not to physician/investigators conducting their own or multi-institutional clinical trials with investigational drugs or new combinations of approved drugs. To them every clinical trial is a trial of a new therapy, i.e., a treatment use trial. In any other context treatment use is the use of a treatment, and that is therapy as medicine has been practiced for centuries. Claiming that treatment use occurs when the patient pays for a drug is not a sufficient discriminator either. In many clinical trials utilizing new combinations of approved drugs, the patient, or his/her insurer now pays for the drug. These drugs are no longer free. Thus, one more distinction between clinical trials and clinical treatment is being lost. Given the eagerness of many physicians to escape from the rigors of clinical trials, the new regulations and the new terminology would seem to offer a welcome escape hatch.

The IRBs

Within IRBs the fairness doctrine has been paramount. This concern has led some IRBs to modify the standard informed consent form to ensure that all, regardless of social situation, have the right to participate and benefit from controlled clinical trials. For one IRB* this issue was brought into focus by a multi-centered clinical trial designed to test the efficacy of calcium blockers to minimize brain damage in comatose cardiac arrest survivors.19 This is a randomized clinical trial in which the controls receive current standard therapy. The study design requires that the test drug (Lidoflazin) be given within thirty minutes of the restoration of

adequate blood pressure and oxygen- ation to patients who remain comatose following a cardiac arrest. Subsequent doses are administered over the first twenty-four hours and follow-up and assessment continues for six months. To accommodate this study design a deferred informed consent form was developed.20 This is presented to the patient or to the next of kin within twenty-four hours of the patient's enrollment. The permission is for follow-up and the use of the data in the study.

In approving the deferred informed consent form for local use our Medical Research Committee and IRB consid- ered the rights of those without next of kin. In the original protocol it was said that if a patient did not become conscious, or the next of kin could not be located within twenty-four hours, the data collected on such patients would be discarded. That is, if a deferred informed consent form could not be obtained, the patient would be dropped from the study.

This seemed both wrong and unethical to the committee members. It seemed wrong because being dropped from the study denied these patients the right to participate in the trial. One of the benefits of a clinical trial, and an often cited one, is the opportunity to contribute to the acquisition of new knowledge. It seemed unethical because as Austin Bradford Hill has said, "If a trial was ethical in the first place it is quite unethical to conclude it...or to (waste) all the (collected) material... until an acceptable degree of probability has been achieved."21

And it seemed unethical because it violated the fairness doctrine, which asserts that all patients without regard to race, gender, or social standing will be equally eligible for, and asked to participate in, controlled clinical trials. To discriminate against the friendless is to deny them the right to participate and possibly to invalidate the trial since patients with identifiable next of kin may differ in ways that are prospec- tively hard to define from those without such support. If they are different, the differences should be examined and factored into therapeutic regimens. If they are not, then this too is important in making treatment plans.

It was, of course, easier to ensure the fairness doctrine when there was no further intervention, and at the time deferred informed consent was requested, there were no further research risks or inconveniences to the patient. Excluded from the study, the friendless would have been exposed to the treatment risks while losing the

benefits that accrue to participants purely from enrolling in a clinical trial. The reasons for these benefits, closer medical attention, more rigorous fol- lowup, involvement of more health care personnel with the patient, undoubtedly vary from study to study but the effects do seem to be real,I' and the friendless are entitled to them.

In applying the fairness doctrine, this IRB like others has modified and extended the original regulations. Con- sent by proxy as reported in the New England Journal of Medicine in October 1986,22 has gained a somewhat shaky foothold for research, especially among the elderly. The foothold is shaky because almost half of the proxies, who were family members, refused consent, which makes research among this group more difficult, and also because 31%6 gave consent although they felt that if the patient had been asked he or she would have refused consent. This suggests that few groups in society, patients or proxies, recognize the value of clinical research even when it is only observational. Society's understanding of the value of controlled clinical trials appears, at best, to be marginal. It may, in fact, mirror the grudging involvement by physicians in clinical trials.

The Investigators

Physicians in general have been slow to appreciate that the development of the controlled clinical trial is as important to medicine as the discovery of penicillin.2' Why this is so one can only guess although it may have something to do with the fact that much of the pioneering work was done by statisti- cians. Whatever the reason, there can be no doubt that physicians tend to undermine clinical trials through what Richard Day calls bootlegging of research.23 Physicians want to treat patients. And it has been easier in the past to treat one patient with a new drug and if one patient does well, why not use it on a second patient, and a third. Even with the occasional setback, as when the patient does poorly, an extenuating circumstance can usually be found. It is not long before it seems unethical to conduct a placebo arm randomized controlled clinical trial since everyone "knows" that the new treatment is better than the old. It is just this type of knowledge, as we have seen, that requires a controlled clinical trial to refute and to establish a truly effective, safe therapy.

While the first modern, American clinical trial was done without an IRB or written informed consent, society has since deemed it necessary to have IRBs *One of us (SCM) was chair and staff of this IRB

for four years.

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and written consent. But comfortable old ways die hard, especially when reinforced by usual and accepted medical practice. So well-controlled clinical trials are resisted by patients, by physicians, and now are hampered by the new regulations.

Clinicians also resist controlled clinical trials because it takes a lot of time, effort, and energy to approach every eligible patient, explain the study, re- explain it to their relatives and obtain the signed, informed consent form. One shortcut to this desired end is to pay the patient to participate. This makes it easier to obtain consent since doing something for money requires little explanation in our society. Studies with "reverse fees" to the patient encourag- ing participation are becoming more and more common.

But, this introduces another new problem. The situation is altered com- pletely if the patient is being paid to take significant risk. While there is general agreement that reimbursement for out- of-pocket expenses, for time spent and effort expended by the patient to participate in a study is appropriate,' there is less unanimity about direct monetary inducements to participate in a clinical trial. Such inducements, if trivial, as in free vouchers for ice cream cones for youngsters cooperating in supplying baseline physiologic data, present no ethical problem. But more substantial inducements do. And the definition of substantial is inversely proportional to one's wealth. $200 or even $500 may have no effect on the top level manager but it may be an irresistible temptation to an unem- ployed parent. Inducements may also be veiled. Sponsor-provided medical care is one type of veiled inducement but not the only type. Moreover, these inducements may make it impossible to explain the true nature of the trial and the risks involved even when these are clear-cut and actually explicable.

Explicable risks and payments to cover them which our IRB finds jus- tifiable are payments covering the pain and discomfort of blood drawing, or the injection of an investigational drug, or the inconvenience of fasting. Payments to cover the cost of extra visits to the clinic, baby-sitter fees, lost time from work or from job seeking are also acceptable. These are quantifiable and verifiable in the local situation. Similarly risks of bleeding, infection, foreseeable side effects, and study design risk such as washout periods eliminating all medication are acceptable because appropriate precautions can be taken and needed treatment implemented.

But other risks are not so self-evident.

These are the risks that, somewhat subliminally, haunt IRBs as they review studies, and that will undermine controlled clinical trials unless they are recognized and addressed. In vaccine trials, for example, the major risk, the omnipresent risk, is that one may actually get the disease that the vaccine is designed to prevent, and suffer serious, permanent, complications. Usually the complications are rare but that scarcely helps the patient who acquires them from an imperfect vaccine.

Giving a few hundred dollars to each participant in a vaccine trial does not seem to be the best way to deal with the risk of permanent complications. The money may cover the inconvenience and the pain inherent in the study design but it cannot cover the cost of permanent disability. It would seem far more realistic to put the inducement money into an insurance policy, which would be paid to any individual or individuals if a catastrophic event should occur. Assuming the vaccine to be as safe as it is usually thought to be, and a common insurance pool, it would then be possible to tell potential participants that if such an unlikely event occurred their costs would be fully covered. In this way, the poor could be enabled to participate but not unduly induced.

Society

Money has changed clinical trials in other ways. As Stuart E. Lind noted in the March/April 1987 issue of IRB, third party payers and the patients themselves are becoming sponsors of clinical trials.24 Since he who pays the piper calls the tune, this is sure to directly, over time, affect study designs. Society is often swayed by a vocal minority, and rarely to the advantage of society as a whole. Special interest groups can often arrange special circumstances. Where these are "for-profit," i.e., insurance companies, they are unlikely to be interested in studies primarily to determine etiology, to assess treatment for rare diseases, or to put new knowledge above cost containment. Individual patient sponsors are not likely to be willing to pay for studies of no direct benefit to themselves.

Sponsorship alterations will have an indirect effect as well since, if wide- spread, they could eliminate the poor from participating in clinical trials. If an insurance company underwrites a trial, it is likely that only the insured will be eligible. If all were eligible, the company would be subsidizing medical care or providing it outright. It is extremely

unlikely that they would be willing or able to do so. If the patients themselves are paying for the research only the wealthy will be able to afford to enroll.

In the treatment use situation, clinical trials may be restricted to the poor. This, in our view, is just as wrong as eliminating them from the chance to participate in a clinical trial because they are poor. Investigators have had to take a hard look at sponsors to ensure that their results will be free of apparent bias. While most institutions write contracts with a freedom to publish clause, most avoid sponsorship that suggests coercion or bias. Sponsorship by the Tobacco Institute of studies dealing with the health effects of smoking presents the most obvious conflict of interest. But investigators and IRBs should consider the sponsor as one element in an ethical trial, particularly as more and more studies are supported by corporations not federal agencies. A trial whose results will not be believed because of the nature of the sponsor is not an ethical trial.

The new regulations introduce another reason for IRBs to look at sponsors. Up to now, investigational drugs have been supplied free of charge to patients enrolled in clinical trials on the presumption that the costs of clinical trials are a normal cost of doing business. Now, however, if the developer of the drug can show economic necessity (clearly the developer's, not the patient's) then the patient, even though enrolled in a clinical trial of an investigational new drug can be charged for that drug.9 As has been pointed out,1' such charges make a placebo arm controlled clinical trial impossible. Should the IRB settle for a compromised study design, or allow patients to be charged for a placebo equal to the cost of the investigational drug, a cost which the developer was able to prove it could not bear? Or should all such trials be ruled "a priori" unethical and thus unacceptable?

Conclusion

Controlled clinical trials are changing, of that there can be little doubt. They are being changed by the regulators, by the clinical investigators, by the IRBs and by society.

These changes could make controlled clinical trials almost impossible to conduct. They could expose patients to ineffective, risky treatments for long periods of time, preclude the prompt establishment of effective but unsus- pected treatments, and disenfranchise or exploit the poor which, in turn, might



July/August 1988

invalidate the studies. The IRBs seem to be in the best position to appreciate all of these changes, to address the issues, to assess the underlying causes and to ensure that an essential research tool does not become so altered that it no longer serves its function. Twenty years, one generation, have brought us much by way of controlled clinical trials ethically conducted. It is all too easy for a new generation to lose something of unperceived value. It would seem to be an appropriate role for the IRBs to ensure that this does not happen and that neither they, nor the clinical trials they guide, become obsolete.

REFERENCES 'Medical Research Council: Streptomycin in

tuberculosis trials committee. British Medical Journal 1948; 2:769.

2Medical Research Council: Special Committee 1950a, British Medical Journal2, 425.

3Quin, C.E., Mason, R.M., Knowelden, J.: Clinical assessment of rapidly acting agents in rheumatoid arthritis. British MedicalJournal 1950; 2:810.

4Hill, A.B.: The clinical trials. British Medical Bulletin. 1951; 7:278-2824.

5Francis, T. Jr., Korns, RF., Voight, R.B., et al.: An

evaluation.of the 1954 poliomyelitis vaccine trials. American Journal of Public Health. 1955; 45:1- 50.

6Francis, T. Jr.: Evaluation of the 1954 Field Trial of Poliomyelitis Vaccine. Edwards Brothers, 1957.

7Paul, J.R.: A History of Poliomyelitis, Yale University Press, New Haven and London, 1971, p. 407 ff.

sMeinert, C.L: Clinical Trials. New York, Oxford University Press, 1986.

9FederalRegister, Vol 52 No. 99, Friday May 22, 1987. 19466-19477.

'tLevine, RJ.: FDA's new rule on treatment use and sale of investigational new drugs. IRB- A Review of Human Subjects Research 1987; July-Aug. 9(4):1-4.

"Schneiderman, M.A.: Looking backward: Is it worth the crick in the neck? or: pitfalls in using retrospective data. American Journal of Roent- genology, Radium Therapy and Nuclear Med- icine 1966; 96: 230-35.

'2Cobb, L.A., Thomas, GI, Dillard, D.H. et all.: An evaluation of internal mammary artery ligation by a double blind technic. New England Journal of Medicine 1959; 260.1115-18.

'3Cooperative Urea Trials: Group treatment of sickle cell crisis with urea in invert sugar. Journal of the American Medical Association 1974; 228:1125-28.

'4Fisher, B.F, Bauer, M., Margolise R. et al: Five- year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. NewEnglandJournal

of Medicine 1985; 312:665-73. 'SLambert, EC.: Modern Medical Mistakes. Bloom-

ington: Indiana University Press, 1978, 98-101. '6Spodick, DJ.: Revascularization of the heart-

Numerators in search of denominators. Amer- ican Heart Journal 1971; 81:149-57.

'7Willerson, J.T: Acute myocardial infraction Cecil Textbook of Medicine. ed. by Wyngaarden & Smith, 17th edition. Philadelphia, WB Saunders, 1985.

'tReview and Outlook: Today AZT, Tomorrow TPA. The Wall Street Journal March 23, 1987.

'gKelsey, S., Abramson, N.S., Detre, K et al.: Randomized clinical study of cardiopulmonary- cerebral resuscitation: design, methods and patient characteristics. American Journal of Emergency Medicine 1986; 4:72-86.

20Abramson, N.S., Meisel, A., Safar, P.: Deferred consent, a new approach for resuscitation research on comatose patients. Journal of the American Medical Association 1986; 255:2466- 71.

21Atkins, H.: Conduct of a controlled clinical trial. British Medical Journal 1966; 2:377-79.

22Warren, J.W., Sobal, J; Tenney, J.H. et al: Informed consent by proxy, an issue in research with elderly patients. New England Journal of Medicine 1986; 315:1124-28.

23Day, R.L.: Faith, doubt and statistics. Pediatrics 1981; 67:101-105.

24Lind, S.E.: Dilemmas in paying for clinical research: the view from the IRB. IRRB A Review of Human Subjects Research, March/April 1987; 9:1-5.

The Role of Community Advisory Committees in Clinical Trials of Anti-HIV Agents by Ronald O. Valdiserri, Geraldine Maiatico Tama, and Monto Ho

Randomized clinical trials (RCT) are among the most important tools available to clinical researchers faced with the responsibility of evaluating new drugs or therapeutic modalities. The basic elements of these trials are as follows: they are controlled; assignment to a treatment or control group is randomized; whenever feasible, they are "double-blinded"; and finally, the results of the randomized clinical trial are evaluated statistically.' Although the elements of a randomized clinical trial are well defined, and deceptively simple, the issue of research on human subjects, "remains the focus of ethical, legal and methodological concern."2

The special circumstances of research involving individuals with AIDS (Acquired Immunodeficiency Syndrome) and other manifestations of human immunodeficiency virus (HIV) infection, have already been well de- scribed in a number of publications outlining the issues unique to AIDS,3 and the need to pay particular heed to confidentiality when dealing with research subjects who are "highly vulnerable socially, economically and politically."4 Ronald Bayer and his colleagues recommended that a contin- uing advisory board be established to "assess the adequacy" of the implemen- tation of confidentiality guidelines and to "provide a forum for discussing issues" that might arise in the course of research involving subjects with AIDS.

Based on this recommendation, researchers from the University of Pittsburgh, after being awarded a federal research grant to evaluate a variety of experimental therapies in individuals infected with HIV (AIDS

Treatment Evaluation Unit), created an advisory committee to act in this capacity. This committee consists of leaders in the gay community, individuals with experience in community health programs, persons who work in programs for hemophiliacs and intra- venous drug abusers, volunteers and health care workers who care for HIV- infected persons, and individuals with family members who are infected with HIV. It is staffed by one of the physician investigators and the project coordinator. The group meets regularly; issues that are discussed in committee are brought to the attention of the other investigators at weekly research meetings. The committee disseminates information about our research protocols within the target communities from which we are recruiting volunteers, advises us on matters that are sensitive or potentially controversial, and heightens our understanding of the special issues confronting individuals who are infected with HIV.

Many of our early meetings were

Ronald O. Valdiserri is Associate Professor of Pathology and Assistant Professor of Infectious Diseases, University of Pittsburgh Schools of Medicine and Public Health, and Co-Investigator Pittsburgh AIDS Treatment Evaluation Unit; Geraldine Malatico Tama is Project Coordinator, Pittsburgh AIDS Treatment Evaluation Unit; and Monto Ho is Chief of the Division of Infectious Diseases, University of Pittsburgh Schools of Medicine and Public Health, and Principal Inves- tigator, Pittsburgh AIDS Treatment Evaluation Unit

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the changing clinical trials scene: the role of the irb

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