Review the IRB Case Study from Yale University. FOUND BELOW
Discuss why you believe the determination was made and whether you believe it was the right or wrong decision.
Type of Institution: Large academic medical center
Type of IRB: Biomedical Research
Type of Case: Ethical/Regulatory case
Author: Chairman of the IRB
From the Editors:
Researchers who conduct biomedical or socio-behavioral studies involving substance abusers are often confronted with a range of ethical, regulatory and administrative challenges in implementing and evaluating such research. This case was chosen because it illustrates several such problems routinely encountered in these studies that require the researchers and the IRB to creatively recognize the appropriate balance in order to safely and effectively conduct these studies:
How much remuneration is the right amount to offer subjects to enroll in the study without the payment being seen as an inducement or as coercive yet ensure adequate recruitment?
What kind of payment arrangements will ensure acceptable rates of subject recruitment and study completion while not unduly coercing subjects to complete the study?
How can researchers minimize the risks of substance abuse relapse in study subjects who have been abstinent?
How can researchers obtain effective informed consent from this population when the amount of remuneration may impact on enrollment decisions?
It is well known that substance abusers have a high incidence of HIV/AIDS, making it critically important that clinicians adequately address both problems simultaneously. Effective concomitant management of these two illnesses requires a thorough understanding of the pharmacokinetic interactions of the drugs required to treat each disease, permitting appropriate dosing revisions to optimize therapeutic effects and avoid the ill effects seen with over- and under- dosing. Until recently, the drug of choice to facilitate detoxification and promotion of long-term abstinence from narcotic abuse was methadone. Currently, however, in many areas of the country, buprenorphine has supplanted methadone as the standard treatment, as it is a drug devoid of a number of the more common problems often seen with methadone maintenance therapy. While the drug interactions of methadone with a number of standard anti-retroviral therapies have been well described, such is not the case with buprenorphine, necessitating pharmacokinetic research to better characterize the interactions between buprenorphine and the anti-retroviral medications commonly in use.
The study in this case proposed to enroll known substance abusers who were otherwise healthy and who were already receiving buprenorphine maintenance therapy at a stable dose for at least three weeks. Subjects were to be admitted to the hospital for an overnight stay to obtain baseline pharmacokinetic blood measurements of buprenorphine and were then to be administered Kaletra, a commonly used anti-retroviral therapy. The investigators planned to monitor subjects for the next 14 days on an outpatient basis with daily administration of both buprenorphine and Kaletra and at the end of the two weeks, subjects were to be re-admitted to the hospital for repeat pharmacokinetic blood testing of buprenorphine and Kaletra for comparison with baseline testing performed two weeks prior. At the completion of the study, the researchers planned to remunerate each subject $1000 for complete study participation but subjects would receive no payment unless they completed all study interventions. The investigators allowed for a pro-rated payment schedule for subjects forced to withdraw secondary to adverse events.
Several ethical/regulatory issues arose during initial IRB review of this study.
Is it ethical to remunerate substance abusers a large lump sum payment for participation in research?
The IRB questioned the ethics of allowing a lump sum payment of $1000 be made to subjects who were known substance abusers, expressing concerns that the size of the payment might contribute to a relapse of substance abuse. Concerns were based on the ethical principle of Beneficence, which requires that risks be minimized to the extent possible.
OHRP Guidance indicates that,
“…the IRB should review both the amount of payment and the proposed method of disbursement to assure that neither entails problems of coercion or undue influence. Such problems might occur, for example, if the entire payment were to be contingent upon completion of the study or if the payment were unusually large. Payments should reflect the degree of risk, inconvenience, or discomfort associated with participation.”
“Volunteers are often compensated for their participation according to an established fee schedule, based upon the complexity of the study, the type and number of procedures to be performed, the time involved, and the anticipated discomfort or inconvenience. Standard payments may be established.”
“subjects may be paid an hourly rate or a fixed amount, depending on the duration of the study and whether the study requires admission to research ward. Extra payments are usually provided for a variety of additional inconveniences. Payments may vary according to a number of factors, and, therefore, IRBs may need to become familiar with the accepted standards within their community as well as the anticipated discomforts and inconveniences involved in a particular study to judge appropriateness of payments.”
Subjects were required to stay overnight in the hospital at the beginning and at the end of the study as well as keep daily visits to the research site clinic for the 14 days in between. Such demands on study subjects were considered significantly inconvenient as they had the potential to markedly disrupt the lives of the subjects to accommodate the daily visits as well as the discomfort from the overnight hospital stays with the multiple blood draws. The IRB agreed that the study requirements placed reasonable but significant demands on subjects’ schedules in order to participate and thereby justified the size of the payment accordingly, consistent with OHRP guidance above.
Does the size of the remuneration create sufficient incentive for someone to participate in the study solely for financial gain? Does this financial incentive negatively impact on the ability to obtain proper informed consent?
The IRB considered the possibility that a large lump sum payment might provide enough incentive for substance abusers to participate in the study based solely on the desire for financial gain. The high level of remuneration in this protocol might result in some individuals consenting to participate in the study in order to obtain the payment without fully comprehending the demands of the study and without any real desire to be part of such research. Such hyper-focusing on the remuneration might negate or minimize the informed consent process thereby creating a coercive participatory environment.
The IRB considered this potential for inadequate informed consent to be a significant concern and required the investigators take additional steps in the informed consent process. They asked those obtaining informed consent confirm their subjects’ understanding of the protocol by requiring them to effectively communicate the contents and demands of the study to the researcher. While this is often a standard component of the consent process, the IRB asked the researchers to make certain such was the case in this study.
Is it acceptable to delay full payment for study participation till the subject completes all study interventions? When does the timing or the size of the remuneration become coercive?
The IRB considered the issue of the acceptability of a single payment at the completion of the study, and whether that placed any undue influence on subjects to continue participation. The principle of Respect for Persons calls for voluntary participation such that coercion or undue inducement placed upon subjects to continue participation is reason for concern.
The IRB noted this study was not a treatment study but rather a protocol that involved a pharmacokinetic evaluation of drug interactions. As such, non-completion would yield no usable study data making it critical that subjects complete the study. Additionally, subjects who did not complete the study were in no way compromising their health since no treatment was involved. Finally, the IRB noted that the protocol provided a reasonable mechanism for withdrawal from the study in case of adverse effects from the drug combination with a concomitant pro-rated payment schedule. The payment procedures were thus found to be acceptable.
Is the protocol optimally designed to minimize the risk of relapse once the subject completes the study and the payment is made?
The initial protocol submitted to the IRB noted that the minimum length of maintenance time for these chronic buprenorphine users to be eligible for enrollment was at least three weeks on stable dosing but without any discussion regarding the length of time they had been in drug treatment for their substance abuse. The literature, however, is clear that the longer such individuals continue on drug maintenance, the less likely they will relapse for any reason. Achieving a milestone such as staying on maintenance treatment for a longer time period, say for three months, may indicate that patients are at less risk for relapse than are those individuals in treatment for a shorter period of time. The IRB expressed concern that for these individuals who had been on stable buprenorphine dosing for only a relatively short time of 3-4 weeks, the sudden acquisition of a somewhat large sum of cash at the completion of the study might be a significant stimulus for relapse for some of those enrolled. During IRB deliberations, however, it was also noted that in the course of daily living, these individuals may receive other large sums of money, either through such things as monthly payroll or settlement of insurance claims, etc., without any good evidence that such payments contribute to relapse.
Subject eligibility criteria were evaluated as noted, and in an effort to protect participants from relapse potentially related to the level and timing of study compensation, the IRB required a change in inclusion criteria: recruitment would be restricted to subjects enrolled in long-term buprenorphine maintenance therapy for at least three months, and have been on a stable dose of drug for at least three weeks. Three months of continuous buprenorphine treatment as a condition for enrollment was considered long enough to minimize the possibility of relapse of study participants secondary to the level and timing of study compensation.
Why did the researchers avoid enrolling substance abusers who were HIV+, the concomitant disease of interest?
IRB members questioned whether HIV+ individuals were not a more appropriate subject population for this study. That is, why not simply enroll subjects who were already taking both meds or were scheduled to begin one or the other in the near future? This concern is based on the ethical principle of Justice, balancing risks and benefits so as not to subject one group to risks for the benefit of a different group.
This issue was resolved by noting that almost all HIV+ individuals being treated with anti-retroviral drugs are taking several such medications at the same time. Monotherapy with Kaletra would be considered beneath the standard of medical care for this disease at this time and would thus prevent anyone who is HIV+ from enrolling in the study. It would also be unethical to require HIV+ individuals to revise their standard therapy to Kaletra alone, just to meet study inclusion criteria. With regard to adverse events in the study as proposed, all such occurrences could readily be attributed to Kaletra and its interaction with buprenorphine. Such would not be the case if HIV+ substance abusers who were being treated with standard multi-drug anti-retroviral therapy were able to enroll after revision of their drug regimen by substituting Kaletra for another drug. Based on this discussion, the IRB felt it reasonable to exclude HIV+ individuals from participating in this study in order to test this particular drug-drug interaction given the frequent co-existence of substance abuse and HIV infection.
Comment 1: Fair compensation or undue inducement?
Comment 2: On withholding payments until study completion
Comment 3: Motives and protection
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