• 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.
• 150-250 words

IRB Case: Payments to subjects who are substance abusers

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 orsocio-behavioral studies involving substance abusers are oftenconfronted with a range of ethical, regulatory and administrativechallenges in implementing and evaluating such research. This case waschosen because it illustrates several such problems routinelyencountered in these studies that require the researchers and the IRB tocreatively recognize the appropriate balance in order to safely andeffectively conduct these studies:

• How much remuneration is the right amount to offer subjectsto enroll in the study without the payment being seen as an inducementor as coercive yet ensure adequate recruitment?
• What kind of payment arrangements will ensure acceptable ratesof subject recruitment and study completion while not unduly coercingsubjects 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 thispopulation when the amount of remuneration may impact on enrollmentdecisions?

Background

It is well known that substance abusers have ahigh incidence of HIV/AIDS, making it critically important thatclinicians adequately address both problems simultaneously. Effectiveconcomitant management of these two illnesses requires a thoroughunderstanding of the pharmacokinetic interactions of the drugs requiredto treat each disease, permitting appropriate dosing revisions tooptimize therapeutic effects and avoid the ill effects seen with over-and under- dosing. Until recently, the drug of choice to facilitatedetoxification and promotion of long-term abstinence from narcotic abusewas methadone. Currently, however, in many areas of the country,buprenorphine has supplanted methadone as the standard treatment, as itis a drug devoid of a number of the more common problems often seen withmethadone maintenance therapy. While the drug interactions of methadonewith a number of standard anti-retroviral therapies have been welldescribed, such is not the case with buprenorphine, necessitatingpharmacokinetic research to better characterize the interactions betweenbuprenorphine and the anti-retroviral medications commonly in use.

Study Design

The study in this case proposed to enroll knownsubstance abusers who were otherwise healthy and who were alreadyreceiving buprenorphine maintenance therapy at a stable dose for atleast three weeks. Subjects were to be admitted to the hospital for anovernight stay to obtain baseline pharmacokinetic blood measurements ofbuprenorphine and were then to be administered Kaletra, a commonly usedanti-retroviral therapy. The investigators planned to monitor subjectsfor the next 14 days on an outpatient basis with daily administration ofboth buprenorphine and Kaletra and at the end of the two weeks,subjects were to be re-admitted to the hospital for repeatpharmacokinetic blood testing of buprenorphine and Kaletra forcomparison with baseline testing performed two weeks prior. At thecompletion of the study, the researchers planned to remunerate eachsubject $1000 for complete study participation but subjectswould receive no payment unless they completed all study interventions.The investigators allowed for a pro-rated payment schedule for subjectsforced to withdraw secondary to adverse events.

Ethical/Regulatory Issues

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, expressingconcerns that the size of the payment might contribute to a relapse ofsubstance 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 paymentand the proposed method of disbursement to assure that neither entailsproblems of coercion or undue influence. Such problems might occur, forexample, if the entire payment were to be contingent upon completion ofthe study or if the payment were unusually large. Payments shouldreflect the degree of risk, inconvenience, or discomfort associated withparticipation.”

“Volunteers are oftencompensated for their participation according to an established feeschedule, based upon the complexity of the study, the type and number ofprocedures to be performed, the time involved, and the anticipateddiscomfort or inconvenience. Standard payments may be established.”

Or,

“subjects may be paid anhourly rate or a fixed amount, depending on the duration of the studyand whether the study requires admission to research ward. Extrapayments are usually provided for a variety of additionalinconveniences. Payments may vary according to a number of factors, and,therefore, IRBs may need to become familiar with the accepted standardswithin their community as well as the anticipated discomforts andinconveniences involved in a particular study to judge appropriatenessof payments.”

IRB Decision:

Subjects were required to stay overnight in thehospital at the beginning and at the end of the study as well as keepdaily visits to the research site clinic for the 14 days in between.Such demands on study subjects were considered significantlyinconvenient as they had the potential to markedly disrupt the lives ofthe subjects to accommodate the daily visits as well as the discomfortfrom the overnight hospital stays with the multiple blood draws. The IRBagreed that the study requirements placed reasonable but significantdemands on subjects’ schedules in order to participate and therebyjustified the size of the payment accordingly, consistent with OHRPguidance above.

• Does the size of the remuneration create sufficientincentive for someone to participate in the study solely for financialgain? Does this financial incentive negatively impact on the ability toobtain proper informed consent?

The IRB considered the possibility that a large lump sum paymentmight provide enough incentive for substance abusers to participate inthe study based solely on the desire for financial gain. The high levelof remuneration in this protocol might result in some individualsconsenting to participate in the study in order to obtain the paymentwithout fully comprehending the demands of the study and without anyreal desire to be part of such research. Such hyper-focusing on theremuneration might negate or minimize the informed consent processthereby creating a coercive participatory environment.

IRB Decision:

The IRB considered this potential for inadequateinformed consent to be a significant concern and required theinvestigators 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 effectivelycommunicate the contents and demands of the study to the researcher.While this is often a standard component of the consent process, the IRBasked the researchers to make certain such was the case in this study.

• Is it acceptable to delay full payment for studyparticipation till the subject completes all study interventions? Whendoes the timing or the size of the remuneration become coercive?

The IRB considered the issue of the acceptability of a singlepayment at the completion of the study, and whether that placed anyundue influence on subjects to continue participation. The principle of Respect for Personscalls for voluntary participation such that coercion or undueinducement placed upon subjects to continue participation is reason forconcern.

IRB Decision:

The IRB noted this study was not a treatmentstudy but rather a protocol that involved a pharmacokinetic evaluationof drug interactions. As such, non-completion would yield no usablestudy data making it critical that subjects complete the study.Additionally, subjects who did not complete the study were in no waycompromising their health since no treatment was involved. Finally, theIRB noted that the protocol provided a reasonable mechanism forwithdrawal from the study in case of adverse effects from the drugcombination with a concomitant pro-rated payment schedule. The paymentprocedures were thus found to be acceptable.

• Is the protocol optimally designed to minimize the riskof relapse once the subject completes the study and the payment ismade?

The initial protocol submitted to the IRB noted that the minimumlength of maintenance time for these chronic buprenorphine users to beeligible for enrollment was at least three weeks on stable dosing butwithout any discussion regarding the length of time they had been indrug treatment for their substance abuse. The literature, however, isclear that the longer such individuals continue on drug maintenance, theless likely they will relapse for any reason. Achieving a milestonesuch as staying on maintenance treatment for a longer time period, sayfor three months, may indicate that patients are at less risk forrelapse than are those individuals in treatment for a shorter period oftime. The IRB expressed concern that for these individuals who had beenon stable buprenorphine dosing for only a relatively short time of 3-4weeks, the sudden acquisition of a somewhat large sum of cash at thecompletion of the study might be a significant stimulus for relapse forsome of those enrolled. During IRB deliberations, however, it was alsonoted that in the course of daily living, these individuals may receiveother large sums of money, either through such things as monthly payrollor settlement of insurance claims, etc., without any good evidence thatsuch payments contribute to relapse.

IRB Decision:

Subject eligibility criteria were evaluated asnoted, and in an effort to protect participants from relapse potentiallyrelated to the level and timing of study compensation, the IRB requireda change in inclusion criteria: recruitment would be restricted tosubjects enrolled in long-term buprenorphine maintenance therapy for atleast three months, and have been on a stable dose of drug for at leastthree weeks. Three months of continuous buprenorphine treatment as acondition for enrollment was considered long enough to minimize thepossibility of relapse of study participants secondary to the level andtiming 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 moreappropriate subject population for this study. That is, why not simplyenroll subjects who were already taking both meds or were scheduled tobegin one or the other in the near future? This concern is based on theethical principle of Justice, balancing risks and benefits so as not to subject one group to risks for the benefit of a different group.

IRB Decision:

This issue was resolved by noting that almostall HIV+ individuals being treated with anti-retroviral drugs are takingseveral such medications at the same time. Monotherapy with Kaletrawould be considered beneath the standard of medical care for thisdisease at this time and would thus prevent anyone who is HIV+ fromenrolling in the study. It would also be unethical to require HIV+individuals to revise their standard therapy to Kaletra alone, just tomeet study inclusion criteria. With regard to adverse events in thestudy as proposed, all such occurrences could readily be attributed toKaletra and its interaction with buprenorphine. Such would not be thecase if HIV+ substance abusers who were being treated with standardmulti-drug anti-retroviral therapy were able to enroll after revision oftheir drug regimen by substituting Kaletra for another drug. Based onthis discussion, the IRB felt it reasonable to exclude HIV+ individualsfrom participating in this study in order to test this particulardrug-drug interaction given the frequent co-existence of substance abuseand HIV infection.

Comment 1: Fair compensation or undue inducement?

Comment 2: On withholding payments until study completion

Comment 3: Motives and protection