Toward Improved Understanding of the Ethical and Clinical Issues Surrounding Mandatory Research Biopsies (2012)

To date, the terms of the debate, occurring within scientific meetings and the literature, have focused on the presumed scientific necessity for mandatory research biopsies versus the rights of prospective trial participants to freely consider consent to a research biopsy separately from consent to a clinical trial. Proponents argue that some important scientific questions can only be addressed by evaluation of tumor tissue from all trial participants. They claim that in the era of molecular medicine, clinical researchers frequently need to understand not just who benefits or fails to benefit from a drug, but why benefit has occurred as assessed by whether the drug reached its intended target, and whether there are molecular factors that can predict response or guide further therapy. They assume that clinical samples will be unavailable or inappropriate to address some questions, that participation rates in optional research biopsies will be inadequate, and that biopsies can be conducted safely, with informed consent, and yield meaningful knowledge to advance the field. Opponents of mandatory research biopsies do not dispute the need for research biopsies in some settings. However, they argue that linking consent to a biopsy to trial participation is at minimum unfair, and at worst coercive. Access to promising, if unproven, experimental therapy within a trial is viewed by many as an important component of quality cancer care. It is clear that patients in some settings feel that they will be harmed, through loss of access to the experimental intervention, if they fail to pursue trial care. This arguably creates a sense of coercion that violates the principle of voluntarily informed consent to the research biopsy. Further, some trial participants mistakenly assume that all aspects of trial care and procedures are intended to provide direct clinical benefit. This therapeutic misconception complicates achieving informed consent in this setting. In addition, some argue that technical limitations in our ability to conduct meaningful correlative science make requirements for universal biopsies within a trial inappropriate at this time. Achievement of evaluable molecular analysis on all patients is rareevenwhenallarerequiredtoparticipate,andevaluationofasubsetof participants can be achieved through optional biopsies. The science, according to this view, should be improved before mandatory research biopsies are considered. It should be noted that no one supports asking trial participants to undergo a biopsy for research purposes in the absence of a strong scientific rationale, meaningful informed consent, and a low to minimal risk of expected complications. In addition, there is very little, if any, debate over trials that require a biopsy to guide management within the study, such as dose of a drug or choice of intervention, termed “integral biomarker” trials. Concerns arise when the purpose of the mandatory research biopsy is correlative science, or, most controversially, when a research biopsy is planned for purely exploratory purposes or for collection for future unspecified research. Acknowledged in most of the policy statements and position papers on this subject is a relative lack of data to inform discussions of the strength of the scientific rationale used to justify inclusion of mandatory research biopsies in a protocol, the quality of informed consent, participation rates and efficiency of accrual, safety, and outcomes of the procedures. Into this relative void, and a debate that at times brings more heat than light, step Overman et al, with a welcome report on the experience with mandatory research biopsies at a single institution over a recent 5-year period. The authors conducted a retrospective analysis of clinical trials contained in the MD Anderson interventional radiology database. They identified 19 clinical trials involving mandatory research biopsies conducted for purely correlative or exploratory purposes. For these trials, they reviewed the protocol, the informed consent document, and the medical record. Overman et al found that in the trial protocols the rationale for the biopsy was inconsistently explained and a statistical plan justifying the collectionofmandatorybiopsieswasfoundinonly30%oftrials involving correlativescience.Consentdocumentswerealsoproblematic.Only40% of informed consent documents for studies using mandatory research biopsies for correlative purposes explained the research nature of the biopsy, 70% explained the scientific rationale for the biopsy, and 30% addressed biopsy safety. With regard to safety, in analysis that included trials with optional biopsies and integral biomarker studies, the investigators reported an overall complication rate of 5.2% and a major complication rate (indicating need for hospitalization or surgery) of 0.8%. When considering intrathoracic and abdominal biopsies alone the overall complication rate rose to 9.8% with a major complication rate of 1.5%. They reported no biopsy-related deaths. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 1 JANUARY 1 2013