In an article appearing in the May 8 edition of Science Translational Medicine, Spencer Phillips Hey, Ph.D., a postdoctoral fellow in the Biomedical Ethics Unit at McGill University, and Jonathan Kimmelman, Ph.D., of the Studies for Translation, Ethics, and Medicine Group (STREAM), Biomedical Ethics Unit, McGill University point out the potential ethical and social trade-offs resulting from clinical trial reforms aimed at boosting Phase II positive predictivity.

The scientists say that many trial reforms being considered to raise Phase II positive predictibility (reduction of late-phase attrition) have repercussions for human subjects, as well as the capacity of the research enterprise to “execute its social mission.”

As about two thirds of therapeutic interventions that enter Phase III fail to reproduce success observed in Phase II trials. The high rate of negative confirmatory trials, they say, have prompted innovations in Phase II design including the use of more predictive biomarkers, tiered approaches to outcome assessment, patient enrichment, seamless Phase II/III designs, larger trials, use of clinical endpoints, real-time pharmacokinetic analysis, randomization (for areas such as oncology, in which Phase II studies use historical controls), variations in statistical error rates, and adaptive designs.

Reducing false-positives in Phase II trials, the authors say, is ethically attractive because, for example, it reduces the occurrence of failure in Phase III, and can limit the number of patient-volunteers exposed to unsafe and ineffective drugs. Given that the number of patients in Phase III studies is typically 10-fold greater than in Phase II, these reductions in subject burden can be substantial.

But, they say, some of the gains in subject welfare described above are offset by greater burdens on patients participating in trials. Introducing randomization in Phase II studies, for example, roughly doubles the number of patients in trials because the trials now require comparator arms. Using enrichment designs, pharmacodynamics, or real-time pharmacokinetics all entail more frequent (and often invasive) tissue collection from volunteers. In areas of vaccine development, the quest for predictive Phase II designs has kindled interest in Phase II “challenge studies,” which deliberately infect healthy volunteers with a manageable form of disease.

These and other extra “burdens” in Phase II trials, the ethicists say, are not morally equivalent to those found in Phase III trials because risks of drug administration in confirmatory trials are ethically justified by clinical “equipoise”, or a state of collective uncertainty about whether experimental treatment is preferable to standard care, and therefore plausibly claim therapeutic value for subjects.

In contrast, the case for clinical equipoise is far weaker in initial tests of efficacy because evidence of clinical utility is lacking at the outset, and base rates for discovering a useful intervention low. The risk of more intensive tissue collection or disease challenge are morally justified by ends that are predominantly external to the volunteer.

For these and other reasons, the authors suggest four considerations for achieving equipoise in Phase II. These include establishing the upper and lower bounds on evidence needed to initiate Phase III studies, limiting nontherapeutic risks for trial patient-subjects, and consideration of the potential knowledge-value of decisively negative Phase III results.

Dr. Kimmelman directs the Group for Studies of Clinical Translation (G-SCT), which studies scientific, policy, and ethical challenges encountered in transforming laboratory discoveries into medical applications.

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