Empowering phase II clinical trials to reduce phase III failures.

The large number of failures in phase III clinical trials, which occur at a rate of approximately 45%, is studied herein relative to possible countermeasures. First, the phenomenon of failures is numerically described. Second, the main reasons for failures are reported, together with some generic improvements suggested in the related literature. This study shows how statistics explain, but do not justify, the high failure rate observed. The rate of failures due to a lack of efficacy that are not expected, is considered to be at least 10%. Expanding phase II is the simplest and most intuitive way to reduce phase III failures since it can reduce phase III false negative findings and launches of phase III trials when the treatment is positive but suboptimal. Moreover, phase II enlargement is discussed using an economic profile. As resources for research are often limited, enlarging phase II should be evaluated on a case-by-case basis. Alternative strategies, such as biomarker-based enrichments and adaptive designs, may aid in reducing failures. However, these strategies also have very low application rates with little likelihood of rapid growth.

Ethical Challenges in Biomarker-Driven Drug Development.

The increasing importance of biomarkers-as drivers of research and drug development activity, surrogate outcomes in clinical trials, and the centerpiece of precision medicine-raises many new ethical challenges. In what follows, I briefly review some of the major ethical challenges and debates already identified in the literature, and then describe a new ethical challenge that arises from the abstract nature of biomarker hypotheses.

Ethics and Medical Toxicology Research.

Optimizing care in medical toxicology necessitates designing and conducting ethical research. Nevertheless, the context of medical toxicology can make clinical research ethically challenging for a variety of reasons: medical toxicology is typified by relative rare conditions; making precise and rapid diagnoses is often fraught with uncertainty; emergent and urgent clinical exigencies make consent difficult or impossible; and some exposures are stigmatized or related to illegal activities that can compromise collecting accurate data from patients. In this paper, we examine some of the ethical issues in medical toxicology research that are especially salient in effort to promote optimal research in the field. The particular issues to be addressed are as follows: (1) rare conditions and orphan agents, (2) randomization and control arms, (3) inclusion and exclusion criteria, (4) outcome measures, (5) consent, (6) confidentiality, (7) registries, (8) oversight, and (9) transparency and reporting. Thinking about these ethical issues prospectively will help researchers and clinicians appropriately navigate them.

Adaptive designs from a Data Safety Monitoring Board perspective: Some controversies and some case studies.

This article describes vignettes concerning interactions with Data Safety Monitoring Boards during the design and monitoring of some clinical trials with an adaptive design. Most reflect personal experiences by the author.

Robust inference for group sequential trials.

For ethical reasons, group sequential trials were introduced to allow trials to stop early in the event of extreme results. Endpoints in such trials are usually mortality or irreversible morbidity. For a given endpoint, the norm is to use a single test statistic and to use that same statistic for each analysis. This approach is risky because the test statistic has to be specified before the study is unblinded, and there is loss in power if the assumptions that ensure optimality for each analysis are not met. To minimize the risk of moderate to substantial loss in power due to a suboptimal choice of a statistic, a robust method was developed for nonsequential trials. The concept is analogous to diversification of financial investments to minimize risk. The method is based on combining P values from multiple test statistics for formal inference while controlling the type I error rate at its designated value.This article evaluates the performance of 2 P value combining methods for group sequential trials. The emphasis is on time to event trials although results from less complex trials are also included. The gain or loss in power with the combination method relative to a single statistic is asymmetric in its favor. Depending on the power of each individual test, the combination method can give more power than any single test or give power that is closer to the test with the most power. The versatility of the method is that it can combine P values from different test statistics for analysis at different times. The robustness of results suggests that inference from group sequential trials can be strengthened with the use of combined tests.

Zinc disc implantation model of urinary bladder calculi and humane endpoints.

The zinc disc implantation-induced urinary bladder calculi model in the rat is commonly used for preclinical evaluation of the antiurolithiatic activity of test compounds. Certain published reports state that relatively long durations for which zinc discs must be implanted in the bladders of rats. Hence, there is a need to refine this model. These investigations aimed to determine whether long-term studies using the zinc disc implantation model provide any additional data that affect the final outcomes of the study. In this study, we evaluated the effects of a well-known antiurolithiatic polyherbal drug, Cystone, for different treatment durations of 10, 20 and 48 days postimplantation. Our results indicate that even the shortest duration of 10 days is sufficient to reveal antiurolithiatic effects of a test drug. Hence, in the zinc disc implantation-induced urinary bladder calculi model, the study duration is proposed to be minimized so as to reduce the distress caused to the rats due to long-term exposure to the implant. Further, it is suggested that the growth of the bladder calculi can be monitored by taking X-ray radiographs of the bladder deposits to decide the time to terminate the study. Use of preformed calcium oxalate crystal instead of zinc discs, as suggested in earlier reports by others, may also be considered to avoid the sacrifice of rats at the end of the study.

Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology.

Clinical investigators in oncology are increasingly interested in using molecular analysis of cancer tissue to understand the biologic bases of response or resistance to novel interventions and to develop prognostic and predictive biomarkers that will guide clinical decision making. Some scientific questions of this nature can only be addressed, or may best be addressed, through the conduct of a clinical trial in which research biopsies are obtained from all participants. However, trial designs with mandatory research biopsies have raised ethical concerns related to the risk of harm to participants, the adequacy of voluntary informed consent, and the potential for misunderstanding among research participants when access to an experimental intervention is linked to the requirement to undergo a research biopsy. In consideration of the ethical and scientific issues at stake in this debate, the Cancer and Leukemia Group B Ethics Committee proposes guidelines for clinical trials involving mandatory research biopsies. Any cancer clinical trial that requires research biopsies of participants must be well designed to address the scientific question, obtain the biopsy in a way that minimizes risk, and ensure that research participants are fully informed of the risks, rationale, and requirements of the study, as well as of treatment alternatives. Further guidelines and discussions of this issue are specified in this position paper. We feel that if these principles are respected, an informed adult with cancer can both understand and voluntarily consent to participation in a clinical trial involving mandatory research biopsy for scientific end points.

Principles of early stopping of randomized trials for efficacy: a critique of equipoise and an alternative nonexploitation ethical framework.

Recent controversial decisions to terminate several large clinical trials have called attention to the need for developing a sound ethical framework to determine when trials should be stopped in light of emerging efficacy data. Currently, the fundamental rationale for stopping trials early is based on the principle that equipoise has been disturbed. We present an analysis of the ethical and practical problems with the "equipoise disturbed" position and describe an alternative ethical framework based on the principle of nonexploitation. This framework acknowledges the need for balancing the dual ethical obligations of clinical research, the protection of human subjects and the generation of new medical knowledge. Based on this framework, we put forward a proposal to make early stopping guidelines more stringent under specified conditions. The temporary withholding of apparent benefits in certain circumstances is justified by achieving a fair contract with the research participants, one that protects them from undue harm and exploitation while reducing the many uncertainties surrounding new investigational treatments that arise when trials are stopped prematurely.