Search

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses the manuscripts submitted by people on the methodology of clinical trials conducted in the healthcare industry.

Summary Much of the statistical methodology underlying the experimental design of phase 1 trials in oncology is intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the maximally tolerated dose, the highest dose that can be administered with an acceptable level of toxicity. A fundamental assumption of these methods is monotonicity of the dose-toxicity curve. This is a reasonable assumption for single-agent trials in which the administration of greater doses of the agent can be expected to produce dose-limiting toxicities in increasing proportions of patients. When studying multiple agents, the assumption may not hold because the ordering of the toxicity probabilities could possibly be unknown for several of the available drug combinations. At the same time, some of the orderings are known and so we describe the whole situation as that of a partial ordering. In this article, we propose a new two-dimensional dose-finding method for multiple-agent trials that simplifies to the continual reassessment method (CRM), introduced by (1990, Biometrics 46, 33-48), when the ordering is fully known. This design enables us to relax the assumption of a monotonic dose-toxicity curve. We compare our approach and some simulation results to a CRM design in which the ordering is known as well as to other suggestions for partial orders. [ABSTRACT FROM AUTHOR]