Seamless Designs: Current Practice and Considerations for Early-Phase Drug Development in Oncology

Abstract

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.

Single‐Arm Clinical Trials as Pivotal Evidence for Cancer Drug Approval: A Retrospective Cohort Study of Centralized European Marketing Authorizations Between 2010 and 2019

“…The traditional paradigm of drug development in malignancies is a sequential evaluation of efficacy and safety, from primary safety evaluation in phase I and first-in-human studies, to be followed by dose finding and preliminary efficacy studies in phase II. 1 When successful, these exploratory findings in patients with advanced disease would then lead to confirmation of clinical efficacy and safety, and benefits relative to the existing, best available standard-of-care, in a randomized phase III clinical trial. Generally, randomized clinical trials are also recommended by the European Medicines Agency (EMA) anticancer guideline and have been considered a way to obtain high-quality data for clinicans and patients to make informed treatment decisions, and to faciliate evidence-based global access to new anticancer products.…”

“…Generally, randomized clinical trials are also recommended by the European Medicines Agency (EMA) anticancer guideline and have been considered a way to obtain high-quality data for clinicans and patients to make informed treatment decisions, and to faciliate evidence-based global access to new anticancer products. [1][2][3] Advances in molecular biology and immunology have refined and challenged our understanding of cancer biology and new therapeutic targets for anticancer products. 2 Leading to concepts of personalized cancer therapy, targeted agents, and precision oncology, these findings have had multiple consequences on the evolution of clinical study designs.…”

<p>The European Medicines Agency Clinical Data Website Enables Insights Into Clinical Development Timelines And Strategy</p>

“…37 The incorporation of a biomarker-based strategy in drug development timelines for new oncology drugs has been reported to reduce the time to approval. 38 Unfortunately, this could not be analyzed as the non-personalized carfilzomib was the only common CDP. Innovative concepts related to the Phase I program have also been debated but not analyzed.…”

The Future of Clinical Trial Design in Oncology

“…This may take the path of the traditional paradigm of distinctive trial phases or morph to seamless or tissue-agnostic designs to speed up subsequent steps. Regardless of the strategy, investigators must comply with established scientific, ethical, and biostatistical principles and standards to ensure data integrity and study subject protection (27).…”