There are many different types of clinical trial design, but most of the approaches we take to clinical research have been around for many years. Innovation in trial design could help improve outcomes and efficiency – and the FDA has shared some examples.
Clinical trials have been at the heart of drug development for centuries. Our approach to clinical research has evolved and refined over the years, but many aspects have remained similar.
One way to make clinical trials more efficient and effective is to modernize trial design. The U.S. Food & Drug Administration (FDA) wants to drive innovation in trial design through its Complex Innovative Trial Design Pilot Meeting Program.
“One of the most promising ways to make drug development more efficient—while enabling providers and patients to get better information about how a new medicine works—is by developing the science around innovative approaches to the design of clinical trials.” – Scott Gottlieb, M.D., Former FDA Commissioner
Through the Program, the FDA aims to support innovation in medical product development and advance the use of complex innovative trials (CIDs) and increase dialogue among stakeholders. Ultimately, the aim is to support the development of therapeutic options that benefit patients.
Complex trial case studies
The FDA has recently published case studies of three innovative study designs. Each case study focuses on a single design submitted to the Program: a master protocol to study chronic pain, a systemic lupus study that uses an adaptive rule to consider changing the primary endpoint 52 weeks into the study, and a proposed diffuse B-cell lymphoma trial that uses external control data.
Master Protocol Case Study – a proposed master protocol “permits multiple sub-studies to investigate proof of concept for several investigational products that may be intended to treat several types of chronic pain.” The innovative aspect of this design is that the study will borrow placebo information from sub-studies that investigated different products for the same type of chronic pain, and treatment effect information from sub-studies looking at the same treatment for different pain. With a master protocol in place, results of sub-studies would be standardized and therefore could be borrowed in this way. The benefit would be that fewer participants would be needed for future sub-studies. Read more.
Lupus Case Study – a randomized, double-blind, Phase 2 study in patients with systemic lupus erythematosus (SLE). This study design features an innovative ‘adaptive rule’ that allows investigators to change the study endpoint based on interim results. Another adaptive rule allows “for the possibility of pooling data from different dose levels in the comparison to placebo for the primary analysis.” With this design, the study can act as a dose-ranging study and evaluate the drug compared to placebo at the same time, therefore saving time and resources. Read more.
DLBCL Case Study – a randomized, open-label, multicenter trial in patients with first-line diffuse large B cell lymphoma. The trial design uses external control data for about half of the control, and data will be borrowed dynamically. A Bayesian parametric model is proposed to be used as the primary analysis of a secondary endpoint. This means fewer patients would be needed to randomize the control arm, and by borrowing data dynamically, there is a lower risk of incompatibility. Read more.
Submitting novel trial designs
The Piot Meeting Program is led by FDA statisticians and includes people from different disciplines within the FDA. Through the Program, clinical trial sponsors can interact with experts at the FDA and share their proposed new designs for complex innovative trials. Sponsors can submit trial designs until 30 June 2022.
The FDA evaluates submissions based on the therapeutic need, appropriateness of the trial design, the need for simulations, the level of innovation and the value proposition of the design.