Clinical Trials: FDA Releases Two Draft Guidances

Regulatory NewsRegulatory News | 28 September 2018 |  By 

The US Food and Drug Administration (FDA) on Friday unveiled two draft guidances focused on adaptive clinical trial designs and master protocols for cancer treatment trials.

Adaptive Trials

The 32-page adaptive design draft guidance describes the principles for designing, conducting and reporting the results from an adaptive clinical trial. The draft also advises sponsors on the types of information FDA needs to evaluate the results from trials with adaptive designs, including Bayesian adaptive and complex trials that rely on computer simulations for their design.

For the purposes of this guidance, which replaces a previous 2010 draft guidance, FDA defines an adaptive design “as a clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial.” FDA also explains how adaptive trial designs can allow a trial to adjust to information that was not available when the trial began.

Examples of adaptive designs featured in the guidance focus on an HPV vaccine, an Ebola treatment and several other treatments and trials that proved successful in their use of an adaptive design.

The draft also features discussions on limitations of adaptive trials, how to control the chance for erroneous conclusions, estimating treatment effects, adaptive designs based on comparative data vs. non-comparative data, and adaptations to the patient population, among other sections.

Under the special considerations section, the draft also discusses simulations in adaptive design planning, Bayesian adaptive designs, adaptations in time-to-event settings, adaptations based on a potential surrogate or intermediate endpoint, secondary endpoints, adaptive design in early-phase exploratory trials, unplanned design changes based on comparative interim results and design changes based on information from a source external to the trial.

Maintaining trial integrity and regulatory considerations are also included to help sponsors navigate the process of using an adaptive trial design.

Master Protocols

The 21-page draft guidance on master protocols, also known as “umbrella,” “basket” or “platform” trial designs, is meant to help sponsors of cancer drugs or biologics regarding the design and conduct of clinical trials intended to simultaneously evaluate more than one investigational drug and/or more than one cancer type within the same overall trial structure in adult and pediatric cancers.

FDA Commissioner Scott Gottlieb said in a statement: “Well-designed master protocols that look at multiple therapies in a single disease, a single therapy in multiple diseases, or multiple therapies across multiple diseases or disease subtypes, can provide answers more quickly and efficiently than traditional clinical trials.”

The draft comes as sponsors increasingly are interested in expediting late-stage drug development with trial designs that test multiple drugs and/or multiple cancer subpopulations in parallel under a single protocol, without the need to develop new protocols for every trial.

“In general, the recommended phase 2 dose (RP2D) has been established for an investigational drug or drugs evaluated in a master protocol,” FDA said, noting that the document describes aspects of master protocol designs, trial conduct and related considerations, such as biomarker co-development and statistical analysis considerations. It also provides advice on the information that sponsors should submit to FDA and on how sponsors can interact with FDA to facilitate efficient review.

FDA notes opportunities and challenges in using master protocols, highlighting three potential challenges:
“Difficulty in attribution of adverse events to one or more investigational drugs can occur when multiple drugs are administered within various arms and the trial lacks a single internal control for those drugs,” multiple study groups can allow for potential overinterpretation of findings, resulting in delays in drug development, and, “With multiple drugs being studied across multiple protocols and investigational new drug applications (INDs), assessing the safety profile of any given investigational drug is difficult.”

The draft includes a section on specific design considerations, featuring information on the use of a single common control arm, the novel combination of two or more investigational drugs, studies with drugs targeting multiple biomarkers, adding and stopping treatment arms and an independent data monitoring committee.

Biomarker, statistical, safety and regulatory considerations are also included as sections of the draft.

Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics: Draft Guidance for Industry

Adaptive Designs for Clinical Trials of Drugs and Biologics: Draft Guidance for Industry


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