6:17 AM
Aug 10, 2018
 |  BC Extra  |  Politics & Policy

FDA rolls out guidance for seamless cancer trials

FDA released draft guidance Friday outlining how companies can use seamless trial designs to consolidate the traditional three-phase approach into one first-in-human study to expedite development of cancer drugs and biologics.

Seamless trials use a single protocol that runs continuously and is amended to expand cohorts and/or add new ones until there is enough evidence to approve a candidate, or scrap its development. BioCentury's 2016 Back to School issue recommended that drug sponsors plan seamless studies to rapidly confirm early signals of exceptional responses and evaluate dosing regimens and candidate biomarkers without the need to set up new studies (see "Haste, not Waste").

"A lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials," FDA Commissioner Scott Gottlieb said in a statement. "Expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time. These clinical trial improvements can help ensure that innovative new therapies can be advanced efficiently to patients confronting a cancer diagnosis."

In Friday's guidance, FDA outlined ways to mitigate potential safety risks posed by seamless trials, which can expose a large number of patients to candidates with unknown efficacy and minimally characterized toxicity profiles due to rapid enrollment and the evolving nature of the information generated during the trial.

First, seamless trials should be limited to patient populations with serious diseases for which no curative therapies are available and products that have the potential to meet the criteria for breakthrough therapy designation.

The agency recommended sponsors establish an infrastructure to streamline trial logistics, facilitate real-time data collection and disseminate interim results to investigators, institutional review boards and regulators.

Additionally, the guidance detailed three aspects for inclusion in expansion cohorts evaluating cancer therapies: the rationale for inclusion of each population based on the candidate's proposed mechanism of action and acceptable risks; a statistical analysis plan that justifies maximum sample size and futility stopping rules; and an updated safety profile gleaned from the dose-escalation portion and other expansion cohorts.

The draft guidance also recommends patients be randomized to two or more dose regimens to increase the confidence that differences in outcomes between treatment arms are not due to chance alone.

Friday's guidance builds upon previous FDA recommendations for seamless trials. In a 2016 article in the New England Journal of Medicine, FDA's Richard Pazdur, Tatiana Prowell and Marc Theoret said sponsors should prospectively provide "a rationale for the definition, number and sample size of the expansion cohort." The authors suggested that companies also should have a prospective plan for how to adapt a seamless study as new evidence related to the agent's safety and efficacy is generated (see "Pazdur's Perspective").

In September 2017, FDA Commissioner Scott Gottlieb outlined steps FDA is taking to modernize the collection of clinical data, including the use of seamless trials. FDA has identified more than 40 active NDAs “for large first-in-human oncology trials alone that use these seamless strategies,” he said. To ensure adequate oversight and interactions with sponsors, comparable regulatory milestones need to be built into the seamless trial process, he added (see "Drug Development Costs Unsustainable, Gottlieb Warns").

Comments on the draft are due Oct. 9.

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