Two recent approvals underscore what the FDA says is its commitment to precision medicine treatments—a commitment the agency yesterday said it will carry out by expanding master protocols, case studies, and biomarker qualification standards.

In a post on FDA’s blog, Janet Woodcock, M.D., director of the agency’s Center for Drug Evaluation and Research (CDER), cited the May approvals of new indications for Merck & Co.’s cancer-fighting anti-programmed cell death protein 1 monoclonal antibody Keytruda® (pembrolizumab) and Vertex Pharmaceuticals’ cystic fibrosis treatment Kalydeco® (ivacaftor).

Keytruda won accelerated approval for pediatric and adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair solid tumors that have progressed following prior treatment and for which there is no suitable alternative therapy and colorectal cancer that has progressed following therapy with fluoropyrimidine, oxaliplatin, and irinotecan. 

More significant, as the FDA noted at the time, the Keytruda additional approval was granted based on tumor response rates and durability of response, with continued approval to depend upon data from confirmatory trials.

A week earlier, the FDA approved Kalydeco for people with cystic fibrosis ages 2 and older who have one of 23 residual function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. That approval was based on analyses of in vitro data and supported by more than five years of clinical data, Vertex said at the time.

“(CDER) has approved more than 25 new drugs that benefit patients with specific genetic characteristics. And we have approved many more new uses—also based on specific genetic characteristics—for drugs already on the market,” Dr. Woodcock stated. “Precision medicine holds great promise, but to continue developing targeted therapies, we will need scientific advances in the use and development of ‘biomarkers'.”

Focus on Biomarkers

To that end, Dr. Woodcock and Lisa M. LaVange, Ph.D., director of CDER’s Office of Biostatistics Organization, wrote a review article published earlier this month in The New England Journal of Medicine (“Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both”) discussing master protocols for clinical trials, designed to “evaluate more than one or two treatments in more than one patient type or disease within the same overall trial structure.”

More master protocols have been developed for studies of cancer therapy than other therapeutic areas, Drs. Woodcock and LaVange noted, due to advances in identifying tumor subtypes or mutations. One such protocol is I-SPY 2, an exploratory-phase platform trial designed to investigate new treatments for biomarker-identified subtypes of early-stage breast cancer in the context of neoadjuvant therapy.

I-SPY 2 has been used for evaluating 12 therapies from nine sponsors as of March, of which five have advanced for further study, according to the authors—with discussion under way on an I-SPY 3 master protocol designed to provide evidence of effectiveness for therapies that successfully complete I-SPY 2.

Master protocols, Drs. Woodcock and LaVange wrote, are also distinguished by two types of innovation: One is the use of a trial network capable of streamlining trial logistics, improving data quality, and facilitating data collection and sharing. The other is the use of a common protocol that incorporates statistical approaches to study design and data analysis, enabling a broader set of objectives to be met more effectively than would be possible in independent trials.

Under the 21st Century Cures Act, enacted last year, the FDA was required to establish a qualification process for “drug development tools,” a category that includes biomarkers as well as clinical outcome assessments.

The agency has since created a Biomarker Qualification Program, through which biomarkers can be qualified for use “in any drug development program under the context for which it obtained qualification.” The qualification process consists of three stages: initiation, consultation, and advice, including preparation and submission of an initial briefing package; and review of the full qualification package.

As part of the program, CDER last month posted on FDA’s website fictional case studies “intended to help patients, patient advocacy groups, health professionals, small businesses, and pharmaceutical and clinical innovators learn more about the role of biomarkers and biomarker qualification in drug development.”

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