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FDA Updates Guidance for Clinical Trial Design in Oncology

WASHINGTON — In its efforts to modernize clinical trials in oncology, the FDA announced new recommendations on Wednesday to guide drugmakers in choosing endpoints for judging treatment success in cancer.

“Today, we’re revising guidance for the first time in more than a decade that outlines our thinking on oncology endpoints based on the specific context of use, as well as the advantages and disadvantages of these endpoints in clinical development programs,” FDA Commissioner Scott Gottlieb, MD, said in a statement, noting that using meaningful endpoints is “key” to the agency’s efforts to modernize trials.

The 19-page document walks through the various endpoints frequently used in cancer trials (overall survival, progression-free survival, event-free survival, objective, and compete response rates) and as Gottlieb noted, lists the pros and cons for each. It also breaks down different trial designs (single-arm, randomized trials for radiotherapy and chemotherapy protectants, etc.) and explains when each may be the most appropriate.

The guidance also discusses the use of endpoints involving symptom assessment, blood and body-fluid based biomarkers, and one section focuses on the use of emerging endpoints, noting that the agency recognizes that scientific advances are leading to new types of cancer drugs, which may result in the “identification of additional endpoints” that may be used to support these approvals.

The agency recently updated its table of surrogate endpoints — nonclinical outcomes that have been used as the basis of accelerated and traditional drug approvals in cancer and other disease states — and earlier this month issued new guidance on biomarkers to clarify evidence needed to support their use during drug development.

“Over the past several decades, we’ve seen an evolution in cancer care in how treatment effect is measured, and which endpoints are successful measures of disease activity or clinical benefit to patients,” said Gottlieb. “As part of these advances, there’s been a robust debate about the use of surrogate endpoints to support both traditional and accelerated approvals.”

In February, the agency broke new ground in accepting metastasis-free survival as the basis for approving apalutamide (Erleada), a new-generation androgen receptor inhibitor, for the treatment of nonmetastatic castration-resistant prostate cancer. A randomized trial showed that adding the agent to androgen deprivation therapy (ADT) led to a 2-year increase in the time to metastatic progression compared to ADT alone.

And then in March, the FDA expanded the approval of blinatumomab (Blincyto) to include the treatment of B-cell precursor acute lymphoblastic leukemia, for patients in remission who still have minimal residual disease (MRD) after treatment with the bispecific T-cell engager (BiTE), which resulted in MRD-negative disease in 70 of 86 of these patients. This was the first to use MRD as the basis for an approval.

“If a sponsor is planning to use an emerging endpoint in its clinical development program, we recommend discussing such use with the applicable FDA Division or Office prior to initiating a trial,” the guidance states.