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FDA releases draft guidance on pCR as potential endpoint for breast cancer drugs
The FDA recently issued draft guidance intended to help manufacturers of breast cancer drugs design clinical trials that use pathologic complete response as a potential endpoint.
The goal is to allow manufacturers to use pathologic complete response (pCR) to support accelerated approval of drugs for neoadjuvant treatment of early-stage breast cancer.
Accelerated approval regulations currently require confirmation of a clinical benefit, such as DFS or OS. The ability to use pCR as an endpoint could allow potential clinical benefits of investigational drugs to be determined much quicker, allowing treatments to come on the market up to a decade earlier.
“Despite advances in systemic therapy of early-stage breast cancer over the past few decades, there remains a significant unmet medical need for certain high-risk or poor prognosis populations of early-stage breast cancer patients,” the FDA wrote. “This guidance is intended to encourage industry innovation and expedite the development of breakthrough therapies to treat high-risk early-stage breast cancer.”
Tatiana Prowell, MD, medical officer for the breast oncology group in the FDA’s division of oncology products, described the FDA’s ideal study design for trials supporting accelerated approval.
“Our preferred design would be an add-on design in which standard adjuvant therapy is given, to which an investigational agent is added and compared with standard therapy,” Prowell said at a press conference. “Potentially, a placebo would be added if the toxicity does not unblind the trial.”
Prowell recommended that all studies supporting accelerated approval be randomized control trials. Patients at high-risk for recurrence and death despite systemic therapy are preferred for this pathway.
“It is important to note that … a single trial could potentially support both accelerated and regular approval if adequately powered to detect a statistically meaningful improvement in either DFS or OS endpoints,” Prowell said.
Although neoadjuvant therapy is increasingly common in early-stage breast cancer patients, the FDA had been concerned about considering pCR as an appropriate primary endpoint. The lack of a standard definition of pCR had made it difficult for researchers to report and interpret data from neoadjuvant trials, according to the draft guidance.
For its purposes, the FDA defined pCR as “the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy.”
“[pCR] has been defined in a number of different ways by investigators in different trials,” Patricia Cortazor, MD, clinical team leader for the breast oncology group in the division of oncology products, said during the press conference. “We felt for regulatory purposes it was important to have a uniform definition that best predicted long-term clinical outcomes.”
For more information:
- Guidance for industry. Pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: Use as an endpoint to support accelerated approval. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf. Accessed on July 9, 2012.