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FDA Expected to Approve Surrogate End Point for Neoadjuvant Breast Cancer Trials

TON - July 2013 Vol 6 No 6 published on July 29, 2013 in FDA Updates
Caroline Helwick

For years, the cancer research community has pushed for the use of surrogate end points in clinical trials as a means of hastening the drug approval process. These efforts will soon bear fruit, with the release by the US Food and Drug Administration (FDA) of its final guidance for accelerated drug approval in the neoadjuvant breast cancer treatment setting. At the 2013 American Society of Clinical Oncology Annual Meeting, the speakers discussed the potential implications for researchers, providers, and patients.

Under the new guidance for the pharmaceutical industry, accelerated approval could be granted based on a surrogate end point that predicts clinical benefit; accelerated approval would require subsequent confirmation in a clinical trial.

For neoadjuvant breast cancer, this end point would likely be pathologic complete response (pCR) rate. The achievement of a pCR has been associated with superior outcomes in multiple studies, but the correlation needs further validation, said Tatiana M. Prowell, MD, medical officer for the Breast Oncology Group at the FDA, and assistant professor at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

While pCR will most likely be the surrogate end point, other outcomes have been studied in patients with breast cancer, including tumor response on imaging, measurement of the tumor proliferation marker Ki-67, preoperative endocrine prognostic index (PEPI), and residual cancer burden after treatment.

Faster Approval of Drugs to Most Benefit High-Risk Patients

The traditional drug approval process averages 10 to 15 years. The goal of accelerated approval is to provide early access to effective drugs and to provide incentives for developing drugs for particular breast cancer subtypes with unmet needs.

Under the new approval process, a single trial or a short-duration trial would be appropriate for accelerated approval and a simultaneous longer trial would be conducted to support “regular” approval, according to speakers at the “Pushing the Limits of Upfront Care and Drug Development: Neoadjuvant Opportunities in Breast Cancer” session.

The use of pCR to support accelerated approval is appropriate “for highly promising drugs and high-risk patient populations,” Prowell maintained.

Session Chair Angela DeMichele, MD, of the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, noted there is a “fertile environment” for new drug development in the neoadjuvant breast cancer treatment setting, as the many benefits of neoadjuvant therapy are now established.

Moving clinical trials from the adjuvant to the neoadjuvant setting can yield important information about the drugs that are under evaluation, such as the ability of pharmacodynamic markers to provide in vivo evidence of biologic effects. But most importantly, they should identify active agents faster, which serves patients, DeMichele said.
She emphasized that surrogate markers must be robust, ie, reproducible and standardized, and their correlation with the true end point (such as overall survival) must be more than a simple “correlation.” In this case, pCR must be strictly defined as the elimination of all invasive and noninvasive disease in the breast and lymph nodes, rather than a “looser” definition. Its relationship with the final end point can be assured only through long-term follow-up of patients, she added.

DeMichele also proposed that pCR may not be a valid surrogate end point for every breast cancer. While it may be appropriate for human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, and highly proliferative estrogen receptor (ER)-positive disease, it may not be a good surrogate for low-proliferation ER-positive tumors. At present, she believes Ki-67 is the best surrogate for the latter, though it is not perfect. Better surrogates are needed for this subset, she said.

DeMichele A. Pushing the limits of upfront care and drug development: neoadjuvant opportunities in breast cancer. Presented at: 2013 Annual Meeting of the American Society of Clinical Oncology; June 1, 2013; Chicago, IL. Education Session.

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Last modified: April 27, 2020