Accelerated Approval & Early-Stage Breast Cancer

In a draft guidance issued last week, the FDA has proposed allowing drugmakers to test medications for only a few months on women who suffer from highly aggressive breast cancers before undergoing surgery, instead of waiting until a drug has shown evidence of offering improvement to patients who are very ill. The new approach would be part of the accelerated approval program.

"We're looking at introducing drugs into a very early stage of breast cancer, where a patient has a primary tumor and the chemotherapy is given before surgery," Richard Pazdur,who heads the FDA Office of Hematology and Oncology Products, tells Reuters at the American Society of Clinical Oncology meeting this week. "The aim of this therapy would be to cure the woman of breast cancer. It's moving a very promising drug into a early stage of the disease with a curative intent."

A drugmaker would have to demonstrate that its treatment eradicated cancer to the point whether there is no indication in the breast or lymph nodes, which the agency describes as pathologic complete response, or pCR. Currently, drugs are tested in earlier stage cancers only after demonstrating evidence of safety and effectiveness in advanced, metastatic breast cancer (here is the guidance).

"We believe that the definition of pCR proposed in this guidance has the greatest likelihood of predicting clinical benefit for regulatory purposes in patients with early-stage breast cancer who achieve pCR following (preoperative) systemic therapy," the FDA writes. "...We believe that use of pCR as an endpoint to support accelerated approval in high-risk populations in the neoadjuvant setting has the potential to help address unmet need in these populations in a far shorter time frame than would be required via the conventional approach to breast cancer drug development."

A Cochrane meta-analysis of 5500 patients enrolled in 14 randomized trials comparing preoperative with postoperative chemotherapy showed that the risk of death among patients who had a pCR was about half that of patients with residual tumor at the time of surgery, Pazdur and Tatiana Prowell, a cancer specialist at Johns Hopkins in Baltimore and an FDA medical officer, wrote in The New England Journal of Medicine (read here).

There are safety issues, though, since this new approach will expose women to drugs that, unlike the current approach, have not been administered to thousands of patients. And so, the FDA suggests restricting the pCR to women who have so-called triple-negative breast cancers, which is particularly deadly. These generally grow and spread more quickly than most other types of breast cancer, Reuters notes.

"This is not for every patient. It should be for patients that are most likely to benefit and also those that are at highest risk of having a recurrence of the disease," Pazdur tells Reuters. Clinical trials would be designed so that women are treated with either chemotherapy or chemotherapy plus an experimental drug for a few months prior to surgery. If no sign of the cancer is found during surgery, the woman has achieved a complete pathological response.

Researchers would then compare response rates in the two groups, and if the drug has helped cure significantly more cancers, it would be given accelerated approval. Drugmakers would have to follow women for several years to determine if cancer recurs. If patients are considered free of disease, then full approval would be granted, Reuters writes.

And to limit the risk that this new approach may lead to ineffective treatments remaining on the market for a prolonged period of time, the FDA suggests limiting randomized, preoperative trials that are conducted with "marketing intent" to subpopulations who are at a high risk for recurring breast cancer, and that confirmatory trials should be ongoing at the time of accelerated approval," Pazdur and Prowell wrote in the New England Journal of Medicine.

And even after accelerated approval is granted, a drugmaker would have to demonstrate an improvement in disease-free or overall survival or the FDA has the right to withdraw the indication from product labeling if confirmatory trials have not shown a clinical benefit.