A new final guidance document issued by the US Food and Drug Administration (FDA) outlines the processes by which the regulator will accept surrogate endpoints to support the accelerated approval of treatments intended for high-risk early-stage breast cancer.
Under normal circumstances, FDA requires "substantial evidence"—generally two Phase III clinical trials—indicating that a product is safe and effective at treating, preventing or curing a given condition.
However, for serious conditions such as terminal or aggressive cancers, FDA is sometimes willing to accept less substantial evidence based on "surrogate" endpoints, which in turn can support "accelerated" approvals.
As explained in FDA's June 2013 guidance, Expedited Programs for Serious Conditions - Drugs and Biologics, FDA is permitted to grant accelerated approval to:
a product for a serious or life-threatening disease or condition . . . upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
In other words: If a disease or condition is serious enough, FDA will permit a product to enter the market based on incomplete (but "reasonable") evidence while the results of a full trial are forthcoming. If the final evidence does not support clinical benefit or safety, such as in the case of Avastin for certain forms of breast cancer, FDA can also rescind approval.
Treatments must also demonstrate a "meaningful therapeutic benefit over existing treatments," making the use of the accelerated approval pathway relatively uncommon compared to other accelerated approval methods, including Fast Track designation and Priority Review designation.
Thinking About Surrogate Endpoints
But what constitutes an effective surrogate endpoint will vary wildly depending upon the disease or condition being studied. Even among different types of cancer, FDA accepts many different types of endpoints.
One such endpoint, used in breast cancer, is known as "pathologic complete response," or pCR. Though a standard definition for pCR is contested, it is generally either defined as the absence of all detectable cancer cells, or the absence of invasive cancer cells in a patient. Previous studies have indicated that a pCR response after neoadjuvant therapy in early-stage breast cancer was a powerful indicator for future survival. "A Cochrane meta-analysis of 14 trials of preoperative versus postoperative chemotherapy enrolling 5,500 patients with a median follow-up of 18 to 124 months reported that the risk of death in patients who attained pCR was reduced by almost half compared with patients who had residual tumor present at the time of surgery," FDA noted.
With those results in mind, for years researchers have been looking into the use of pCR as a surrogate endpoint for breast cancer. "pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors," wrote the authors of one study published in the May 2012 issue of the Journal of Clinical Oncology. Results from another January 2014 study generated similar findings.
And in FDA's latest guidance document, Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint To Support Accelerated Approval, the agency seems to agree with the results of those studies.
For neoadjuvant therapies—i.e. pre-operative therapy—FDA said it will accept either of two definitions of pCR as surrogate endpoints:
- Pathological complete response (pCR) is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the current AJCC staging system)
- Pathological complete response (pCR) is defined as the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 in the current AJCC staging system)
Both definitions represent an "evolving paradigm," FDA said, but were nevertheless associated with significant "prognostic value" in patients.
This should substantially benefit companies developing neoadjuvant therapies, FDA explained.
"Existing adjuvant therapy for breast cancer will effectively delay or eliminate recurrence for many patients so that large sample sizes and prolonged follow-up in randomized trials are needed to demonstrate a difference in DFS or OS adequate to support drug approval in the adjuvant setting," the regulator said. "As a result, the time from initiation of a phase 3 trial of a drug in metastatic breast cancer to approval for its use in an adjuvant population has historically been a decade or more."
In other words, neoadjuvant therapies are often victims of their own success, as generating overall survival (OS) and disease-free survival (DFS) data can prove difficult.
No longer. Under FDA's guidance, companies can use pCR as a surrogate endpoint in support of accelerated approval so long as they adhere to acceptable designs for their clinical trials. For example, FDA wants trials to support a finding of superiority over existing regimens—a key component of the accelerated approval pathway.
The guidance contains extensive recommendations regarding the appropriate design of clinical trials in support of accelerated approval.
Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint To Support Accelerated Approval
Federal Register Notice
More from BioCentury