Industry groups and professional organizations like the American Society of Clinical Oncology (ASCO) are calling on the US Food and Drug Administration (FDA) to clarify key definitions in its new draft guidance to industry on the agency’s framework for accelerated approval of neoadjuvant drugs for very high-risk breast cancers. 

The new framework promises to dramatically accelerate the drug-approval process for such treatments, theoretically allowing a single randomized clinical trial employing pathological complete response (pCR) as a surrogate endpoint to secure FDA approval for a new treatment.

Traditionally, the FDA has granted approvals for breast cancer drugs first for patients with metastatic disease, for whom standard therapies have already failed. Only after subsequent, long-term clinical studies aimed at reducing the mass of existing metastatic lesions, has the agency typically granted approval for a drug’s use among patients with earlier stages of malignancy. Indeed, despite widespread off-label administration of neoadjuvant systemic chemotherapies, the FDA has yet to approve such drugs for the preoperative treatment of breast cancer – prompting calls for a dramatic overhaul of the clinical trial system to improve oncologists’ toolkit for preventing metastasis in the first place.

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For an agency eager to accelerate the drug-approval process, neoadjuvant trials offer an appealing tool for hastening the expansion of officially-sanctioned drugs.

As the name suggests, these trials begin at the other end of a malignancy’s life history, testing agents expected to improve the probability of successful surgery for patients with early-stage, localized, but high-risk breast cancers prior to surgery. These trials typically employ pCR (the absence of pathologically-detected residual tumor cells in breast and lymph node tissue) as their primary surrogate endpoint — a strategy justified by evidence that pCR is predictive of disease-free and overall survival among breast cancer patients receiving neoadjuvant therapies. A 2007 Cochrane meta-analysis of data from 14 randomized trials showed, for example, that pCR is significantly associated with lower mortality rates than residual disease (HR 0.48 [95% CI: 0.33 – 0.69]; P<0.0001).

The FDA’s draft guidance spotlights the promise of pCR as a surrogate endpoint for early drug approvals, but critics say the agency must more-concretely define key terms like “large difference” — and even “pCR.”

References in the draft guidance for trials that would require a “large difference” in pCR rates to yield significant and “clinically meaningful” improvements in DFS (disease-free survival) and OS (overall survival), for example, have prompted requests by ASCO, the Biotechnology Industry Organization (BIO), and biotech giant Genentech, that the agency get more specific – and more realistic – about exactly what would qualify as a “large difference.”

Trastuzumab trials cited in the guidance nearly doubled pCR rates over those seen with chemotherapy alone, for example — setting the bar very high for what constitutes a “large” difference, critics worry.

The draft guidance’s definition of pCR “could benefit from additional details or reference(s) that define standards for surgical material, techniques, pathologic sampling methods, etc,” including “more technical details … to improve consistency and quality across multiple treatment centers,” wrote BIO’s managing director of science and regulatory affairs, Andrew Emmett, MPH, in comments submitted to the FDA, July 30. 

“In addition, it would be helpful to clarify the definition of ‘clinically meaningful’ differences in the context of this particular guidance on pCR,” Emmett wrote, noting that the phrase is used frequently throughout the draft guidance.

BIO and Genentech also both advocate adding regimen safety to the the draft guidance’s definition of “appropriate magnitude of benefit.”

The FDA is limiting the draft guidance to trials recruiting from very high-risk patient populations (ie, patients with triple-negative breast cancer), because the unknown toxicity profiles of new treatments are most justified among patients who are unlikely to benefit from approved therapies. But ASCO would like to see the agency explore the possibility of including trials for HER2-positive populations.

Others, including Emmett, even argued that the agency should consider surrogate endpoints for other life-threatening diseases, as well.

Even after more precise definitions are provided, however, intrinsic ambiguities will likely remain, others have cautioned. For any given drug, it will be difficult to predict what degree of pCR will yield “clinically meaningful” DFS or OS benefits – or what percentage of patients must achieve pCR to convincingly demonstrate an investigational drug’s “non-inferiority,” wrote Jose Perez-Garcia and Javier Cortes of the Breast Cancer Program, Vall d’Hebron Institute of Oncology, in Barcelona, Spain, in a recent commentary in The Lancet Oncology. Furthermore, toxicities may emerge after pCR, raising questions about the ability of regulators to take them into consideration during the draft regulatory framework’s early-approval process, they noted.

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