The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.” BIO commends FDA on releasing this Draft Guidance, which will help to develop life-saving medicines for patients with high-risk early-stage breast cancer.
BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.
BIO was pleased to see Agency highlight this particular Guidance in the FDA report on Driving Biomedical Innovation (October 2011) as an example of “a relatively seamless pathway that could be followed from a multi-drug screening trial such as I-SPY 2 to an Accelerated Approval” to speed the availability of targeted therapies for breast cancer. BIO appreciates the thought and consideration that FDA has placed into this Guidance and accompanying New England Journal of Medicine article (Prowell & Pazdur, June 2012). In general, the Draft Guidance is helpful and well constructed, providing thorough guidelines on the use of pathologic complete response (pCR) as an endpoint to support Accelerated Approval.
A. BIO Appreciates FDA’s Efforts to Develop and Broaden Surrogate Endpoints for Unmet Medical Needs
We hope that FDA considers expanding the use of pCR as a surrogate endpoint to a broader population. Under the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA, P.L. 112-144), Congress encouraged FDA to “utilize innovative and flexible approaches to the assessment of products under Accelerated Approval for treatments for patients with serious or life-threatening diseases or conditions and unmet medical needs” and to “establish a program to encourage the development of surrogate and clinical endpoints, including biomarkers, and other scientific methods and tools.” (§ 901) The development of this Draft Guidance is an excellent example of FDA and the scientific community working together in the spirit of collaboration and improved patient outcomes to expedite the development of the next generation of therapies for devastating illnesses. BIO and the biotechnology industry look forward to supporting and contributing to FDA’s efforts to identify and develop additional surrogate and intermediate clinical endpoints that can expand the Accelerated Approval pathway to encompass a broader array of life-threatening diseases and conditions.
B. Definition of pCR:
Under the Draft Guidance, “Pathologic complete response (pCR) is defined 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 (i.e., ypT0 ypN0 in the current AJCC staging system).” (lines 154-157)
We agree with this definition of pCR, and agree that residual in situ carcinoma (ductal carcinoma in situ(DCIS)or lobular carcinoma in situ(LCIS)) should not be used to judge the efficacy of neoadjuvant therapy. However, we believe the staging criteria for pCR should be ypT0/is ypN0 — not ypT0 ypN0, as is currently stated in the Guidance.
Further, the pCR definition could benefit from additional details or reference(s) that define standards for surgical material, techniques, pathologic sampling methods, etc. Recent efforts to evaluate pCR from I-SPY are conducted in major U.S. centers where these features are fairly well established, so the I-SPY examples likely do not require detailed descriptions, given shared working practices among U.S. surgical oncologists. To enroll larger numbers for disease-free-survival (DFS) / overall survival (OS)endpoints, new sites, including many outside the U.S. will likely need to participate, and the larger number of sites may introduce more variation in working practices, quality, and technical approaches such as time to fixation that can impact marker readout. Thus, more technical details may be of value in this guidance, possibly including specific references from publications designed to improve consistency and quality across multiple treatment centers.,
C. Additional Considerations should be Evaluated for Ex-U.S. Registration Trials
The I-SPY achievements represent major contributions to academic medicine and demonstrate that experienced U.S. centers could participate in multicenter, randomized neoadjuvant protocols to generate efficacy signals by pCR leading to quality publications. A pivotal protocol would likely require expansion by industry Sponsors to include ex-U.S. centers. Thus, the Guidance would likely benefit from additional considerations for marketing approval that may not be sufficiently described in this Draft Guidance.
D. Other “High-Risk” Settings may be Appropriate
Additionally, there is a risk that the document focuses too much on triple-negative disease as the setting in which Accelerated Approval can be contemplated. While we recognize that the draft does indicate “high-risk” disease, it should be emphasized that triple-negative is only an example and that other settings may be appropriate. The data today may not reflect the state of science in five years, so we encourage an appropriate level of flexibility in FDA’s guidelines.
E. Interim Analyses may be Appropriate
Finally, the Draft Guidance points out, correctly, that a much larger sample size is required to verify benefit in DFS/OS than pCR. The Draft Guidance suggests a seamless design with one study designed to give both endpoints and no interim analysis of pCR except for a futility analysis. Thus, the Sponsor is required to commit to enrolling the larger sample size without knowing whether the experimental agent is effective based on PCR.
Sponsors may be unwilling to invest in the large trial sample size without supportive clinical data. One large and potentially long study with only a futility analysis provides limited information about the potential benefit/risk profile of the product during, what is essentially, early development. An interim analysis would allow for this.
We suggest the Guidance also allow an initial study (or sub-study) sized for evaluating pCR only, and then either a second study or an expansion of the first to evaluate to DFS/OS if the pCR endpoint is positive.
BIO appreciates this opportunity to comment on the “Draft Guidance for Industry on Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.
Hammond ME et al, American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version), Arch Pathol Lab Med.2010 Jul; 134(7):e48-72;
Hicks DG et al, Breast cancer predictive factor testing: the challenges and importance of standardizing tissue handling. J Natl Cancer Inst Monogr.2011; 2011(42):43-45)