On May 26, the National Breast Cancer Coalition (NBCC) submitted public comments on proposed draft guidance from the U.S. Food and Drug Administration (FDA) to sponsors of anti-cancer drugs or biological products on considerations for designing trials intended to support accelerated approval.
NBCC is an evidence-based patient advocacy organization with a mission to end breast cancer. Since its inception, NBCC has set a legislative and public policy agenda that supports that mission. The FDA plays a vital role in ending breast cancer and saving lives. We need an FDA that approves drugs with clinically meaningful benefits for patients. Among a number of health policy topics we pursue, NBCC seeks to address systemic deficiencies in FDA regulation of the drug and biologic approval process, including accelerated approval, that keep us from achieving our mission.
While we appreciate the draft guidance that FDA has outlined regarding study designs for accelerated approval of new cancer treatments, we have several key concerns that we believe must be addressed. We also believe it is imperative to keep in mind the rationale for the accelerated approval program. This program is not meant to help sponsors get their drugs to the market faster. Rather, its sole purpose is to advance promising drugs to patients with life-threatening conditions, in this case, terminal cancer, where there is an unmet need, and the drugs have the potential to lengthen or improve patients’ lives. In addition to providing guidance on preferred study designs, FDA should also define “unmet need” and provide guidance to sponsors on when the use of this pathway is appropriate. We are quickly getting to a point where most cancer drugs come to the market through this pathway.
CONCERN #1: Progression-Free Survival as a Clinical Endpoint.
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NBCC strongly opposes the inclusion of “progression-free survival” (PFS) as an acceptable clinical endpoint for the conversion of accelerated approval to regular approval as currently written in the draft guidance.
PFS is not a measure of clinical benefit for a patient and frankly is a term that misleads the public about survival benefits by virtue of its name.[i] PFS represents the time from randomization or the initiation of treatment to measurable (typically by radiographic measurement in solid tumors) disease progression or death. Progression is defined by the Response Evaluation Criteria in Solid Tumors as an increase in the sum of maximum tumor diameters of at least 20%, the development of any new lesions, or an unequivocal increase in non-measurable malignant disease.[ii] PFS was originally developed to support the advancement of drugs in Phase 2 clinical trials to Phase 3 testing and is not a measure of clinical benefit: how a patient feels, functions, or survives. PFS is also subject to various forms of bias (e.g., informative censoring[iii],[iv] and intermittent assessment of progression bias[v]). Despite this, its use as an endpoint for regulatory approval of cancer drugs is extensive.
Surrogate endpoints like PFS have been permitted by the FDA if they have demonstrated in validation studies that they are strongly correlated with a true measure of clinical benefit such as overall survival. And yet, PFS has routinely failed to demonstrate a strong correlation with overall survival in validation studies across many different cancer types [vi], [vii] and in breast cancer studies specifically[viii],. Furthermore, in breast cancer, there are many distinct subtypes as well as numerous drug and biological treatment modalities (e.g., cytotoxic, hormonal, immunotherapies, molecular inhibitors, and others) and complex combinations thereof. While PFS may be validated in some limited scenarios, it should not be allowed for general use across cancer clinical trials as indicated by the current draft guidance. Studies have demonstrated variable associations between PFS and OS in different disease contexts,[ix] specifically in breast cancer, again supporting our concern about the use of PFS broadly as an acceptable endpoint.
According to FDA’s own public guidance on endpoints for cancer clinical trials, the use of PFS either as a surrogate endpoint for accelerated approval or as an endpoint for traditional approval depends on the disease context and the magnitude of the effect, among other factors. As such, the FDA’s broad application of PFS in an extremely heterogeneous cancer such as breast cancer (and many others) as an acceptable endpoint for regular approval[x] is not justified. Patients deserve either a true clinical endpoint or a truly validated surrogate endpoint. Importantly, the evidence supporting the validation of a surrogate endpoint in a given context should be cited and made available to the public.
CONCERN #2: Power of Trials.
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Regarding trial sample size, and in consideration of NBCC CONCERN #1 noted above, we request the FDA require study sample sizes to provide adequate power to detect clinically meaningful improvements in overall survival, for both the “2-clinical trial” (specifically in the confirmatory trial) and the “single trial” study designs preferred by FDA. Most current clinical trials of cancer drugs are powered specifically for time-to-event endpoints like PFS which require smaller sample sizes, so even when overall survival is included as a secondary or co-primary endpoint, the power of the trial is often insufficient to assess clinically relevant endpoints like overall survival. In NBCC’s opinion, these are uninformative trials. The public deserves to know if a drug that is ultimately made available on the market provides real clinical benefit.
CONCERN #3: Educated Patient Advocate Involvement.
The current guidance offers no recommendations for sponsors on partnering with educated and trained patient advocates and advocacy groups in their clinical trial design and implementation process. The educated patient voice is imperative to ensuring that trials are being designed to bring new treatments forward that will address patients’ goals and values, particularly for terminal illness and unmet need, which is the only setting in which accelerated approval should be employed.
We are all desperate to find interventions that will save lives or significantly prolong lives without reducing the quality of life. We should not accept anything less than real, high-level evidence that approved treatments actually do this. That would be progress. We should not redefine progress to include what is possible in the short term, rather than what is meaningful.
[i] Gyawali B, Eisenhauer E, Tregear M, Booth CM. Progression-free survival: it is time for a new name. Lancet Oncol. 2022 Mar;23(3):328-330. doi: 10.1016/S1470-2045(22)00015-8. PMID: 35240080.
[ii] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–47
[iii] Gilboa S, Pras Y, Mataraso A, Bomze D, Markel G, Meirson T. Informative censoring of surrogate end-point data in phase 3 oncology trials. Eur J Cancer. 2021 Aug;153:190-202. doi: 10.1016/j.ejca.2021.04.044. Epub 2021 Jun 26. PMID: 34186504.
[iv] Templeton AJ, Amir E, Tannock IF. Informative censoring – a neglected cause of bias in oncology trials. Nat Rev Clin Oncol. 2020 Jun;17(6):327-328. doi: 10.1038/s41571-020-0368-0. PMID: 32273582.
[v] Zeng L, Cook RJ, Wen L, Boruvka A. Bias in progression-free survival analysis due to intermittent assessment of progression. Stat Med. 2015 Oct 30;34(24):3181-93. doi: 10.1002/sim.6529. Epub 2015 May 24. PMID: 26011411; PMCID: PMC4744753.
[vi] Belin L, Tan A, De Rycke Y, Dechartres A. Progression-free survival as a surrogate for overall survival in oncology trials: a methodological systematic review. Br J Cancer. 2020 May;122(11):1707-1714. doi: 10.1038/s41416-020-0805-y. Epub 2020 Mar 26. PMID: 32214230; PMCID: PMC7250908.
[vii] Haslam A, Hey SP, Gill J, Prasad V. A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology. Eur J Cancer. 2019 Jan;106:196-211. doi: 10.1016/j.ejca.2018.11.012. Epub 2018 Dec 5. PMID: 30528804.
[viii] Gyawali B, Hey SP, Kesselheim AS. Evaluating the evidence behind the surrogate measures included in the FDA’s table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine. 2020 Apr 13;21:100332. doi: 10.1016/j.eclinm.2020.100332. PMID: 32382717; PMCID: PMC7201012.
[ix] Courtinard C, Gourgou S, Jacot W, Carton M, Guérin O, Vacher L, Bertaut A, Le Deley MC, Pérol D, Marino P, Levy C, Uwer L, Perrocheau G, Schiappa R, Bachelot F, Parent D, Breton M, Petit T, Filleron T, Loeb A, Pélissier SM, Robain M, Delaloge S, Bellera C. Association between progression-free survival and overall survival in women receiving first-line treatment for metastatic breast cancer: evidence from the ESME real-world database. BMC Med. 2023 Mar 8;21(1):87. doi: 10.1186/s12916-023-02754-5. PMID: 36882736; PMCID: PMC9993797.
[x] Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure | FDA (Accessed 5/24/2023)
