FDA Guidance on Surrogate Endpoints Lacks Specificity

Not a Perfect System

Dr Gyawali acknowledged that his study looked at correlation studies only and that the validity of any surrogate endpoint could change at any time with the introduction of new trial data. This potential for constant change further supports the need for a database that could house information and allow for updates on trials that prove or disprove surrogate endpoint correlation.

Dr Bardia agreed that the validity of surrogates could change with the revelation of new data. Surrogate endpoints, he said, are just that: surrogates.

“In the neoadjuvant setting, the safety profile of therapy is a very important consideration,as it is in the curative setting. In addition, it is important to consider breast cancer subtype, degree of improvement in pathologic complete response, [and] available adjuvant therapy options — all of which could impact the relationship between pathologic complete response and recurrence-free survival,” Dr Bardia said.

At the end of the day, we want to provide the best therapies to our patients and need to carefully weigh the risk/benefit profile, Dr Bardia added.

The idea that companies can get accelerated approval and go on to conduct confirmatory trials has been done successfully, with pertuzumab in HER2-positive disease, for example, Dr Yee said.

“There are very clearly women who have benefited in the neoadjuvant setting — that if we had had to wait for full approval to get more data, would have been denied access to that drug,” Dr Yee said. “On the flip side, we do have to examine whether women have been harmed with accelerated approval of drugs — but in [operable] breast cancer, that has not been the case so far.”

Disclosures: Dr Bardia has been a consultant or served on the advisory board of Novartis, Pfizer, Daiichi Sankyo/AstraZeneca, PUMA, Sanofi, Genentech/Roche, Radius Health, Merck, Immunomedics, Phillips, and Foundation Medicine. He has received research funding from Biothernostics, Novartis, Pfizer, Sanofi, Genentech/Roche, Radius Health, Merck, and Immunomedics.

Dr Gyawali had no conflicts of interest.

Dr Yee has been a consultant or served on an advisory board of PUMA, Lilly, NanoString Technologies, Apogen, and Martell Diagnostics. He has received research funding from Merck & Co., Inc., and Boehringer Ingelheim.

References

1. US Food and Drug Administration. Table of surrogate endpoints that were the basis of drug approval or licensure. Updated March 17, Accessed April 9, 2020.
2. US Food and Drug Administration. Accelerated Approval Program. Updated March 10, 2016. Accessed April 9, 2020.
3. Gyawali B, Phillips S, Kesselheim AS. Assessment of the clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med. 2019;179(7):906-913.
4. Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176.
5. 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. doi: 10.1016/j.eclinm.2020.100332
6. Quantum Leap Healthcare Collaborative. The I-SPY Trials. Long-term efficacy results from the I-SPY 2 TRIAL indicate pathological complete response (pCR) is a powerful predictor for breast cancer survival [press release]. Published December 7, 2017. Accessed April 9, 2020.
7. Spring L, Greenup R, Niemierko A, et al. Pathologic complete response after neoadjuvant chemotherapy and long-term outcomes among young women with breast cancer. J Natl Compr Canc Netw. 2017;15(10):1216-1223.