One of the tools frequently mentioned by the FDA is the PRO-CTCAE, which was developed by the NCI for measuring patient-reported symptomatic adverse events in cancer trials. This tool is increasingly used in industry trials, and the FDA has been evaluating approaches for showing PRO-CTCAE results in labels. Otherwise, the FDA is focusing more on recommending PRO methodology than specific instruments or tools. The agency previously released guidance for the use of PRO measures in labeling claims. (Dr Basch anticipates updated guidance from the FDA within the coming year or 2.)
A recent analysis of PRO data inclusion in FDA submissions between 2007 and 2017 found that while most trials submitted to the FDA that provided PRO information, that information tended to be completed at similar rates between study arms.4,5 But when large differences in PRO information completeness did exist between study arms, those tended to favor the experimental arm and were more common in open-label than double-blind clinical trials, the authors found.5
The SISAQOL Consortium, based in Europe, also includes American pharmaceutical researchers and representatives from the FDA and NCI, Dr Basch noted. “They are developing standardized statistical analytic techniques for PROs in trials,” he said.
In the context of recent controversies about the use of surrogate end points such as progression-free survival (PFS) rather than overall survival for regulatory approvals, it is not yet clear to what extent PROs will be used in drug-approval applications when overall survival data are unavailable or unconvincing.
“I do think what we will start seeing is PROs paired with another trial outcome that is not [overall] survival to try to approve a drug,” he acknowledged. “For example, PFS plus symptomatic improvement, or biomarkers and radiographic change — and PROs, together.”
Drug developers will point to biomarker or imaging evidence that the drug is impacting tumor progression and that it’s improving how patients feel and function, he explained.
“I don’t think that that would replace overall survival but I think that we know that there are many cases where survival just isn’t a feasible or practical end point for a trial, so I think having these kinds of end points are going to be really beneficial for sponsors because it will accelerate development,” he said.
Indeed, in the past, oncology drugs have been approved based on benefits to patients outside of survival, Dr Basch noted.
“Mitoxantrone is a cytotoxic chemotherapy that was fully approved for metastatic prostate cancer based on improvement of pain with no improvement in overall survival,” he said. “That drug has been replaced by newer products and isn’t used that much anymore. But it was the first chemotherapy approved by the FDA on that basis. There needs to be a net win for the patient. Jakafi is another drug that was approved, in myelofibrosis, based on reduction in spleen size and improvement in disease-related symptoms [as] measured by PROs”
“I don’t think that we want to be approving toxic analgesics, but if a drug is improving how our patients feel, then the FDA has been very clear that PROs could be the basis for full approval with no [overall] survival benefit,” he said.
- Basch E. Patient-reported outcomes: an essential component of oncology drug development and regulatory review. Lancet Oncol. 2018;19(5):595-597.
- Kluetz PG, O’Connor DJ, Soltys K. Incorporating the patient experience into regulatory decision making in the USA, Europe, and Canada. Lancet Oncol. 2018;19(5):e267-e274.
- Goldberg KB, Blumenthal GM, McKee AE, Pazdur R. The FDA Oncology Center of Excellence and precision medicine. Exp Biol Med (Maywood). 2018;243(3):308-312.
- Basch E. High compliance rates with patient-reported outcomes in oncology trials submitted to the US Food and Drug Administration. JNCI. 2019;111(5):djy183.
- Roydhouse JK, King-Kallimanis BL, Howie LJ, Singh H, Kleutz PG. Blinding and patient-reported outcome completion rates in US Food and Drug Administration cancer trial submissions, 2007-2017. JNCI. 2019;111(5):djy181.