Expedited Approval Is Successful for Cancer Therapies, FDA Says

Reviewing 25 years of experience with accelerated approvals (AAs) for malignant hematology and oncology drugs and biologics, FDA officials say that the AA program has demonstrated that it can be used successfully to expedite approval of safe, effective cancer therapies that balance uncertainty with the need to provide faster access to promising agents for serious and life-threatening diseases.

The findings come from a paper—authored by professionals from the FDA’s Office of Hematology and Oncology Products, Office of Translational Services, Center for Drug Evaluation and Research, and the Oncology Center for Excellence—newly published in JAMA Oncology.

Prior to 1992, when an accelerated approval pathway was added to federal regulations in response to the HIV crisis, regular approval was the only way drugs could gain the FDA’s authorization. Today, to qualify for the AA pathway, drug and biologic products must demonstrate either an effect on an endpoint that is likely to produce a clinical benefit or an endpoint that can be measured earlier than irreversible morbidity or mortality, and that show an ability to provide a meaningful advantage over existing treatment options. Drugs approved under this program are further studied in post-approval trials to verify their clinical benefit.

The new paper reports on all drugs approved under this pathway between December 1992 and May 2017. The 64 malignant hematology and oncology drugs approved for 93 indications during this time period include pembrolizumab (Keytruda) for melanoma and non—small cell lung cancer indications, cetuximab (Erbitux) for metastatic colorectal cancer, and palbociclib (Ibrance) for metastatic breast cancer.

Randomized comparative trials supported the AA pathway in 26 of these indications. Among these trials, 13 were supported by a primary endpoint of response rate (RR), 7 had an endpoint of progression-free survival (PFS), 4 had disease-free survival, 1 had time to progression, and 1 had pathologic complete response. Single-arm trials accounted for 67 of the indications, and all had RR as the primary endpoint. Trials supporting an AA had a median efficacy population of 143 patients (range, 17-9366).

Of the 93 AA indications, 51 have now fulfilled their postmarketing requirements and have verified their benefit, with a median time to verification of 3.4 years (range, 0.5-12.6 years). Thirty-seven indications have not yet completed confirmatory trials or verified their benefit, and the median time from approval to the data cut-off for drugs not yet verified was less than 18.5 months (range, 1 month-12.4 years).

According to the authors, “The benefit of having the postmarketing trial actively accruing at the time of AA is illustrated by the more than 2-year median difference in confirmatory trial completion and verification of benefit for indications that had confirmatory trials under way compared with those that did not.”

Responding to criticism that endpoints should have improvement in overall survival (OS) or health-related quality of life, the authors say that the feasibility of these endpoints can be problematic, and that the complexity of FDA regulation can be difficult to convey to the public: “Oncology is a unique therapeutic area because our most common AA end points (RR and PFS) reflect direct measures of the disease and have been considered suitable for regular approval or AA depending on the magnitude of effect, safety profile, and disease context.” They add that, for some drugs, requiring OS as an endpoint might be unethical. “It is unlikely that patients would participate in a trial in which they could be randomized to the control arm without the opportunity to cross over to investigational therapy on disease progression,” write the authors. They add that, in terms of safety data, while the FDA generally has fewer safety data at the time of an AA than a drug granted regular approval, on average, there are approximately twice as many data available on safety than on efficacy for these drugs.

The review cautions that “AA brings products to the market years before confirmatory trials are typically completed. The time on the market before verification reflects earlier access to safe and effective cancer drugs but also may reflect the period during which an ineffective drug may be marketed,” but say that the time interval between approval and verification of these drugs is an “accepted tradeoff” for the value of the program.

Reference

Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review [ublished online March 1, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2017.5618.