With Accelerated Approval Pathway, Risk of Withdrawal Looms

MHE Publication, MHE July 2021, Volume 31, Issue 7

The FDA’s accelerated pathway gets drugs to market quickly, but it also can mean patients are put on therapies that do not actually provide a clinical benefit.

For many patients a cancer diagnosis can feel like the start of a timer. When will the test results come back? How quickly can I initiate therapy? How long do I have to live?

In some types of cancer, the timer feels especially short. Donna R. Cryer, J.D., president and CEO of the Global Liver Institute, says many patients with liver cancer already have advanced disease by the time they are diagnosed.

“There’s a very short time frame to be able to utilize any (treatment) option, let alone be able to find the best option,” Cryer says.

The number of treatment options has been growing, thanks in part to the creation of the Accelerated Approval Program at the FDA in 1992. As revised in 2012, it allows the agency to approve therapies based on “surrogate end points” that are, as the name suggests, substitutes for clinical outcomes, although they are supposed to correlate with them. The pathway is restricted to therapies that treat serious conditions and fill unmet medical needs.

But while accelerated approval helps speed beneficial therapies to market, it also has led to withdrawals of therapies that hit the market and then were shown to have no clinical benefit after further study.

In April, the FDA’s Oncology Drugs Advisory Committee recommended the withdrawal of indications for two therapies: Opdivo (nivolumab) for patients with hepatocellular carcinoma who had previously been treated with Nexavar (sorafenib), and Keytruda (pembrolizumab) for patients with metastatic gastric or gastroesophageal junction adenocarcinoma who had already tried two lines of therapy and whose tumors express PD-L1.

But the wave of withdrawals had already started. In February, AstraZeneca withdrew the indication for Imfinzi (durvalumab) as a treatment for previously treated locally advanced or metastatic bladder cancer in adults. In March, Genentech said it was withdrawing the indication for Tecentriq (atezolizumab) as a treatment for metastatic urothelial carcinoma that had previously been treated with platinum-based chemotherapy agents, and Merck withdrew Keytruda’s indication as a treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

Andrew Powaleny, a spokesperson for the trade group Pharmaceutical Research and Manufacturers of America, says the pathway has worked well, noting that therapies approved under the program “must meet the same standards of safety and efficacy for approval as all other medicines.” If a drug cannot prove its worth in confirmatory trials, he noted, they risk losing the indication.

Critics of accelerated approval say the problem is that the drug companies have been slow to produce data from confirmatory trials. In a report released in April, the Institute for Clinical and Economic Review, a drug-pricing think tank based in Boston, said the pathway’s performance has been mixed. “Although the FDA can fine companies or withdraw approval to penalize noncompliance with postmarketing requirements, it acts with significant restraint in deploying these measures,” the report stated. ICER pointed to Sarepta Therapeutics’ Exondys 51 (eteplirsen), a high-cost therapy for Duchenne muscular dystrophy, as an example. It was given accelerated approval in five years. Some private insurers have refused to cover the drug because of doubts about its efficacy. As of the April report, the company had yet to produce confirmatory data; the FDA has set a 2021 deadline for it to do so.

Philosophies vary as to when and why the FDA should withdraw indications and whether it should err on the side of safety or on the side of patient access. Cryer, who advocated for Opdivo’s continued use as a treatment for hepatocellular carcinoma, said she was “incredibly disappointed” by the decision, which she felt did not adequately consider the patient perspective. “That’s just sort of basic psychology: You don’t really know what you would or could tolerate and what you would or could trade off until you’ve gone through it,” she says. “And so that, that lived experience, is so, so important.”

In its report, ICER outlined 10 potential policy reforms it said would improve the accelerated pathway, including increasing enforcement, creating an annual review process and adding a label alert to the patient materials to make sure patients know the therapy was approved under the accelerated pathway.

Cryer believes the accelerated approval pathway could be improved by adding more patient voices to review committees. She says the risks associated with speedy approval are outweighed by the benefits of getting new treatment options to patients as quickly as possible.

“Our perception is that they’re striving for perfection in the midst of complexity,” she says. “And that has a risk.”

Jared Kaltwasser, a regular contributor to Managed Healthcare Executive®, is a freelance writer in Iowa.

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