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FDA Panel Revisits Accelerated Approvals for Cancer Treatment

FDA Panel Revisits Accelerated Approvals for Cancer Treatment
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Published on May 12, 2021

Accelerated Approvals for Cancer Treatment Revisited by FDA

A U.S. Food and Drug Administration (FDA) panel has voted to maintain four out of six accelerated approvals for three cancer immunotherapies.

In April 2021, the Oncologic Drugs Advisory Committee (ODAC), which is responsible for evaluating the safety and efficacy of cancer therapies, recommending keeping indications for pembrolizumab (Keytruda) in bladder, liver, and breast cancer, as well as atezolizumab (Tecentriq) in bladder cancer. The committee also voted to remove indications for pembrolizumab in gastric cancer and nivolumab (Opdivo) in liver cancer, saying that they did not meet the threshold for clinical benefit.

The recommendations now move to acting FDA Commissioner Janet Woodcock, MD, who will make the final decision on the accelerated approval indications. Until then, these six indications will stay in place — and remain available to patients — as the agency consults with the drug manufacturers.

“The ODAC results demonstrate that it is helpful to have a transparent, and hopefully more regular, public review of confirmatory trial evidence,” David Whitrap, Vice President of Communications and Outreach for the Institute for Clinical and Economic Review (ICER), told Patient Power. 

What Is the Accelerated Approval Program?

The FDA created its Accelerated Approval Program in 1992 when its standard drug approval process could not keep pace with the high number of deaths from HIV/AIDS. Under the program, the agency can give early approval to drugs that fill medical needs for serious conditions based on a surrogate endpoint, such as a laboratory measurement or physical sign, with the potential to predict clinical benefit. The drug manufacturer is then required to confirm the benefit through current, and potentially additional, clinical trials to receive full approval from the FDA.

“That's what accelerated approvals are all about: being patient-centric. It's trying to get a promising drug that has met some endpoint that is clinically meaningful that you get a readout on sooner so that patients can get the drugs and insurance will pay for the drugs, while still doing the studies required to show the longer-term impact and survival,” said Julie R. Gralow, MD, Chief Medical Officer of the American Society of Clinical Oncology (ASCO).

Over the past 10 years, 85 percent of the FDA’s accelerated approvals have been granted for oncology treatments and the agency reports that nearly half convert to regular approval within about three years. In some instances, since surrogate endpoints are used early in the research, they are not always accurate in predicting clinical benefit. As a result, there are some accelerated indications that still lack the data to prove a real benefit for patients.

Whitrap also noted that once a drug is approved, it is more challenging to enroll patients in a placebo-controlled trial where they might not receive the actual therapy.

“The trials may not even be started within the first few years after accelerated approval because companies don’t have the same financial incentive, and the FDA has not been consistent in how it manages failures to produce the evidence,” he added.

Required trials have not confirmed clinical benefit in 10 indications across pembrolizumab, atezolizumab, nivolumab, and durvalumab (Imfinzi). The four therapies are PD-1 inhibitors and PD-L1 inhibitors, which block the activity of PD-1 and PD-L1 immune checkpoint proteins on the surface of cells.

After conversations with the FDA, the drug manufacturers voluntarily withdrew four indications and the remaining six were evaluated during an ODAC hearing on April 27-29, 2021, to determine whether the drugs could continue to be marketed for those indications. The following is a breakdown of the committee’s votes.


The committee voted 10-1 to maintain the approval of atezolizumab for first-line treatment for patients with urothelial carcinoma who are not eligible for cisplatin (Platinol® and Platinol®-AQ), as the final data for its confirmatory trial is expected in 2022.

In a 7-2 vote, ODAC recommended keeping the approval of atezolizumab in combination with nab-paclitaxel (Abraxane) for patients with metastatic triple-negative breast cancer (TNBC) whose tumors are positive for PD-L1 expression.


The committee voted 5-4 to pull the approval of nivolumab for patients with hepatocellular carcinoma who were previously treated with sorafenib (Nexavar).


ODAC voted 6-2 to pull the approval of pembrolizumab for patients with PD-L1–positive metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more lines of therapy.

The committee voted 5-3 vote to maintain the approval of pembrolizumab for metastatic urothelial carcinoma patients who are ineligible for treatment with cisplatin and carboplatin (Paraplatin).

In an 8-0 vote, ODAC unanimously recommended keeping the pembrolizumab indication for patients with advanced hepatocellular carcinoma who were previously treated with sorafenib.

Strengthening the FDA Approval Process

Drugs that are granted accelerated approval, but ultimately do not demonstrate clinical benefit, should not be viewed as a failure of the program, Julia Beaver, MD, Chief of Medical Oncology at the FDA’s Oncology Center of Excellence and acting Deputy Director of the agency’s Offices of Oncologic Diseases and New Drugs, said at the ODAC hearing. It is an expected tradeoff, she said, in order to expedite promising agents for severe and life-threatening diseases like certain cancers.

“Since the goal of accelerated approval is patient benefit when postmarketing studies do not meet their primary objective, the drug products should be reevaluated in the context of currently available therapy and if deemed to no longer benefit patients, the accelerated approval indication should be withdrawn,” she said.

In late April, ICER and the Drug Pricing Lab at Memorial Sloan Kettering Cancer Center published a white paper that lays out 10 potential ways to strengthen the FDA’s Accelerated Approval Program. A more consistent and enforced confirmatory trial process is one potential way to achieve that goal. Another strategy for strengthening the accelerated approval process is to incorporate real-world evidence to help complement the review. Dr. Gralow said this would allow the FDA to further evaluate a treatment’s indication in populations outside of trials, as well as consider potential toxicities and other outcomes.

“You test the drug in a narrow population and then it gets approved and then all of the sudden you're giving it to older patients or patients with more comorbidities or patients with different liver or renal function,” she told Patient Power.

The ICER/Drug Pricing Lab paper explores other novel approaches, such as tying payment for a drug to evidence that it is effective, possibly by requiring a lower price until the confirmatory trial is completed or requiring an automatic price drop if a company misses a deadline in confirming efficacy. However, the authors do not endorse any one specific reform since all options have potential benefits and risks.

“Each option would likely have different effects on uncertainty, access, innovation, and cost; policymakers will need to ensure that attempts to strengthen accelerated approval maintain the program’s overall benefits for patients,” Whitrap said.

While there are ways to improve accelerated approval, Dr. Gralow emphasized that the program is achieving its goal of giving patients access to promising agents through their physicians, while collecting the long-term data in the process.

“I would just say what we've learned from all this is the system works,” she said.

~Aaron Tallent

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