The FDA is conducting an industrywide evaluation of drugs with indications given accelerated approval in an effort to determine whether confirmatory clinical trials verified the therapies’ clinical benefits. Manufacturers already have withdrawn indications approved in the U.S. for four drugs, and an upcoming meeting will scrutinize six additional indications. It’s important that the agency speed approvals of cancer drug indications if they look promising, contend experts, but it’s equally important that the FDA confirms their efficacy.
“The FDA has a large toolbox of options for getting important products to the market,” says Nancy Dreyer, Ph.D., chief scientific officer at IQVIA Real World Solutions. These include priority review, accelerated approval, fast track and breakthrough therapy designations, as well as emergency use authorizations (EUAs), which are used in emergency situations, such as the COVID-19 pandemic (SMA 3/15/21, p. 1). “It appears that we are well covered in terms of having EUA for emergencies and other fast-track options that assure that the risks are not likely to outweigh the benefits of a new treatment and that the new treatment offers meaningful therapeutic benefit.”
Asked if any particular therapeutic areas might see accelerated approval rates, Dreyer tells AIS Health, “I expect we will continue to see more accelerated approvals in rare diseases, including oncology. It is important to keep in mind that the number of rare and ultra-rare diseases we can treat will likely continue to skyrocket as we are better able to design targeted treatments for subgroups of interest.”
However, while it is crucial to get life-saving therapies to patients as quickly as possible, early market access may pose an issue in certain situations. Since December, four manufacturers have revealed that they are voluntarily withdrawing certain accelerated approval indications after their drugs failed to meet primary endpoints in post-marketing trials. In addition, the FDA revealed it would hold an April meeting on six other indications. All the impacted therapies are immune checkpoint inhibitors that target programmed death-1/programmed death ligand-1 (PD-1/PD-L1), and all of the agents have multiple FDA-approved indications.
The moves come as part of an industrywide evaluation by the FDA of oncolytics with accelerated approvals, which are granted based on a surrogate endpoint that is thought to predict clinical benefit. Companies must conduct postmarketing trials to confirm a drug’s anticipated benefit.
On Dec. 29, Bristol Myers Squibb said it was withdrawing the Opdivo (nivolumab) indication in the U.S. for the treatment of people with metastatic small cell lung cancer whose cancer has progressed after platinum-based chemotherapy and at least one other line of therapy. That accelerated approval came Aug. 17, 2018.
AstraZeneca said Feb. 22 that it would voluntarily withdraw the Imfinzi (durvalumab) indication in the U.S. for previously treated adults with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA gave the indication accelerated approval on May 1, 2017.
Merck & Co., Inc. said March 1 that it was voluntarily withdrawing the U.S. indication for Keytruda (pembrolizumab) for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other line of therapy. The FDA gave the drug accelerated approval on June 18, 2019, for the indication.
And on March 8, Roche said it was voluntarily withdrawing subsidiary Genentech USA, Inc.’s U.S. indication for Tecentriq (atezolizumab) for the treatment of people with locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-based chemotherapy. The agency gave the indication accelerated approval on May 18, 2016.
In a press release about the industry evaluation and upcoming meeting, the FDA pointed out that since the accelerated approval program’s start in 1992, only 6% of accelerated approvals for oncology indications — including the four most recent ones — have been withdrawn.
However, a 2019 article in the journal Manufacturing & Service Operations Management revealed that one-third of drugs approved through this pathway had not completed postmarketing studies. In a statement, Liang Xu, the study’s lead researcher and a professor of supply chain and analytics at the University of Nebraska-Lincoln College of Business, said that “manufacturers apparently have little incentive to do the post-market studies because they are not easily enforced and they are expensive. Withdrawing a drug from the market takes time and without proof of ineffectiveness cannot be enforced immediately.”
ODAC Will Examine Six Indications
On March 12, the FDA published a notice in the Federal Register (86 Fed. Reg. 14125) explaining that its Oncologic Drugs Advisory Committee (ODAC) would hold an online public meeting from April 27 to April 29 on “updates on certain supplemental biologics license applications” granted accelerated approval “with confirmatory trial(s) that have not verified clinical benefit.” Specifically, the updates will address the status and outcomes of these trials, as well as ongoing and planned studies. According to the notice, “based on the updates provided, the committee will have a general discussion focused on next steps for each product including whether the indications should remain on the market while additional trial(s) are conducted.” Participants will include both outside oncology experts and people with cancer.
The FDA is accepting comments on the issue until April 26.
The first day of the meeting, April 27, ODAC will be updated on Tecentriq for use in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1, as determined by an FDA-approved test.
On April 28, the committee will be updated on two products: Keytruda for the treatment of people with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy, and Tecentriq for the same indication.
On the final day of the meeting, updates will be provided on two Keytruda indications: (1) for the treatment of people with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma for tumors expressing PD-L1, as determined by an FDA-approved test, with disease progression on or after at least two lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and (2) for the treatment of people with hepatocellular carcinoma who have been treated with sorafenib. Bristol Myers Squibb will also give an update on Opdivo as a monotherapy for the treatment of people with hepatocellular carcinoma who have been treated with sorafenib.
The FDA revealed that its Oncology Center of Excellence “requested this meeting as part of an industry-wide evaluation of accelerated approvals in oncology in which confirmatory trials did not confirm clinical benefit.”
In a press release unveiling the meeting and industry evaluation, Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated that “we are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible. The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”
“If every drug is going to be accelerated, what does it mean?” asks one longtime industry expert who asked to remain unidentified. “I think overall one could say that you know an evaluation of the value and success of each of these programs actually is important because any of these special programs take additional resources. I think it’s also clear…[that] as we understand better the mechanisms of action, the idea that in oncology you increasingly see patterns is maybe important. I think that whole idea of patterns [is] it’s not a disease of an organ so much as a pattern of a pathway. I think that may be the more interesting aspect here. Because you add indications piecemeal because [a drug] works, but if you could know which ones are going to work because you can diagnose better because you know which are the disorders in the pathways, then that allows you a whole different approach, at least in principle, to developing oncology therapeutics and to combining their use.”
In a March 19 Health Affairs blog, Peter Pitts, president of the Center for Medicine in the Public Interest — which accepts general funding from the biopharmaceutical industry — and a former associate commissioner with the FDA, maintained that “the expedited pathways introduced by the FDA that incorporate new uses of data collection and regulatory science are a potent tool in America’s public health armamentarium. Speedier review has resulted in more drugs for serious and life-threatening diseases, with solid benefit/risk profiles. In short, the speed with which the FDA moves saves lives.”
That’s particularly true in oncology, notes the anonymous source: “Oncology has got the advantage, sadly, of it being life or death. You know, I think we’re always going to see attention on anything that’s life or death because that’s ultimately a metric that’s fairly easy to measure. These are acute diseases, whereas if you look at some of the bigger devastating neurological [conditions], we just don’t have the things to measure them by.”
Sources agree that oncology is a unique area when it comes to the evolution of treatments. “I think if things work in oncology, you learn about it fairly quickly, and then you look at if it’s applicable to everything else,” comments the source.
In an interview posted on The American Journal of Managed Care website, Joseph Alvarnas, M.D., editor-in-chief of Evidence-Based Oncology, an AJMC publication, stated, “I think that unlike many other care domains, where you get approval and you have guidances or pathways and move forward, outside of the domain of oncology, you’re apt not to see the speed of change, including the introduction of new therapeutics and biosimilars and then the postmarketing data sets, which may in fact lead to evolutions in indications.”
Commercial health plans and providers, however, may look beyond a drug’s FDA-approved label when determining treatment pathways. In oncology, the National Comprehensive Cancer Network (NCCN) Guidelines are considered by many to be the gold standard when it comes to pathways. According to Wui-Jin Koh, M.D., chief medical officer of NCCN, “the withdrawal of an accelerated approval indication for an agent results in prompt NCCN review of the recommendations for that particular indication. If the agent is completely removed from the market (i.e., no other FDA-approved indications), then it will be removed from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), as that agent is no longer commercially available.”
Many Cancer Agents Are Used Off-Label
However, he tells AIS Health, “if the agent has FDA approval for other indications, the NCCN Guidelines panel in question will review the available data for the withdrawn indication application and take action based on the best available scientific evidence. This can result in the removal of the agent from the guideline for the indication in question, or the panel may choose to retain the agent recommendation (with or without a change in the Category of Evidence and Consensus associated with the recommendation). Many oncologic agents are used in off-label settings — i.e., the agent may have efficacy in a particular clinical scenario, even if there is no FDA approval (which is used for marketing) in that specific situation.”
Asked how much of an influence that a drug’s FDA-approved label has on NCCN Guidelines, Koh responds, “FDA approval, or withdrawal of approval, starts the process of consideration by the panel(s), but FDA approval is not the only data considered. While most FDA-approved indications are accepted by the panel(s) as a recommendation, final decision for inclusion in the NCCN Guidelines is left to the expertise and judgment of the panel members, based on their review of the available data. There are rare cases where the panel considers the clinical benefit of a new agent indication to be insufficient to include as an NCCN recommendation, despite FDA approval.…Every NCCN recommendation is based on all available scientific evidence, plus the expert consensus of the panel members.”
“Oncology is special,” contends the unidentified source. “And when people don’t have any more options, there is a greater willingness to just try whatever might work. I think it goes back to the treatment guidelines. I think when you go to the payers and providers, there’s a lot more of perhaps following the treatment guidelines. In oncology, they’re probably the most current of all the therapeutic areas because there’s such high interest.”
When an indication is withdrawn, that obviously impacts providers and payers. According to Alvarnas, “one of the qualities that a high-quality, high-excellence clinician-patient relationship enjoys is the ability to bring forth new data in a timely way so patients and families can be appropriately advised and move forward in a way that embraces the data and also informs the patient in a patient-centered manner.…One of the opportunities and challenges of oncology is we have the opportunity to benefit from new data with new molecules coming into the marketplace. We also have to adapt to data that lets us know when those things are most effective and when they’re not.”
Payers “make their decisions in evidence-based fashion, but I think they realize there’s a certain amount of time required for clinicians and patients to have those conversations and make appropriate changes,” he explained. “Nothing is instantaneous, and I have in general found health plans and payers to be very respectful. They just want to make sure that things move in a way that represents the best data that’s available at that time.”
The anonymous source suggests that perhaps NCCN has an additional role to play in a situation where providers are prescribing drugs off-label for withdrawn indications that are included in its guidelines. “When things are used off-label, how do you capture that information, because that’s always an interesting question, too. We keep going on about real-world evidence and everything else, but is there a way to capture the information if the off-label use continues…in a manner in which it’s useful for regulatory purposes?” NCCN, asserts the source, should have a role in gathering that real-world evidence around these therapies.
With “any of these things, there’s a balance: You’re trying to make a product available but you don’t know yet” how effective it will be, but “it’s life or death, so you kind of have to err in favor of giving people a chance at life,” says the industry expert. But if the data are not supporting that use, then perhaps that drug should not be administered. “I think we have to recognize that there’s a judgment in there because you can’t give somebody back their life after they’ve died, so to speak. I think in oncology, that’s a particularly tough one. But it’s also true that just because some of these drugs work phenomenally for some tumors doesn’t mean they’re going to work for all” of them.