Califf, experts eye legislative fix for accelerated approval program

Regulatory NewsRegulatory News | 19 January 2022 |  By 

Regulatory and industry experts agree that completing confirmatory studies quickly is essential to the success of the US Food and Drug Administration’s (FDA) accelerated approval program, with some suggesting that new legislation might be necessary to reliably get results from these trials in a timelier manner.
Robert Califf, head of clinical policy and strategy for Verily and Google Health and the Biden Administration’s nominee to be FDA commissioner, said a legislative framework is needed to stimulate confirmatory evidence generation because current incentives are not properly aligned. (RELATED: Senate committee advances Califf’s nomination as FDA commissioner, Regulatory Focus 13 January 2022)
“Unless we have teeth in this, it’s not going to work,” Califf said at the recent UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI) Innovations in Regulatory Science Summit.
He also indicated that the legislators he’s met with during the confirmation process have been particularly interested in the accelerated approval program. “It was part of the conversation with almost every senator on the [Health, Education, Labor, and Pensions] HELP committee in our one-on-one meetings, and I can assure you that Congress is very eager to understand what’s going on with accelerated approval because there’s such a division of views in the public domain, even among notable academics,” Califf said. (RELATED: Califf previews priorities if confirmed as FDA commissioner, Regulatory Focus 18 January 2022)
Califf added that he thinks there is “wisdom” in how the accelerated approval program is designed, but that its biggest liability is “the failure to produce confirmatory evidence quickly and in a way that really gives us the information that we need as patients and clinicians to decide which treatments are most effective and in which order.”
Rep. Anna G. Eshoo (D-CA.), who chairs the health subcommittee in the US House of Representatives, said legislators need to answer the question on whether there should be financial incentives for confirmatory evidence generation. “Money can be a very effective motivator in all of our systems,” she said, adding that legislators are taking a cautious approach in this area and need more input from scientists.
Sean Tunis, principal at Rubix Health and former chief medical officer at the Centers for Medicare and Medicaid Services (CMS), said that delays in obtaining confirmatory evidence pose a challenge for making reimbursement decisions.
“A lot of reluctance about open reimbursement or market access for products that either go through accelerated approval or have less definitive evidence at the time approval is the feeling that there are inadequate tools to ensure that the additional evidence is going to be generated rapidly,” he said.
 Tunis suggested that any legislative framework should also include the creation of an office of the chief scientist at CMS who would coordinate with FDA to create a paradigm for accelerated approval policy, evidence generation and a mechanism for the two agencies to confer prior to accelerated approvals being finalized.
Drug developers are also eager to get confirmatory data, said Michelle McMurry-Heath, president and CEO of the Biotechnology Innovation Organization (BIO), who participated in the CERSI Summit panel on accelerated approvals. “They want to be able to iterate their innovations. They want to be able to make the business case and the case to clinicians that this a drug or a product that is going to make a substantial improvement for patients.”
But in order to build the infrastructure necessary to quickly collect this data, it is going to take a collaborative effort by FDA, CMS, private payers and industry to figure out a pragmatic way to collect confirmatory data in a way that is “faster, cheaper, with less of a burden on patients,” she said.
Generating confirmatory evidence
Julie Beaver, chief of medical oncology at the FDA’s Oncology Center of Excellence, said the accelerated approval program has worked well in expediting cancer therapies to patients. She noted that there have been more than 160 oncology accelerated approvals, and about half have confirmed clinical benefit in a median of three years. The remainder of indications that do not yet have a confirmed benefit are mostly from recent accelerated approvals, and less than 10% of accelerated approval indications have been withdrawn, according to Beaver.
FDA is urging drug developers to have the confirmatory trial underway, if not fully enrolled, at the time of the accelerated approval action. Putting in place an early agreement on a plan to generate confirmatory evidence can play into the agency’s risk-benefit decision making and support for the accelerated approval action, Beaver said.
But the timing on confirmatory trials can be complicated, especially for smaller companies. Hal Barron, chief scientific officer at GlaxoSmithKline, said it may be difficult for companies to decide to initiate the confirmatory trials before unblinding their surrogate trials. “It’s a bit of a risk to start your confirmatory trial before seeing the results, and the longer you wait the less valuable accelerated approval is,” Barron said.
Whatever type of legislative framework potentially moves forward, Barron urged legislators to carefully consider how incentives will impact different groups. “If you’re sitting there waiting for your confirmatory trial to unblind and it’s really good when it’s delayed because it’s continuing to be on the market, the [incentives] aren’t in the right place,” he said. “Put them in a place where everybody’s incentivized to accelerate approvals, to get to patients faster with innovative science, but at the same time incentivized to quickly figure out whether you made a smart decision that was wrong or a smart decision that was right.” 
He also expressed concerns about using real-world evidence in the accelerated approval space. “I’m not convinced that that will help as much as really robust randomized trials where you really do need to see efficacy and the real world has enormous confounding,” Barron said.
Barron added that more work needs to be done to validate surrogate endpoints and noted the relative lack of accelerated approvals in areas outside of oncology. “There are a number of diseases where I think accelerated approval could be applied as robustly as it is in oncology,” he said.
CERSI Summit


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