Califf Still Seeking Revamp of Accelerated Approval
With the recent user fee reauthorization having abandoned sought-after FDA reforms when time ran out for Congress to act, commissioner Robert Califf has revived his previous support for revamping the drug accelerated approval program. Delivering remarks 10/17 at the 2022 National Organization for Rare Disorders (NORD) Breakthrough Summit in Washington, DC, Califf said improvements in the accelerated approval program are needed as soon as possible.
“While the process is intended to ensure the integrity of the data and analyses, the fact is that accelerated approvals based on biomarkers leave more uncertainty about the true risk and benefit,” Califf told the NORD conference. “And regardless, many of these interventions will be approved based on a limited time frame of a clinical trial. And yet, the potential effects, both benefits and risks, will be manifested over a lifetime. Through the same type of collaboration that will lead to discovery and introduction of new treatments, we need a system of evidence generation that provides the confirmation of benefits and risks over years.”
Califf’s latest remarks echo earlier comments over the summer when he voiced support for provisions added at that time to the user fee reauthorization to enhance the program. Language involving changes to the accelerated approval program and other agency reforms were wiped away from the user fee reauthorization when Congress needed to pass a “clean” bill to avoid layoff notices being issued to FDA employees as time ran out on reaching a compromise (see earlier story).
Califf has said he does not think a total revamp of the accelerated approval program is needed in response to criticism that followed a number of drug indications being withdrawn when companies failed to generate confirmatory effectiveness data. In fact, he told the Food and Drug Law Institute’s (FDLI) annual meeting 6/14 that he is still a fan of the program due to his personal experience with his mother gaining an extra three to four years of living with multiple myeloma after taking an accelerated approval drug.
Califf acknowledged then that the program’s biggest fault is probably companies being “too focused on just the acceleration and not enough on the evidence that’s needed to fill in that gap between when approval occurs and when you need the definitive evidence that the treatment fulfills its promise.” He said he supported user fee provisions, such as requiring sponsors to have a confirmatory trial underway at the time of approval, and additional authorities to more efficiently deal with companies who don’t fulfill their confirmatory evidence requirements.
At the NORD conference, Califf also addressed challenges in developing products efficiently and effectively because the “vast majority of drugs evaluated in early phase human testing will probably not make it to market because of unexpected toxicity or failure to have the expected beneficial effect on clinical outcome… A key piece of this system involves something that has been of particular importance to me throughout my professional life — the need to strengthen the systems we use to generate and gather new and better data and ensure that we have the most reliable evidence to inform and improve the decisions we make.”
Califf acknowledged the importance of real world data (RWD) and real-world evidence (RWE) to accelerate product development. “For example, real world data could be used to expedite the identification and enrollment of patients into clinical studies,” he told NORD, “and it can inform the design of traditional clinical trials, such as the selection of endpoints and trial duration. A further important benefit of the use of RWD and RWE is the potential it offers to reveal previously unknown interactions of drugs to patients, which can both improve patient care and help make clinical trials more efficient and productive. It’s important to note, however, that there are important considerations, such as whether real world data are fit for a particular use.”
Additionally, Califf touched on biomarker development and how RWD may help connect biomarkers to clinical outcomes that matter to patients. “The best biomarkers are backed by solid translational science programs in development and are reasonably likely to predict clinical outcomes,” he said. “Developing useful biomarkers is hard work and it takes extensive collaboration and attention to detail to get it right.”
And he mentioned the agency’s work advancing endpoint development like clinical outcome assessments, which measures how an individual feels, functions or survives. “One way the FDA is working to advance this approach is through CDER’s Standard Core Clinical Outcome and Related Endpoints Grant Program, which currently has funded the development of five core sets of clinical outcome assessments,” he said. “Three of these grants are related to rare diseases. In addition, a new combined CDER/CBER commitment funded through the Prescription Drug User Fee Act (PDUFA VII), the Rare Disease Endpoint Advancement (RDEA) Pilot Program will support novel efficacy endpoint development for drugs that treat rare diseases.”