Expert proposes changes to accelerated approval reforms in user fee bills

Regulatory NewsRegulatory News | 08 June 2022 |  By 

With the Senate Committee on Health, Education, Labor and Pensions (HELP) recently releasing the Food and Drug Administration Safety and Landmark Advancements (FDASLA) act from committee, some stakeholders are proposing Congress make changes to the user fee authorization bill to address issues with the US Food and Drug Administration’s (FDA) accelerated approval pathway.
While some of the accelerated approval reforms in the House and Senate user fee billl are similar, the Senate version contains some key differences, such as the formation of an intra-agency council that will meet a minimum of three times per year to discuss issues surrounding the accelerated approval pathway, issue guidance, and advising review divisions on accelerated approval products. (RELATED: New diagnostics authorities, accelerated approval council featured in Senate user fee bill, Regulatory Focus 31 May 2022)
In an interview, Reshma Ramachandran, MD MPP, board-certified family physician and Veterans Affairs Scholar in the National Clinician Scholars Program at Yale University School of Medicine, said the council is an interesting idea, but it comprises many of the directors from FDA centers, has a “fairly broad” focus, and doesn’t seem to contain an opportunity for public stakeholders to engage in council meetings. In addition, prior to this legislation, FDA had the discretion to issue more guidance on accelerated approval and could have revisited the accelerated program as issues arose, she noted.
“It’s unclear to me what it will achieve and what makes it different than what already exists now,” she said. “I’m curious in terms of whether or not this will do anything more than what FDA could have done in the first place.”
Ramachandran, who is also chair of the Doctors for America FDA Task Force and co-director of the Yale Collaboration for Research Integrity and Transparency (CRIT), recently wrote a letter to Senate HELP outlining a series of proposed changes to user fee reauthorization bill. The proposed changes include ensuring adequate representation and diversity in clinical trials with enforcement measures, adding an automatic expiration date for accelerated approval drugs if post-approval studies don’t show evidence of clinical benefit after 5 years, a mandate that drugs receiving accelerated approval have post-approval studies, a requirement that FDA hold advisory committee meetings for every accelerated approval drug, and a clarification in the bill noting real-world evidence augments rather than fully supports post-approval studies.
The House version of the bill, released by the House Committee on Energy and Commerce, contained a section on improving diversity and clinical trials, which the Senate bill does not have. Ramachandran said one of the big focuses of her group was getting the clinical trial diversity provision reinserted into the Senate bill.
Regarding adding an expiration date to automatically withdraw drugs that have received accelerated approval but fail to show a clinical benefit within 5 years in post-marketing trials, Ramachandran said that it is an “important safeguard” because of the lag time between manufacturers receiving accelerated approval for their drugs and conducting or completing the post-approval studies.
Recently, the question of under what circumstances oncology drugs should have their accelerated approval status withdrawn has been at the center of FDA advisory committee meetings; in April 2021, FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended pulling 2 of 6 accelerated approval indications for oncology drugs despite all six indications failing to show clinical benefit. (RELATED: ODAC recommends pulling 2 of 6 accelerated approvals, Regulatory Focus 30 April 2021)
Requiring FDA to issue post-approval studies for accelerated approval drugs was another important proposal, Ramachandran explained. Currently, the Senate bill says FDA “may” require post-approval studies, but codifying it in legislation was key, she noted. “[I]f there might be any sort of chance that the agency could be swayed by an industry sponsor to not require those post-approval studies, that was kind of the concern that we put forward,” she said.
The accelerated approval pathway has received increased scrutiny due to the high-profile approval of aducanumab, a novel Alzheimer’s drug treatment that was approved by FDA despite a Peripheral and Central Nervous System (PCNS) Drugs advisory committee of independent experts voted nearly unanimously in the negative in response to a question asking whether the clinical trials that led to its approval supported efficacy claims. (RELATED: FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 07 June 2021)
Ramachandran said requiring FDA to hold advisory committees for accelerated approval drugs was a “lesson learned from aducanumab.” In the process leading to the drug’s approval, “the advisory committee was not even asked about accelerated approval, they were asked just about traditional approval,” she said. (RELATED: FDA defends Aduhelm's accelerated approval, while others call for reform, Regulatory Focus 14 July 2021)
“For these drug candidates in particular, where evidence is uncertain even upon approval, they’re approving a potentially promising drug, but clinical benefit has not yet been confirmed,” she added. “We wanted to make sure that advisory committees would be convened for these candidates at the very least.”
Another important component is clarifying in the bill that “FDA, in addition to having oversight over the post-approval studies, specify they would also have oversight of the study endpoints so that they can make sure that the endpoints are being selected for the confirmatory trials actually demonstrate clinical benefit and actually show a clinical benefit,” she said.
The Senate bill also contains a provision real-world evidence in post-approval studies. Ramachandran said her group also wants to change the language that says real-world evidence, rather than supports post-approval studies.
“[F]or accelerated approval drugs in particular, the real-world evidence that we have right now in terms of electronic health record data or medical claims data, we could not actually replicate clinical trials using that for drugs that were approved between 2009 and 2018,” she said. “We just want to clarify that real-world evidence can be used to supplement or augment clinical trial data but would not be sufficient to replace or support post-approval studies on their own.”
“Until that evidence base can be built up and demonstrate that it actually can emulate clinical trials, putting it in legislation to allow FDA to use that as a basis of conferring clinical benefit we thought was just premature,” she said.
House bill
Senate bill


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