The FDA could remove from the market any drugs that obtained accelerated approval if they fail to show a clinical benefit under a proposed package reauthorizing must-pass user fee legislation.
The bipartisan proposal, unveiled Wednesday by leaders of the House Energy and Commerce Committee, would push sponsors of drugs approved through the accelerated pathway to complete required postmarket studies. Both the Food and Drug Administration and lawmakers have pushed for legislative changes to minimize the amount of time between when an accelerated approved drug enters the market and the completion of studies demonstrating if there’s a clinical benefit.
The FDA may approve drugs under the accelerated pathway for treatments to address rare diseases or life-threatening conditions for which there are little to no other treatment options available. Drug sponsors may use surrogate endpoints, such as tumor shrinkage, as a predictor of whether a treatment could help improve a patient’s condition or help them live longer.
But the pathway has come under increased scrutiny, especially after the approval of Biogen’s Alzheimer’s drug despite mixed evidence on the drug’s efficacy and safety. There have also been criticisms that drugs linger on the market without proving that they have a clinical benefit.
FDA Commissioner Robert M. Califf said Tuesday at the World Medical Innovation Forum that the main area that needs to be fixed in accelerated approval is the assurance to patients and public that the follow-up studies will be done. “That’s a real lesion in the system that we need to work on,” he said.
He noted the law passed by Congress allows the FDA to use unvalidated biomarkers based on a opinion as to whether it’s reasonably likely that changes in those biomarkers will predict a clinical benefit. “This reasonably likely means that people are accepting more uncertainty in return for earlier access to treatment,” he said.
The accelerated approval mechanism reflects the American ethos that “one is willing to take more risk in return for the potential for more benefit,” Califf said. At the same time, “it should come under scrutiny, because it’s a very large proportion of initial marketing approvals now are using the accelerated pathway.”
The user fee bill also would give the FDA powers to require drug and device companies to submit diversity action plans for their clinical trials as part of a push to address a longstanding lack of diversity in these studies.
“In addition to providing FDA with authority to collect user fees to fulfill its mission, the bill includes new provisions that will strengthen the Accelerated Approval pathway and help ensure clinical trials better represent the diverse patients that need these products,” the House members, led by Energy and Commerce Committee Chairman Frank Pallone, Jr. (D-N.J.) and ranking member Cathy McMorris Rodgers (R-Wash.), said in a statement.
Both Pallone and McMorris Rodgers had previously proposed their own versions of potential additions to the user fee package to address the accelerated pathway’s postmarket requirements. The user fees, which help fund the agency’s review and approval of new product applications, must be reauthorized every five years, and make up nearly half of the FDA’s budget.
Health Subcommittee Chairwoman Anna G. Eshoo (D-Calif.), and Health Subcommittee ranking member Brett Guthrie (R-Ky.) plan to officially introduce the proposed user fee package to the House later this week, with a markup planned for next week.
Post-Approval Studies
Reshma Ramachandran, a Yale School of Medicine physician and chair of the Doctors for America FDA Task Force, said the House bill takes a number of steps in the right direction, such as settling what the post-approval studies will look like before granting accelerated approval and clarifying milestones in those studies.
The measure prevents any delays in starting the post-approval studies because the FDA wants the studies to be underway when accelerated approval is granted to the sponsor, Ramachandran, who testified before the House panel in March on accelerated approval, said in an interview.
She also applauded the lawmakers’ steps to give the FDA more efficient authority to withdraw the accelerated approval if there’s a clear violation of not providing progress reports, failure to start confirmatory trials in a timely manner, or if the trials are found to be negative.
Jeff Allen, president and CEO of Friends of Cancer Research, said in a statement that the bipartisan agreement ensures the accelerated approval pathway “continues to be a critical tool for developing new medicines into the future.”
However, Ramachandran expressed disappointment the House bill doesn’t include a proposal by Democrats that would automatically have a drug’s accelerated approval status expire one year after studies demonstrating clinical benefit are scheduled to be done, or five years after the FDA grants accelerated approval, unless the drug company has met its post-approval requirements.
“This would this be an automatic mechanism in place that would compel the sponsor to complete their trials in a timely manner and also make sure that the FDA has adequate oversight of clinical benefit being verified,” she said.
Trial Diversity
The House bill also calls for drug and device manufacturers to inform the FDA on how they will incorporate diverse populations in their trials as soon as practicable during the drug development process. Diversity action plans should include the sponsor’s goals for diverse enrollment, their rationale behind determining those goals, and an explanation for how those goals will be met, according to the bill text.
Drug industry members have expressed opposition to mandating specific clinical trial diversity benchmarks. The Pharmaceutical Research and Manufacturers of America has said requiring diverse participation may make trial sponsor efforts to expand minority outreach seem disingenuous. The requirements would also push trial sponsors to put their time and attention on meeting target numbers while pulling resources away from addressing systemic barriers to medical research access, the trade group said.
But Bloomberg Intelligence analyst Duane Wright says he believes the user fee provisions on diversity “should be fairly well received by the industry as a whole,” arguing it builds on diversity action plan draft guidance released by the FDA in April.
“This tracks what the FDA, Califf, and the Hill have been looking at in terms of trying to address the underrepresentation in trials,” Wright said.
Timely Reauthorization
Biotech and pharma representatives underscored the importance of passing the user fee bill before the current authorization expires Sept. 30.
PhRMA spokesman Andrew Powaleny said the release of the legislative text for this year’s reauthorization process marks an important step to ensure these programs continue without interruption.
“As the legislation moves forward, it is important that the integrity of the reauthorization of these critical programs not be undermined by the inclusion of extraneous policies that would slow the reauthorization process and jeopardize the U.S. Food and Drug Administration’s (FDA) timely review and approval of critical new medicines,” he said in an email. “It is vital FDA’s workforce can continue to support patient safety, maintain high standards of independent regulatory review and promote timely access to safe and effective medicines for patients.”
Cartier Esham, chief science officer for the Biotechnology Innovation Organization, said the biotech industry trade group is still analyzing the bill but would like to see the user fee agreements quickly reauthorized.
“These agreements between the industry and FDA include important provisions to improve the use of real-world evidence, modernize, streamline, and diversify clinical trials, and ensure that the Agency has the resources necessary to support the world-leading innovation our companies bring to patients every day,” she said.
