One of BIO’s top priorities is preventing FDA from routinely requiring that trials confirming clinical benefit be under way before it grants accelerated approval. Many small biotechs do not have sufficient funds to start confirmatory trials prior to approval, according to BIO. The trade association’s arguments are unlikely to resonate at the agency.
FDA officials believe that allowing sponsors to defer launching confirmatory trials to after accelerated approval can create unacceptable risks for patients because it can increase the time ineffective or unsafe drugs are on the market.
The debate is timely because the agency is developing policies for implementing the accelerated approval provisions of the Food and Drug Omnibus Reform Act (FDORA) of 2022, which was enacted in December as part of the omnibus appropriations law in the last hours of the 117th Congress.
FDORA gave FDA explicit authority to require that a confirmatory study or studies be “underway prior to approval, or within a specified time period after the date” of accelerated approval.
The agency is considering crafting a policy that would explicitly make initiation of a confirmatory trial prior to accelerated approval the default assumption. The final policy is likely to be set by an intra-agency coordinating council on accelerated approval that was mandated in FDORA. The law requires FDA to create the council this year, and for it to meet at least three times per year.
“We really need to be clear how impossible it could make it for some of the smaller companies to get things across the finish line.”
The timeliness of confirmatory trials attracted the attention of Congress as part of the fallout from the accelerated approval of Aduhelm aducanumab-avwa for Alzheimer’s disease — FDA gave Biogen Inc. (NASDAQ:BIIB) nine years to complete a trial to confirm the drug’s clinical benefit — but accelerated approval is most widely used for cancer drugs. Over the past decade, about 85% of accelerated approvals have been for oncology indications.
“We’re very concerned about what appears to be an erosion of the accelerated approval pathway,” Rachel King, interim CEO of BIO, said in an interview with The BioCentury Show.
One of the things that BIO is most worried about, she added, is the “idea that an approval could be contingent on the initiation of a confirmatory trial. I think that would be a terrible outcome for small biotechnology companies.”
The requirement could make it impossible for some companies to complete development of innovative medicines, King said. “A lot of companies who face their first approval are running out of cash. They’re limping across the finish line sometimes to get the clinical trial completed and to get to the data, and if at the same time they had to initiate a confirmatory trial, if that were a requirement of approval, they just wouldn’t get there.”
She added that the requirement “would negatively impact larger companies as well, but we really need to be clear how impossible it could make it for some of the smaller companies to get things across the finish line.”
King made it clear that BIO is not calling for FDA to do anything that could harm patients. “FDA should retain their flexibility to make good judgments and to do so in a way that helps patients, but that also makes it possible for companies to continue to innovate.”
The rule or the exception?
Last year, FDA, BIO and other stakeholders made cases to Congress for and against requiring ongoing confirmatory trials at the time of accelerated approval.
BIO believes that it achieved a compromise that gives FDA power to require ongoing confirmatory trials but does not mandate that it do so routinely. The trade association “worked hard with Congress so ongoing confirmatory trials would not be a requirement for all accelerated approvals,” Cartier Esham, BIO’s CSO and EVP of emerging companies, told BioCentury.
“Accelerated approval has been successful in making innovative medicines available to patients in a timely manner,” she added, “and we don’t want to see the pathway eroded.”
Jeff Allen, president and CEO of Friends of Cancer Research, also participated in the discussions with congressional staff. He thinks Congress presumes that FDA will require confirmatory trials to start prior to accelerated approval. The law “allows flexibility should there be a compelling reason for an exception” from the presumption of an ongoing trial, Allen said.
Exceptions, he said, could be provided for rare diseases when confirmatory studies are not feasible, and in “extreme cases” such as when a drug has a “highly meaningful result on an interim endpoint” and there is an urgent need for access, or because unforeseen circumstances such as a pandemic make it impossible to conduct a trial.
“In most instances it is entirely feasible to have a confirmatory trial enrolling at the time accelerated approval is granted.”
“Lack of planning on the part of a sponsor” is not a legitimate reason for relaxing that expectation, Allen argued. “Sponsors should be planning to have these trials up and running in a timely manner. That will foster confidence in the accelerated approval pathway.”
“In most instances it is entirely feasible to have a confirmatory trial enrolling at the time accelerated approval is granted,” Allen said.
Friends of Cancer Research, BIO and FDA all agree that the key to making accelerated approval work is close coordination and communication between sponsors and regulators.
Esham noted that BIO worked with FDA to include provisions in the PDUFA reauthorization that create more opportunities for sponsors and FDA to discuss and agree on postmarket study requirements.
The key to effective accelerated approval, Allen said, is “early planning, early engagement with the regulators and not just thinking about drug development as one trial at a time, but rather generating a portfolio of data that demonstrates the safety and efficacy of a product.”
BIO’s concerns about confirmatory trial requirements slowing product development are not hypothetical.
ADC Therapeutics S.A. (NYSE:ADCT) announced in November 2022 that it had dropped plans to submit a BLA in 2023 for camidanlumab tesirine to treat Hodgkin lymphoma and had paused material investments in the program following “strong guidance” from FDA that a randomized, confirmatory Phase III trial “must be well underway and ideally fully enrolled” at the time of filing for the agency to consider the therapy under accelerated approval.
ADC is not a member of BIO.
Regeneron Pharmaceuticals Inc. (NASDAQ:REGN), which is a BIO member, also announced in November that FDA’s requirement for an ongoing confirmatory trial was causing a delay in submitting an accelerated approval application.
Discussing the regulatory status of odronextamab during a 3Q22 earnings call in November, Regeneron President and CEO Leonard Schleifer noted that “some of the most recent timelines are pushed back a little bit based on recent regulatory feedback. The regulators have recently been focused on having Phase III trials substantially enrolled at the time of submission before they’ll grant accelerated approval.”
Richard Pazdur, director of FDA’s Oncology Center of Excellence, has expressed no sympathy for the notion that FDA should adjust its requirements to help biotechs overcome financial challenges.
Pazdur has also made it clear that he views rapid completion of confirmatory studies as essential for protecting patients from ineffective or unsafe drugs, and that the best way to ensure completion of postmarket studies is for them to be ongoing at the time of approval.
In a perspective published in October in The New England Journal of Medicine, Pazdur and colleagues noted that with the exception of rare diseases, “oncology drug sponsors have typically conducted a single-group study to support AA and subsequently conducted a randomized, controlled trial evaluating a long-term outcome such as survival to verify clinical benefit.”
The paper noted that although “FDA has recommended that confirmatory trials be well under way, if not fully enrolled, at the time of the AA, sponsors frequently delay initiating these trials until the single-group study is completed or AA has been granted.”
“It was not, not, not — can I make this any clearer? — an incentive program for the pharmaceutical industry.”
The paper suggested alternative approaches to meeting the confirmatory requirement, including conducting a “single randomized trial, potentially in an earlier treatment setting, that could both support AA and subsequently verify clinical benefit.” In that scenario, accelerated approval “could be granted on the basis of a planned interim analysis of overall response rate, and traditional approval granted on the basis of clinical benefit (usually improvement in overall survival) at the trial’s conclusion.”
It also reported that the initiation of a confirmatory trial prior to accelerated approval leads to a “striking” reduction in the length of time ineffective or unsafe drugs remain on the market. The median time to withdrawal of a drug following accelerated approval was 3.8 years if a confirmatory trial was under way at the time of approval, compared with 7.3 years if the trial had not been initiated at approval.
Speaking at the Friends of Cancer Research annual meeting in December, Pazdur denounced companies that ask FDA to approve development programs based on a “single-arm trial because they are inadequately capitalized to do randomized trials.”
He strongly rejected the notion that FDA should consider the financial impacts of its implementation of accelerated approval. “The whole idea behind accelerated approval was a patient-centric approach. It was not, not, not — can I make this any clearer? — an incentive program for the pharmaceutical industry,” Pazdur said.
Over the years, Pazdur said, accelerated approval has been misconstrued as “an incentive program to do less.” Rather than look for ways to cut development costs, he suggested that companies that do not have the resources to meet FDA’s requirements “should be questioning whether [they] have the ability to be in the game.”
Pazdur emphasized the importance of companies coming to FDA with comprehensive development plans. He noted that large pharmas often present and adhere to such plans, citing the development of PD-1 inhibitors.
“Where we do get into trouble is with a drug company that may not be adequately capitalized” and “wants to get their foot in the door with a single-arm study of a very limited number of patients,” Pazdur said.
Bare bones development programs “put the patient at risk,” Pazdur argued. “There is a period of vulnerability that we have to control and that period of vulnerability is between the time of accelerated approval, if it is granted, and the confirmation or lack of confirmation of clinical benefit in the confirmatory study. We should try to reduce that period of vulnerability as much as possible,” including by requiring that confirmatory studies are under way at the time of accelerated approval.