The Accelerated Approval Integrity Act of 2022 (H.R. 6963) aims to remove loopholes in the Food and Drug Administration‘s accelerated approval pathway. The bill, however, fails to adequately consider the whole picture, and may inadvertently remove medications that simply can’t complete confirmatory trials within the narrow timeframe allowed.
“Patients deserve to know that the drugs they are taking are safe and effective,” Rep. Frank Pallone, Jr. (D-NJ), sponsor of H.R. 6963 and chairman of the Committee on Energy and Commerce, said during the recent hearing titled, “The Future of Medicine: Legislation to Encourage Innovation and Improve Oversight.”
To illustrate the problem, he said, “Aduhelm…was approved (for Alzheimer’s disease) last June…and nine months later the sponsor has not screened a single patient for its required confirmatory trial. Other drugs have stayed on the market for eight or nine years without proving a clinical benefit. Removing these drugs from the market is cumbersome and can take months or even years.”
H.R. 6963 proposes to require the FDA and trial sponsors to develop a clinical trial plan before the drug is approved under an accelerated pathway, to enact a one-year timeframe to conclude confirmatory trials (with certain exceptions) and to streamline the process for withdrawing approval when no clinical benefit is shown or when the trials are not conducted with due diligence. Rep. Pallone was unavailable to discuss the rationale behind the shortened timeline.
As Jeff Allen, Ph.D., president & CEO of Friends of Cancer Research, pointed out in testimony before the Committee, “In the past 10 years (2010- June 2021), 80% of FDA’s accelerated approvals were granted for oncology indications.” He also noted, “One assessment of oncology treatments concluded that therapies receiving accelerated approval were made available a median of 3.4 years earlier than if approval had been based on a full clinical endpoint, such as overall survival.”
Furthermore, he noted that nearly half of all drugs approved in the program were converted to full approval. Less than 10% of all accelerated approvals were withdrawn. This left 43% of treatments in this program that have neither been approved nor withdrawn. These are not dangling applications, however.
Allen told the committee that a look at the approval timeline showed that “for oncology indications, conversions to full approval took a median time of 3.1 years, while withdrawals took 3.8 years to generate the evidence necessary for action.” The drugs in the pathway that have not yet gained full approval have held accelerated approval status for 1.8 years. “Therefore, it is unrealistic to expect their post-approval studies to be complete already.”
In written testimony, however, Reshma Ramachandran, M.D., M.P.P. of Yale University School Of Medicine and head of the Doctors for America FDA Task Force, pointed to a study in the British Medical Journal that indicated that 112 of the 253 drugs approved using this accelerated pathway between 1992 and 2020 had not been confirmed as clinically effective. “Of these, 24 have been on the market for more than five years. Only 16 were withdrawn.”
Rep. Pallone’s bill sets automatic expiration at one year after a study is completed, and in no case longer than five years, unless the predicted benefit has occurred or adequate progress has been made.
While agreeing that dangling approvals are of concern, this legislation may not be the best recourse, Coleen Klasmeier, a partner in Sidley Austin LLP’s Food, Drug and Medical Device Regulatory group, told BioSpace. She formerly served in the FDA Office of the Chief Counsel.
The existing code has accountability that includes consequences for delays, she said, but the FDA is concerned when the confirmatory trial fails to show clinical benefit.
Rep. Pallone’s concern is broader, however. “It covers accelerated approvals when the study hasn’t been completed. It seems to say that if a company hasn’t done the confirmatory trials, regardless of the reasons, it is susceptible to the FDA taking the product off the market,” Klasmeier said.
Consequently, it appears that effective products could be removed, too. “To me, that doesn’t compute. The rationale for accelerated approval is that you want patients to have access based on the reasonable likelihood of clinical benefit, so the timeframe to do the study should not matter in that case.”
There are valid reasons why some confirmatory trials may be slow. “There often is a lot of competition for a finite number of eligible subjects,” Klasmeier pointed out. “Especially during COVID, it is hard to get patients to participate. And, from a patient’s perspective, if you can already get the therapy, there’s no reason to sign up for a trial.”
The confirmatory data can’t be gathered through retrospective studies that mine patients’ medical records. That isn’t the same thing as a randomized clinical trial, she explained. “You have to conduct a particular type of study to confirm clinical benefit. It’s spelled out in the law.”
The use of surrogate – rather than clinical – endpoints as a confirming benefit is a concern mentioned in the proposed legislation. Ramachandran noted that 40% of the drugs in the accelerated pathway program used such endpoints and called for legislation to “explicitly state that post-approval studies should use clinical endpoints, not surrogate endpoints.” His goal is to ensure that trials are scientifically robust.
Klasmeier pointed out a problem with such a blanket approach. Validated surrogate endpoints are meaningful in many diseases, such as measuring cholesterol levels in heart disease. “It’s the more speculative surrogate endpoints that are the issue. The worry is that product development is occurring without adequate scientific validation. In oncology, there’s a certain comfort level around using surrogate markers to predict an outcome, but in rare diseases, more scientific work is needed to achieve consensus around a surrogate,” she said.
Using only clinical endpoints, however, could delay trials significantly. In cancer, improved survival is one common endpoint, but “the design would have to follow subjects until they die,” Klasmeier said. As treatments become more effective, survival times are extended, sometimes for years. This could ultimately push a study’s conclusion beyond the timeframe allowed by H.R. 6963 for accelerated approval. This would make many innovative treatments unavailable outside clinical trials.
“The legislation seems crafted to turn an existing regulatory program into something more punitive in nature and doesn’t seem to account for the impact on patients,” Klasmeier concluded.