The FDA’s accelerated approval of Alzheimer’s drug Aduhelm (aducanumab) last year was extremely controversial, prompting harsh criticism and calls for reform of the accelerated approval process itself. Congress has taken up the issue and is considering one bill from each major party that would revamp the process in the hope of addressing concerns that the pathway has allowed flawed drugs to stay on the market without being revisited.
Medical research and health care policy experts have raised a number of critiques of the current accelerated approval framework. Two critiques stand out: The first concerns the quality of data used in measuring the effectiveness of accelerated approval drugs. After a drug is granted accelerated approval, the FDA mandates that the drug be evaluated using confirmatory clinical trials. Experts have criticized the quality of data collected for accelerated approval drugs; in particular, the measurements used to gain approval for Aduhelm were heavily criticized by clinicians.
The other major point of contention is the lifespan of accelerated approval, especially the frequency of withdrawals: Some experts argue not enough withdrawals happen, even when a drug’s trials have not been completed or shown clinical benefit. At present, there is no standard process or timeline for later review of accelerated approval drugs; while some drugs do lose their accelerated approval status, some policy experts say that the FDA should withdraw more accelerated approvals than it does at present.
Two bills have been introduced by members of the House of Representatives to change the accelerated approval pathway. One was introduced by the chair of the House Energy and Commerce Committee, New Jersey Democrat Frank Pallone. The other was introduced by the committee’s ranking Republican member, Cathy McMorris Rodgers of Washington.
The Democratic bill revamps the way that the FDA and drug sponsors decide what data to consider in accelerated approvals. In addition, the bill would automatically rescind accelerated approvals after five years if their sponsor has not met post-market testing requirements (and allows the FDA to rescind approvals sooner under some circumstances.) The Republican bill does not have an automatic sunset period. Nor does it revamp the process for designing trials, but instead directs the FDA commissioner to issue guidance that would do so.
Steven Pearson, M.D., president of the Institute for Clinical and Economic Review (ICER), tells AIS Health, a division of MMIT, that the two bills reflect differing perceptions of the way the accelerated approval process needs to be reformed. (Pearson, who coauthored a 2021 white paper on reforming the accelerated approval process, emphasized that ICER has not taken a position on either bill.)
“The legislative proposals right now are just coming at the issue from different directions,” Pearson says. “In the main, the Republican proposals are seeking to enlarge the number of products that could be considered for accelerated approval. In a sense, I think you could characterize [the Republican position] as, ‘Things are working well, and if anything we should expand it and open up earlier access to a wider variety of treatments.’”
Meanwhile, Pearson adds that “largely, from the Democratic side….the idea is [Democrats] are willing to accept greater uncertainty around the use of what are called surrogate outcomes. When there’s a serious condition with a lot of unmet need, [they’re] willing to do that, with the quid pro quo being that we have a well-scripted and well-managed process for getting confirmatory trial information quickly.”
A fundamental difference between the two proposals, Pearson says, is that the Democrats hold the premise that “it’s kind of a conditional approval, but the condition of taking [approval] away if the data aren’t there has kind of fallen apart. [For Democrats], it’s falling apart partly because the FDA just hasn’t exercised the powers that it currently has, and they might not have enough clarity around how to tee up the studies early enough to get the data.”
Aduhelm Prompted Higher Scrutiny
Rachel Sachs, an attorney and professor at the Washington University in St. Louis School of Law, tells AIS Health that Aduhelm is largely responsible for the higher scrutiny on the accelerated approval process.
“Aduhelm — and some of these other examples of cases in which the program has not gone as initially envisioned — means that [accelerated approval] is in the news. It’s unfortunate, given the other successes that the program has had,” Sachs says. “But it is a much-needed chance to revisit some of these initial assumptions about how the program was going to work.”
“There are multiple criticisms that have been levied against the accelerated approval program. Aduhelm is a very clear example of some of those criticisms,” Sachs adds. “But because it was only approved very recently, it actually hasn’t had enough time to know if it’s a good example of all of them. For instance, people have often expressed concern with the amount of time that companies have on the market before completing their trials, or that companies fail to complete their confirmatory trials — or that when they do, even if they fail, [the drug] may not be removed from the market. But for all we know, [Biogen] will complete the trials [for Aduhelm] quickly and it won’t be an issue. It’s too soon to say whether that concern is relevant in this context.”
However, Sachs observes that Aduhelm was submitted for accelerated approval because its traditional clinical trials didn’t pass muster for a conventional approval process. Aduhelm’s sponsors hoped that accelerated approval’s real-world evidence standard could be used as an alternative.
Drugs Should Fail if System Is Functioning
“And that’s not the way it’s supposed to be used,” Sachs says. “When [Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research] has repeatedly said things like, ‘the FDA agreed with the advisory committee that Aduhelm did not merit a traditional approval, but we decided that it did merit an accelerated approval’ — that’s not normally how we think about it. Normally, you have an accelerated approval, because you’ve demonstrated a particular surrogate endpoint, an intermediate endpoint, but it will take many more years to develop the full clinical endpoints. That’s not the case here.”
“I think the FDA has made this point frequently, and it’s true — if you have this system conceptually set up right, you would expect some of the drugs not to pan out,” Pearson says. “That’s not a failure of the system. That’s why some people say we actually have too few of the drugs not panning out. On the other hand, we have a high number of drugs that take years and years, and the final data that come out aren’t really helpful — they’re not designed well, the studies can’t answer the original question, and people shrug their shoulders and the FDA doesn’t do anything. So people kind of feel like it’s not really clear whether the system is getting the answers that we need — and certainly soon enough to make sense.”
This confusion isn’t just scientific, Peterson adds. It has meaningful financial implications for insurance carriers.
“There’s another side to this, which is many of these drugs, because they are usually considered promising for serious conditions of unmet need, they’re basically impossible for payers. They don’t want to say no,” he explains. “And yet the prices, they feel, don’t reflect the added uncertainty around the ultimate benefit. Also, some of the data comes out in a way that makes it harder for payers to really know how to focus their coverage to make sure that the patients who are most likely to benefit get it. So they see additional problems stacked on top of accelerated approval — the evidence is weak, and they never seem to go away, even if the evidence doesn’t come out later. And the cost of these types of drugs seem only to escalate.”
This story was reprinted from AIS Health’s biweekly publication RADAR on Drug Benefits.