FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1898 (Published 30 July 2021) Cite this as: BMJ 2021;374:n1898
Since the US Food and Drug Administration established its accelerated approval pathway for drugs in 1992, nearly half (112) of the 253 drugs authorised have not been confirmed as clinically effective, an investigation by The BMJ has found.
Of these 112 drugs approved in the past 28 years, a fifth (24) have been on the market for more than five years and some for more than two decades—often with a hefty price tag, shows an in-depth analysis of FDA data1 to 31 December 2020, conducted by The BMJ.
The accelerated pathway allows drugs onto the market before efficacy has been proved. As part of this approval, however, the manufacturer must conduct post-approval studies—known as phase IV confirmatory trials—to “verify the anticipated clinical benefit.” If these trials show no benefit the drug’s approval can be cancelled.
Further analysis of FDA data shows that only 16 drugs approved through the pathway have ever been withdrawn. Most of these were shown to lack efficacy, but in some cases the confirmatory trials were never done. Celecoxib (Celebrex), which was given accelerated approval in 1999 for the treatment of familial adenomatous polyposis, was on the market for 12 years before the FDA finally asked Pfizer to voluntarily withdraw it for this indication because the efficacy trials were never done.2
The BMJ asked the manufacturers of 24 treatments that have been on the market for more than five years whether they had conducted phase IV trials. Six drugs had been withdrawn, approved, or postponed. Of the remaining 18 drugs, relevant trial information was provided for just one third (6/18). And only four of these had started to recruit patients, while two companies said that they were still in discussion with the FDA over the final study design.
Eleven companies (representing 12 drugs) did not respond to the request, including Sanofi Genzyme, which is responsible for clofarabine (Clolar), a drug for paediatric relapsed or refractory acute lymphocytic leukaemia that has been on the market for 17 years without a confirmatory trial.
Despite the pathway’s good intentions to accelerate “the availability of drugs that treat serious diseases” experts are concerned that it is now being exploited, to the detriment of patients—who may be given a drug that offers little benefit and possible harm—and of taxpayers.
Huseyin Naci, associate professor of health policy at the London School of Economics, UK, said, “These products routinely have side effects, but the benefit information is a lot less certain. That’s what we’re concerned about—that we may have drugs on the market that don’t have any benefits but certainly predictably have harms associated with them.”
All carrot and no stick
In 2015 a review of the FDA’s expedited pathways by the US Government Accountability Office said that the “data on post-market safety issues and studies were found to be incomplete, outdated, [and] to contain inaccuracies.”3
The Institute for Clinical and Economic Review (ICER)—which, like The BMJ, receives funding from Arnold Ventures—dug a little deeper in April 2021,4 reporting that a lack of “credible threats” to withdraw approval if companies didn’t carry out confirmatory trials meant that study sponsors had little incentive to do them.
It also highlighted the FDA’s “inconsistent decisions following negative or ambiguous confirmatory data.” The review’s white paper said that, “barring safety concerns, the agency has generally preferred to steer clear of withdrawing approval, even when post-marketing trials do not support a treatment effect on the primary clinical endpoint.”
Evidence standards are “too low”
In light of such incidents some medical leaders have argued that the FDA’s standards for evidence are too low.
When efficacy is not clear the FDA uses surrogate endpoints as a substitute for a direct measure of how a patient feels, functions, or survives, and while benefit may not be measured, a prediction of clinical benefit is expected. In some cases there is a strong indication that the surrogate endpoint predicts meaningful benefit; however, where the situation is less straightforward, inconsistencies and a lack of transparency surrounding decisions have led to serious questions over the standards of evidence being accepted.
Steven Pearson, ICER president and a lecturer at Harvard Medical School in Massachusetts, said, “Sometimes we just don’t really know how well the surrogate outcome correlates with future patient outcomes. That’s where there’s always going to be some judgment about whether that seems reasonably likely.
“[But] there’s really very little transparency around how these decisions are being made. There’s no kind of compendium that the FDA returns to look at to try to calibrate its thinking and to make it more transparent to outside observers. So, it feels a bit ad hoc, and certainly to some people’s eyes, it feels like what it takes to be reasonably likely is almost meaningless now—it seems very, very small.”
Another problem is that even when confirmatory trials are carried out, many use the same surrogate endpoints that were used in the pre-approval trials, rather than clinical outcomes. This means that no real understanding of efficacy is gained.
Naci said, “I think regulators across the board need to really raise the bar for using surrogates in general. Regulators really need to think very carefully about what would constitute a valid surrogate and whether companies can actually provide that level of evidence.”
The current process—which allows drugs to be on the market with such a low evidence base—sends the wrong signals to other drug companies, which will assume that they can also gain approval with little evidence, he said.
Rachel Sachs, an associate professor of law at Washington University in St Louis, Missouri, said, “There are some instances where the companies really do seem to be taking advantage of the accelerated approval pathway and are using it in a way that makes it harder to get at the truth about whether these products really are safe and effective.”
Can it be reformed?
Despite the concerns raised, all experts who spoke to The BMJ agreed that the accelerated pathway was still useful and could be truly beneficial to patients, although some changes were needed. One effective reform could be for confirmatory trials to be designed, agreed, and even started as part of the approval, and the FDA needs to be stricter in enforcing its own rules.
Sachs said, “One important piece of the puzzle is for the FDA itself to be tougher on these companies, to hold them to the bargain that they have agreed to, and to take action when the company has not met their obligations. Knowing that it is difficult to take these products off the market should be a factor in whether they think about granting accelerated approval in the first place.”
Other suggestions set out in the ICER’s white paper include strengthening the selection of surrogate endpoints, regulating the price of accelerated drugs, and regularly re-reviewing and renewing the approval to ensure that it continues to justify the risk-benefit trade-off.
Pearson told The BMJ, “I’m not shy in saying that some of [the suggested modifications] would just take the FDA a little bit closer to the way that the Europeans manage these things, where even the term conditional approval sends a different signal than accelerated approval.
“We could move the needle and get the true goal of accelerated approval, which is still a very viable one, [but] get it done in a way that really is more beneficial for patients in the long run.”
An FDA spokesperson said that the agency was “committed to working with sponsors to ensure that confirmatory studies are completed in a timely manner . . . We expect sponsors to commit all resources needed to move trials forward as effectively as possible, with the aim of completing trials as soon as is feasible, while assuring the quality of the data and the robustness of the results.”
Elusive confirmatory trials
Midodrine hydrochloride (Proamatine), a treatment for orthostatic hypotension, has languished on the market for 25 years despite the required confirmatory studies never being performed. As of 2009 the treatment had amassed $257m (£185m; €217m) in sales5; at that point, with generics on the market, any hope that the company would fulfil its approval conditions was lost. Eventually, in 2010, the FDA said that it would remove the drug from the market, but it U turned after patient complaints.
Mafenide acetate (Sulfamylon) has been on the market for 23 years. A spokesperson for the manufacturer Mylan told The BMJ that the company had submitted the clinical study report for the phase IV confirmatory trial to the FDA in 2014—around 16 years after it was approved. Seven years later discussions are still ongoing regarding “modifications to the study design.”
Bevacizumab, a drug approved for treating glioblastoma, was granted full approval “despite failure to demonstrate improvements in overall survival.” The FDA said that its decision was based on patient input on gains in progression-free survival and reduction in corticosteroids. However, the Institute for Clinical and Economic Review said that this was seen as “inconsistent with the stated goals of the confirmatory trial, contributing to a sense of a lack of consistency in decision making.” Roche, the manufacturer, told The BMJ that although the drug did not meet the primary endpoint in the confirmatory trial, in other studies it had “demonstrated clinically meaningful results across multiple clinical trial endpoints, including progression-free survival, tumour shrinkage, and reduced need for corticosteroids.”
Aducanumab controversy
Aducanumab (Aduhelm), which costs $56 000 (£40 000; €47 000) per year per patient, was approved in June 2021 through the accelerated approval pathway, despite the advisory committee raising serious concerns6 about efficacy and uncertainty over whether the reduction in amyloid plaque would lead to cognitive improvement.7
The FDA’s acting commissioner has since asked the US health department’s inspector general to investigate allegations of improper contact between FDA regulators and the manufacturer Biogen.8 The agency has also restricted the drug’s use to people who have not progressed beyond mild cognitive impairment or early dementia. Biogen has been given nine years to complete the confirmatory trials, but it has promised not to raise the price further only for four years.
Although Biogen has not yet filed for approval in the UK, the European Medicines Agency is currently reviewing aducanumab, and a decision is expected this year.