Over 100 Drugs Given Speedy Approvals Still Lack Proof of Clinical Efficacy

Of 253 drugs authorized through the FDA’s accelerated approval pathway, 112 have not been confirmed as clinically effective, according to a new investigation.

As of the end of last year, 24 of those 112 drugs have been on the market for more than 5 years, and some have been on the market for more than 2 decades — often with a high price tag, according to clinical reporter Elisabeth Mahase, writing in The BMJ.

Though the accelerated approval pathway allows drugs onto the market before efficacy has been proven, the manufacturer must conduct post-approval studies, or confirmatory trials. If these trials show no benefit, the drug’s approval can be walked back.

However, only 16 drugs authorized through the accelerated approval pathway — established in 1992 — have been withdrawn, Mahase noted. Most of those that were withdrawn were shown to lack efficacy, but in some cases, confirmatory trials were never done. For example, celecoxib (Celebrex) — which was given accelerated approval in 1999 for the treatment of familial adenomatous polyposis, a genetic disorder that carries a high risk of bowel cancer — was on the market for some 12 years before the FDA asked Pfizer to voluntarily withdraw it for this specific indication because efficacy trials were never completed.

The BMJ asked the manufacturers of 24 drugs that have been on the market for more than 5 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 Six drugs had been withdrawn, approved, or postponed.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 a third. Four manufacturers of those six drugs reported patient recruitment for trials, and two reported being in discussions with the FDA over final trial design. Finally, 11 companies representing 12 drugs did not respond to The BMJ‘s request, said Mahase.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” an FDA spokesperson said in a statement provided to MedPage Today. “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies.”

If post-marketing clinical trials do not verify a drug’s clinical benefit or are not completed in a timely manner, the FDA may choose to initiate proceedings to withdraw a drug’s approval, the spokesperson added.

“Because the FDA continues to use this pathway to accelerate access to drugs for serious and life-threatening diseases for which there is an unmet medical need, at any point in time there will be drugs that are not converted because the confirmatory trials are ongoing,” the spokesperson said.

“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,” she continued.

Concerns about the accelerated approval pathway include a lack of threats from the FDA to withdraw a drug should confirmatory trials not be done, the agency’s use of indirect (or surrogate) measures of clinical benefit in some cases, and the potential for drug manufacturers to take advantage of the pathway when it comes to actual measures of safety and effectiveness, Mahase wrote.

However, even given these concerns, experts still concur that the accelerated approval pathway is useful and can yield benefits to patients, she noted.

Recommended changes to the accelerated approval pathway include designing, agreeing upon, and even starting confirmatory trials as part of the approval, as well as taking a closer look at the selection of surrogate measures (or endpoints), regulating drug prices, and reviewing and renewing the approval, she said.

In the latest high-profile example of debate about a drug authorized through the accelerated approval pathway, Biogen’s controversial Alzheimer’s disease treatment aducanumab (Aduhelm) got the green light from the FDA via the process last month. In this case, the FDA’s decision was based on the surrogate endpoint of reduction of amyloid-beta plaque in the brain.

While some have maintained that the drug offers a rare bit of hope for those suffering from a largely hopeless disease, the approval has also been met with a fair share of pushback. Critics of the drug have argued that there is a lack of evidence showing that the drug slows the progression of Alzheimer’s disease, and that its sky-high $56,000-a-year pricetag is simply unreasonable.

FDA’s most recent data — as of June 30 — show that there have been 269 drugs approved through the accelerated pathway since 1992. Of these, 132 have been converted to full approval, and 115 have not yet been converted; 84 of the 115 have been approved through the accelerated pathway since 2018.