FDA's drug approval process has accelerated over the last four decades, but a study published last week in JAMA indicates the evidence behind the approvals is getting weaker.
Following complaints that FDA's review process was too slow, Congress in the 1980s passed new laws and established regulations that aimed to speed up the approval of some much-needed medications. However, the number of new drugs in the market has caused researchers to question whether the agency is sacrificing quality to improve efficiency.
To better examine that question, researchers reviewed FDA drug approvals, as well as new regulatory initiatives and drug industry funding of FDA reviews, from 1983 through 2018. The results revealed that these initiatives had a major impact on drug approvals at FDA.
FDA expedited approvals led to drop in evidence quality
The researchers found that mean annual number of new drug approvals, including biologics, increased from 34 new approvals per year between 1990 and 1999 to 41 new approvals per year between 2010 and 2018. The number of approvals did decrease momentarily to 25 between 2000 and 2009. However, the average number of biologic product approvals increased steadily from 2.5 approvals per year between 1990 and 1999, to five approvals per year from 2000 to 2013, and then up to 12 from 2014 and 2018, according to the study.
The researchers also found those drug approvals are occurring faster than ever before. The median review time for standard drug applications was 10.1 months in 2018, up from 2.8 years for standard and priority applications that occurred from 1986 to 1992. However, the total time from the beginning of clinical testing to approval has remained the same at 8 years.
An analysis of the legislation approved in the 1980s found that a change in regulations likely played a part in the growing volume and increasing speed of drug approvals. For instance, the researchers found the percentage of drugs approved through the Orphan Drug Act of 1983, which was established to encourage drugmakers to develop more rare disease treatments, increased from 18% from 1984 to 1995 to 41% from 2008 to 2018.
The researchers also found that FDA's use of the Accelerated Approval, Fast-Track, and Priority Review increased over time. The Accelerated review enabled FDA to approve drugs based solely on surrogate measures that are "reasonably likely to predict clinical benefit," instead of requiring measures that clearly demonstrate a benefit or improvement. About 53% of drug approvals between 2015 and 2017 were supported by at least two pivotal clinical trials, compared with nearly 81% of approvals between 1995 and 1997, according to the study.
Drug industry funding also saw major changes in the 1980s, with more drugmakers providing funding to accelerate FDA's review process. In 1993, the year that Congress passed the Prescription Drug User Fee Act, FDA received nearly $30 million in fees, an amount that increased sharply to $908 million in 2018. In 2018, those fees accounted for 80% of the money spent on FDA employee salaries for drug reviews, the researchers found.
The study authors concluded that regulations and industry funding designed to increase the number of drug approvals have led to a more lax review process.
Jonathan Darrow, lead author of the study and a lawyer with Harvard Medical School, said the study results imply "there has been a gradual erosion of the evidence that's required for FDA approval," meaning clinicians "should not expect that new drugs will be dramatically better than older ones."
Similarly, the discovery that review fees covered the vast majority of FDA review salaries in 2018 raises "some concern about the incentives that this is created within the FDA, and whether it has created a culture in the FDA where the primary client is no longer viewed as the patient, but as the industry," he said.
Former FDA Principal Deputy Commissioner Joshua Sharfstein, who was not involved in the research, said regulations established in the 80s and 90s make clear that FDA wanted to approve more drugs, but the falling evidence standards raise some concerns about the quality of some of the new drugs on the market.
"Some of them are really great, and some of them [are] not so great," he said. "And a lot of them are very expensive."
In an accompanying editorial, Sharfstein wrote that FDA should consider reevaluating its expedited approval programs to ensure the drugs it's approving are effective and not just driving up costs. "We've kind of reached a point where it makes sense to pause and see whether we can do things better," he said. "And I think we can" (Anderson, Becker's Hospital Review, 1/15; Lupkin, NPR, 1/14).