Hundreds of new – but noninnovative – drugs have been approved in the United States in the last 20 years using expedited review programs designed especially to push forward first-in-class agents for unmet medical needs.
An extensive review of publicly available Food and Drug Administration records also concluded that few of these drugs rely on the more rigorous clinical trials intended to screen out ineffectively or potentially harmful drugs – potentially increasing the availability of poorly investigated agents that may or may not provide much clinical benefit*.
Dr. Aaron Kesselheim
“These data have important implications for patient care,” Dr. Aaron S. Kesselheim and his colleagues wrote (BMJ 2015;351:h4679 doi: 10.1136/bmj.h4679).
“Special regulatory designations allow drugs to be approved at earlier stages based on less rigorous clinical testing; for example, one review showed drugs with orphan designations or granted accelerated approval are also more likely than drugs without these designations to be tested in single-arm studies without placebo or active comparators,” said Dr. Kesselheim of Harvard University and his coinvestigators. “While many physicians and patients trust that FDA-approved products are effective and safe for use, products approved on the basis of more limited data are at greater risk for later changes to their effectiveness or safety profiles.”
A twin study, published in the same issue, found that a lesser class of evidence often supports the approval of supplemental indications. Of 295 supplemental indications approved since 2005, only about one-third were based on trials with active comparators. The rest used nonclinical endpoints like historical controls and biomarkers or imaging data.
Most striking of all, most of the supplemental indications were aimed at pediatric patients, and many extrapolated adult evidence to these young patients, said the authors.
“Although we do not conclude that any of these approvals were mistaken, pediatric patients have unique physiologies and pharmacokinetic characteristics that may require more rigorous trials to confirm both the efficacy and the safety of drugs previously approved only for use in adults.”
Study 1: Expedited review
The authors used the Drugs@FDA database, FDA annual reports, and the Federal Register to identify 774 new agents representing first-in-class agents. Overall, this accounted for a significant increase of 2.6% per year in the number of expedited review and approval programs for each new agent (rate ratio, 1.06) and a 2.4% increase per year in the proportion of agents involved in at least one of these programs. Many approvals were associated with more than one program, and this proportion increased over the study period, from a low of 0.54 in 1987 to a high of 1.72 in 2014.
“Driving this trend was an increase in the proportion of approved, non–first-in-class drugs,” associated with at least one [expedited] program,” the authors noted.
Additionally, not all of the drugs could reasonably be considered as treatments for an urgent, unmet medical need. “For example, bimatoprost (Latisse: Allergan, Dublin) was granted priority review when it was first approved in 2008 for hypotrichosis of the eyelids, a clearly less serious condition.”
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While the “breakthrough therapy” pathway was intended for only a handful of drug approvals each year, the FDA received nearly 250 applications in the first 2 years; 68 of these were granted, despite the agency’s prediction than only 2-4 such applications would be approved.
Four of these were for chronic lymphocytic anemia alone – a number the authors suggested might be excessive. “It is doubtful that a single disease condition can be the subject of four true ‘breakthroughs’ in such a short time frame.”
The situation is likely to accelerate, they noted. The 21st Century Cures Act, passed in July by the U.S. House of Representatives, instructs the FDA to develop a new pathway for repurposing approved drugs on the basis of early stage investigators and “high-risk, high-reward research. ... The FDA would also be permitted to approve such indications on the basis of only summaries of data in such circumstances, rather than being required to review the data in detail.”
New antibiotics and antifungals would have particularly lenient evidence requirements, according to the investigators.
However, expedited review is a double-edged sword, the paper noted. An FDA review found that most cancer drugs are later found to be safe and effective in postapproval studies, although such studies are often delayed or – in some cases – never conducted.
The FDA should be granted more authority to punish manufacturers who lag behind these requirements, including having the ability to impose fines and even suspend approval until additional studies are complete, the investigators said.