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Majority of results from late-stage trials of failed drugs not published

Over the course of a decade, 54% of drugs and biologics in late-stage trials failed due to poor efficacy or safety concerns, according to findings published in JAMA Internal Medicine.

Researchers published the trial results in peer-reviewed journals for 40% of these drugs, Thomas J. Hwang, AB, from the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women's Hospital and Harvard Medical School, and colleagues wrote.

"It is difficult to derive lessons from the experiences of unsuccessful experimental drugs," Hwang and colleagues reported. “Negative clinical trial findings and the reasons for discontinuing the development of investigational products, including lack of approval by regulators, are often not disclosed. Trial data are often not reported publicly in a timely manner and may be worse for unapproved drugs. As a result, there are limited systematic data on why and how frequently novel agents fail in late-stage development. Previous studies have found that most new drug applications not approved by the [FDA] were reported to have efficacy deficiencies, safety deficiencies, or both. However, these studies did not assess the reasons for failure of drugs that did not reach regulatory filing or were not reviewed by the FDA."

Noting that failures can "inform clinical practice, regulatory decisions, and future research," the researchers assessed 640 investigational drugs in phase 3 or pivotal trials between 1998 and 2008.

Hwang and colleagues found that 344 (54%) of the drugs failed during clinical development, 230 (36%) were approved by the FDA and 66 (10%) were not approved by the FDA, but were approved in other countries. The drugs failed for a variety of reasons: 195 (57%) due to inadequate efficacy, 59 (17%) due to safety concerns and 74 (22%) due to commercial reasons.

Analysis showed that researchers published trial results in peer-reviewed journals for 138 (40%) of the failed drugs.

After adjusting for various factors, Hwang and colleagues found that drugs with an orphan designation were more likely to be approved compared with nonorphan drugs (46% vs. 34%; adjusted OR = 2.3; 95% CI, 1.4-3.7).

They also discovered that specific drugs were less likely to be approved, including cancer medications (27% vs. 39%; adjusted OR = 0.5; 95% CI, 0.3-0.9) and drugs from small and medium-sized companies (28% vs. 42%; adjusted OR = 0.4; 95% CI, 0.3-0.7).

"Recent policymaking aimed at stimulating pharmaceutical innovation has focused on allowing drugs to be approved on the basis of smaller data sets," Hwang and colleagues wrote. "Some commentators have proposed waiving the need for phase 3 testing, although others have responded that approval before rigorous study could worsen health outcomes by leading to widespread use of toxic or ineffective drugs that would have otherwise been shown to have failed."

They concluded: "As many investigational products fail in late-stage development because of inadequate efficacy or safety, our findings suggest that additional efforts to promote drug development should be directed at improving the validity of preclinical models for use in translational research and increasing the number of innovative products entering trials. The timely publication of trial results for all investigational agents, including those that fail in late-stage clinical development, is imperative." – by Chelsea Frajerman Pardes

Disclosure: Hwang reported previous employment from Blackstone and Bain Capital, which have invested in health care companies. Please see the full study for a complete list of all authors’ relevant financial disclosures.