About half of all investigational drugs fail late-stage clinical development, according to a new study published in the Journal of the American Medical Association (JAMA), and the results of most of these failed studies never reach print. Unfortunately, the lack of reports of failed drugs hinders the advancement of medical knowledge, in that failures can actually inform clinical practice, shape regulatory decisions and support future studies.

Researchers from Brigham and Women's Hospital and Harvard Medical School used public sources and commercial databases to identify investigational therapeutics entering trials between 1998 and 2008, with a follow-up in 2015. The investigators classified agents by therapeutic area, fast-track designation, company size, orphan designation status, novelty of biological pathway, and as a biologic or pharmacologic product.

The researchers noted which drugs gained approval and identified reasons for failure and rates of publication of trial results. Among the 640 novel therapeutics included in the study, 54 percent failed in clinical development. The U.S. Food and Drug Administration (FDA) approved another 36 percent, and 10 percent received approval in other countries but did not receive approval by the FDA.

Of the products that failed in pivotal trials, 57 percent failed due to inadequate efficacy and 17 percent failed out of safety concerns. Another 22 percent of drugs failed due to commercial reasons. Researchers published trial results in peer-review journals in only 40 percent of failed agents, and only 8.1 percent of the trials that failed for commercial reasons reached print.

Researchers found that orphan-designated drugs were significantly more likely than nonorphan drugs to gain approval, at 46 percent versus 34 percent. Cancer drugs and agents sponsored by small- and medium-sized companies were also significantly less likely to gain approval.

Availability of new drugs and biological products creates new treatment options for patients and advances healthcare for the American public. Late-phase clinical studies usually include human testing to determine efficacy and long-term effects, but many drugs never make to the approval stage.

The FDA approved only 51 medications in 2015, including 45 new drugs and six recombinant therapies. While that number may seem low, a total of 51 new therapies is considered large in comparison to other years.

"It is difficult to derive lessons from the experiences of unsuccessful experimental drugs," says lead author of the study, Thomas J. Hwang, AB. "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."

Publishing the results of failed studies can provide valuable information to other scientists working on bringing similar products to market.