A group of studies, editorials, and exposés have been published this week that criticize the US Food and Drug Administration’s (FDA’s) role as gatekeeper for new therapies. And, while some of the coverage could seem too critical, the approval processes and mechanisms that speed drugs to market appear to need tweaking — rather than a complete overhaul.
Take, for instance, the overall development time for a drug, which is defined as the date of an Investigational New Drug (IND) application to approval of a New Drug Application (NDA) or a Biologics License Application (BLA). This pace has remained relatively stagnant at 8 years, despite the introduction of many new policies and expedited programs during the period of 1983 to 2012, according to a new paper published in JAMA.1
What has changed dramatically, however, are review times by the agency: they went from more than 3 years in 1983 to less than 1 year in 2017 — and by 2018, median review time was just 10.1 months for standard drug applications and 7.6 months for priority applications.
Out of 59 new drugs developed in 2018, 48 of them, or 81%, benefited from an expedited pathway (Accelerated Approval, Fast-Track, or Priority Review). New biologic approvals, specifically, shot up from a median of 2.5 drugs in 1990 to 1999, to a median of 12 therapies from 2014 to 2018. More than half (58%) of the 59 new drugs in 2018 had an Orphan designation, 41% of them used the Fast-Track pathway, and 24% harnessed the Breakthrough Therapy designation to get approval.
Not only has the agency seen shortened FDA review times — but it is requiring less evidence of clinical benefit for approval to occur, the authors of the JAMA article asserted. The proportion of approvals based on single-arm, nonrandomized trials increased from 4% in 1995 to 1997, to 17% during the period of 2015 to 2017. Over the same time, the proportion of new drugs that were supported by at least 2 pivotal trials dropped from 80.6% to 52.8%.
“By the 2015-2018 period the FDA approved 90% of 172 drugs (both priority and standard) after just 1 review cycle, compared with 77% of 137 drugs from 2011 to 2014,” the authors observed. It also appears that simply applying for a NDA or BLA means a manufacturer will have a good chance of having an investigational drug approved; since 1988, the agency has approved approximately 80% of NDAs/BLAs.
Meanwhile, approvals that rely on surrogate end points are increasing. Surrogate measures of benefit were used in 44.3% of new drug approvals from 2005 to 2012, whereas this percentage rose to 59.3% for drugs approved from 2015 to 2017. Of most concern, wrote the study authors, was that the use of surrogate measures that were “not yet designated as well established” but that were still used for justification of approval under the Accelerated pathway, rose from 9% during 1993 to 2001 to 13% in 2011 to 2018.