Pivotal Studies Supporting US FDA Drug Approvals Have Declined, JAMA Research Finds
Executive Summary
Over 30-year period, approvals increasingly used expedited programs and were based on fewer pivotal trials with less robust comparators, authors report.
Looking at the US Food and Drug Administration's approval of new drugs and biologics over a 30-year period, a group of academicians found differences in the quality of evidence supporting their approval, with fewer pivotal studies being conducted over time.
Audrey Zhang, New York University School of Medicine, and her co-authors published their study, "Assessment of Clinical Trials Supporting US Food and Drug Administration Approval of Novel Therapeutic Agents, 1995-2017," on 21 April in JAMA Network Open.
They reviewed 273 new drugs and biologics approved by FDA for 339 indications over three periods: 1995-1997, 2005-2007, and 2015-2017. They found that the proportion of therapeutic approvals using at least one expedited regulatory program (priority review, accelerated approval, fast track or breakthrough therapy) increased from 34.6% in 1995-1997, to 57.9% in 2005-2007, and 64.2% in 2015-2017, as did indication approvals receiving an orphan designation.
"The aggregated evidence supporting indication approvals has become less rigorous in some ways, with the proportion of approvals supported by the commonly understood standard of at least 2 pivotal trials declining from 81% to 53% and the proportion of approvals supported by at least 1 trial using a comparator declining from 96% to 83%," they wrote. "Meanwhile, it has become more rigorous in other ways, with the proportion of indications supported by as least 1 trial of 6 months' duration increasing from 26% to 46%."
The authors said a key question is whether these overall trends are driven by changes in the baseline characteristics of drug approvals, such as the frequency with which approvals use special regulatory programs or orphan designation, or whether there has been an evolution in the standards needed to secure approval within these strata. They said their findings suggest both explanations may play a role.
Increasing Need For Postmarket Evaluation
Zhang, et al, found that there was a decrease in the number of pivotal trials supporting an indication approval only among therapeutics using a special regulatory program, while therapeutics not using a special regulatory program showed increases in the number of treated patients and the proportion of indications supported by a trial of at least 6 months' duration.
They noted that specialty regulatory programs are intended to encourage development in areas of unmet need and to facilitate approvals based on fewer trials, shorter trials, or trials using surrogate markets and thus require less time to determine an effect and enable products to reach the market sooner.
"The findings of this study suggest that quality of clinical trial evidence used to support new drug and biological approvals has changed during the past 3 decades, requiring fewer pivotal trials with less robust comparators but with longer durations," the authors conclude. "This change has implications for physicians and patients as they consider using newly approved drugs as well as for regulators, given that it suggests an increasing need for continued evaluation of therapeutic safety and efficacy after approval."
The authors noted that one of the limitations of their study is that it included only three-year samples of approvals in each period and could not capture the full range of therapeutic agents and variations in approval trends across entire decades. They also could not fully adjust for associations between all combinations of drug attributes and special regulatory programs and orphan status. They noted that it was not uncommon for a therapeutic approval to use multiple special regulatory programs and they could not fully account for the possibility that a single program or attribute had disproportional influence on the associations they observed.
In addition, they analyzed only clinical trials identified as pivotal trials. They said other nonpivotal studies and data, such as observational studies or previous marketing experience from other countries, may contribute to FDA reviewers' holistic evaluations of drugs that they could not capture.
FDA Finds Abundance Of Safety Data
Previous studies have analyzed the impact of FDA's expedited approval pathways. Joseph Ross, of Yale University School of Medicine, the corresponding author for the current piece, was also corresponding author for a 2017 JAMA study that found postmarketing events were statistically significantly more frequent among novel drugs and biologics approved between 2001 and 2010 that received accelerated approval. (Also see "Safety Events For Accelerated Approval Drugs Highlighted As Expansion Looms" - Pink Sheet, 14 May, 2017.)
Other researchers conducted an analysis of priority reviews, accelerated approval and fast track status of a single annual cohort of drug approvals, which was published in JAMA Internal Medicine in 2013. They found considerably fewer patients were studied prior to approval and that more safety questions remained unanswered. (Also see "Not So Fast On Expedited Approvals, Drug Safety Researchers Caution" - Pink Sheet, 19 Nov, 2013.)
The agency has often been criticized because its expedited approval programs are perceived as allowing products on the market too soon or with too little evidence.
Tackling this criticism, two years ago, FDA conducted an analysis of the agency's use of the accelerated approval mechanism for cancer treatments over the past 25 years. It found that cancer drugs receiving accelerated approval generally have twice the amount of safety data as efficacy, and more than half have confirmed clinical benefit after approval. (Also see "Accelerated Approval: US FDA Defends Size Of Premarket Safety Databases, Confirmatory Endpoints" - Pink Sheet, 5 Mar, 2018.)
More recently, a Government Accountability Office analysis found that when all else is equal, the assessment of a new drug application qualifying for one expedited program will on average only be seven days shorter than an application that does not qualify for an expedited program. (Also see "Drug Review Times Are Not Shortened Much By Single Expedited Review Designation" - Pink Sheet, 8 Apr, 2020.)