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Posted 17 May 2022 | By Jeff Craven 

Study: Novel drug approvals in 2020 continue trend of fewer preapproval pivotal trials, surrogate endpoints

2755 More than half of the novel drugs approved by the US Food and Drug Administration (FDA) in 2020 were supported by a single pivotal trial, and slightly less than half of pivotal trials supporting novel drug approval used surrogate endpoints as a primary outcome, according to new research published in JAMA Network Open.
The use of fewer pivotal trials and acceptance of surrogate endpoints is the continuation of a trend with the development of new regulatory pathways and a goal to reduce drug development costs and expedite drug approval, Mayookha Mitra-Majumdar, MPH, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues said.
However, the trade-off is a reliance on the postapproval period for evidence collection, the authors noted. “These changes in the regulatory landscape raise questions about the nature of evidence underlying recent drug approvals and the extent to which the clinical value of each new drug is robustly characterized at the time of approval,” they said.
Mitra-Majumdar and colleagues identified 49 novel oncology and non-oncology drugs approved in 2020 by the FDA’s Center for Drug Evaluation and Research (CDER) as well as 75 pivotal trials supporting approval of those drugs. The authors evaluated aspects of the trial design, the number of pivotal drugs per drug, trial comparators, trial hypothesis, endpoints of the trials, trial results, approval pathway, postmarket requirements (PMRs) and postmarket commitments (PMCs).
They found 28 drugs approved in 2020 (57.1%) had one pivotal supporting trial, with number of participants in the trials ranging from 19 participants to 2,230 participants. A majority of trials measured superiority (66 trials; 88.0%), were randomized (57 trials; 76.0%), double-masked (46 trials; 61.3%) and compared the novel drug with placebo or vehicle (39 trials; 52.0%). A minority of trials had a historical or other control (21 trials; 28.0%), an active control (13 trials; 17.3%), or a placebo and an active control (2 trials; 2.7%).
Slightly less than half of pivotal trials (34 trials; 45.3%) measured surrogate endpoints for primary outcomes, the authors found. Oncology drugs (13 of 18 trials; 72.2%) were significantly more likely to use historic controls in their pivotal trials leading to drug approval compared with non-oncology drugs (8 of 57; 14.0%; P < .001). Surrogate measures as primary endpoints were also more common in oncology drugs (17 trials; 94.4%) than non-oncology drugs (17 trials; 29.8%; P < .001).
There were 178 PMRs and PMCs overall, and least one PMR or PMC was present for 40 drugs. “PMRs and PMCs were common and take on increased importance in cases in which they are intended to fill gaps in efficacy and safety left by preapproval evidence limited in amount and/or quality,” the authors said.
The authors attributed the variation in levels of evidence across novel drug approvals on an increase in the use of first-in-class drugs and drugs for rare diseases as well as incremental changes to FDA’s evaluation framework. “These efforts aim to accelerate the development and approval of drugs for serious conditions. Increasing flexibility in evidence standards may shorten development time, lower costs, and advance the start of drug companies’ revenue streams. Taken together, these may induce drug companies to pursue development programs that might otherwise be less attractive, potentially facilitating more drugs to market over time,” they said.
However, Mitra-Majumdar and colleagues expressed concern about the use of surrogate endpoints for drug approvals, noting that in some cases, postapproval confirmatory studies also use unestablished surrogate endpoints as evidence. “The shift from direct clinical end points to surrogates over time decreases confidence that these drugs improve patient outcomes,” they explained.
“The FDA and consumers may benefit from a reexamination of how the agency balances time to market with ensuring that approved drugs are sufficiently safe and effective,” the authors concluded.
JAMA Network Open Mitra-Majumdar et al.


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