IMPORTANCEIn recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. OBJECTIVE To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. DESIGN, SETTING, AND PARTICIPANTS This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. EXPOSURES Drug names, date of approval, indication on labeling, and clinical and regulatory details. MAIN OUTCOMES AND MEASURES Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. RESULTSThe 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. CONCLUSIONS AND RELEVANCEThese findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may (continued) Key Points Question What were the key design characteristics of the pivotal trials supporting novel drugs approved by the US Food and Drug Administration (FDA) in 2020? Findings This cohort study of 49 drugs approved by the FDA in 2020 found that they were supported by 75 pivotal trials, of which nearly two-thirds were double-masked, more than threefourths had a randomiz...
Context: New drug approvals in the US must be supported by substantial evidence from “adequate and well-controlled” trials. The Food and Drug Administration (FDA) has flexibility in how it applies this standard. Methods: We conducted a systematic literature review of PubMed for studies between 2005-2020 evaluating the design and outcomes of the key trials supporting new drug approvals in the US. We extracted data on the trial characteristics, endpoint types, and expedited regulatory pathways. Findings: Among 48 publications eligible for inclusion, 30 covered trial characteristics, 23 covered surrogate measures, and 30 covered regulatory pathways. Trends point towards less frequent randomization, double-blinding, and active controls, with variation by drug type and indication. Surrogate measures are becoming more common but are not consistently well-correlated with clinical outcomes. Drugs approved through expedited regulatory pathways often have less rigorous trial design characteristics. Conclusions: The characteristics of trials used to approve new drugs have evolved over the past two decades, along with greater use of expedited regulatory pathways and changes in the nature of drugs being evaluated. While flexibility in regulatory standards is important, policy changes can emphasize high quality data collection before or after FDA approval.
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