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Miller J, Ly S, Mostaghimi A, Barbieri JS. Use of Active Comparator Trials for Topical Medications in Dermatology. JAMA Dermatol. 2021;157(5):597–599. doi:10.1001/jamadermatol.2021.0356
Spending on prescription medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new products.1 Medication costs place a substantial financial burden on patients, with nearly 30% not taking their prescription as directed because of costs.2 While some new medications may improve patient outcomes, others may not offer meaningful benefits vs existing less costly alternatives, especially in dermatology, in which subtle changes in the concentration or combination of topical agents can be classified as a novel product.3,4 While placebo-controlled trials are valuable to understand the efficacy of new medications, active comparator trials designs, in which the new medication is compared with an established treatment, provide data that can guide clinical decision-making by allowing direct comparisons between similar drugs. These designs are particularly relevant when inexpensive alternatives are already available for the same indication.3 In this study, we evaluated the use and trends of active comparator trial designs in dermatology.
To evaluate trends in the use of active comparator trial designs, topical medications approved between January 2002 and December 2020 were identified through the 2020 US Food and Drug Administration (FDA) Orange Book. For each medication, associated phase 2 to 4 clinical trials were identified using ClinicalTrials.gov, which requires trial registration for drugs seeking FDA approval or if 1 or more sites are in the US (eFigure in the Supplement). The study was deemed exempt from institutional review board approval because it did not qualify as human participants research.
For each trial, the use of an active comparator trial design was determined. Subgroup analyses were performed by clinical indication, trial phase, and whether the medication had a novel mechanism of action, was a novel molecule in an existing class, was a novel combination of existing medications, or was a new vehicle. Trends were evaluated using linear regression.
A total of 157 trials met the inclusion criteria. Between 2002 and 2020, the proportion of clinical trials for acne, psoriasis, and atopic dermatitis with an active comparator decreased (–5.2% per year; 95% CI, –1.7% to –8.6%; Figure). Phase 2 studies were most likely to include an active comparator (34 [71%]), whereas phase 3 studies were least likely (109 [32%]). Studies for medications that were a new combination (36 [66%]) were most likely to use an active comparator design, whereas studies of a new vehicle (36 [19%]) or new molecule in an existing class (19 [26%]) infrequently included an active comparator (Table).
Although there is a greater need for comparative effectiveness data in the setting of a growing number of available treatments, our results highlight that the use of active comparator trials has decreased over time. A potential limitation of this study is its cross-sectional design. When performed, active comparator trials were more common for phase 2 than phase 3 studies. Companies may view phase 2 studies as a lower-risk setting, because if the trial is not successful, they can move on to a vehicle-controlled phase 3 study and avoid promoting the phase 2 data. This is a missed opportunity for dermatology, especially when there are clear alternatives to the new medication, such as when the new medication is a change in vehicle (eg, lotion formulation of an existing molecule) or a new molecule in a well-established therapeutic class (eg, new topical retinoid).
Phase 3 trials of new combination drugs had the highest frequency of active comparators (24 [71%]). This finding may reflect the effect of the FDA policy that requires that “each component makes a contribution to the claimed effects” for fixed-combination products.5 This observation suggests that regulatory procedures stipulated by the FDA could be an effective approach to increase the frequency of active comparator designs. Pressure from clinicians or payers (eg, preferred coverage tier) could also encourage the use of active comparator designs.3 Given the concerning changes noted regarding the use of active comparator trial designs, it will be important for clinicians, patients, payers, and regulators to consider strategies to encourage the use of these important trials to guide clinical decision-making.
Accepted for Publication: February 2, 2021.
Published Online: April 7, 2021. doi:10.1001/jamadermatol.2021.0356
Corresponding Author: John S. Barbieri, MD, MBA, Department of Dermatology, University of Pennsylvania Perelman School of Medicine, PCAM 7 S Pavilion, 3400 Civic Center Blvd, Philadelphia, PA 19104 (email@example.com).
Author Contributions: Mr Miller had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis Mr Miller and Ms Ly contributed equally to the study.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Miller, Ly, Barbieri.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Miller, Ly, Barbieri.
Administrative, technical, or material support: Miller.
Conflict of Interest Disclosures: Dr Mostaghimi receives consulting fees from Pfizer, hims, and 3derm, has equity in Lucid and hims, receives licensing fees from Pfizer, serves on the medical advisory board for hims, and is a clinical trial investigator for Incyte, Lilly, Aclaris, and Concert. No other disclosures were reported.
Funding/Support: Dr Barbieri receives partial salary support through a Pfizer Fellowship in Patient Oriented Research grant to the trustees of the University of Pennsylvania.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: Dr Mostaghimi is an Associate Editor of JAMA Dermatology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.