Pivotal clinical trials associated with FDA ophthalmic drug approval were found to underreport and conflate sex and gender in analysis.
Data analysis of pivotal ophthalmology clinical trials associated with US Food and Drug Administration (FDA) drug approvals between 1995 and 2022 suggested greater integration of sex and gender is necessary to improve the validity of ophthalmic trials.1
Among 85 trials representing 34 ophthalmic drugs, the observational study revealed more than three-quarters of ophthalmology trials associated with FDA drug approvals conflated sex and gender. More than two-thirds of these trials lacked any sex- and gender-based data analyses.
“This cross-sectional analysis of clinical trials associated with FDA approval of ophthalmic drugs demonstrated marked conflation of sex and gender terminology, underreporting of sex and gender assessment methods, and inattention to sex- and gender-based analysis,” wrote the investigative team, led by Edward Margolin, MD, department of ophthalmology and visual sciences, department of medicine, division of neurology, University of Toronto.1
In recognition of sex and gender as critical determinants of scientific rigor, reproducibility, and equity, Congress passed the National Institutes of Health (NIH) Revitalization Act of 1993 to promote the inclusion of women and minority groups in health research.2 Future amendments to the Act aimed to clearly define clinical research and provide tailored recommendations for future clinical trials.
A review of ophthalmology trials associated with FDA approvals showed that demographic data on sex and gender were reported for all trials. However, these trials did not assess the accuracy of sex and gender reporting, nor the proportion of trials that performed sex- and gender-based analysis. Margolin and colleagues thus evaluated the accuracy of sex and gender reporting, as well as the extent of sex- and gender-based analysis, in clinical trials over a more than 25-year period.1
Ophthalmic drugs that received FDA approval between January 1995 and December 2022 were identified from the Drugs@FDA database. The team noted that 1995 served as the cutoff as FDA drug labels were not publicly accessible for most ophthalmic drugs registered before that date. For each trial, independent reviewers reviewed documents, including the peer-reviewed publication, ClinicalTrials.gov report, and FDA medical and statistical reviews.
The analysis’ primary outcome consisted of the proportion of trials that correctly applied sex and gender terminology, reported the assessment method, and conducted sex- or gender-based analysis. Investigators defined incorrect application of sex and gender terminology as the interchangeable or incorrect use of sex- and gender-related terms without clear justification.
Among 978 FDA new molecular entities approved during the study period, investigators identified 34 drugs corresponding to 85 trials as being related to ophthalmic disease (3.5%). All included trials were a randomized controlled study design and 32 trials corresponding to 16 ophthalmic drugs (47.1%) were associated with a peer-reviewed publication.
Analyses revealed only 16 (19.5%) trials correctly used sex and gender terminology. Of the 80.5% of trials that conflated sex and gender, more than half (58.5%) used sex- and gender-related terms interchangeably, 20.7% used sex-related terms about gender, and 1.2% used gender-related terms about sex.
Most studies reported sex- and gender-disaggregated demographic data (96.5%), but few studies disaggregated data on the dropout rate (1.2%), primary outcomes (28.2%), secondary outcomes (2.4%), and adverse events (5.9%) by sex or gender. Moreover, erroneous sex and gender reporting were associated with a later publication year and higher journal influence metrics, including its impact factor and citation indicator (all P <.001).
Margolin and colleagues noted no trial defined sex or gender, reported collection methods of sex and gender data, nor enrolled participants from sexual and gender identity minority populations. Comprehensive reporting and analysis of sex and gender can be critical for maintaining reproducibility and equity across medicine.
“It is imperative that clinical trials, especially those that inform regulatory decisions, include sex and gender as variables of interest and apply concepts related to sex and gender correctly,” they wrote. “Improper use of terminology does not change the nature or magnitude of trial findings, but it detracts from one’s ability to interpret and apply this information.”