Trial publications, FDA sources exclude sex-based dosing recommendations

Researchers reported substantial variability in information on sex-based differences in drug safety and efficacy across trial publications and FDA sources for medications that were approved in 2019 and 2020.

They also found that these sources excluded information on sex-based dosing recommendations for drugs with reported sex differences. Moreover, women were frequently underrepresented in the trial cohorts that the FDA used to approve the medications. The findings were published in the Journal of General Internal Medicine.

“To support informed treatment decisions, health care professionals rely on different sources of medical evidence such as trial publications, drug labels and other FDA sources,” Kyungwan Hong, PharmD, MSc, a PhD candidate at the University of Maryland School of Pharmacy, told Healio. “The information on potential sex-based differences should be consistent across sources and easily accessible. When important information is missing about potential sex-based differences, this may inhibit informed treatment decisions and optimal patient care.”
Hong and colleagues analyzed data for 39 new molecular entities and therapeutic biological products that were approved by the FDA in 2019 and 2020. They reviewed trial publications for efficacy and safety data by sex, statements concerning sex differences in adverse events and primary outcomes and the availability of sex-based dosing recommendations.

The researchers reported that out of 53,189 participants in 80 pivotal trials, 65% were women. Yet, they were underrepresented in trials for 13 of the 39 therapeutics. For example, women accounted for just 22% of the study cohort in the single trial that evaluated Rukobia (fostemsavir, ViiV Healthcare) for HIV infection. Among the three trials that evaluated Caplyta (lumateperone, Intra-Cellular Therapies, Bristol Myers Squibb) for schizophrenia, 23% of the participants were women. In addition, in the five trials that evaluated Skyrizi (risankizumab-rzaa, AbbVie) for moderate-to-severe plaque psoriasis, women accounted for 30% of participants.

Hong and colleagues further examined 67 of the 80 pivotal trials. They reported that safety data by sex were discussed in all FDA clinical reviews and FDA Drug Trials Snapshots, but were only discussed in one of 39 (2.6%) FDA drug labels. None of the trial publications included safety data by sex, including those for Veklury (remdesivir, Gilead Sciences), “a medication that has received much attention due to the emergence of COVID-19,” Hong said.

“By contrast, such information was available in Drug Trials Snapshots or clinical review documents,” he said. The problem is whether health care professionals review those sources in everyday practice is questionable.”

In terms of efficacy, sex differences were discussed in 31 of 39 (79.5%) FDA clinical review documents, all FDA Drug Trials Snapshots, eight (20.5%) FDA drug labels and 12 (19.4%) trial publications, according to the researchers.

Among the medications that reported sex differences in adverse events and primary efficacy outcomes, none of the sources provided dosing recommendations or adjustments based on sex. The absence of dosing recommendations or adjustments by sex raised “questions about the actionability of the information,” Hong and colleagues wrote.

“As rational prescribing requires convenient access to reliable information regarding potential sex-based differences, we recommend that regulators help ensure we have reliable information regarding potential sex-based differences in drug efficacy and safety,” Hong said. “Trials need to be designed to adequately study this and the results should be explicitly reported in the trial publications and consistently noted in all sources of FDA information.”