Expedited approvals and adverse drug reactions in women
Authors: Constance Viehbeck
Journal: The Lancet (2024)

Over 65% of all new drugs undergo expedited drug approval in the USA.1US Food and Drug AdministrationNew drug therapy approvals.https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022#Date: 2022Date accessed: October 16, 2023Google Scholar Such drugs have been linked to a higher prevalence of adverse drug reactions, raising concerns about safety.2Wallach JD Ross JS Naci H The US Food and Drug Administration's expedited approval programs: evidentiary standards, regulatory trade-offs, and potential improvements.Clin Trials. 2018; 15: 219-229Crossref PubMed Scopus (4) Google Scholar It is well documented that women generally report a higher frequency of adverse drug reactions than men.3Pouyanne P Haramburu F Imbs JL et al.Admissions to hospital caused by adverse drug reactions: cross sectional incidence study.BMJ. 2000; 3201036Crossref Google Scholar However, it is unknown whether women have more adverse drug reactions than men from drugs approved via expedited pathways. I conducted a systematic literature review to assess sex differences (male or female, as reported in clinical trials) in data reporting. The review focused on the cardiovascular drug Multaq (dronedarone), which received expedited approval in 2009, intended as a safer replacement for amiodarone, a known proarrhythmic drug linked to severe arrhythmias, including Torsade de Pointes.4Drici MD Clément N Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome.Drug Saf. 2001; 24: 575-585Crossref PubMed Google Scholar Womens' naturally longer QT intervals make them more susceptible to the proarrhythmic effects of drugs, which is well documented in the case of amiodarone.4Drici MD Clément N Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome.Drug Saf. 2001; 24: 575-585Crossref PubMed Google Scholar, 5Li G Cheng G Wu J Zhou X Liu P Sun C Drug-induced long QT syndrome in women.Adv Ther. 2013; 30: 793-802Crossref PubMed Scopus (0) Google Scholar My research focused on assessing the extent of female participants' inclusion in both pre-approval and post-approval trials, and it scrutinised the availability of sex-disaggregated data on proarrhythmic effects. Female participants were under-represented in five of the six pre-approval trials, averaging at 32% of the sample. None of the pre-approval trials provided sex-disaggregated data on adverse drug reactions, which is concerning as the trials substantiate the drug's proarrhythmic potential. Post-approval observational evidence showed a greater occurrence of Torsade de Pointes among female than male participants,6US Food and Drug AdministrationFDA Adverse Events Reporting System (FAERS) public dashboard.https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysisDate: March 31, 2024Date accessed: August 29, 2023Google Scholar with approximately two-thirds of cases attributed to the female group. Notably, the drug recorded the highest number of reported Torsade de Pointes cases in the USA in 2011—surpassing its predecessor, amiodarone. These findings question the preventability of these outcomes through thorough sex-disaggregated reporting of adverse drug reactions in pre-approval stages. I highlight a knowledge gap that leaves the question of whether women face a higher risk of harm through expedited approval pathways than men. I declare no competing interests.