Adverse effects in women: implications for drug development and regulatory policies

Abstract

The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.

Sex as a Biological Variable: Who, What, When, Why, and How

“…The observation that female sex is a risk factor for a wide range of adverse drug reactions bears additional discussion given the readership and mission of this Journal with respect to pharmacology (Parekh et al, 2011;Franconi et al, 2012;Spoletini et al, 2012). Early limitations on recruitment of women to randomized clinical trials and the delay in considering SABV in drug studies have resulted in a number of cautionary tales.…”

“…Estradiol effects on stress responses varies in pre-vs post-menopausal women (Dumas et al, 2012;Albert et al, 2015). (g) Females are at greater risk of dementia and adverse effects of many pharmacologic agents used in the treatment of adult disorders (Parekh et al, 2011;Franconi et al, 2012;Spoletini et al, 2012). brain (Chura et al, 2010;Baron-Cohen et al, 2015). Programming of important regulatory brain regions, including the neuroendocrine hypothalamus, via such steroid hormone effects on cell migration patterns during early development likely also contributes to sex differences in how the individual responds to environmental perturbations throughout life .…”

Gender differences in clinical registration trials: is there a real problem?

“…Traditionally, studies have been carried out in predominantly Caucasian countries, using mainly adult white males, especially for phase I clinical trials investigating tolerability, clinical pharmacology, dose‐related side effects and early evidence of efficacy 1. Historically, women of child‐bearing age have been discouraged from participation in phase I trials because of undue risk to fetal development, especially after the thalidomide scandal of the 1960s 2. This approach seems plausible and responsible in early clinical drug development, to avoid teratogenic effects in studies of compounds of which the vast majority will never reach the market anyway.…”

Sex Influence on the Efficacy and Safety of Sacubitril/Valsartan

“…There are also important pharmacokinetic differences between sexes, and the response to a treatment or the occurrence of adverse effects can vary widely [3, 4]. From a cardiovascular perspective, there are also major differences among sexes, including the prevalence of cardiovascular risk factors.…”