Exclusion of Women of Childbearing Potential in Clinical Trials of Type 2 Diabetes Medications: A Review of Protocol-Based Barriers to Enrollment

Abstract

OBJECTIVEWomen of childbearing potential are often excluded from participating in clinical trials owing to concerns about adverse fetal effects of treatment. This study aims to determine the prevalence of fertility-related exclusion criteria in clinical trials of type 2 diabetes medications and to determine whether these criteria are commensurate with drug risk.RESEARCH DESIGN AND METHODSClinicalTrials.gov was queried for trials of type 2 diabetes medications that were phase 2 or 3, were based in the U.S., and enrolled participants 18–40 years old. Six hundred eighty-eight trials met criteria. Information collected about each trial included enrollment, trial length, exclusion and inclusion criteria, trial sponsor, and pregnancy category of drug(s) administered.RESULTSMost studies (59%) included one or more fertility-related exclusion criteria, most often excluding current pregnancy (55%) and breast-feeding (44%). Trials of medications with increased fetal risk were not more restrictive: trials of category C drugs (evidence of fetal risks in animals) were less likely to exclude pregnancy compared with trials of category B drugs (no known human or animal fetal risks) (45.6% vs. 69.8%, odds ratio [OR] 0.37 [95% CI 0.20, 0.65], P = 0.0005) or to require contraceptive use (29.9% vs. 57.1%, OR 0.32 [95% CI 0.18, 0.56], P = 0.001).CONCLUSIONSIn clinical trials of type 2 diabetes medications, exclusion criteria affecting women of childbearing potential are often disproportionate to risk to the participant and fetus. These criteria have the potential to impede young women’s access to clinical trials and may hinder the acquisition of clinical knowledge critical for improving the care of women with diabetes.

Using Real‐World Data to Extrapolate Evidence From Randomized Controlled Trials

“…Similarly, even when not explicitly excluded, women remain under‐represented, in part due to fertility‐related exclusions. Although diabetes is a chronic condition with significant morbidity that affects men and women differently, nearly 60% of trials for type 2 diabetes medications registered at clinicaltrials.gov had at least one fertility‐related exclusion criterion; 7% had exclusions for women with child‐bearing potential . Patients with complex comorbidities are also often excluded from trials.…”

“…Although diabetes is a chronic condition with significant morbidity that affects men and women differently, 4 nearly 60% of trials for type 2 diabetes medications registered at clinicaltrials.gov had at least one fertility-related exclusion criterion; 7% had exclusions for women with child-bearing potential. 5 Patients with complex comorbidities are also often excluded from trials. One report found that although chronic kidney disease is associated with a high risk of death from coronary artery disease and that effectiveness of treatment can be different in this population, 75% of registered trials for drugs to treat coronary artery disease excluded patients with chronic kidney disease.…”

Against Consent Form Language Requiring Multiple or Specific Methods of Contraception

“…Fourth, the National Institutes of Health and the Food and Drug Administration have issued standards for the inclusion of women of reproductive age in clinical trials . However, coercive policies and language regarding contraception in the consent form may ultimately lead to lower enrollment rates of women or to significant differences between women who choose to enroll in a study and those who do not . Differential enrollment is problematic from a scientific as well as an ethical standpoint.…”

The moral imperative to approve pregnant women’s participation in randomized clinical trials for pregnancy and newborn complications

“…However, this conservative stance enhances neither fetal nor maternal safety. Besides, there is evidence that this risk to the fetus may be overestimated in some studies [30] and that potential benefits may far outweigh this risk in other studies such as gene transfer research [21].…”