Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.

Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis.

OBJECTIVE: The objective of this investigation was to assess the potential effect of obesity on the effectiveness of hormonal contraceptives (HCs). STUDY DESIGN: A meta-analysis was conducted using individual participant data directly from the Phase 3 clinical trials of combination oral contraceptives (COCs) rather than extracting summary data from literature. Trials selected were reviewed by the US Food and Drug Administration (FDA) between 2000 and 2012, conducted in North America, had more than six 28-day cycle equivalents of exposure, and had readily retrievable participant-level data. Contraceptive effectiveness was measured by the Pearl Index (PI: the number of pregnancies per 100 woman-years) in women aged 18-35 at risk of unintended pregnancy. The incidence rate ratio (IRR), a ratio of PIs for obese women (defined as body mass index [BMI] ≥30 kg/m(2)) compared to non-obese women (BMI <30 kg/m(2)) was calculated. A Cox proportional-hazard regression model with fixed and random-effects were used to estimate hazard ratios (HRs) for unintended pregnancy in obese women compared to non-obese women. RESULTS: Seven clinical trials with COCs (N=14,024: 2707 obese and 11,317 non-obese women) met the inclusion criteria for the meta-analysis. The PI for each trial varied: 2.05-5.08 for obese and 1.84-3.80 for non-obese women. The pooled PI estimated using direct weighted average method was 3.14 (95% CI: 2.33-4.22) for obese and 2.53 (95% CI: 1.88-3.41) for non-obese women. The pooled IRRs estimated using direct weighted average and Mantel-Haenszel adjustment methods were comparable: 1.37 (95% CI: 1.02-1.84) and 1.43 (95% CI: 1.07-1.92), respectively. The overall HR of 1.44 (95% CI: 1.06-1.95; p=.018) in the meta-analysis suggested a 44% higher pregnancy rate during COC use for obese women after adjusting for age and race. IMPLICATIONS STATEMENT: Obesity may increase the risk of unintended pregnancy in women using COCs; more data on obese women from ongoing and future Phase 3 clinical trials are necessary to allow further evaluation of this topic. CONCLUSIONS: Results of this meta-analysis suggest that obese women may have a higher pregnancy rate during COC use compared to non-obese women. Future analysis should assess differences in pharmacodynamics or compliance that could potentially account for the observed difference in unintended pregnancy rates.