Application of exposure bracketing to streamline the development of contraceptive products

Abstract

Developing new long-acting products of well-characterized contraceptive drugs is one way to address some of the reasons for unmet need for modern methods of family planning among women in low- and middle-income countries. Development and approval of such products traditionally follow a conventional paradigm that includes large Phase 3 clinical trials to evaluate efficacy (pregnancy prevention) and safety of the investigational product. Exposure-bracketing is a concept that applies known pharmacokinetics and pharmacodynamics of a drug substance to inform its safe and efficacious use in humans. Several therapeutic areas have applied this concept by leveraging established drug concentration-response relationships for approved products to expedite development and shorten the timeline for the approval of an investigational product containing the same drug substance. Based on discussions at a workshop hosted by the Bill & Melinda Gates Foundation in December 2020, it appears feasible to apply exposure-bracketing to develop novel contraceptive products using well-characterized drugs.

Keywords: BMGF, The Bill & Melinda Gates Foundation; Contraceptive development; Exposure-bracketing; FDA, US Food and Drug Administration; LNG, Levonorgestrel; Levonorgestrel; MHRA, UK's Medical and Healthcare Products Regulatory Agency; PD, Pharmacodynamics; PK, Pharmacokinetics; Pharmacokinetics; Progestin; RWDA, real world data analyses; Real world data.

Fig. 1

Application of exposure-bracketing to ensure safety and efficacy of a novel implant/injectable product of levonorgestrel, with levonorgestrel concentration presented in logarithmic scale (i.e., idealized data). Top and lower brackets are safety and efficacy thresholds that can be defined based on decades of clinical experience with various levonorgestrel products. For illustration purposes, if the levonorgestrel pharmacokinetic profile of the novel product is bracketed well within the thresholds (e.g., the fictional “Novel Injectable/Implant”), the product should be safe and efficacious for the intended duration (e.g., for 12 months). Oral daily only pill represented on this graph assumes the use of the lowest dose of levonorgestrel of 30 micrograms .

Fig. 2

Alternative product development scenarios for products with well-characterized drug substances in contrast to the full development program traditionally designed for new molecular entities. ^aHypothetical estimates. A full development program to obtain approval by a stringent regulatory authority for a new molecular entity historically can take 10–15 years; ^b Reduced programs include an abridged pathway in the European Union and a 505b(2) pathway in the US; ^c Captured in recent US FDA draft guidance^{[12] d} Full exposure bracketing approach maximally leverages existing knowledge of a drug substance to further shorten the clinical program by reducing the size and focusing on evaluating safety specific to the new product (e.g., the performance of a novel formulation in a phase III trial). Overall duration of follow-up in a phase III trial will depend on the targeted duration of the new product. Abbreviations: PK = pharmacokinetics; PD: pharmacodynamics.