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

Li Li,Shirley K Seo,Ping Zhao,Gerald Willett,Hao Zhu,Yaning Wang,Doanh Tran,Kirsten M Vogelsong,Stephen E Gerrard,Praveen Balimane

doi:10.1146/annurev-pharmtox-031120-015212

Abstract

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.

Highlights

Poor patient compliance due to pill fatigue has been a major barrier to optimal outcomes with pharmacotherapy [1]
The Food and Drug Administration (FDA) and the Bill & Melinda Gates Foundation have entered into a cooperative research and development agreement to examine the feasibility of an exposure-based paradigm for the development and review of alternative contraceptive products of well-established drug substances with prior safety and efficacy data
This opportunity is a collaborative engagement to explore ways to modernize and streamline approval pathways for alternative contraceptive products of well-established drug substances. Results of these analyses may provide the FDA with evidence that can be used to enhance health-care communication and product labels and inform updates of regulatory guidelines and harmonization of global regulatory review standards associated with contraceptive products

Summary

INTRODUCTION

Poor patient compliance due to pill fatigue has been a major barrier to optimal outcomes with pharmacotherapy [1]. Overall, based on observed relative bioavailability data for oral formulations and predicted D2-RO levels, 90 and 120 mg were selected to be studied in the phase III program, which demonstrated statistically significant efficacy on the primary end point (change from baseline in Positive and Negative Syndrome Scale total score) and secondary end point (change from baseline in Clinical Global Impressions–Severity) at both doses (90 and 120 mg) compared with placebo in subjects experiencing acute exacerbations of schizophrenia [25]. Both doses were approved as initial starting doses.

CONCLUSIONS

Findings

DISCLOSURE STATEMENT