Science‐Based Approach to Harmonize Contraception Recommendations in Clinical Trials and Pharmaceutical Labels

Abstract

This review presents a European Federation of Pharmaceutical Industries and Association/PreClinical Development Expert Group (EFPIA‐PDEG) topic group consensus on a data‐driven approach to harmonized contraception recommendations for clinical trial protocols and product labeling. There is no international agreement in pharmaceutical clinical trial protocols or product labeling on when/if female and/or male contraception is warranted and for how long after the last dose. This absence of consensus has resulted in different recommendations among regions. For most pharmaceuticals, contraception recommendations are generally based exclusively on nonclinical data and/or mechanism. For clinical trials, contraception is the default position and is maintained for women throughout clinical development, whereas appropriate information can justify removing male contraception. Conversely, contraception is only recommended in product labeling when warranted. A base case rationale is proposed for whether or not female and/or male contraception is/are warranted, using available genotoxicity and developmental toxicity data. Contraception is generally warranted for both male and female subjects treated with mutagenic pharmaceuticals. We propose as a starting point that contraception is not typically warranted when the margin is 10‐fold or greater between clinical exposure at the maximum recommended human dose and exposure at the no observed adverse effect level (NOAEL) for purely aneugenic pharmaceuticals and for pharmaceuticals that induce fetal malformations or embryo‐fetal lethality. Other factors are discussed, including contraception methods, pregnancy testing, drug clearance, options for managing the absence of a developmental toxicity NOAEL, drug‐drug interactions, radiopharmaceuticals, and other drug modalities. Overall, we present a data‐driven rationale that can serve as a basis for consistent contraception recommendations in clinical trials and in product labeling across regions.

Responding to the Call to Action: Framework to Accelerate Clinical Data Generation for Antiretroviral Use in Pregnant Individuals with HIV

“…Provided the safety and efficacy data generated in early-phase studies have an acceptable benefit–risk profile, phase 3 study protocols should recommend rather than require contraceptive use by individuals of childbearing potential. Detailed guidance for contraception recommendations in clinical trials and labelling has recently been proposed by the PreClinical Development Expert Group of the European Federation of Pharmaceutical Industries and Associations [ 13 ]. Healthcare providers should discuss benefits and risks with individuals who become pregnant, and they should be permitted to re-consent and continue study treatment.…”