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Review
. 2023 Feb;113(2):226-245.
doi: 10.1002/cpt.2602. Epub 2022 May 5.

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

Christopher J Bowman  1 , Nathalie Becourt-Lhote  2 , Virginie Boulifard  3 , Rüdiger Cordts  4 , Solange Corriol-Rohou  5 , Brian Enright  6 , Linda Erkman  7 , Jayne Harris  8 , Andreas Hartmann  7 , Jan Hilpert  9 , Sophie Kervyn  10 , Britta Mattson  11 , LaRonda Morford  12 , Mireille Muller  13 , Marcy Powell  14 , Zhanna Sobol  11 , Rajamuthu Srinivasan  15 , Claudia Stark  16 , Kary E Thompson  17 , Katie J Turner  17 , Paul Barrow  18
Affiliations
Review

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

Christopher J Bowman et al. Clin Pharmacol Ther. 2023 Feb.

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.

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Conflict of interest statement

All authors are employed by the pharmaceutical industry as stated in their respective affiliations.

Figures

Figure 1
Figure 1
Female germ cell development and time to clear potentially damaged oocyte.
Figure 2
Figure 2
Male subject contraception flow chart. See Table 4 for determination of clinically relevant genetic and developmental toxicity as it relates to contraception recommendations. See Table 6 for methods of highly effective contraception methods. If the pharmaceutical has marketing authorization, follow contraception recommendation in the appropriate labeling. EFD, embryo‐fetal development; NOAEL, no observed adverse effect level; WOCBP, women of child‐bearing potential.
Figure 3
Figure 3
Female subject contraception flow chart. See Table 4 for determination of clinically relevant genetic and developmental toxicity as it relates to contraception recommendations. See Table 6 for methods of contraception and Table S3 for association between risk of malformations/embryo‐fetal lethality and contraception method. If the pharmaceutical has marketing authorization, follow contraception recommendation in the appropriate labeling. NOAEL, no observed adverse effect level; WOCBP, women of child‐bearing potential.
Figure 4
Figure 4
Example of difference in exposure and threshold of developmental toxicity concern between female subjects and female partners of male subjects. Example shown using human subject C max of 150 ng/mL during treatment and developmental NOAEL of 1 ng/mL. Female subject contraception should be recommended for at least five half‐lives but likely longer (e.g., 11 half‐lives would result in >10‐fold margin). Estimated exposure in a female partner of a male subject would be 0.195 ng/mL based on assumptions described in Table 5 . Male subject contraception would be recommended for at least 1 half‐life to get >10‐fold safety margin (bold values at >10‐fold and 1 half‐life or greater are in bold). C max, maximum plasma concentration; NOAEL, no observed adverse effect level.
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