title: Clinical trial considerations on male contraception and collection of pregnancy information from female partner: update.
abstract: BACKGROUND
  This is an update to our 2012 publication on clinical trial considerations on male contraception and collection of pregnancy information from female partner, after critical review of recent (draft) guidances released by the International Council for Harmonisation [ICH] the Clinical Trial Facilitation Group [CTFG] and the US Food & Drug Administration [FDA].
  
  
  METHODS
  Relevant aspects of the new guidance documents are discussed in the context of male contraception and pregnancy reporting from female partner in clinical trials and the approach is updated accordingly.
  
  
  RESULTS
  Genotoxicity The concept of a threshold is introduced using acceptable daily intake/permissible daily exposure to define genotoxicity requirements, hence highly effective contraception in order to avoid conception. The duration for highly effective contraception has been extended from 74 to 90 days from the end of relevant systemic exposure. Teratogenicity Pharmacokinetic considerations to estimate safety margins have been contextualized with regard to over- and underestimation of the risk of teratogenicity transmitted by a vaginal dose. The duration of male contraception after the last dose takes into account the end of relevant systemic exposure if measured, or a default period of five half-lives after last dose for small molecules and two half-lives for immunoglobulins (mAbs). Measures to prevent exposure of the conceptus via a vaginal dose apply to reproductively competent or vasectomized men, unless measurements fail to detect the compound in seminal fluid.
  
  
  CONCLUSIONS
  Critical review of new guidance documents provides a comparison across approaches and resulted in an update of our previous publication. Separate algorithms for small molecules and monoclonal antibodies are proposed to guide the recommendations for contraception for male trial participants and pregnancy reporting from female partners. No male contraception is required if the dose is below a defined threshold for genotoxic concern applicable to small molecules. For men treated with teratogenic mAbs, condom use to prevent exposure of a potentially pregnant partner is unlikely to be recommended because of the minimal female exposure anticipated following a vaginal dose. The proposed safety margins for teratogenicity may evolve with further knowledge.
authors.affiliation: Safety Risk Management, Licensing & Early Development, F. Hoffmann-La Roche AG, Basel, Switzerland. maria.longauer_banholzer@roche.com.
authors.forename: Maria Longauer
authors.initials: ML
authors.lastname: Banholzer
authors.affiliation: Safety Risk Management, Licensing & Early Development, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wandel
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Barrow
authors.affiliation: Safety Risk Management, Licensing & Early Development, F. Hoffmann-La Roche Ltd, New York, NY, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Mannino
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Schmitt
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guérard
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Lutz
authors.initials: L
authors.lastname: Müller
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Greig
authors.affiliation: Non-Clinical Safety Department, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Kenjie
authors.initials: K
authors.lastname: Amemiya
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Peck
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.affiliation: , Zürich, Switzerland.
authors.forename: Lucette
authors.initials: L
authors.lastname: Doessegger
keywords: Clinical trials; Genotoxicity; Male contraception; Paternal exposure; Teratogenicity