Abstract
BackgroundThis 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].MethodsRelevant 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.ResultsGenotoxicity 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.ConclusionCritical 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.
Highlights
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 guidances released by the International Council for Harmonisation [ICH] the Clinical Trial Facilitation Group [CTFG] and the US Food & Drug Administration [Food and Drug Administration (FDA)]
The current update was triggered by three guidance documents which became available since 2014, namely, the International Council for Harmonisation (ICH) guideline M7 on mutagenic impurities in drugs [2], the guidance from the Clinical Trial Facilitation Group (CTFG) on recommendations related to contraception and pregnancy testing in clinical trials [3] and the draft guidance for industry from the US Food and Drug Administration (FDA) regarding assessment of male-mediated developmental risk for pharmaceuticals [4]
The term threshold is used in two different types of data contexts: (a) to describe non-linear thresholded dose–effect relationships for genotoxic compounds, which mostly interact indirectly with the genetic material; (b) to describe a Threshold of Toxicological Concern (TTC) below which even for a linear dose– effect relationship, the predicted risk is so low that further risk minimization efforts are not warranted
Summary
Genotoxicity The concept of a threshold is introduced using acceptable daily intake/permissible daily exposure to define genotoxicity requirements, 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
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