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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. 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. 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. The current update was triggered by three guidance documents which became available since , 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Group CTFG on recommendations related to contraception and pregnancy testing in clinical trials [ 3 ] and the draft guidance for industry from the US Food and Drug Administration FDA regarding assessment of male-mediated developmental risk for pharmaceuticals [ 4 ].

Relevant aspects of the new guidance documents are summarized and the approach to male contraception in clinical trials has been updated accordingly. Mutations in germ cells can lead to spontaneous abortions, infertility or heritable damage to the offspring and possibly to the subsequent generations [ 5 ]. Thus, standard genotoxicity assays performed in somatic cells in vitro and in vivo are appropriate to assess the risk of potential genetic damage of germ cells.

For genotoxicity, 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.

Non-linear dose—responses suggest that a threshold dose is required in order to induce an adverse effect. Non-linear dose—responses have been reported for low doses of genotoxic compounds with diverse indirect e. It is however unlikely that small genotoxic effects, i. Thus, published data mostly report practical thresholds where non-linear dose—responses are described through statistical approaches to define a point of departure. The regulatory approach to such compounds can be based on the identification of a NOGEL and use of uncertainty factors to calculate a permissible daily exposure when data are available.

For the majority of direct DNA genotoxins there is no experimental evidence of a threshold relative to a genotoxic effect—dose concentration curve. In these instances, the dose concentration - response curve is linear i. The TTC has originally been allocated for mutagenic impurities in drug formulations at a calculated risk level of one additional cancer case in , exposed patients for a lifetime intake.

The TTC concept was developed to define an acceptable daily intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects.

The TTC-based acceptable intake of 1. To address less-than-lifetime exposure to mutagenic impurities in pharmaceuticals, an approach is applied in which the acceptable cumulative lifetime dose 1.

This would allow a higher daily intake than would be the case for lifetime exposure and still maintain comparable risk levels for daily and non-daily treatment regimens. However, a uniform distribution ignores experimental data, which have demonstrated a higher risk for cancer mediated by mutations if the same cumulative dose is taken over a shorter than a longer duration.

The CTFG supports the Heads of Medicines Agencies, a network of the heads of the National Competent Authorities whose organizations are responsible for the regulation of medicinal products for human and veterinary use in the European Economic Area.

Highly effective and acceptable contraceptive measures and categorization of contraceptives. A high follicle stimulating hormone FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The key messages of the CTFG guidance paper concerning contraception in context of exposed men in clinical trials are listed below.

In case of a genotoxic Investigational Medicinal Product, the principle of TTC as available for mutagenic impurities should be considered. Referring to Klemmt and Scialli [ 8 ], CTFG assumes the estimated drug exposure level in the female partner of child-bearing potential after a vaginal dose to be three or more orders of magnitude lower than the plasma concentration in the male clinical trial participant [ 3 ].

However, sub-therapeutic systemic exposure level is not further described and quantified. In cases where reproductive toxicity studies are available, the anticipated systemic exposure in trial participants should have a sufficient exposure margin below the no adverse effect level NOAEL in the non-clinical embryo-fetal development EFD studies; otherwise, condom use is required. However, a margin is not quantified.

In case of insufficient or unavailable non-clinical data, the impact on the risk categorization should be evaluated. The FDA draft guidance for industry was distributed for comments in June It provides recommendations to sponsors for assessing risks to embryo-fetal development resulting from administration of an active pharmaceutical ingredient to males, either through an effect on the male germ cell or from seminal transfer of an active pharmaceutical ingredient that has been shown to be genotoxic or a potent developmental toxicant.

A potent developmental toxicant is defined as one associated with adverse fetal outcomes at or near clinical exposures or for which a NOAEL has not been defined.

The guidance does not consider the situation where no EFD studies were performed and does not specify safety margins. Examples are provided with estimated exposure multiples of fold and fold between C max in female partners and C max associated with NOAEL in EFD studies with the conclusion that no further assessment of the drug in seminal fluid would be needed.

The impact of positive genotoxicity findings on the development of a small molecule depends on the indication, the patient population and the duration of treatment.

Genotoxic compounds are generally not tested in healthy volunteers and if so, require an extensive risk assessment. According to literature, in general, single-dose clinical studies are permitted by the FDA regardless of the genotoxicity test results [ 9 ].

However, some other Health Authorities may not agree to test genotoxic compounds with single doses in healthy volunteers or may request a rationale to do so and safety margins have been accepted on a case-by-case basis.

The existence of mechanisms leading to a dose response that is non-linear and has a practical threshold is increasingly recognized, not only for compounds that interact with non-DNA targets but also for DNA-reactive compounds [ 10 ].

Those effects may be modulated, for example, by rapid detoxification before coming into contact with DNA, or by effective repair of induced DNA lesions. For drugs with an indirect non-DNA genotoxic mechanism, a non-linear genotoxic effect to dose concentration curve is typical, allowing the identification of a NOGEL.

Based on the integrated data, the genotoxic risk and the safety margin need to be assessed, including the cut-off concentration or permissible daily exposure in the female partner below which the predicted genotoxic risk is low, hence, for which highly effective contraception including condom use is not needed. Also for some molecules with a direct genotoxic mechanism, a non-linear dose genotoxic response with a range of non-mutagenic low concentrations and a NOGEL has been found in vitro, as it is typically seen for molecules with an indirect mode of genotoxicity [ 12 , 13 ].

This process cannot be generalized and for the majority of direct DNA genotoxins there is no experimental evidence of a threshold relative to a genotoxic effect—dose concentration curve. In these instances, the dose concentration response curve is linear i.

In comparison to the publication [ 1 ], the concept of a threshold in line with ICH M7 is introduced using acceptable daily intake or permissible daily exposure to define genotoxicity requirements. However, application of the TTC concept with acceptable daily intake, adopted from CTFG, very likely results in recommending highly effective contraception based on the very low acceptable daily intake.

Finally, a reference has been added supporting testing of single doses in clinical trials in the US, regardless of genotoxicity test results.

Preclinical reference parameters In this scenario the preclinical pharmacokinetic reference parameter taken for safety margin calculations is the Area Under the Curve AUC associated with the NOAEL from the more sensitive animal species. Indeed, drug induced teratogenicity in animals has been found to be associated with maximum concentration C max or AUC [ 14 ]. In consequence, calculating safety margins based on AUC represents the more conservative approach compared to safety margins calculated with C max.

Small molecules: The dose-exposure relationship for plasma concentrations is assumed to be similar for the female partner and the exposed male. The seminal concentration is assumed to equal the plasma concentration in the exposed male. Preclinical reference parameters In this scenario, the MABEL derived from an AUC in animal studies or representing a concentration resulting from a cellular experiment may be considered. Clinical reference parameters In case the MABEL represents an in vitro concentration, the estimated C max for the female partner after a vaginal dose should be used.

Please note, the use of AUC was not specified in the publication. The approach for estimating the exposure in female partner is outlined for scenario 1. PK considerations should then translate the MABEL concentration to the associated predicted concentrations in the plasma compartment.

Margin calculations use the estimated female exposure, here C max , and the relevant plasma concentration corresponding to the MABEL. No toxicities linked to pharmaceutical properties e. For small molecules administered vaginally this may include the absence of intestinal-hepatic first pass effect and the presence of uterine first pass effect.

The latter may also be applicable for mAbs. In case an estimate for a first pass effect is available, the safety margin may be individualized. Intestinal - hepatic first pass effect The extrapolation from vaginal dose to exposure in female partner refers to available PK information. If this PK information is derived from PK after oral administration and if the molecule undergoes relevant first pass effect by intestine and liver, the estimated female exposure after vaginal dose will underestimate the true exposure because of the absence of first pass intestine and hepatic effects after the vaginal route of administration.

Uterine first pass effect The uterine first pass effect describes the extraction of drug by the uterus following the countercurrent transfer of a molecule after vaginal absorption via vaginal vein drainage to uterine arteries.

When measured in non-pregnant subjects or in perfused hysterectomy, the ratio of drug concentration in endometrium or uterine artery versus systemic vein concentration is about two to sevenfold higher after vaginal than after systemic drug administration based on reports for progesterone [ 24 ], danazol [ 25 ], thalidomide [ 26 ]. Regulatory guidelines lack recommendations regarding safety margins for teratogenicity between NOAEL in EFD studies a and maximum doses tested in clinical trials.

For first-in-human studies applying a range of escalating doses, the FDA suggests a default safety factor of ten between the exposure for the starting dose and that of the Human Equivalent Dose, which should be individualized [ 27 ]. In our experience, for non-monitorable and potentially irreversible and severe toxicities, a safety factor of ten is usually applied between exposure associated with the maximum dose in a clinical trial and the NOAEL in EFD studies.

Of note, the FDA draft guidance states that a margin of at least tenfold between NOAEL in EFD studies and the estimated exposure to embryo-fetus due to vaginal dose would not mandate evaluation of drug in seminal fluid.

The smaller margin for mAbs appears justified because the exposure in the female partner is more predictable than for small molecules, given the more generalizable PK of mAbs. If the seminal concentration for a small molecule is not estimated, but has been measured, we propose to reduce the required safety margin from to For a Hill coefficient e.

In the safety margin considerations below, a factor of instead of 81 is considered between MABEL, taken as sub-therapeutic level, and therapeutic level. The safety margin estimations supporting contraceptive recommendations are summarized in Fig.

Safety margin estimations: small molecules. Safety margin estimations: monoclonal antibodies. Factors to estimate the exposure in the female partner after a vaginal dose: comparison with the approach from the fda draft guidance.

For mAbs, the FDA approach estimates C max in female partner as vaginal dose absorbed divided by blood volume instead of plasma volume. Consequently, the dilution factor to estimate female exposure from vaginal dose is half in our approach compared with the one suggested in the FDA draft guidance.

Because the PK derived from animals typically refers to measurements of mAbs in plasma, it is therefore important to ensure that exposure comparisons between species apply the same matrix and compartment. For small molecules, the FDA approach estimates the female C max as vaginal dose divided by blood volume which corresponds to C max after rapid iv injection. Given the delayed time to maximum plasma concentration after vaginal administration this overestimates C max. Indeed, PK data for drugs administered vaginally show that the time to maximum plasma concentration is not instant as per IV administration but takes several hours, e.

It is acknowledged that the vaginal absorption rate is dependent on the physico-chemical properties of the molecule, the formulation used, and the vaginal epithelium status. The C max in female partners is influenced by the volume of distribution, which varies across small molecules. Consequently, C max is likely lower compared to the estimate as suggested in the FDA draft guidance. As stated previously, in case an estimate for a first pass effect is available, the safety margin may be individualized.

The FDA approach is not associated with such an underestimation because this approach does not refer to available PK data after oral administration when estimating female exposure after vaginal route of administration. The CTFG makes reference to sub-therapeutic and therapeutic levels for assessing the need for contraception.

Neural basis of romantic partners’ decisions about participation in leisure activity

Account Options Sign in. My library Help Advanced Book Search. Get print book. CRC Press Amazon. Walter O.

Metrics details. South Africa faces numerous reproductive challenges that include high rates of unplanned and adolescent pregnancies.

We conducted surveys of reproductive-aged women and semi-structured interviews with reproductive-aged women, men, and physicians completing their social-service year in CES communities from to Of the survey respondents, The most common methods were female sterilization Interviews were completed with 27 women, 24 men, and 5 physicians and analyzed through an inductive approach.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. A Nature Research Journal. Leisure activity is one of key ingredients for individual happiness and life satisfaction. Thirty-seven soon-to-be married heterosexual couples were participated in functional MRI while deciding participation in specific leisure activities in the individual, partner, with-friend, and with-partner conditions.

While there are many books available on statistical analysis of data from experiments, there is significantly less available on the design, development, and actual conduct of the experiments. Laboratory Experiments in the Social Sciences summarizes how to design and conduct scientifically sound experiments, be they from surveys, interviews, observations, or experimental methods. The book encompasses how to collect reliable data, the appropriate uses of different methods, and how to avoid or resolve common problems in experimental research. Case study examples illustrate how multiple methods can be used to answer the same research questions and what kinds of outcome would result from each methodology.

Walter O.

Stanton L. Jones is provost and professor of psychology at Wheaton College in Wheaton, Illinois. During his tenure as chair of the psychology department , he led the development of Wheaton's Doctor of Psychology program in clinical psychology. He received his B.

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. 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.

Viviana A. She received her Ph. Todd K. Shackelford received his Ph. He led the founding of new Ph.

When it comes to birth control methods, women have more options than ever before. However, for men, the choice is limited to condoms, withdrawal, and vasectomy. In the last 40 years, studies have demonstrated that reversible hormonal suppression of spermatogenesis — the process of sperm cell development — in men can prevent pregnancies in their female partners, although the commercial development of the product has been stalled. In previous studies, testosterone management in men demonstrated birth control efficacy comparable with female methods. However, participants had to be given much greater doses than are typically found in the body and the method caused long-term adverse effects in healthy men.

requirement for consent to collect information on pregnancy and its outcome from female partners of male research participants. When does this guidance apply.








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