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

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.

Influence of gender and body hemisphere on the occurrence of wavy ribs: An analysis of spontaneous skeletal abnormalities in Wistar rat fetuses.

The differentiation of background findings from anomalies relevant for the safety evaluation of a future drug is a major task in the interpretation of developmental toxicity studies. The anomaly wavy rib often occurs in litters exposed to the test substance, but is also frequently present in control litters. Therefore, the relevance of this finding for risk assessment is under discussion. We characterized the skeletal morphology of fetuses with wavy ribs from our background data. Differences in the incidence of wavy ribs between the genders, with approximately twice as many male fetuses having wavy ribs, compared to females, and an overrepresentation of the right body hemisphere were observed. Affected fetuses often occurred clustered in single litters. The presented data might be useful for differentiation of spontaneously occurring wavy ribs from abnormal patterns induced by a test substance.