Analysis of exposure margins in developmental toxicity studies for detection of human teratogens

Andrews, Paul A.; Blanset, Diann; Costa, Priscila Lemos; Green, Martin A.; Green, Maia L.; Jacobs, Abigail; Kadaba, Rajkumar; Lebrón, José Antonio; Mattson, Britta A.; McNerney, Mary Ellen; Minck, Daniel R.; Oliveira, Luana de Castro; Theunissen, Peter T.; DeGeorge, Joseph J.

doi:10.1016/j.yrtph.2019.04.005

Cited by 14 publications

(8 citation statements)

References 18 publications

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“…3 ○ Evidence that all human teratogens for which nonclinical data are available induce malformations in a rodent and/or rabbit at ≤ 4-fold the human exposure at the MRHD. 46 Whereas this paper provides a base case for consistently addressing contraception, pharmaceutical characteristics and therapeutic context should be considered on a case-by-case and thus additional topics are addressed including methods of contraception, pregnancy testing, drug clearance, options for managing the absence of a NOAEL for developmental toxicity, DDIs, radiopharmaceuticals, and other drug modalities.…”

Section: Discussionmentioning

confidence: 99%

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

Bowman

Bécourt-Lhote

Boulifard

et al. 2022

Clin Pharma and Therapeutics

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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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Section: Discussionmentioning

confidence: 99%

“…○Accepted reduced concern for developmental toxicity in nonclinical studies that only occurs at > 10‐times the clinical exposure at the MRHD 3 ○Evidence that all human teratogens for which nonclinical data are available induce malformations in a rodent and/or rabbit at ≤ 4‐fold the human exposure at the MRHD 46 …”

Section: Discussionmentioning

confidence: 99%

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

Bowman

Bécourt-Lhote

Boulifard

et al. 2022

Clin Pharma and Therapeutics

Self Cite

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“…In other words, the information obtained from EFD studies with rodents and rabbits is as significant as that obtained from studies with non-human primates, and that the replacement can greatly contribute to implementation of the 3R principles. This is not the argument I am making here, but, rather, I suggest that this is a question in regulatory science-if the teratogenicity of some pharmaceuticals cannot be detected by EFD studies in rodents and rabbits, which have successfully shown embryo-fetal malformation and lethality caused by human teratogens so far [26].…”

Section: Animal Speciesmentioning

confidence: 92%

Research topics in regulatory science: Developmental and reproductive toxicity of human pharmaceuticals

Sekizawa

2020

Translational and Regulatory Sciences

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In this review, I have discussed current issues related to risk assessments of developmental and reproductive toxicities during the use of pharmaceuticals in pregnant women or women of childbearing potential. Owing to the lack of empirical information on the use of pharmaceuticals (including those approved for the market) in pregnant women, the toxicity of these drugs has been generally evaluated in animal studies. In the case of embryo-fetal developmental (EFD) toxicity, in particular, testing of small-molecule pharmaceuticals in animals (namely rodents and rabbits) is required. The body of research in animal studies affords us an opportunity to explore numerous topics in regulatory science research. However, there are three major issues: risk communication, use of animals, and reduction or deferral of EFD toxicity studies for the development of human pharmaceuticals. Although regulatory science research may not be necessary for some topics, it would contribute to the reduction or replacement of testing in animals. It is hoped that regulatory science research in this field will proceed rapidly, with the goal of safe use of pharmaceuticals for women.

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“…On the other hand, pharmaceuticals are developed in consideration of the risks and benefits to humans. The results from animal studies are compared to results from clinical studies, and the exposure margin between the “no observed adverse effect level,” determined in the animal studies, and “the maximum recommended human dose” 13 is analyzed to predict human teratogenicity. When a pharmaceutical is shown to have adverse effects, such as teratogenicity and/or reproductive toxicity in humans, it can be regulated with contraindication; for example, its use can be prohibited in pregnant women or in women that may become pregnant.…”

Section: Different Industrial Views Regarding Gzsmentioning

confidence: 99%

Current activities between the DevTox Berlin workshops and the Japanese Teratology Society Terminology Committee in harmonizing the terminology for classifying anomalies in laboratory animals in developmental toxicity studies: Report from the Satellite Workshop of the 60th Annual Meeting of the Japanese Teratology Society

Kuwagata

Sato²,

Izumi

et al. 2022

Congenital Anomalies

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In recent years, the Japanese Teratology Society has worked with the DevTox Berlin Workshops project to provide internationally consistent terminology for teratogenic effects. This paper summarizes a satellite workshop of the 60th Annual Meeting of the Japanese Teratology Society, which was entitled "Current activities between DevTox Berlin Workshops to develop a harmonized terminology for classifying anomalies in laboratory animals in developmental toxicity studies." The Japanese Teratology Society -Laboratory Animal Terminology Project (JTS-LATP) reviewed "gray zone" anomalies and focused on developing criteria for reclassifying a large number of gray zone anomalies to clarify them and to make it easier to judge fetal categories. This effort will lead to international agreement, based on shared conceptions. The present article aimed to provide the reader with a summary of the issues discussed at the 2020 satellite meeting, which included discussions on open issues from the DevTox Berlin Workshops, ongoing work by the JTS-LATP on gray zone (GZ) anomalies, current industrial concerns, and future challenges.

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Analysis of exposure margins in developmental toxicity studies for detection of human teratogens

Cited by 14 publications

References 18 publications

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

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

Research topics in regulatory science: Developmental and reproductive toxicity of human pharmaceuticals

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