This Challenge aims to develop and qualify an in vitro approach that can reliably predict early or surrogate indicators of teratogenicity of pharmaceutical drug candidates.
Challenges briefing webinar
Find out more about this Challenge in the webinar recording and summary of the Q and A session with the Sponsors below.
The application deadline for this Challenge is now closed.
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Sponsored by AbbVie, AstraZeneca, Bayer AG, Boehringer Ingelheim, LEO Pharma A/S, Merck Healthcare KGaA, MMV Medicines for Malaria Venture, Novartis and Roche, this Challenge aims to develop and qualify an in vitro approach that can reliably predict early or surrogate indicators of teratogenicity of pharmaceutical drug candidates.
Drugs intended for the treatment of women of child-bearing potential (WoCBP) must be tested for teratogenicity – the potential for the drug to cause harm to a developing embryo or fetus (1). Embryo-fetal development is a complex process which involves coordinated biological events that are susceptible to external influences. Exposure of the mother to a teratogenic drug can disrupt the normal formation of organs and may result in a wide range of malformations.
Studies to assess the potential teratogenicity of a drug typically involve evaluation in pregnant animals in two species (a rodent and non-rodent) as specified in the International Council for Harmonisation (ICH) S5 (R3) guideline (1). These embryo-fetal development (EFD) studies are generally conducted on the drug candidate once it has entered clinical development, but the animal models are not always predictive of humans and often do not provide mechanistic insight (2). Several alternative models exist that are used to predict teratogenicity during the selection of candidate drug molecules, but improved models are needed to address the current limitations and permit their broader use:
- In silico QSAR models have predictivity limited to defined chemical spaces (3, 4).
- Ex vivo embryo assay cultures (e.g. using rodent, rabbit) and non-mammalian models such as Caenorhabditis elegans or zebrafish may have limited mechanisms in common with human development (5-15).
- In vitro stem cell-based models (4, 16-29):
- Rely on adherent monolayer cultures or disorganised 3D structures, both of which lack the spatiotemporal and morphological context of the developing embryo.
- Can only recapitulate certain aspects of embryo development and do not cover mechanisms such as neurulation and the effect on the trophoectoderm/placenta.
- Do not provide an accurate method to extrapolate in vitro culture concentration to pharmacokinetic (PK) parameters of drug exposure in humans.
- Qualification of human in vitro models is hampered by the availability of human data and the limited relevance of animal data.
There is a need to develop improved in vitro assays both in human and in preclinically relevant species (e.g. rat, rabbit, non-human primate (NHP)) to aid with translation and understanding of species-specific effects and human relevancy.
The aim of this Challenge is to develop and qualify an in vitro approach that can reliably predict early or surrogate indicators of teratogenicity of pharmaceutical drug candidates. The proposed approach should cover as many mechanisms of embryo development as possible. To support validation and translation, the approach must cover human as well as selected preclinical species used for EFD studies (rat, rabbit, NHP).
A standard EFD study requires multiple pregnant females (80 to100 for rodents and rabbits; and 48 for NHPs). In the case of EFD findings, additional mechanistic studies requiring further animals might be performed to identify if the findings are relevant to human. The packages of drugs approved by the FDA currently include around 67 EFD studies per year (around 6,000 animals) (30). For biopharmaceuticals which are not pharmacologically active in rodents, the EFD study can be replaced by an enhanced pre- and postnatal development (ePPND) study in NHPs.
This Challenge has the potential to deliver 3Rs benefits in the pharmaceutical industry by:
- Providing more predictive approaches that can be used for early screening and derisking to prevent drug candidates with teratogenic potential from progressing into animal studies.
- Use in mechanistic studies to investigate species differences/species-specific effects and human relevancy especially in the case of equivocal EFD results.
- Replacing in vivo studies for drugs which have a mode-of-action that is suspected to adversely influence morphogenesis, as specified in the ICH S5(R3) guideline.
- In the longer term, once qualified and accepted by regulatory authorities, substituting or deferring EFD studies in one of the two species required.
The assays developed through this Challenge will also have applicability to the food, chemical and agrochemical industries where teratogenicity assessment is also required.
- ICH S5 (R3) guideline on reproductive toxicology: Detection of toxicity to reproduction for human pharmaceuticals - step 5 - Scientific guideline | European Medicines Agency (europa.eu)
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Challenge Panel membership
|Professor Ian Kimber (Chair)||The University of Manchester|
|Dr Bernd Baier (Sponsor)||Boehringer Ingelheim|
|Dr Anthony DeLise (Sponsor)||Novartis|
|Dr Claudia Demarta (Sponsor)||Merck Healthcare KGaA|
|Dr Mikael Mandrup Egebjerg (Sponsor)||Leo Pharma A/S|
|Dr Phil Hewitt (Sponsor)||Merck Healthcare KGaA|
|Dr Stefan Kustermann (Sponsor)||Roche|
|Dr Mira Pavkovic (Sponsor)||Bayer AG|
|Dr Thomas Steger-Hartmann (Sponsor)||Bayer AG|
|Dr Karen Thacker (Sponsor)||AstraZeneca|
|Dr Belen Tornesi (Sponsor)||MMV Medicines for Malaria Venture|
|Dr Axel Vicart (Sponsor)||Novartis|
|Dr Silke Weber (Sponsor)||Abbvie|
|Professor Mark Cronin||Liverpool John Moores University|
|Professor Jenny Nichols||The University of Edinburgh|
|Professor Roger Sturmey||Hull York Medical School|
|Dr David Turner||University of Liverpool|
|Dr Mathew Van de Pette||UKHSA|
|Professor Neil Vargesson||Aberdeen University|