Assessing Safety Earlier in Drug Development

Posted by cdavenport on Wednesday Aug 1, 2012 Under Biomarker, Drug Safety, Preclinical, Risk Management

The objective of a recent survey by Cambridge Health Associates was to identify trends in safety biomarkers and their utilization in drug development.  Regardless of company size, recurrent themes for assessing drug safety in early preclinical development were noted.

  • Greater knowledge of safety biomarkers improved mechanistic understanding and helped to determine the relevance of nonclinical findings for clinical risk assessment.
  • Preclinical inclusion of systems or pathway modeling was deemed important for the selection and interpretation of biomarkers of organ toxicity.
  • Physical chemical prediction software or other forms of genetic or developmental and reproductive toxicity (DART) prediction software (e.g., DEREK, M-CASE, Leadscope) were being incorporated into early preclinical development by most companies.  All 3 software companies have Cooperative Research and Development Agreements (CRADA) with the FDA.
  • For cellular parameter screens, most companies are using image-based multi-parametric approaches of cellular analysis and cytotoxicity at the single-cell and subcellular level (via High Content Analysis [HCA])
  • Off-target screening (usually a CEREP panel) was performed by most companies early in preclinical development.

As might be expected to “slow the burn,” smaller companies ran fewer preclinical screens to predict drug safety and  performed these screens later in the drug development process.  Given that larger companies expect to have this information sooner than later, companies wanting to partner and/or be acquired may consider including more screens for drug safety earlier in their preclinical development programs.


SourceDSEC Drug Safety Executive Blog

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The increased requirement for combined chronic toxicity and fertility assessment of biologics has led to greater use of sexually mature non-human primates.  Older animals have different needs compared to the younger, adolescent animals with which we are used to working.  In addition, the establishment of sexual maturity requires additional parameter measurements, such as assessment of menstrual cycling, hormone analyses, and seminology.  Changes in caging are required to reflect the social hierarchy inherent with the interaction of older primates, especially since subordinate animals mature later than their dominant peers.  Provision of complex environmental stimuli also becomes a greater necessity.  Due to the increased size and weight of older primates, handling becomes more of a potential source of stress and injury, to both animals and their handlers.  Differential criteria for assessment of sexual maturity in primates are discussed.

Source:  Developments in Life Sciences

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