14 research outputs found
Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples
To illustrate the process of addressing adverse preclinical findings (APFs) as
outlined in the first part of this review, a number of cases with unexpected APF
in toxicity studies with drug candidates is discussed in this second part. The
emphasis is on risk characterization, especially regarding the mode of action
(MoA), and risk evaluation regarding relevance for man. While severe APFs such
as retinal toxicity may turn out to be of little human relevance, minor findings
particularly in early toxicity studies, such as vasculitis, may later pose a
real problem. Rodents are imperfect models for endocrine APFs, non-rodents for
human cardiac effects. Liver and kidney toxicities are frequent, but they can
often be monitored in man and do not necessarily result in early termination of
drug candidates. Novel findings such as the unusual lesions in the
gastrointestinal tract and the bones presented in this review can be difficult
to explain. It will be shown that well known issues such as phospholipidosis and
carcinogenicity by agonists of peroxisome proliferator-activated receptors
(PPAR) need to be evaluated on a case-by-case basis. The latter is of particular
interest because the new PPAR α and dual α/γ agonists resulted in a change of
the safety paradigm established with the older PPAR α agonists. General
toxicologists and pathologists need some understanding of the principles of
genotoxicity and reproductive toxicity testing. Both types of preclinical
toxicities are major APF and clinical monitoring is difficult, generally leading
to permanent use restrictions
Global Recognition of Qualified Toxicologic Pathologists: Credential Review as a Potential Route for Recognizing the Proficiency of Pathologists Involved in Regulatory-type Nonclinical Studies*
Recent international summits of the International Federation of Societies of Toxicologic
Pathologists (IFSTP) have debated the desirability and potential means by which the
proficiency of an individual toxicologic pathologist might be recognized and communicated
throughout the world. The present document describes the advantages and disadvantages of
implementing such a global recognition system by any means, and provides a proposal
whereby recognition might be accorded via rigorous credential review of a practitionerâs
education and experience
International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies*
The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a
common global framework for training future toxicologic pathologists who will support
regulatory-type nonclinical toxicology studies. Trainees optimally should undertake a
scientific curriculum of at least 5 years at an accredited institution leading to a
clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more
years of intensive pathology practice during a residency and/or on-the-job
âapprenticeship,â at least 2 years of which must be focused on regulatory-type toxicologic
pathology topics. Possession of a recognized pathology qualification (i.e., certification)
is highly recommended. A non-clinical pathway (e.g., a graduate degree in medical biology
or pathology) may be possible if medically trained pathologists are scarce, but this
option is not optimal. Regular, lifelong continuing education (peer review of nonclinical
studies, professional meetings, reading, short courses) will be necessary to maintain and
enhance oneâs understanding of current toxicologic pathology knowledge, skills, and tools.
This framework should provide a rigorous yet flexible way to reliably train future
toxicologic pathologists to generate, interpret, integrate, and communicate data in
regulatory-type, nonclinical toxicology studies