The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results and a discussion of the relevance of the findings to the investigated product and the possible unfavourable and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
• Species tested
• Number and sex of animals in each group
• Unit dose (e.g., milligram/kilogram (mg/kg))
• Dose interval
• Route of administration
• Duration of dosing
• Information on systemic distribution
• Duration of post-exposure follow-up
• Results, including the following aspects:
Nature and frequency of pharmacological or toxic effects
Severity or intensity of pharmacological or toxic effects
Time to onset of effects
Reversibility of effects
Duration of effects
Dose response
Tabular format/listings should be used whenever possible to enhance the clarity of the presentation.
The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels or human equivalent dose rather than on a mg/kg basis.
(a) Nonclinical pharmacology
A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).
A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites and their relationship to the pharmacological and toxicological findings in animal species.
A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:
• Single toxicity
• Repeated dose toxicity
• Genotoxicity
• Carcinogenicity
• Reproductive and developmental toxicity
• Local tolerance
• Other toxicity studies