Non-rodent studies

Data from 6 months of administration in non-rodents should be available before the initiation of clinical trials longer than 3 months. Alternatively, if applicable, data from a 9-month non-rodent study should be available before the treatment duration exceeds that which is supported by the available toxicity studies. 

The table also reflects the marketing recommendations in the three regions except that a chronic non-rodent study is recommended for clinical use >1 month. 

An ICH guideline entitled Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing) indicates that a non-rodent study of 9 months may be acceptable in the United States, Japan and EU. 

Duration of human trial Rodent study Non-rodent study... 

In case of non-rodent studies the minimum requirement is 3 animals per dose level and sex (one month studies). In longer term studies animal numbers should be increased up to 6 animals per dose and sex (e.g. in chronic studies). 

In the EU and the USA, two week studies are the minimum duration. In Japan, 2 week non-rodent and 4 week non-rodent studies are needed. In the USA, as an alternative to 2-week studies, single dose toxicity studies with extended examinations (hematology, clinical chemistry, urinalysis, macroscopic and microscopic pathology) can support single dose human trials. 

Toxicological Chronic toxicity Carcinogenicity Fertility study (multi-generation) Embryotoxicity (non-rodent) Acute/subacute toxicity in 2nd species Toxicokinetics... 

A 90-DAY FEEDING STUDY BOTH IN A RODENT SPECIES (USUALLY THE RAT) AND IN A NON-RODENT MAMMALIAN SPECIES (USUALLY THE DOG). 

Repeated Dose 90-day Oral Toxicity Study in Non-Rodents (Updated Guideline, adopted 21 September 1998)... 

Repeated dose 90-day oral toxicity study in non-rodents... 

B.26 Sub-chronic oral toxicity test. Repeated dose 90-day toxicity study in rodents B.27 Sub-chronic oral toxicity test Repeated dose 90-day toxicity study in non-rodents B.28 Sub-chronic dermal toxicity test 90-Day repeated dermal dose study using rodent species B.29 Sub-chronic inhalation toxicity test 90-Day repeated inhalation dose study using rodent species B.30 Chronic toxicity test... 

Repeat-dose toxicity - rodent and non-rodent species are required. The duration of the test depends on the duration of clinical exposure but many companies conduct two 14-day studies before going into man. Studies should be done using the proposed clinical route... 

Single-dose studies are performed in two species, usually rat and mouse, by two routes of administration, usually intravenous, to ensure systemic exposure, and the proposed clinical route. Following the ICH guidance in November 1991, non-rodent, single-dose tests are no longer required. If the proposed clinical route is intravenous, then one route is usually acceptable. 

The FDA allows single-dose human studies based on single-dose animal studies. A rodent and non-rodent species are required and signs of major toxicity must be demonstrated. The study design is outlined in the publication by Munro and Mehta and requires an observation period of 14 days after dosing. 

Repeat-dose toxicity studies should be performed in a rodent, typically the rat, and a non-rodent. The longer the duration of human exposure, the longer must be the duration of the toxicity studies. The ICH guideline indicates that for Phase I and Phase II studies, the clinical duration can equal the duration of the toxicity studies in all regions. This concords with the UK guidelines revised by the Medicines Control Agency (MCA) in December 1995. ... 

The FDA allows women to enter carefully controlled and monitored trials in which adequate contraceptive measures and pregnancy testing are performed without requiring results from animal reproductive toxicity tests. In Japan and Europe, because of the high level of concern regarding imintentional exposure of the developing embryo or foetus, an assessment of fertility in a rodent, and embryo/foetal development in a rodent or non-rodent are required if women of childbearing potential are to be included in a Phase I trial. The FDA would expect such results to support Phase II and Phase III studies. 

Toxicity studies are performed in healthy animals. Eor NCEs two species are to be used, one rodent (most often rats or mice) and one non-rodent (dog, rabbit, monkey or others). Biologies should be tested in a species in which they are pharmacologically active, usually a monkey. The route of administration is the same as that of the intended use in clinical studies. 

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