Dose toxicity studies, duration

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

TABLE 2.7. Duration of Repeated Dose Toxicity Studies to Support Clinical Trials and Marketing3... 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

Duration of Repeated Dose Toxicity Studies to Support Phase 1 and Phase 2 Clinical Trials in the EU, and Phase 1, 2, and 3 Clinical Trials in the United... 

Minimum Duration of Repeated Dose Toxicity Studies... 

Repeated dose toxicity studies differ with respect to duration. In principle, any duration is possible, but for the sake of harmonization it has become necessary to limit the study durations to a number of standard durations in the test guideline studies. 

The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) is, for the repeated dose toxicity part, concordant with the standard 28-day oral toxicity study (OECD TG 407) except for use of pregnant females and longer exposure duration (about 6 weeks for males and approximately 54 days for females) in the combined study compared to the standard 28-day study. 

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. ... 

Table 3.1 Duration of repeated-dose toxicity studies to support Phase I and II trials in EU and Phase I, II and III trials in the United States and Japan ...

Duration of clinical trials Minimum duration of repeated-dose toxicity studies ... 

The September 2000 draft guidance considers excipient databases associated with drug products with three different therapeutic durations. For a drug product intended for a 14-day therapy or less, and for infrequent use, the excipient should be tested in acute toxicity studies and in one-month, repeat-dose toxicity studies in two mammalian species (one being a nonrodent), using the intended route of therapeutic administration. 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

In repeated-dose toxicity studies when a dosing duration adequate for evaluation is attained, no preneoplastic lesions are observed. 

The duration for Repeat Dose Toxicity Studies is related to the duration of clinical trials and their therapeutic indication. In principle, the duration of animal studies are equal to or exceed the duration of the human clinical trials. 

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. 

Repeat-dosing toxicity studies are conducted to determine what side effects will arise from repeated administration of a drug at lower dosages than those used in acute toxicity studies and to determine safe dosages to be used in the initial human clinical trials. These studies range in duration from 1 to 2 weeks to 1 to 2 years. The length of studies required for a drug depends mainly upon the duration of treatment and the... 

Table 6.2 Duration of repeated-dose toxicity studies to support phase III clinical trials in the EU, and product marketing in all jurisdictions3...

---