Toxicological Support Preind And For Phase I Clinical Studies

The preliminary evaluation of the safety assessment of any new drug requires multiple studies, some of which evaluate general and multiple endpoints (such as toxicity studies). Other studies evaluate more specific and defined endpoints (such as muta-genicity studies and safety pharmacology studies). Drugs that are derived from a biological origin, such as proteins, monoclonal antibodies, or drugs produced by biological vectors (or what are generally referred to as 'biotechnology products'), present additional problems that require a significantly modified approach. The ICH guidelines recognize that unique approaches may be needed, has addressed this in a further guideline (ICH 1997), and poses additional problems for the toxicologist (Terrell and Green 1994). This section will elaborate on those studies needed to support the safety of a typical xenobiotic agent, although the same general principles follow for biotechnology products, often being necessary but not sufficient. There are two types of guidelines that must be considered in initiating the non-clinical program. The first relates to the types of studies required; the second relates to protocol requirements for the studies themselves.

The types of studies needed are dictated by national regulatory requirement, although the ICH has promulgated a international guideline (Federal Register November 25 1997) that is progressing through the final review stage at the present time. These studies, outlined in Tables 6.1 and 6.2, vary somewhat by the phase of the clinical trial, and may still vary among countries where the trial is being conducted. The US Food and Drug Administration (FDA) has also published guidelines that outline the requirements necessary to initiate initial clinical studies (FDA 1995). This latter document focuses more on the extent of study documentation required than the study types, and allows for data to be submitted that is not in final report form.

The following sections briefly describe the studies that would typically be performed to support

Table 6.1 Duration of repeated-dose toxicity studies to support Phase I and Phase II clinical trials in the EU, and Phase I, II, and III clinical trials in the USA and Japan"

Duration of clinical trial Minimum duration of repeated-dose toxicity studies

Duration of clinical trial Minimum duration of repeated-dose toxicity studies

Table 6.1 Duration of repeated-dose toxicity studies to support Phase I and Phase II clinical trials in the EU, and Phase I, II, and III clinical trials in the USA and Japan"

Rodents

Non-rodents

Single dose

2-4 weeksh

2 weeks

< 2 weeks

2-4 weeksh

2 weeks

< 1 month

1 month

1 month

< 3 months

S months

3 months

< 6 months

6 months

6 months^

> 6 months

6 months

Chronic^

a In Japan, if there are no Phase II clinical trials of equivalent duration to the proposed Phase III trials, then non-clinical toxicology studies of the durations shown in Table 6.2 should be considered. b In the EU and USA, 2 week studies are the minimum duration. In Japan, 2 week non-rodent and 4 week rodent studies are needed. In the USA, with FDA concurrence, single-dose toxicity studies with extended examinations can support single-dose human exposures. c Data from 6 months of administration in non-rodents should be available before clinical exposures of more than 3 months. Alternatively, if applicable, data from a 9 month non-rodent study should be available before clinical treatment duration exceeds that supported by other toxicology studies.

a In Japan, if there are no Phase II clinical trials of equivalent duration to the proposed Phase III trials, then non-clinical toxicology studies of the durations shown in Table 6.2 should be considered. b In the EU and USA, 2 week studies are the minimum duration. In Japan, 2 week non-rodent and 4 week rodent studies are needed. In the USA, with FDA concurrence, single-dose toxicity studies with extended examinations can support single-dose human exposures. c Data from 6 months of administration in non-rodents should be available before clinical exposures of more than 3 months. Alternatively, if applicable, data from a 9 month non-rodent study should be available before clinical treatment duration exceeds that supported by other toxicology studies.

Table 6.2 Duration of repeated-dose toxicity studies to support Phase III clinical trials in the EU, and product marketing in all jurisdictions0

Duration of clinical trial

Minimum duration of repeated-dose toxicity studies

Rodents

Non-rodents

< 2 weeks

1 month

1 month

< 1 month

S months

S months

< 3 months

6 months

S months

> 3 months

6 months

Chronic

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

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

initial studies in man. Additional specialized studies might be needed in order to study the potential for an effect that might be characteristic of drugs in the particular class in question (e.g. antibody determinations for some biological products; neuro-toxicity studies for drugs acting on the central nervous system, etc).

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