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Page 62 TABLE 5 Essential Elements of a First Plan Study description Comment Result required for item Estimated duration, months 1. Clinical studies 1.1. Basic phase I studies Basic tolerability and kinetics in increasing single and multiple doses 1.3. 6 1.2. Extended phase I studies Interaction, bioequivalence, special patient groups 1.5., 8.2. 12 1.3. Efficacy pilot studies If necessary; may be pharmacodynamic studies in 1.1. 1.4. 8 1.4. Dose finding studies (phase II) E.g., two studies @ 300 patients 2 months treatment 1.5. 18 1.5. Pivotal phase III efficacy studies E.g., three studies @ 500 patients 3 months treatment 8.2. 30 1.6. Long-term safety studies Number of patients and duration according to guidelines 8.2. 30 1.7. Special studies Depending on therapy class and marketing requirements 8.2. 624 2. Toxicological studies 2.1. Acute toxicity 1.1. 2 2.2. Subacute toxicity 24 weeks in two species 1.1. 3 2.3. Subchronic toxicity 3 months in two species 8.2. 1218 2.4. Chronic toxicity 612 months in two species 8.2. 1218 2.5. Reproduction studies Embryotoxicity first species 1.1. Fertility, embryotox. 2nd species, perinatal toxicity 1.5. 12 2.6. Cancerogenicity 24 months in mice and rats 8.2. 3048 2.7. Mutagenicity Selection from several in vitro and in vivo tests 1.1 to 1.4. 3 3. Pharmacokinetic studies 3.1. Prephase I package E.g., basic kinetics two species, single dose ADME two sp.; autoradiographic distribution, metabolism in vitro; protein binding 1.1. 610 (table continued on next page)
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