Human experiments progress in a commonsense manner that is conventionally divided into four phases. These phases are divisions of convenience in what is a continuous expanding process. It begins with a small number of subjects (healthy subjects and volunteer patients) closely observed in laboratory settings and proceeds through hundreds of patients, to thousands before the drug is agreed to be a medicine by a national or international regulatory authority. It then is licenced for general prescribing (though this is by no means the end of the evaluation). The process may be abandoned at any stage for a variety of reasons including poor tole rability or safety, inadequate efficacy and commercial pressures.
• Phase 1. Human pharmacology (20-50 subjects)
— Healthy volunteers or volunteer patients, according to the class of drug and its safety.
— Pharmacokinetics (absorption, distribution, metabolism, excretion).
— Pharmacodynamics (biological effects) where practicable, tolerability, safety, efficacy.
• Phase 2. Therapeutic exploration (50-300)
— Pharmacokinetics and pharmacodynamic dose-ranging, in carefully controlled studies for efficacy and safety,12 which may involve comparison with placebo.
• Phase 3. Therapeutic confirmation (randomised controlled trials; 250-1000+)
— Efficacy on a substantial scale; safety; comparison with existing drugs.
• Phase 4. Therapeutic use (post-licensing studies)
— Surveillance for safety and efficacy: further formal therapeutic trials, especially comparisons with other drugs, marketing studies and pharmacoeconomic studies.
12 Moderate to severe adverse events have occurred in about 0.5% of healthy subjects (Orme M et al 1989 British Journal of Clinical Pharmacology 27:125; Sibille M et al 1992 European Journal of Clinical Pharmacology 42: 393).
OFFICIAL REGULATORY GUIDELINES AND REQUIREMENTS13
For studies in man (see also Chapter 5) these ordinarily include:
• Studies of pharmacokinetics and (when other manufacturers have similar products) of bioequivalence (equal bioavailability) with alternative products.
• Therapeutic trials (reported in detail) that substantiate the safety and efficacy of the drug under likely conditions of use, e.g. a drug for long-term use in a common condition will require a total of at least 1000 patients (preferably more), depending on the therapeutic class, of which at least 100 have been treated continuously for about one year.
• Special groups. If the drug will be used in, e.g. the elderly, then elderly people should be studied if there are reasons for thinking they may react to or handle the drug differently. The same applies to children and to pregnant women (who present a special problem) and who, if they are not studied, may be excluded from licenced uses and so become health 'orphans'. Studies in patients having disease that affects drug metabolism and elimination may be needed, such as patients with impaired liver or kidney function.
• Fixed-dose combination products will require explicit justification for each component.
• Interaction studies with other drugs likely to be taken simultaneously. Plainly, all possible combinations cannot be evaluated; an intelligent choice, based on knowledge of pharmacodynamics and pharmacokinetics, is made.
13 Guidelines for the conduct and analysis of a range of clinical trials in different therapeutic categories are released from time to time by the Committee on Proprietary Medicinal Products (CPMP) of the European Commission. These guidelines apply to drug development in the European Union. Other regulatory authorities issue guidance, e.g. the Food and Drug Administration for the USA, the MHW for Japan. There has been considerable success in aligning different guidelines across the world through the International Conferences on Harmonisation (ICH). The CPMP Guidelines source is [email protected] or EuroDirect Publications Officer, Medicines Control Agency, Room 10-238, Market Towers, 1 Nine Elms Lane, Vauxhall, London SW8 5NQ.
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