Pa Rr 2.4 Drug Development Drug Development ‘The drug development process starts with the synthesis of novel chemical compounds. Sub- stances with complex. structures may be obtained from various sources, e.g., plants (car- diac glycosides), animal tissues (heparin), microbial cultures (penicillin G) or cultures of human cells (urokinase), or by means of gene technology (human insulin). As more insight is gained into structure-activity relationships, the search for new agents becomes more clearly focused. Preclinical testing yields information on the biological effects of new substances. Initial screening may employ biochemical-pharmaco- logical investigations (e.g., » Fig. 8.3) or experi- ments on cell cultures, isolated cells, and isolated organs. Since these models invariably fall short of replicating complex biological processes in the intact organism, any potential drug must be tested in the whole animal. Only animal experiments can reveal whether the desired effects will actually occur at dosages that produce little or no toxicity. Toxicological investigations serve to evaluate the potential for: (1) toxicity associated with acute or chronic administration; (2) genetic damage (genotoxicity, mutagenicity); (3) production of tumors (oncogenicity or carcinogenicity); and (4) causation of birth defects (teratogenicity) In animals, compounds under investigation also have to be studied with respect to their absorption, distribution, metabolism, and elimination (pharmacokinetics). Even at the level of preclinical testing, only a very small fraction of new compounds will prove poten- tially suitable for use in humans, Pharmaceutical technology provides the is for drug formulation. Clinical testing starts with Phase 1 studies on healthy subjects to determine whether effects observed in animals also occur in humans. Dose-response relationships are deter- mined, In Phase Il, potential drugs are first tested on selected patients for therapeutic effi- cacy in the illness for which they are intended. If.a beneficial action is evident, and the incidence of adverse effects is acceptably small, Phase Ill is, entered, involving a larger group of patients in whom the new drug is compared with conven- tional treatments in terms of therapeutic out- come. As a form of human experimentation, these clinical trials are subject to review and approval by institutional ethics committees according to international codes of conduct (Dec- larations of Helsinki, Tokyo, and Venice). During clinical testing, many drugs are revealed to be ‘unusable, Ultimately, only one new drug typically remains from some 10000 newly synthesized substances, ‘The decision to approve a new drug is made by a national regulatory body (Food and Drug Administration in the United States; the Health Protection Branch Drugs Directorate in Canada; the EU Commission in conjunction with the European Medicines Agency [EMA] London, United Kingdom) to which manufac- turers are required to submit their applica tions, Applicants must document by means of appropriate test data (from preclinical and clinical trials) that the criteria of efficacy and safety have been met and that product forms (tablet, capsule, etc.) satisfy general standards of quality control. Following approval, the new drug (p. 26) may be marketed under a trade name (p. 380) and so be available for prescription by phys cians and dispensing by pharmacists. At this time regulatory surveillance continues in the form of postlicensing studies (Phase IV of clini- cal trials). Pharmacovigilance is the name given to activities intended to identify and guard against drug risks during clinical trials and subsequent marketing. This includes report- ing of suspected cases of adverse drug effects (ADEs) to the national regulatory authorities Only on the basis of long-term experience will the risk-benefit ratio be properly assessed and, thus, the therapeutic value of the new drug be determined. If the new drug offers hardly any advantage over existing ones, the cost-benefit relationship needs to be kept in mind.[— A. From drug synthesis to approval, 2.4 Drug Development Clinical trial Phase IV Approval AS 3 ae Pe Substances Animals (Bio)chemical synthesis Isolation of natural substance General use 7 Long-term benefit-risk evaluation ol. Clinical trial Phase | Phase I! Phase Il Healthy subjects: Selected patients: Patient groups: effects on body functions, effects on disease; | ‘comparison with dose definition, safety, efficacy, dose, | standard therapy pharmacokinetics Blood pharmacokinetics | orplacebo FG pressure Pond ip ip cis is a Isolated organs Preclinical testing: effects on body functions, mechanism of action, toxicity fm | Tissue homogenate Fig.24 23 g 5 Bi & 2 z rs