Drug Development

This process starts with the synthesis ofnovel chemical compounds. Substanceswith complex structures may be obtained from various sources, e.g., plants(cardiac glycosides), animal tissues(heparin), microbial cultures (penicillinG), or human cells (urokinase), or bymeans of gene technology (human insulin). As more insight is gained into structureactivity relationships, the searchfor new agents becomes more clearlyfocused.Preclinical testing yields information on the biological effects of new substances. Initial screening may employ biochemical pharmacological investigations (e.g., receptorbinding assaysp. 56) or experiments on cell cultures,isolated cells, and isolated organs. Sincethese models invariably fall short ofreplicating complex biological processes in the intact organism, any potentialdrug 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 orchronic administration; (2) geneticdamage (genotoxicity, mutagenicity);(3) production of tumors (onco or carcinogenicity); and (4) causation of birthdefects (teratogenicity). In animals, compounds under investigation alsohave to be studied with respect to theirabsorption, distribution, metabolism,and elimination (pharmacokinetics).Even at the level of preclinical testing,only a very small fraction of new compounds will prove potentially fit for usein humans. Pharmaceutical technology provides the methods for drug formulation.Clinical testing starts with Phase Istudies on healthy subjects and seeks todetermine whether effects observed inanimal experiments also occur in humans. Doseresponse relationships are determined. In Phase II, potential drugsare first tested on selected patients for therapeutic efficacy in those diseasestates for which they are intended.Should a beneficial action be evidentand the incidence of adverse effects beacceptably small, Phase III is entered, involving a larger group of patients inwhom the new drug will be comparedwith standard treatments in terms oftherapeutic outcome. As a form of human experimentation, these clinicaltrials are subject to review and approvalby institutional ethics committees according to international codes of conduct (Declarations of Helsinki, Tokyo,and Venice). During clinical testing, many drugs are revealed to be unusable.Ultimately, only one new drug remainsfrom approximately 10,000 newly synthesized substances.The decision to approve a newdrug is made by a national regulatorybody (Food & Drug Administration inthe U.S.A., the Health Protection BranchDrugs Directorate in Canada, UK, Europe, Australia) to which manufacturers are required to submit their applications. Applicants must document bymeans of appropriate test data (frompreclinical and clinical trials) that thecriteria of efficacy and safety have beenmet and that product forms (tablet, capsule, etc.) satisfy general standards ofquality control.Following approval, the new drugmay be marketed under a trade name(p. 333) and thus become available forprescription by physicians and dispensing by pharmacists. As the drug gainsmore widespread use, regulatory surveillance continues in the form of postlicensing studies (Phase IV of clinicaltrials). Only on the basis of longtermexperience will the risk: benefit ratio beproperly assessed and, thus, the therapeutic value of the new drug be determined.