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The Drug Development and Approval Process (1997)

In reviewing the following information, it is important to keep in mind the realities of the drug discovery and development process. The U.S. system of new drug approvals is perhaps the most rigorous in the world. On average, it costs a company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 report by the Congressional Office of Technology Assessment. It takes 12 years on average for an experimental drug to travel from lab to medicine chest. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved. New medicines are developed as follows:

Synthesis and Extraction - The process of identifying new molecules with the potential to produce a desired change in a biological system (e.g., to inhibit or stimulate an important enzyme, to alter a metabolic pathway,or to change cellular structure). The process may require: 1) research on the fundamental mechanisms of disease or biological processes; 2) research on the action of known therapeutic agents; or 3) random selection and broad biological screening. New molecules can be produced through artificial synthesis or extracted from natural sources (plant, mineral, or animal). The number of compounds that can be produced based on the same general chemical structure runs into the hundreds of millions.

Biological Screening and Pharmacological Testing - Studies to explore the pharmacological activity and therapeutic potential of compounds. These tests involve the use of animals, isolated cell cultures and tissues, enzymes and cloned receptor sites as well as computer models. If the results of the tests suggest potential beneficial activity, related compounds—each a unique structural modification of the original—are tested to see which version of the molecule produces the highest level of pharmacological activity and demonstrates the most therapeutic promise, with the smallest number of potentially harmful biological properties.

Pharmaceutical Dosage Formulation and Stability Testing - The process of turning an active compound into a form and strength suitable for human use . A pharmaceutical product can take any one of a number of dosage forms (e.g., liquid, tablets, capsules, ointments, sprays, patches) and dosage strengths (e.g., 50. 100, 250, 500 mg.) The final formulation will include substances other than the active ingredient, called excipients. Excipients are added to improve the taste of an oral product, to allow the active ingredient to be compounded into stable tablets, to delay the drug's absorption into the body, or to prevent bacterial growth in liquid or cream preparations. The impact of each on the human body must be tested.

Toxicology and Safety Testing - Tests to determine the potential risk a compound poses to man and the environment. These studies involve the use of animals, tissue cultures, and other test systems to examine the relationship between factors such as dose level, frequency of administration, and duration of exposure to both the short- and long-term survival of living organisms. Tests provide information on the dose-response pattern of the compound and its toxic effects. Most toxicology and safety testing is conducted on new molecular entities prior to their human introduction, but companies can choose to delay long-term toxicity testing until after the therapeutic potential of the product is established

Regulatory Review: Investigational New Drug (IND) Application - An application filed with the U.S. FDA prior to human testing. The IND application is a compilation of all known information about the compound. It also includes a description of the clinical research plan for the product and the specific protocol for phase I study. Unless the FDA says no, the IND is automatically approved after 30 days and clinical tests can begin.

Phase I Clinical Evaluation - The first testing of a new compound in human subjects, for the purpose of establishing the tolerance of healthy human subjects at different doses, defining its pharmacologic effects at anticipated therapeutic levels, and studying its absorption, distribution, metabolism, and excretion patterns in humans.

Phase II Clinical Evaluation - Controlled clinical trials of a compound's potential usefulness and short term risks. A relatively small number of patients, usually no more than several hundred subjects, enrolled in phase II studies.

Phase III Clinical Evaluation - Controlled and uncontrolled clinical trials of a drug's safety and effectiveness in hospital and outpatient settings. Phase III studies gather precise information on the drug's effectiveness for specific indications, determine whether the drug produces a broader range of adverse effects than those exhibited in the small study populations of phase I and II studies, and identify the best way of administering and using the drug for the purpose intended. If the drug is approved, this information forms the basis for deciding the content of the product label. Phase III studies can involve several hundred to several thousand subjects.

Process Development for Manufacturing and Quality Control - Engineering and manufacturing design activities to establish a company's capacity to produce a product in large volume and development of procedures to ensure chemical stability, batch-to-batch uniformity, and overall product quality.

Bioavailability Studies - The use of healthy volunteers to document the rate of absorption and excretion from the body of a compound's active ingredients. Companies conduct bioavailability studies both at the beginning of human testing and just prior to marketing to show that the formulation used to demonstrate safety and efficacy in clinical trials is equivalent to the product that will be distributed for sale. Companies also conduct bioavailability studies on marketed products whenever they change the method used to administer the drug (e.g., from injection or oral dose form), the composition of the drug, the concentration of the active ingredient, or the manufacturing process used to produce the drug.

Regulatory Review: New Drug Application (NDA) - An application to the FDA for approval to market a new drug. All information about the drug gathered during the drug discovery and development process is assembled in the NDA. During the review period, the FDA may ask the company for additional information about the product or seek clarification of the data contained in the application.

Postapproval Research - Experimental studies and surveillance activities undertaken after a drug is approved for marketing. Clinical trials conducted after a drug is marketed (referred to as phase IV studies in the United States) are an important source of information on as yet undetected adverse outcomes, especially in populations that may not have been involved the premarketing trials (e.g., children, the elderly, pregnant women) and the drug's long-term morbidity and mortality profile. Regulatory authorities can require companies to conduct Phase IV studies as a condition of market approval. Companies often conduct post-marketing studies in the absence of a regulatory mandate.

Note: Drugs introduced since 1984 are enjoying longer patent lives as a result of the Drug Price Competition and Patent Term Expiration Act of 1984 (Public Law 98-417). On the other hand, generic competition could be much stiffer for recently approved drugs after they lose patent protection, says OTA.

Source: Congress of the United States, Office of Technology Assessment. Pharmaceutical R&D: Costs, Risks and Rewards: 1993; pp. 4-5. Based on Pharmaceutical Manufacturers Association Annual Survey