CLINICAL TESTING AND INTRODUCTION OF NEW DRUGS

Potential new drugs or biological products must first be tested in animals for their acute and chronic toxicity, influence on reproductive performance, carcinogenic and mutagenic potential, and safe dosing range. Early research and preclinical testing often takes 5 to 8 years and costs millions of dollars. Long-term safety testing in animals continues during subsequent trials in humans.

After successful preclinical pharmacological and toxicological studies, the sponsor files an Investigational New Drug (IND) application with the FDA. In addition to animal data, the IND contains protocols for clinical testing in humans. Approximately 2000 INDs are received each year by the FDA. If the IND passes FDA review, clinical trials in humans are initiated. These studies are generally conducted in three phases:

These studies provide the basis for drug labeling. The completion of these clinical studies may take 3 to 10 years and typically costs more than $300 million. Only one out of every five drugs that enter clinical trials receives FDA approval. When that one drug is marketed, it often represents an average $800 million investment, because the pharmaceutical company must pay for the thousands of failed drugs that did not meet approval (Fig. 4-1). The patent protection (17 years) of new drugs may be increased on some drugs, based upon delays in FDA approval (Patent Term Restoration Act, 1984). Extensions in patent life may also occur for products that provide pediatric studies to support pediatric labeling (Best Pharmaceuticals for Children Act, 2002).

FIGURE 4–1 Stages of new drug development and the approval process, patent protection, and generic competition.

Before initiating a study of an investigational drug in humans, an investigator must also obtain approval from the local Institutional Review Board (IRB) of the hospital, university, or other institution where the planned study will be conducted. The IRB is responsible for ensuring the ethical acceptability of the proposed research and approves, requires modification, or disapproves the research protocol. To approve a clinical research study, the IRB must determine that the research design and procedures are sound and that the risk to subjects is minimized. In addition, the IRB must also approve the informed consent document that must be signed by each prospective subject or the subject’s legally authorized representative. IRB approval is usually valid for 1 year.

The basic elements of informed consent include: (1) explanation of the purposes and procedures of the research; (2) description of foreseeable risks; (3) description of expected benefits; (4) statement of available alternative procedures or courses of treatment; (5) statement on confidentiality of records; (6) explanation of compensation or available medical treatments, if injury occurs; (7) description of whom to contact about the research and the subject’s rights and the procedure to follow in the event of injury to the subject; and (8) statement that participation is voluntary and refusal to participate does not involve penalty to the subject.

If suitable preclinical and clinical findings demonstrate efficacy with minimal toxicity, the sponsors can submit a New Drug Application (NDA) to the FDA (see Fig. 4-1). In approving an NDA, the FDA ensures the drug’s safety and effectiveness for each use. Usually, the sponsor and the FDA review the data and negotiate on the detailed information to accompany the drug for its use. This includes contraindications, precautions, side effects, dosages, routes of administration, and frequency of administration. The NDA approval process usually takes 1 to 2 years, with drugs having the greatest potential benefit given priority. Drug applications are identified and placed into specific categories under an FDA classification system (Table 4-1). Postapproval research may be requested by the FDA as a condition of new drug approval. Such research may be used to speed drug approval, uncover unexpected adverse drug reactions, and define the incidence of known drug reactions under actual clinical use.

TABLE 4–1 FDA Drug Classification System

After NDA approval, the manufacturer promotes the new drug for the approved uses described on the label. During the post-NDA approval or marketing period (Phase 4

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