The development of a new drug usually begins with the discovery or synthesis of a potential new drug compound or the elucidation of a new drug target. After a new drug molecule is synthesized or extracted from a natural source, subsequent steps seek an understanding of the drug’s interactions with its biologic targets. Repeated application of this approach leads to synthesis of related compounds with increased efficacy, potency, and selectivity (Figure 1–6). In the United States, the safety and efficacy of drugs must be established before marketing can be legally carried out. In addition to in vitro studies, relevant biologic effects, drug metabolism, pharmacokinetic profiles, and relative safety of the drug must be characterized in vivo in animals before human drug trials can be started. With regulatory approval, human testing may then go forward (usually in three phases) before the drug is considered for approval for general use. A fourth phase of data gathering and safety monitoring is becoming increasingly important and follows after approval for marketing. Once approved, the great majority of drugs become available for use by any appropriately licensed practitioner. Highly toxic drugs that are nevertheless considered valuable in lethal diseases may be approved for restricted use by practitioners who have undergone special training in their use and who maintain detailed records.
Most new drugs or drug products are discovered or developed through the following approaches: (1) screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and (Is it safe, pharmacokinetics?) Phase 1 20–100 subjects 100–200 patients In vitro studies Biologic products Chemical synthesis, optimization 2 204 8–9 Animal testing Clinical testing Marketing Generics become available Lead compound Efficacy, selectivity, mechanism Drug metabolism, safety assessment (Postmarketing surveillance) (Does it work in patients?)Phase 2 (Does it work, double blind?) 1000–6000 patients Phase 3 Phase 4
FIGURE 1–6 The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in life-threatening diseases (see text).
other organic molecules; (2) chemical modification of a known active molecule, resulting in a “me-too” analog; (3) identification or elucidation of a new drug target; and (4) rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure. Steps (3) and (4) are often carried out in academic research laboratories and are more likely to lead to breakthrough drugs, but the costs of steps (1) and (2) usually ensure that industry carries them out.
Once a new drug target or promising molecule has been identified, the process of moving from the basic science laboratory to the clinic begins. This translational research involves the preclinical and clinical steps, described next. While clinical trials in humans are required only for drugs to be used in humans, all of the other steps described apply to veterinary drugs as well as drugs for human diseases.
Drug screening involves a variety of assays at the molecular, cellular, organ system, and whole animal levels to define the pharmacologic profile, ie, the activity and selectivity of the drug. The type and number of initial screening tests depend on the pharmacologic and therapeutic goal. For example, anti-infective drugs are tested against a variety of infectious organisms, some of which are resistant to standard agents; hypoglycemic drugs are tested for their ability to lower blood sugar, etc.