ABSTRACT
The discovery of drugs can be traced to two origins. One is natural products that have been observed to have pharmacological activity. These include compounds such as morphine (from opium), quinine (from Cinchona bark), cocaine (from Coca leaves), and digoxin (from foxglove). The second is chemical synthesis, which began in the late 1800s and led to drugs such as antipyretics and analgesics (antipyrine, aspirin, acetanilide, phenacetin) and the first antimicrobial agent (arsphenamine for treatment of syphyllis). Further impetus came from the discovery of penicillin and the sulfa drugs by 1940. The approaches were merged in the synthetic modification of natural substances, as in the production of semisynthetic antibiotics. After WWII, the pharmaceutical industry developed rapidly based on screening of both natural and synthetic compounds involving bioassays. Later, crystal structure determination of target enzymes and computational modeling permitted drug design based on structural analysis. High throughput screening based on targets identified by gene sequencing became possible in the 1990s. Regulation gradually developed during the century, usually in response to well-publicized incidents that spurred action. These include requirements of (1) labeling of ingredients (1906); (2) prohibition of addictive substances (1912); (3) evidence of safety (1938); (4) evidence of efficacy (1962). Medical devices came under similar regulation in 1976. The current process involves: (1) discovery and preclinical studies leading to an Investigational New Drug (IND) application; (2) Phase I, II, and III clinical studies designed to determine dose, detect side effects and demonstrate efficacy; (3) approval of a New Drug Application (NDA) including indications for use and labeling. Drug approvals of new chemical entities (NCE) have averaged 20 + 5 annually since 2000. About 10–15 new biologic drugs have been approved annually during this period. Controversies have continued since the 1970s about the effectiveness of the regulatory process and drug pricing.
