PHARMACOEPIDEMIOLOGY adverse drug effects, to collect cases of drug controlled investigations, including clinical inves- induced blood dyscrasias. In 1960 the FDA tigations. Functionally, this has generally been began to collect reports of adverse drug reactions interpreted as requiring randomized clinical trials and sponsored new hospital-based drug monitor- to document drug efficacy prior to marketing. ing programs. The Johns Hopkins Hospital and This new procedure also delayed drug marketing gram developed the use of in-hospital monitors some modifications, these are the requirements to perform cohort studies to explore the short. still in place in the US today. In addition, the term effects of drugs used in hospitals&9(see also amendments required the review of all drugs Chapter 12). This approach was later to be approved between 1938 and 1962, to determine if transported to the University of Florida-Shands they too were efficacious. The resulting DESI Teaching Hospital, as well. 1( (Drug Efficacy Study Implementation) process, In the winter of 1961 the world experienced the conducted by the National Academy of Sciences' infamous "thalidomide disaster"Thalidomide National Research Council with support fror was marketed as a mild hypnotic, and had no contract from the FDA, has recently been com- obvious advantage over other drugs in its class. pleted, and has resulted in the removal from the Shortly after its marketing, a dramatic increase US market of many ineffective drugs and drug was seen in the frequency of a previously rare combinations. The result of all these changes has birth defect, phocomelia-the absence of limbs or been a great prolongation of the approval pro- parts of limbs, sometimes with the presence cess, with attendant increases in the cost of drug instead of flippers. Epidemiologic studies estab- development, the so-called drug lag. However, lished its cause to be in utero exposure to thalido. the drugs which are marketed are presumably mide. In the United Kingdom, this resulted in the much safer and more effective establishment in 1968 of the Committee on Safety The mid-1960s also saw the publication of a of Medicines. Later the World Health Organiza- series of drug utilization studies. 3-17 These stu- tion established a bureau to collect and collate dies provided the first descriptive information on information from this and other similar national how physicians use drugs, and began a series of drug monitoring organizations(see Chapter 11) investigations of the frequency of poor prescrib- The US had never permitted the marketing of ing and determinants of poor prescribing(see thalidomide and, so, was fortunately spared this also Chapters 27 and 28) epidemic. However, the "thalidomide disaster" With all of these developments, the 1960s can was so dramatic that it resulted in regulatory be thought to have marked the beginning of the change in the US as well. Specifically, in 1962 the field of pharmacoepidemiology Kefauver-Harris Amendments were passed Despite the more stringent process for dru These amendments strengthened the requirements regulation, the late 1960s, 1970s, and especially for proof of drug safety, requiring extensive pre- the 1980s and 1990s have seen a series of major clinical pharmacologic and toxicologic testing adverse drug reactions. Subacute myelo-optic fore a drug could be tested in humans. The neuropathy (SMON was found to be caused by data from these studies were required to be sub- clioquinol, a drug marketed in the early 1930s mitted to the FDA in an Investigational New but not discovered to cause this severe neurologic Drug Application (IND) before clinical studies reaction until 1970. 8 In the 1970s, clear cell could begin. Three explicit phases of clinical test- adenocarcinoma of the cervix and vagina and Ing were defined hich are described in more other genital malformations were found to be detairbelow. In addition, a new requirement was due to in utero exposure to diethylstilbestrol two added to the clinical testing, for"substantial evi- decades earlier. 9 The mid-1970s saw the dis- dence that the drug will have the effect it pur- covery of the oculomucocutaneous syndrome ports or is represented to have. Substantial caused by practolol, five years after drug market- evidence"was defined as "adequate and well- ing. In 1980 the drug ticrynafen was noted to 第172页第 172 页