Opinion ID: 1432329
Heading Depth: 1
Heading Rank: 2

Heading: development and marketing of des

Text: Crucial to an understanding of this litigation and resolution of the issues is the history of the development and marketing of DES. Much of the history is developed in the record here, and detailed in numerous reported cases and law journals. [2] Estrogen is a female sex hormone present in varying amounts in the body of every woman. This hormone is crucial to female sexual development and fertility. Natural estrogens were first isolated outside the human body in the 1920's. Doctors initially used the hormone to treat menopausal symptoms in women. Natural estrogen therapy, however, had several drawbacks. The process of isolating the hormone was very costly. Furthermore, natural estrogens could only be administered through injections into the buttocks, often resulting in painful abscesses. In the late 1930's, a group of British scientists discovered DES, a synthetic compound which shares some of the characteristics of estrogen. DES could be produced at a fraction of the cost of isolating natural estrogens and could be orally administered. It was never patented. Approval of the Food and Drug Administration (FDA) was required before DES could be marketed in the United States. Pursuant to the Federal Food, Drug, and Cosmetic Act, 52 Stat. 1040 (1938), each company wishing to market DES had to file a New Drug Application (NDA) detailing the proposed uses of the drug, clinical data establishing its safety and efficacy, the drug's chemical composition, methods of manufacturing it and proposed labeling. The first NDA for DES was filed in 1939. By the end of 1940, ten firms had applied. The NDAs sought authorization to market and distribute DES for four purposes: the treatment of postmenopausal symptoms, senile vaginitis, gonorrheal vaginitis, and suppression of lactation. None of the proposed uses relate to problems of pregnancy. All indications from the FDA in 1939 suggested that the FDA would review each manufacturer's NDA separately. This meant that each firm had to stand on the clinical data it submitted in its own NDA. In late 1940, the FDA indicated that it was considering requesting the drug companies to pool their clinical data on DES. On December 20, 1940, the FDA convened a meeting with the drug companies, at which it formally requested that the companies submit their clinical data jointly in a master file. The FDA believed that the individual NDAs did not contain sufficient clinical data to properly evaluate the safety and efficacy of DES. Pooling of the data, in the FDA's view, would eliminate this problem as well as expedite its evaluation of DES. The FDA made three other requests of the drug companies at this time. The first was that each company use the same United States pharmacopeia standard to establish the chemical identity of the drug. The second was that they develop uniform labeling regarding the indications for use of the drug and recommended dosage. The third was that they place a provision in their NDAs authorizing the FDA to use the materials gathered by each firm in considering any other NDAs that might be filed. The companies, for the most part, complied with these additional requests. A small committee of representatives of those firms which had filed NDAs coordinated the pooling of clinical data and submitted the master file to the FDA. The FDA approved the marketing of DES for uses unrelated to problems of pregnancy in late 1941. Thereafter, the small committee was disbanded. Experimental use of DES as a miscarriage preventative began in the early 1940's. Several drug companies supplied DES to independent researchers for such experimentation. The drug companies also sent representatives to medical conferences on this topic. The first supplemental NDAs for the use of DES as a miscarriage preventative were filed in 1947. Only a few companies conducted their own experiments to establish the safety and efficacy of DES for this purpose. Among these, none tested DES on pregnant laboratory animals. The applicants relied instead upon published studies done by independent researchers at medical schools to support their applications. The supplemental NDAs did not refer to the master file of clinical data that had been submitted with the 1941 NDAs. The FDA's policy in reviewing supplemental NDAs, however, was to take into consideration all of the material that it had in support of the original NDAs. The FDA began approving the supplemental NDAs in July 1947. Soon thereafter, DES was marketed as a miscarriage preventative. Some companies marketed the drug under a trade name; others marketed it generically. Several companies supplied DES to competitors. Because the DES compounds produced by the drug companies were chemically identical, pharmacists often filled prescriptions for DES with whatever company's drug was in stock, a practice that the firms were aware of. None of the companies warned physicians about the possibility of carcinogenic or other risks to the offspring of women who took DES. The number of firms marketing DES has fluctuated considerably over the years. Estimates are that up to 200 or 300 companies manufactured and marketed DES between 1947 and 1971. In 1952, the FDA decided that DES was no longer a new drug within the meaning of the Federal Food, Drug, and Cosmetic Act. This meant that companies wishing to market DES for the first time would not have to file NDAs. In 1971, Dr. Arthur Herbst and several other physicians published a study linking the outbreak in young women of clear cell adenocarcinoma, a form of cancer, with the ingestion of DES by their mothers during pregnancy. In November of that same year, the FDA required the drug companies to include a statement on all labels that DES is contraindicated for use in the prevention of miscarriages. Today, the FDA continues to permit the use of DES in treatments unrelated to problems of pregnancy.