Thalidomide applications

Dr Frances Kelsey had the thalidomide application on her desk. She was busy and had simply not got around to it. Then from Europe she heard about a question of peripheral neuropathy, and possibly thyrotoxicity at that point she made an active decision to hold up the approval. It was an Australian dermatologist who identified drug-induced phocomelia, and the rest is well known. Only nine cases of phocomelia were reported in the United States, from an exposure of about 4000 women of childbearing potential, most of whom were pregnant. Kelsey received a medal from President Kennedy. 

The second major change enacted under the 1962 amendment was the change in the approval process from premarket notification to a premarket approval system. Under the terms of the 1938 law, an NDA would take elfect automatically if the FDA did not respond. For example, the only reason thalidomide was not approved was because Dr. Kelsey returned the application to the sponsor with a request for more information. In contrast, the 1962 law required affirmative FDA action before a drug could be put on the market. Under the terms of the 1962 amendments, the FDA was also empowered to withdraw NDA approval and remove the drug from the market for a variety of reasons, including new evidence that the product was unsafe or that the sponsor had misrepresented or under-reported data. 

The enantioselective metabolism of optically active thalidomide (1) has recently been intensively investigated (Scheme 16) [80]. While the (S)-isomer is found to be metabolized preferentially by hydroxylation of the phthaloyl ring, the (A)-isomer undergoes metabolic hydroxylation in the dioxopiperidine ring. Although it is impossible to find the relationship between the teratogenicity and enantioselective metabolism of thalidomide (1), the application of racemic thalidomide (1) in therapy is clearly controversial [81-84]. 

The U.S.-based pharmaceutical company William S. Merrell, Inc., licensed thalidomide from its German manufacturer, Chemie Griinenthal, in 1958. After carrying out laboratory, animal, and initial human tests, the company submitted an application to the FDA for marketing authorization. Frances Kelsey, the medical officer assigned to review the application, found deficiencies in the animal studies and criticized the company s testing methods.20 She then requested additional toxicity tests, putting the application on hold. 

Estimates come from tallies in Bundesarchiv Koblenz, B142—1826 (Bundesverband der Eltern korpergeschadigter Kinder), and U.S. Food and Drug Administration, New Drug Application 12-611 Kevadon (Thalidomide), volume 1 see also Kirk, Der Contergan-Fall. 

W Larkin to Hubert Humphrey, 25 September 1964, New Drug Application 12611 Kev-adon (Thalidomide), v. 1. 

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