366 



Dr. Dolger's criticism of the merits and development procedure of 

 chlorpropamide was promptly challenged by an official of the company 

 responsible for its development in the United States. He presented a 

 detailed description of its test and evaluation history, and other physi- 

 cians present — qualified as experts in diabetes — confirmed the present 

 safety and efficacy of the drug. It had been the product of extensive 

 laboratory research in organic chemistry. It had been tested extensively 

 on dogs, then on rats and monkeys, for indication of chronic toxicity. 

 Further test procedures had been blocked out by the company and re- 

 viewed by FDA ; modifications were suggested and adopted. Four sets 

 of further tests on dogs at different dosage levels were conducted for 

 the company by an independent research group. Next the testing pro- 

 gram proceeded to human pharmacology, to develop comparative data 

 on the action of chlorpropamide in diabetic and nondiabetic subjects. 

 After this, clinical studies by more than 100 independent physicians 

 were arranged for, yielding 2,062 case reports of findings, to form the 

 basis for recommendations on dosage, indications, and cautions. Stud- 

 ies were made of these reports. A new drug application was submitted 

 to FDA, supported by 8,000 pages of case reports of clinical testing, 

 chemical and pharmacological studies, and data covering a 1-year pro- 

 gram of research. To acquaint the medical profession with tlie new 

 drug, a symposium had been held jointly by the company and the New 

 York Academy of Sciences, at which 68 papers by 168 physicians and 

 scientists were presented on research and testing aspects of chlorpro- 

 pamide. In particular, it was noted that the reports included results of 

 "double-blind and cross-over studies." (These were defined in the hear- 

 ing as follows : "A double-blind study is one in which the drug and 

 placebos * * * are given to patients with neither the physician nor 

 the patient knowing which is the drug and which is the placebo. A 

 cross-over study is one in which two or more drugs are given alternately 

 to the same patients.") Emphasis was also placed on the information 

 contained in the "package insert" and a pamphlet distributed by the 

 company, containing information with respect to chlorpropamide on 

 its chemistry, pharmacology, comparative potency and duration of 

 effect, clinical studies, indications, patient selection, dosage, side effects, 

 precautions, and contraindications. It was estimated that at the time 

 of the hearing, more than 60,000 patients had received chlorpropamide 

 therapy.^^ 



The controversy over the respective merits — safety and efficacj — of 

 tolbutamide and chlorpropamide usefully revealed the complicated 

 nature of drug evaluation, and also the many uncertainties and judg- 

 ment factors it involved. For example, tolbutamide had an excellent 

 safety record; chlorpropamide sometimes caused undesirable side ef- 

 fects, especially with unnecessarily high dosage. Tolbutamide was more 

 effective with a majority of patients who responded to this kind of 

 medication, but had to be taken frequently ; chlorpropamide was some- 

 times effective with patients who did not respond to tolbutamide medi- 

 cation, and remained longer in the system so that it could be taken less 

 often. 



Several days later, on May 3, 1960, another piece of medical testimony 

 was presented by Dr. Samuel D. Loube, associate in medicine at the 

 George Washington University School of Medicine, associate at the 



21 Ibid., pt. 20, pp. 11104-11116. 



