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Executive Summary

European clinical trials are less attractive as sources of data for U.S. NDAs because of inadequate monitoring practices, Boehringer Mannheim VP-Medical and Scientific Affairs Richard Crout, MD, told the Drug Information Assn. annual meeting on June 4. Crout said that "European trials have, in the American drug industry, a reputation of having more protocol violations than are desirable . . . and that the most important reason [for the violations] is inadequate monitoring." Crout was the director of FDA's Bureau of Drugs during the 1970s. Crout's comments focused on the differences between European and U.S. methods of trial monitoring and data analysis. The former FDAer suggested that the differences prevent drug companies from submitting NDAs based on European data. Comparing the monitoring procedures in the U.S. and Europe, Crout explained that "typically U.S. trials are monitored every four to eight weeks and there is a long exercise that goes into the quality control of data beginning with a random audit of data in the physician's office." U.S. investigators, Crout noted, "have come to accept this over the past decade, and clinical research associates and monitors are now viewed as essential members of the research team." By contrast, "European trials are monitored with less frequency and with less meticulous quality control and . . . random data audits in the physician's office are almost unheard of," Crout said. Because of the monitoring practices, Crout said, "typical problems" include "things like patients who fail the inclusion criteria; clinic appointments outside the scheduled visits; missed laboratory data; changes in dosage not permitted; and so on." He noted that "this is not to say that all European trials are sloppy and all U.S. trials are error free, but it is to say that our European friends deserve to know that their American counterparts believe that such errors are more frequent in European trials." A second barrier to the use of European trials for NDAs, Crout said, is the "distance from American regulatory science during the report writing phase." He explained that "in most countries the standard for analyzing and writing up a clinical trial is the same as the standard in the medical literature. In the U.S., in contrast, the description of clinical and methodologic details, analyses, displays, statistical results, and so on . . . are well beyond the requirements of any medical journal or any European regulatory agency." Because of the differences in documentation practices, Crout suggested that it would be very difficult to compile and process trial data in Europe that would be acceptable for U.S. NDA submission. "In talking to friends in the industry," he said, "I've yet to encounter a firm that says it submits its reports of foreign clinical trials directly to the agency without U.S. input, commonly reanalysis and all its rewriting." Crout added, however, that FDA's policy statements on its willingness to accept foreign clinical trials "has stimulated . . . in the short-term, the hybrid foreign/U.S. trial." That is, trials "conducted in Europe, but analyzed and written in the U.S." Discussing the possibility of a multinational company moving towards "a common database" with "single reports for international use," Crout said that "the challenge to our European colleagues is to improve the monitoring of clinical trials in Europe, to accomodate in good grace the hybrid European/American trial, and to accommodate in equally good grace the American penchant for excess" data analysis. On the American side, he said, "the challenge is to see that in a well organized and properly administered way, multinationally, the industry finds the right balance between foreign trials, hybrid foreign/American trials, and American trials, such that a worldwide program is conducted in the most efficient, cost-effective way." Crout also commented on FDA clinical trial requirements with respect to investigator qualifications. Noting that "there is a perception [in the industry] that the need for academic credentials is essential for the investigator in the foreign trial," Crout said that at a recent meeting with FDA officials "an FDA representative made clear that a foreign investigator would be considered qualified even if he or she was a practitioner, and not necessarily an academic expert." That is important, Crout emphasized, "because many European multicenter trials are conducted by practitioners."

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