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Executive Summary

POSSIBLE INCREASE IN CLINICAL TRIAL "HOLDS" since publication of the IND Rewrite in March 1987 is currently getting FDA consideration, according to FDA's Linda Carter, special assistant to the director of the agency's Office of Drug Research and Review. Commenting on the effects of the IND Rewrite at the Drug Information Association's annual meeting July 12, Carter said: "We are looking into [a possible increase in clinical holds] very carefully. We're looking at a number of clinical holds in our [information] system, looking at protocols on clinical hold, and we're meeting with each division to look at what's on clinical hold." Tabulation of clinical holds has been difficult because not all holds are imposed by the directors of the divisions. Sometimes they are ordered by medical reviewers, Carter noted. "That's why it's taking us a while to go in and look into it," she commented. "We couldn't really judge by the first numbers we got out because they were lower, and that is why we're going to each division." Carter's comments were made during a July 12 panel session on the IND Rewrite. Carter's remarks followed a presentation by Schering Regulatory Affairs VP Alex Giaquinto, PhD, who suggested that the number of holds have increased, even in Phase I studies, and that companies are having trouble getting FDA to remove holds in a timely manner once problems are resolved. Citing the results of a "recent" informal survey of 26 companies, Giaquinto said that "almost half of the companies, in this case 45%, had clinical holds imposed, and less than 1/4 of them, or 22%, knew why, or were informed in writing." Of those who were notified, "only 25% could proceed without further deliberations, in other words, they could make some change, which was the reason for the hold to begin with, and then continue on." The results, Giaquinto said, "leads me to pose the following question: 'Is the spirit and the intent of the IND Rewrite being followed with regard to the clinical holds?'" FDA director of Metabolic & Endocrine Drug Products, Solomon Sobel, MD, who also participated in the panel, noted that the agency's "intent" in the IND Rewrite "was actually to let Phase I studies go if at all possible, and only stop them if there are safety problems. On the other hand, our policy was to consider more clinical holds in Phase II and Phase III, where we wanted to help the companies . . . avoid poor drug development and disappointing results, at least in the way we would evaluate it at the final stages of development." Sobel added that "the clinical holds I've seen are not for trivial technical reasons, but they are due to real chemistry deficiencies in which the compound is not clearly defined, there are real questions about the safety of the drug with regard to purity." However, he concluded "the phenomenon of increased holds in Phase I really needs to be examined in terms of cause. It has to be established whether it is occurring, and we should try to rectify if it is occurring unfairly." The FDAers also commented on remarks by Beecham Scientific Affairs VP Robert Powell regarding the requirements for three-day and 10-day serious adverse reaction reports to FDA and investigators during IND trials. Powell noted that it is often "impossible" to determine that the serious reaction "is reasonable caused by the investigational drug within the time constraints imposed." Therefore, some of the reports "routinely forwarded to both FDA and investigators" may not detail serious events linked to the drug, he pointed out. "The result," Powell said, "may be desensitization on the part of the investigator to the importance of these reports." He suggested, that "the regulation be modified to provide for notification of investigators only after discussion with the agency and a mutual decision is made by the sponsor and the agency that the nature of the specific event in the context of the drug and the patient population warrants such a report." Although the agency is aware of the problem, FDA's Carter noted, there are currently no plans to change the regs regarding the 10-day reports. "We have discussed the question and in our last discussion of it we said that still, as far as the reporting of the sponsor simultaneously to the FDA and to the investigator, that we still expect that to occur, and we don't want to change our regs," Carter said. However, she continued, "I think we feel that the sponsor needs to look carefully at those reports, and to consider the causality question -- and if there is causality -- and not send them to the investigator blindly."

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