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Executive Summary

FDA CLINICAL TRIAL INTERIM ANALYSIS GUIDELINES will encompass the Pharmaceutical Manufacturers Association's position paper on conducting interim analyses of ongoing human studies, FDA Division of Biometrics Director Robert O'Neill, PhD, said at a Feb. 24-25 PMA/FDA workshop on interim analysis and clinical trial monitoring. O'Neill said the agency is "probably thinking of some kind of guideline," and suggested that the PMA position paper "will be able to be folded into the document that we will be able to put together." FDA will also incorporate conclusions and issues discussed at the workshop into guidelines. The PMA document, distributed to industry in March 1991, was prepared to clarify issues and consolidate opinions about the use of interim analysis. FDA currently does not have a guidance that specifically discusses interim analysis of clinical trial data. The topic is only briefly mentioned in the agency's "Guidelines for Clinical and Statistical Sections of New Drug Applications." Participants in the workshop concurred that clinical trial sponsors need to develop standard operating procedures that address how unblinded information obtained from an interim analysis should be handled. PMA also advocates standard procedures, saying in the position paper that "it is important that the sponsor have an SOP [standard operating procedure] describing who will have access to the randomization code, how the blind will be broken, who will have access to the interim results, and whether ongoing patients will be included in the analysis." The importance of planning ahead for interim analyses was also highlighted by a general agreement that the protocols for most Phase II and Phase III clinicals should have plans to describe procedures for possible interim analyses and early termination of trials. Having predetermined procedures can help to allay questions about the integrity of interim analysis results. Procedures for conducting administrative analyses, which are a type of interim analysis that firms conduct for external reasons such as an NDA submission date, also should be outlined in study protocols, workshop participants agreed. "There should be an SOP to provide for the stopping of a study for purely administrative reasons," PMA's document says. "This SOP should indicate who has the authority to stop a study and establish a clear paper trail to indicate the reasons for stopping the study to show that the decision was not the result of an interim analysis." Summarizing the opinions of other workshop participants, Lilly Research Labs Executive Director Robert Zerbe, MD, said: "Basically you're saying define up front as best you can... [when] planning for these administrative analyses." He added that "it's totally legitimate to have unscheduled analyses provided they are advance according to the [SOP]." The use of external, independent monitoring boards or committees to handle interim analyses of trials that involve mortality and severe morbidity endpoints was another consensus that developed at the workshop. "There are a lot of good reasons why you want an independent monitoring committee for a pivotal Phase III [trial]," David DeMets, PhD, Medical Science Center, University of Wisconsin, said. However, he noted that the cost of independent monitoring could be a roadblock, saying "I don't think that we have the resources to have independent monitoring for all trials." Echoing the position of other participants that FDA should be appraised of interim analysis decisions and results, but should not be part of a data safety monitoring board, DeMets stated: "I happen to believe that there should be some separation of church and state; you can't be a monitor and a regulator at the same time." G. D. Searle Statistics & Clinical Data Management Senior Director Stephen Smeach, PhD, presented the results of a questionnaire that his company sent to 57 drug firms, in December 1991, asking about use of interim analysis and data monitoring committees. Twenty-three firms responded to the survey. "All respondents had performed some kind of interim analysis on some kind of clinical trial," Smeach said. "Use of interim analyses is more prevalent in the megatrials [large scale trials with mortality and morbidity endpoints] in terms of a routine basis." Most of the companies have SOPs or written policies "either formal, informal or under development," Smeach noted. The questionnaire also showed that companies tend to use external experts for their data monitoring committee for interim analyses of megatrials and that companies use their staffs for interim analyses of earlier phases of studies.

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