Who Advises the Data Monitoring Committee (DMC)? A Review of Regulatory Guidance for Sponsors on DMCs After 5 Years and
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Who Advises the Data Monitoring Committee (DMC)? A Review of Regulatory Guidance for Sponsors on DMCs After 5 Years and Advice for DMC Members
Drug Information Journal 46(5) 525-531 ª The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0092861512452123 http://dij.sagepub.com
Josephine Mary Glover, MA(Oxon), MBBS, MFPM1, and Richard Kay, PhD2,3
Abstract Regulatory authorities in the US and EU recommend that pharmaceutical companies employ data monitoring committees (DMCs) to protect the safety of patients taking part in large randomized trials involving diseases with high morbidity or mortality and have provided guidance as to how such committees should be used. This article, whose authors have considerable experience in DMC membership, reviews the applicability of guidance to sponsors after 5 years and suggests that regulatory support for DMC members would be valuable. Advice is offered to members, often very experienced clinicians but inexperienced in pharmaceutical data review, as to how standard DMC data packages should be reviewed, which aspects of trial validity should be addressed, and how communication with the trial sponsor should be handled. It is suggested that DMCs could be supported by regulatory authorities in managing ethical and legal dilemmas to make DMC membership less exposed and more inviting. Keywords data monitoring committees, regulatory guidance on DMCs, drug safety, interim analysis, indemnity
Introduction In recent years, data monitoring committees (DMCs) have increasingly been used by pharmaceutical companies to protect the safety of patients taking part in large, multicenter randomized trials involving diseases with high morbidity or mortality, not least due to regulatory guidance that this should be done. The use of independent DMCs allows the relative safety and efficacy of treatment arms to be compared at intervals during the trial, in an unblinded fashion, by experienced individuals not involved in the day-to-day running of the trial. This ensures that patients in one arm of a trial are not at a significant disadvantage while enabling the sponsor to remain blind to the unfolding treatment-specific data. The DMCs are also charged with monitoring the quality and validity of the trial because to subject patients to investigational and often toxic treatment is unethical if the trial’s original aims cannot be met. After criticism in the early 2000s that DMCs could be subject to untoward influence by commercial trial sponsors, regulatory agencies in Europe and the US issued guidance documents in 2005 and 2006,1,2 which recommend how DMCs should be used and operated. The role of the DMC in assessing
the balance of risk to benefit in a trial involving sick and dying patients on the basis of accumulating data is a tricky one, requiring careful judgment. Senior physicians who have previously been trial investigators may well be asked to be DMC members for their area of therapeutic expertise. In this situation, there is no source of advice as to whic
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