Some further discussions prior to FDA's issurance of DMC guidance are worth to read. These include:
- An internal discussion note.
- FDA internal assessment of annual report burden
- Notes from CBER open public meeting on DMC
- Comments on draft DMC guidance
- NIH policy on data and safety monitoring
- NIH policy on data and safety monitoring of Phase I and II trials
- NCI policy on data and safety monitoring
- NCI's essential elements on data and safety monitoring
- Template from NHLBI
- Template from NIA
- DMC policy from ECOG
- Template from Applied Clinical Trials
- Slutsky et al (2004) Data Safety and Monitoring Board. NEJM 350:1143-1147
- Freidlin, B., Korn, E. L. (2009). Monitoring for Lack of Benefit: A Critical Component of a Randomized Clinical Trial. JCO 27: 629-633
- Miller and Wendler (2008). Is it ethical to keep interim findings of randomised controlled trials confidential?. J. Med. Ethics 34: 198-201
- Borer et al (2008) When should data and safety monitoring committees share interim results in cardiovascular trials? JAMA Apr 9;299(14):1710-2
- Mueller et al (2007) Ethical Issues in Stopping Randomized Trials Early Because of Apparent Benefit. ANN INTERN MED 146: 878-881
- Goodman (2007) Stopping at Nothing? Some Dilemmas of Data Monitoring in Clinical Trials. ANN INTERN MED 146: 882-887
- Silverman (2007) Ethical Issues during the Conduct of Clinical Trials. Proc Am Thorac Soc 4: 180-184
- Chen-Mok et al (2006) Experiences and challenges in data monitoring for clinical trials within an international tropical disease research network. Clin Trials 3: 469-477
- Ellenberg, Fleming, Demets (2002) Data Monitoring Committees in clinical trials: a practical perspective
- Demets, Friedman, Furberg (2006) Data Monitoring in clinical trials: a case studies approach
- Moffett (2006) Statistical monitoring of clinical trials: a unified approach
EMEA guidance said "In case of a submission the working procedures of a DMC as well as all DMC reports (open and closed sessions) should form part of the submission."
The internal discussion notes said "A special circumstance is the case in which the sponsor wishes to use interim data in support of a regulatory submission, with the intent to continue the trial to its conclusion. Because of the risks to the trial’s credibility, analysis and use of interim data for this purpose is often ill advised. Exceptional circumstances may arise, however, in which such use could be appropriate. Before accessing and using interim data for this purpose, sponsors should confer with FDA and the DMC (or DMC chair) and consider all potential implications of such actions. "
According to FDA guidance "The agency recommends in the guidance that the DMC or the group preparing the interim reports to the DMC maintain all meeting records. This information should be submitted to FDA with the clinical study report (Sec. 314.50(d)(5)(ii) (21 CFR 314.50(d)(5)(ii)))."
Post-analysis DMC meeting: what are the pros and cons of having the DMC convene post-analyiss so they can make an assessment on complete and clean data?
The principal role of DMC is to ensure the safety of patients, which they do by analyzing adverse events and by performing interim analyses of the clinical outcome data. Due to the time constraints, the DMC analyses are typically based on the data that is incomplete or not totally cleaned. Analyses post DMC meeting are typically not needed unless there are serious issues with the data.
One interesting question is the role of the DMC after the study has been completed. My understanding is that the DMC plays the big role during the study. After the study has been completed, DMC would hand the responsibilities back to the sponsor and investigator since all subjects have been off the study. If there is any DMC meeting after the study completion, it is mainly for the courtesy or information purpose.
If DMC made the suggestion to stop the trial after reviewing the interim analysis data, after their suggestion, it is up to the sponsor and investigators (or steering committees or executive committees) to handle the rest (close out the study, disclose the study results, write manuscript,…). In this situation, no post-DMC meeting is needed. The final analyses will be performed by the sponsor or investigators. Investigators will publish the study results. Some examples are: Novartis ACCOMPLISH trial - stopped for efficacy; Pfizer’s ILLUMINATE trial - stopped for futility.