Independent data monitoring committee (iDMC) is more commonly used in clinical trials than before for various reasons. For innovative and complex trials, an iDMC is usually a must-to-have external committee. For clinical trials containing the adaptations, interim analyses, iDMC can provide a way to review the unblinded data to recommend some critical suggestions about the ongoing clinical trial while maintaining the study integrity. In some cases, the sponsor just wants to have an independent body to oversee the study for extra credibility.
There are plenty of regulatory guidelines for the general principles for establishing and operating a DMC. There are also recommendations from the industry/academic for successful DMC implementation.
- FDA guidance: Establishment and Operation of Clinical Trial Data Monitoring Committees Guidance for Clinical Trial Sponsors
- EMA: GUIDELINE ON DATA MONITORING COMMITTEES
- EMA: Questions and answers on Data Monitoring Committees issues
- RAPs (2020): EMA offers new Q&A on data monitoring committees
- CTTI: Recommendations for data monitoring committees from the Clinical Trials Transformation Initiative
- Annals of Internal Medicine: Presenting Risks and Benefits: Helping the Data Monitoring Committee Do Its Job
- Tips For A Successful Organizational DMC Meeting (wcgclinical.com)
DMC is also mentioned in the recent guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency (updated August 2021), COVID-19: Developing Drugs and Biological Products for Treatment or Prevention, and Development and Licensure of Vaccines to Prevent COVID-19.
"What are some of the key factors that a sponsor should consider when deciding whether to suspend or continue an ongoing study or to initiate a new study during the COVID-19 public health emergency?
Involvement of a study’s DMC, if one has been established, can provide support for the assessments discussed above. Since a primary responsibility of the DMC is assuring the safety of participating trial participants, the DMC’s assessment of the impact of modifications of trial conduct due to COVID-19 on patient safety is important to consider."
When planning for a DMC, multiple statisticians need to be involved - at least three statisticians (blinded and unblinded statisticians) need to play a role in the successful conduct of a DMC. The diagram below lists three different statisticians that are needed for a successful DMC.
- One of the DMC members
- the voting member
- with biostatistical expertise, applying the statistical methods in the monitoring process.
- understands the complex clinical trial designs (group sequential design, adaptive design, ...), familiar with the application of the stopping rules, Type I error issue, multiplicity issue.
- According to FDA's guidance on DMC: "Most DMCs are composed of clinicians with expertise in relevant clinical specialties and at least one biostatistician knowledgeable about statistical methods for clinical trials and sequential analysis of trial data."
- usually unblinded and have access to the unblinded data
Trial Statistician:
- clinical trial study team member and can not be the DMC member
- can attend the open session of the DMC meetings; can't attend the closed session of the DMC meetings
- only have access to the blinded or pooled study data during the study
- responsible for the statistical section of the study protocol including the statistical methods for group sequential design, adaptive design, stopping rules...
- responsible for simulations (if needed) to address questions about the alpha I error spending, multiplicity issue
- maybe the author to develop the statistical analysis plan for DMC and for interim analysis
- provide the blinded data sets to the SDAC (reporting) statistician
- may work with SDAC statistician and review the blinded statistical outputs from the SDAC statistician to ensure the correctness of the statistical package (blinded version)
SDAC Statistician:
- statistician on the Statistical Data Analysis Center (SDAC) - in industry, this is called reporting statistician or independent statistician.
- non-voting member
- primary responsibility is to prepare the statistical outputs (tables, listings, and figures) for DMC. perform the analyses on unblinded interim data and provide the results of comparative interim analyses.
- Reporting statistician will receive the data sets from the data management group and receive the randomization information (unblinded information) directly from the IRT (interactive response technology) group
- Reporting statistician sends the statistical package (unblinded) to DMC for review.
- Reporting statistician is usually unblinded.
- reporting statistician may have a programming team to help with generating the data sets, tables, listings, and figures. Anybody who is working with the reporting statistician needs to follow the same rules that are applicable to the reporting statistician.
- attend the DMC meeting (open and close sessions) and provide explanations for any issues raised by DMC members related to the DMC statistical outputs
As indicated in the diagram above, the trial statistician and reporting statistician may have close discussions and interactions while working on the blinded data. The reporting statistician and the DMC statistician may also have close interactions while working on the unblinded data. There should be no direct interaction or very little interaction between the trial statistician and the DMC statistician (usually the interaction may be limited to the initial administrative meeting and the open session at the scheduled DMC meetings).
FDA guidance on DMC contains a lengthy section to discuss the reporting statistician's roles in the DMC process. FDA is very concerned about the potential risks that statisticians who conduct the interim analyses may comprise the integrity of the clinical trial. The primary trial statistician should not be the one who conduct the interim analysis. The statistician who conducts the interim analysis should not be in the sponsor's organization.
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