– Written by Shrutimita Pokhariyal, Principal Statistician, Symbio Proinnovera

In the late 1960s, the need for interim statistical reports arose for DSMBs (Data and Safety Monitoring Boards) or similar committees in randomised clinical trials. Initially part of the data coordinating centre, in the 1990s the statistical team was separated from the data management team in industry-sponsored trials. The statistical data analysis centreis now critical to any well-functioning data monitoring committee.

Clinical trials test medicine and involve participants, so it’s important to ensure their safety. A DSMB reports early evidence of benefit or harm and is recommended for high-profile or high-risk trials. The team reviews data and makes recommendations.

What is a DSMB statistician (DS)?

DSMBs are composed of members with scientific expertise in the clinical aspects of the disease/patient population being studied, including a DSMB statistician (DS), who has voting rights. The DS is only a member of the DSMB, not of the core trial management team. Their role is to provide independent statistical expertise to the DSMB, attend both open and closed sessions of DSMB meetings, and have voting rights within the DSMB. The DS must be independent of the trial and not work in the same research institutes as the trial investigators.

What is a trial statistician (TS)?

Teams manage and conduct the day to day running of clinical trials. Teams consist of sponsors, project staff, data managers, programmers and a trial statistician (TS). The TS provides statistical support from protocol development to data analysis and dissemination of results. In blinded clinical trials, the management team is typically blinded to the study treatment.

The TS is involved in drafting the charter for the DSMB, which defines the responsibilities of the board and its procedures. They analyse study objectives and endpoints, develop analysis datasets and reports with support from programmers, and provide unique statistical and logistical solutions. They attend open but not closed sessions of DSMB meetings and remain blinded to treatment allocation and interim results until the final analysis.

What is the role of a TS and an independent statistician (IS) in a DSMB?

Clinical trials require a statistical analysis plan (SAP) for data analysis. An independent statistician (IS) generates the results by rerunning validated programs using actual randomisation information. As per the Use of DSMB in Clinical Trials- Guidance for Industry Draft February 2024 Revision 1, the FDA requires an IS in addition to a TS and DS to prepare and present interim analyses to the DSMB. The IS should have access to unblinded data and provide responsive analyses.

What is the rationale behind the separation of statistical roles (TS versus IS)?

The roles of the TS and IS must be separated to eliminate bias or perception of bias in clinical trials. While the TS is responsible for the statistical design of the trial and collaborating with the sponsor and steering committee, the IS is responsible for preparing and presenting interim analyses to the DSMB. To ensure the trial is confirmatory, decisions about mid-course design changes must be based on external evidence and those responsible for the changes should be blinded to the trial’s emerging efficacy and safety results.

A barrier between stakeholders and committees reduces the risk of leaks that can damage trial integrity.

Items needed by IS to do the work

The IS should be provided with study documentation such as protocol, case report forms (CRFs), charters, interim analysis plans and SAP, including decision rules for interim analysis, proposed TLGs (tables, listings and graphs), special considerations in the studies, and the definition of estimands and intercurrent events in a clinical endpoint.

Organisations that provide data to the IS:

• Statistical data analysis centres

• Interactive response technology (IRT) vendors

• Central clinical labs

• Biomarker labs

The sources of data needed by the IS can include:

• CRF databases

• Analysis databases

• Clinical laboratories

• IRTs

• Biomarkers or specialty laboratories

• Serious adverse events (SAE) database (expedited review – pharmacovigilance)

• Current death lists

• 24-hour reports of SAE/clinical endpoints

Documents supporting the data to be provided:

• Detailed specifications – derivations of derived variables

• Annotated CRFs

• Description of special processes (a clear instruction in the form of standard operating procedure (SOP) or instructions shared by the TS with the IS to smoothly replicate and reproduce the TLGs in an unblinded manner.

Tasks assigned to the IS

• Reproducing and programming of the TLGs

Who will write them?

The charter mandates all TLGs be produced by the TS. The DSMB blinded package, which includes data and programs, is shared with the IS via secure file transfer protocol (sFTP) or other encrypted methods. DSMB members receive the TLGs at least one week before their meeting. The IS may provide additional content, such as graphical presentations or statistical analyses, if requested by the DSMB.

• How will the IS’s work be verified on the IS’s system?

Extra data transfers help meet tight timelines, and reviewing databases is crucial. A 100% check of tables with dummy randomisation is essential, as is comparing TS outputs with IS regenerated outputs using actual randomisation.

The IS prepares closed reports and summarises information for open reports for the DSMB. They attend meetings, present at interim meetings, and ensure confidentiality by limiting information to the Board members.

Conclusion

Statisticians are crucial for clinical trial safety. The DS guides a DSMB from a statistical perspective, the TS provides study-wide statistical support, and the IS maintains a barrier between blinded and unblinded teams to deliver unblinded TLGs to a DSMB. All ensure data integrity and participant safety.

References

DeMets D.L. & Fleming T.R. (2004). The Independent Statistician for Data Monitoring Committees. Statistics in Medicine, 23(10), 1513–1517.

Fleming T.R., Ellenberg S.S. & DeMets D.L. (2018). Data Monitoring Committees: Current Issues. Clinical Trials, 15(4), 321–328.

Use of Data Monitoring Committees in Clinical Trials Guidance for Industry DRAFT GUIDANCE.

O’Meara PhD, P.D. (2005). Using an Independent Statistician to Support a Data Monitoring Committee – FDA/Industry Workshop.

Ellenberg S.S., Fleming T.R. & DeMets D.L. (2002). Data Monitoring Committees in Clinical Trials: A Practical Perspective. Chichester: Wiley.

Whitehead, J. (1999). On Being the Statistician on a Data and Safety Monitoring Board. Stat Med, 18(24), 3425–3434.

Blair Holbein M.E., Hammack B.N., Knox, T.A. & Yasko L. (2018). DSMB Training Manual Version 1.0.

National Health and Medical Research Council (2018). Data Safety Monitoring Boards (DSMBs).

U.S. Food and Drug Administration. (February 2024). Use of Data Monitoring Committees in Clinical Trials. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-data-monitoring-committees-clinical-trials