Data Management Challenges in Clinical Studies with a Data Safety Monitoring Board

DSMB data managementA Data Safety Monitoring Board (DSMB) is a group of independent professionals with pertinent expertise that reviews, on a regular basis, data accumulated from one or more ongoing clinical trials. The DSMB continuously advises the sponsor on the safety of trial subjects and those yet to be recruited to the trial as well as the validity and scientific merit of the trial (*2006 FDA “Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees).

DSMBs are considered to have “stewardship” of a trial. The Board has a responsibility to both subjects (in terms of safety) and to the sponsor (in terms of trial credibility).

Specifically, the purpose of a DSMB includes:

  • Protecting patient safety
  • Ensuring the credibility and integrity of the trial for future subjects
  • Ensuring the timely conclusion of a trial so its results can disseminated

The function of a DSMB is to act as a monitor during the trial and execute a planned follow-up period to evaluate trial effectiveness, participant safety, study conduct and external data relevant to a trial. In addition, the DSMB provides recommendations to the sponsor regarding the continuation, modification, suspension or termination of a trial. The members also ensure written records of outcomes are maintained and the confidentiality of data is preserved.

There are different scenarios in which a DSMB is recommended for a clinical study, such as: to enhance the safety of trial participants or when safety concerns are unusually high, when there is the possibility of serious toxicity or death, if there is a vulnerable subject population (children, pregnant women, elderly, terminally ill, subjects with diminished mental capacity, or imprisoned), or if treatment is invasive, etc.

It is crucial that the DSMB is provided with complete and accurate data because the outcomes of all DSMB meeting involve ensuring that members obtain sufficient information in order to:

  • Adequately review a study
  • Profit from the discussions with the sponsor and investigator representative
  • Identify issues
  • Develop approaches for addressing the issues
  • Reach a consensus concerning trial recommendations

Data is the foundation for DSMB recommendations with respect to trial safety and efficacy, thus it is important that the information they receive is accurate, complete and as up-to-date as possible. The Data Manager is responsible for providing good quality data in order to respond to the DSMB’s requirements and support the biostatistician in the preparation of the tables and statistical analyses that the DSMB will receive and use to make their recommendations.

The Data Manager will plan in advance during the CRF specification developing by defining:

  • Which data is required
  • What level of cleaning is needed
  • Timelines

The Data Manager will discuss and agree on a monitoring plan to ensure the clinical data is captured in a timely manner:

  • For EDC studies: define target for when data has to be entered into CRF (e.g. within 2 days of clinic visit)
  • For paper studies: define monitoring visits and shipment of CRFs (e.g. ship originals vs scanned copies, normal post vs courier, etc)
  • Implement tracking reports/metrics to monitor what is in-house vs what is still outstanding and share updates with the study team to avoid backlogs

Magnifying glass and documents with analytics data lying on tablThe Data Manager also defines and tailors the cleaning strategy by clarifying if there is a cut-off date for subject enrollment, if there is a cut-off date for last data point entered into the clinical data management system, which data are required for the DSMB, if coding of medical terms is required, or whether medical terms should be reviewed before generation of listings for DSMB.

It is important to define if there are any external data required for the DSMB. External data are usually on a critical path in terms of vendor management and data transmission. In this case, the Data Manager will:

  • Define data transfer specifications and method of transfer
  • Define timelines of data transfers with provider
  • Define timelines for reconciliation to allow time for query issue and resolution
  • Keep the study “blinded”, for instance in the case of PK or Biomarkers, data could reveal what the subject is taking – such as active drug or placebo by viewing the data concentrations. In such cases, the Data Manager will perform a data reconciliation on sample nominal time with concentrations.

The Data Manager works closely with the study team having regular meetings to share the status of the clinical study. The Data Manager usually agrees with the study team if there is a need to run listings and tables in advance to check for potential issues or abnormal trends in clinical data entered into the database:

  • Data Manager can generate queries to address issues or get a justification/clarification prior to generating outputs for the DSMB
  • Collection of protocol deviations and evaluation of possible impact on clinical data
  • Define data checks in the clinical data management system: time window, inclusion/exclusion criteria, plausibility, ranges etc.
  • Retrieve deviations collected through monitoring visits – liaise with CRAs

In summary, to successfully complete a clinical study which includes a DSMB, there are three key points related to data management:

  • Clear definition of roles and responsibilities
  • Communication
  • Plan, plan and plan again.