TERMS OF REFERENCE

DATA & SAFETY MONITORING BOARD

Effectiveness of a simplified short regimen for

Multidrug ResistantTuberculosistreatment in Karakalpakstan, Uzbekistan

TERMS OF REFERENCE:

The main aim of the data and safety monitoring board (DSMB) is to safeguard the interests of study participants, assess the safety and efficacy of the interventions during the study, and monitor the overall conduct of the simplified short regimen MDR-TB study.

The DSMB should not make decisions about the study but rather make recommendations to the Uzbekistan 9 months study working group (WG) through the co-principal investigators. The DSMBrecommendationswill then be shared withMSF and the Uzbekistan Ministry of Health (MoH) and the relevant ethics review boards (ERB) who make the decision whether to continue, suspend, modify or stop a study.

The DSMB has access to quarterly study reports and if requested to the raw study data so that they can see any emerging risks such as frequency or severity in adverse events.

Their monitoring should also include considering external factors to the study such as therapeutic or scientific developments that may have an impact on the safety of participants or the ethics of the study.

Confidentiality is paramount. The DSMB must protect the confidentiality of the study data and the results of monitoring. Membership is voluntary and is not paid.

Their role and responsibilities are:

  • To understand the research protocol and the plans therein for data and safety monitoring;
  • To review any proposed modifications to the study prior to their implementation.
  • To review interim summary reports (case finding, safety and interim and final outcome) on 3 monthly basisprovided by the study Principal Investigator (PI) including adverse event reports
  • If there are concerns about the quality of the data analysis, or whether there are safety concerns that require further information the DSMB can:
  • Request further information from the study PI as relevant in order to fulfil the task of assessing safety and effectiveness of this regimen (either in writing or to be present for a DSMB meeting
  • Request a copy of the primary database in order to check analyses or do further sub-analyses in order to check safety (each member of the DSMB viewing the database will be required to sign a data sharig agreement in the event that this is deemed necessary)
  • To inform the Principal investigator on the acceptability of continued recruitment to the study and any concerns with regards to the safety or effectiveness of the regimen
  • To review study abstracts and manuscripts to give an assurance that the results are fairly presented and that the conclusions are appropriate.

In carrying out the above remit, the DSMB operates within the following capacity:

OPERATIONAL:

The Principal investigator (MSF) will produce a quarterly report of the study including progress report and interim analyses as per the study protocol, which will be sent to each member of the committee at least 2 weeks before the meeting date. It is critical that the data in this statistical report is cleaned as far as possible, so that it is as up to date and complete as possible. This will also be provided with data of programme performance with the standard regimen.

In looking at the data, the committee members take into consideration – chance variation, biological/clinical plausibility differences, and primary and secondary endpoints. They will evaluate the progress of the study, assessing:safety data, data quality, timeliness, participant recruitment, accrual and retention, participant risk versus benefit,any other factors that can affect the study outcomes.

FREQUENCY OF MEETINGS:

The committee willreview reports on a 3 monthly basis by email. Teleconference will be conducted on a 6 monthly basis

MEMBERSHIP

  • Kai Blondal (Green light committee)
  • Colleen Acosta (WHO Europe – epidemiologist)
  • Andrei Dadu (WHO Europe – Technical Officer)

If safety concerns occur that the DSMB members feel requires further consultation with experts in specialities beyond the skillset of members then this should be discussed with the PI and external expert consultation can be arranged the PI (examples that could be relevant include cardiologist with electrophysiology expertise, biostatistician). The PI’s role would be to arrange contact of an external expert with suitable qualifications (as verified by CV) who would be put in touch with the chair of the DSMB with costs (if any) arising from this covered by MSF.

MEETING FORMAT:

Review of quarterly reports – by email with the chair of the DSMB sending a combined report back to the PI.

6 monthly teleconference: first half with PI and DSMB, second half closed with discussion by DSMB – 6 monthly DSMB feedback report to be produced (1-2 page summary of findings)

STUDY PROGRESS REPORT

The quarterly report shouldbe sent within a month after the quarter finishes (i.e. by1st May, 1st August, 1st October and 1st February) and the quarterly meeting held within the month that the report is received. Each member needs to have the opportunity to review the data and assess the study’s progress.

The report must be detailed and should include a summary of any published literature relevant to the safety of subjects in the study, or aggregated reports of any other relevant unpublished data known to the PI.

ACTIONS FOLLOWING THE DSMBMEETING

Following each quarterly email meeting the DSMB will send email feedback to the principal investigators for MSF and Ministry of health. If there are any potential safety or efficacy issues then the DSMB should arrange a meeting by teleconference to discuss these issues, including alerting the principal investigators to any information they should provide for this meeting.

The DSMB writes a report after each teleconference (on a 6 monthly basis at a minimum) which must be submitted to the MSF medical director, the principal investigators for MSF and ministry of health. In addition the report will be forwarded to the chair of the MSF ethics research board (forwarded by MSF Medical Director) and the Uzbekistan ethics research board (forwarded by the Uzbekistan principal investigator) with any issues they want to raise or recommendations they wish to make.

If the DSMB makes a recommendation that the study should be stopped or suspended, MSF and the MoH will take the necessary action to ensure that new recruitment to the study is stopped whilst the DSMB’s report is evaluated and the the ethics review boards are informed, and that appropriate medical management of patients continues (new patients as well as patients on treatment) while the study is interrupted/stopped.

If there is disagreement between the DSMB and the principal investigatorson a recommendation to stop or suspend the study, the medical director will discuss with the chair of the MSF ethics review board and may convene an independent external advisory committee to arbitrate. During any such process, recruitment of new participants to the study will be suspended.

GLOSSARY

PIPrincipal Investigator

DSMBData & Safety Monitoring Board

ERBEthics review board

MoH Uzbekistan Ministry of Health

MSFMedecins Sans Frontieres