Data Monitoring Committees

Establishing an independent data and safety monitoring committee (IDSMC)

Primary role

The IDSMC is a committee of experts in relevant areas who review accumulating dat from a clinical trial and other sources and make recommendations to the Trial Management Committee and/or the Sponsor about the continuation or modification of the study. They are distinct and independent from the Trial Management Committee.

Data monitoring committees have to balance the competing interests of trial participants and potential future participants and society (or people that may benefit or be harmed by the intervention in the future)

these interests don’t always coincide
trial participants’ interests are served by closing recruitment as soon as a clear answer is available (so that all patients can receive the best treatment)
society’s interests are served by continuing recruitment until a clear answer is available so that results are sufficient to lead to a change in clinical management of future patients
stopping the trial early may appear to confer benefits to trial participants but if sample is too small to detect a real difference then neither participants or society will benefit
stopping a trial early for apparent benefit has ethical implications and may lead to biased results – inflating the size of the treatment effect, particularly if the event rate is low (Montori 2005, Mueller 2007)

What to consider when putting together a DMC

Is an IDSMC required?	Can safety of participants be assured by the sponsor or investigators without added complexity to the study?
Number of members	usually 3 to 8 members
Independent	need to declare any competing/conflicting interests
Multidisciplinary	including at least one clinician and one statistician
Chair	should be experienced, understand statistics and clinical issues and take a facilitatory approach
Trial statistician	conducts the confidential analyses and attends closed sessions of the DMC but is not a member of the DMC
DMC statistician	provides statistical guidance to the DMC – trial statistician and DMC statistician need to agree on the analytical approach planned

Questions for the IDSMC to consider

Prepare a clear terms of reference for the IDSMC to operate by which includes the following considerations:

The stopping rules

Apparent strong benefit of active treatment on primary outcome • Apparent strong benefit of control on primary outcome
Safety concerns with secondary outcomes
Small chance of eventually showing benefit
Convincing evidence of equivalence or non-inferiority

Part of the study should stop?

Stopping randomisation in a subgroup for one of the above reasons
Stopping randomisation in one arm for one of the above
External evidence
Need to influence clinical opinion

The study should continue with modification?

Additional interim analyses
Extending recruitment or follow-up time See related toolkit – Statistical approaches to data monitoring

SCENARIO ONE

You and your team have just been awarded a large grant to carry out a major perinatal trial and are recruiting participating centres.

A US trial of a similar intervention is closed down very early with widespread publicity on the grounds of a cluster of adverse outcomes.

What do you do? Would a functioning data monitoring committee make a difference to your options? Or to your actions?

SCENARIO TWO

Clinician/researcher A is carrying out a relatively small clinical trial in her/his own work setting. A’s work includes: Recruitment of women or babies; information for potential participants; seeking informed consent from the women. There are no problems.

Clinician/researcher A decides this is a good time to update the systematic review (SR) of the intervention which was carried out before s/he began the current trial. The updated review shows strong but not conclusive evidence that the intervention is harmful.

What should A do? What are the consequences for the trial? What are the consequences for practice?

See related toolkit – Statistical approaches to data monitoring

References:

Ellenberg S, Fernandes RM, Saloojee H, Bassler D, Askie L, Vandermeer B, Offringa M, Van der Tweel I, Altman DG, van der Lee JH; StaR Child Health Group. Standard 3: Data Monitoring Committees. Pediatrics. 2012 Jun;129 Suppl 3:S132-7.

Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann H, Dickersin K, Berlin JA, Doré CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7.

Grant A, Altman D, Babiker A, Campbell M, Clemens F, Darbyshire J, Elbourne D, McLeer S, Parmar M, Pocock S, Spiegelhalter D, Sydes M, Walker A, Wallace S, and the DAMOCLES Study Group. Issues in data monitoring and interim analysis of trials. HTA 2005;9:7.

Edwards S, Lilford R, Braunholtz D, Jackson J, Hewison J, Thornton J. Ethical issues in the design and conduct of randomised trials. HTA 1998;2:15.

Mueller P, Montori V, Bassler D, Koenig B, Guyatt G. Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med 2007;146:878-881.

Montori V, Devereaux P, Adhikari N, Burns K, Eggert C, Briel M, Lacchetti C, Leung T, Darling E, Bryant D, Bucher H, Schunemann H, Meade D, Cook D, Erwin P, Sood A, Sood R, Lo B, Thompson C, Zhou Q, Mills E, Guyatt G. Randomized trials stopped early for benefit. A systematic review. JAMA 2005;294:2203-2209. Last revised: 24 June 2015.

These materials are based on content originally provided by the WOMBAT collaboration. The WOMBAT Collaboration was formed to promote and support high quality randomised clinical trials in the perinatal area in order to improve the health and wellbeing of women and their children (2005 – 2010).

This toolkit is based on material prepared by Caroline Crowther (WOMBAT), Judith Lumley (WOMBAT) and Rebecca Tooher (WOMBAT) in 2007 and updated in 2015 by Lucille Sebastian (NHMRC CTC).

Last revised: 24 June 2015.