Data and safety monitoring

This section contains the following:


Introduction

The principal investigator must ensure the safety and integrity of individual patients participating in the trial.  He or she is responsible for assessing, recording and reporting information of all adverse events related to the treatment or procedure, and all serious or unexpected adverse events that may occur during the conduct of the trial.  

The establishment of a special committee to monitor adverse events should be considered, especially in large trials.  Safety-monitoring committees (often known as Data Monitoring Committees) should include clinicians with expertise in the topic under trial, bio-statisticians, and researchers from other relevant fields (see Trial Management).

Members of the safety-monitoring committee are responsible for giving advice to the principal investigator on whether to a) continue as planned b) stop further recruitment or c) discontinue the intervention if there is evidence that the latter is substantially better (or worse) than the alternatives.  Sometimes it is recommended that the intervention be modified (e.g. treatment dosage reduced or one treatment arm stopped in a multiple arm trial).  Such data and safety monitoring committees often use statistical stopping rules to help with their decision making.

It is important that members of the data monitoring committee are independent of the trial.  Knowledge of the data or emerging trends may make the investigator in charge of patient recruitment reluctant to enrol new patients or to continue treating those already enrolled if the data suggests one intervention is better than the other.


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Things to consider when writing a protocol


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Illustrative example - WHO pre-eclampsia trial

Analysis plan
An analysis plan will be finalised before recruitment starts.  A draft layout of the proposed analysis plan is presented in Appendix 3 in dummy tables.
Principal analyses will be on an intention-to-treat principle with comparisons made between calcium and placebo for primary and secondary outcomes. Stratification will be made for parity.

Interim analysis: A Data Safety and Safety Monitoring Committee (DSMC) with no direct involvement in the trial will be appointed by the trial steering committee.  The role of this committee will be to deal with any ethical issues that may arise while the trial is in progress, and to scrutinise an interim analysis.  An interim analysis is planned after the completion of the first 4500 subjects for which the trial will have the power to detect a reduction of 40% in the rate of pre-eclampsia from 4% to 2.4%.  Reporting and handling of adverse events will be in accordance with the GCP guidelines.

Stopping the trial: The DSMC will be asked to give advice regarding stopping the trial if they have proof beyond doubt of an important advantage or disadvantage for one of the treatment groups, and they consider that the results are likely to affect clinical practice. (WHO Multicentre Randomised Trial of Calcium Supplementation for the Prevention of Pre-eclampsia - go to protocol)

go to protocol )


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Illustrative example - CRASH trial

Organisation

The independent Data Monitoring Committee will conduct interim analyses of mortality and morbidity among all trial participants. It will advise the Steering Group if the randomised comparisons in the trial provide both (i) proof beyond reasonable doubt of a difference in outcome between the study and control groups, and (ii) evidence that would be expected to alter substantially the choice of treatment for patients whose doctors are, in the light of the evidence from other randomised trials, substantially uncertain whether to give corticosteroids to patients with head injury. (CRASH Trial - go to protocol)

go to protocol )


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Illustrative example - Perinatal care trial

Interim Analysis and Study Monitoring

NICHD will determine the members of the DSMB that will be responsible for monitoring the project. (CLAP Trial - go to protocol)

go to protocol )


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Additional resources

Trial Protocol Tool resourceData monitoring checklist

This checklist has been contributed by Dave Sackett, who prepared it for the forthcoming 3rd edition of Clinical Epidemiology; A Basic Science for Answering Questions about Health Care, to be published by Lippincott, Williams & Wilkins in 2005.

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Trial Protocol Tool resource iconSafety, efficacy and futility text from 3rd edition of Clinical Epidemiology

This text has been contributed by Dave Sackett, who prepared it for the forthcoming 3rd edition of Clinical Epidemiology; A Basic Science for Answering Questions about Health Care, to be published by Lippincott, Williams & Wilkins in 2005.


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Further reading

WHO GCP Guidelines on the Reporting of Adverse Events. In: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products. WHO Technical Report Series, No. 850, (pages 97-137). World Health Organization, Geneva, Switzerland, 1995. Chapter 7

Duley L & Farrell B.  Clinical Trials. London, BMJ Books, 2002.

Meinert CL & Tonascia S.  Clinical Trials. Design, Conduct, and Analysis. Oxford, Oxford University Press, 1986.

Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3rd edition New York, Springer-Verlag, 1998.

Shapiro SH, Louis TA.  Clinical Trials, Issues and Approaches. New York, Marcel Dekker, Inc., 1983.

Smith PG & Morrow RH. Methods for Field Trials of Interventions against Tropical Diseases: a ‘Toolbox’. Oxford, Oxford University Press, 1991.


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This page was last updated 19th October 2004.