Lesson 9: Treatment Effects Monitoring; Safety Monitoring

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Introduction

During a clinical trial over a lengthy period of time, it can be desirable to monitor treatment effects as well as tracking safety issues. "Interim analysis" or "early stopping" procedures are used to interpret the accumulating information during a clinical trial. There may be a variety of practical reasons for terminating a clinical trial at an early stage. Some of these are overlapping:

  1. Treatments are found to be convincingly different,
  2. Treatments are found to be convincingly not different,
  3. Side effects or toxicity are too severe to continue treatment, relative to the potential benefits,
  4. The data are of poor quality,
  5. Accrual is too slow to complete the study in a timely fashion,
  6. Definitive information is available from outside the study, making the trial unnecessary or unethical, this is also related to the next item...
  7. The scientific questions are no longer important because of other developments,
  8. Adherence to the treatment is unacceptably poor, preventing an answer to the basic question,
  9. Resources to perform the study are lost or no longer available, and/or
  10. The study integrity has been undermined by fraud or misconduct.

(Piantodosi, 2005)

This lesson will look examine different methods or guidelines that can be used to help decide whether or not to terminate a clinical trial in progress.

Learning objectives & outcomes

Upon completion of this lesson, you should be able to do the following:

  • Differentiate between valid and invalid reasons for interim analyses and early termination of a trial.
  • Identify characteristics of a sound plan for interim analysis.
  • Understand the theoretical framework for a likelihood based interim analysis.
  • Compare and contrast the Bayesian approach to analysis with the frequentist approach.
  • Recognize the general effects of the choice the prior on the posterior probability distribution from a Bayesian analysis.
  • Compare α spending functions for 3 group sequential methods for interim analysis.
  • Comment on the use of a group sequential method in a published statistical analysis.
  • Recognize a futility assessment and define conditional power.
  • List topics that should be covered in an interim report to an IRB.
  • List the advantages and disadvantages of a DSMB and describe who might compose the DSMB.
  • List the issues of concern to a DSMB in a typical clinical study.

References

DeMets DL, Lan KK, 1994, Interim analysis: The alpha spending function approach, Statistics in Medicine 13: 1341-1352.

Ellenberg, SS. Fleming, TR. DeMets, DL. 2002, Data Monitoring Committees in Clinical Trials, New York, NY: Wiley.

Piantadosi, Steven. (2005) Treatment Effects Monitoring. In: Piantadosi Steven. Clinical Trials: A Methodologic Perspective. 2nd ed. Hobaken, NJ: John Wiley and Sons, Inc.

Pocock, S.J. 1983 Clinical Trials: A Practical Approach. Chichester: John Wiley and Sons.