Premature Termination/Clinical Trials (excerpts)

Excerpts from:

Premature Termination of Clinical Trials - Lessons Learned

Domenic A. Sica, MD

Several factors can influence the decision to terminate an ongoing clinical trial including ethical concerns, alterations in accepted clinical practice that make the continuation of a clinical trial unwise, and/or reaching a positive or negative statistical end point earlier than anticipated.

The discontinuation of a clinical trial can be prompted by either the investigator(s), the study sponsor, or by mutual agreement. This decision can be reached with or without the input of a properly constituted independent Data and Safety Monitoring Board.[1]

Investigator-specific considerations are generally more relevant for single-center trials. but may also influence multicenter trials, particularly if the investigative site in question has been a heavy enroller in the clinical trial.

[2]There are a number of "positive" findings that can correctly prompt the early termination of a study.

(A) trial was terminated 9-months before the scheduled closing date on recommendation of the Policy and Data Monitoring Board. At the time of the decision the treatment group had a strikingly lower mortality (26%).

Several issues were considered in this decision including the magnitude and consistency of the overall results across all subgroups, clinical centers, and cause of death, as well as the completeness of follow-up obtained.If ethical considerations exist at the outset of a clinical trial then carefully defined end points should be established, which, if reached, would prompt discontinuation of the trial.

It should also be appreciated that discontinuation of a trial because the results are either strongly positive or negative generally makes it difficult, if not impossible, to conduct a similar trial in the future. If the trial is to be terminated early as per pre-established criteria, the confirming data must be adequate to convince the overwhelming majority of statisticians and clinicians of the validity of the conclusion; otherwise, positive findings of a trial may not be accepted or negative findings dismissed.

The premature termination of a trial can sometimes be fiscally prudent if valuable resources can then be reallocated. When an investigator terminates a clinical trial careful consideration must also be given as to how patients might best return to their pretrial treatment regimen.[6] In many instances this is an easy issue to address.

In other cases, when patients have benefited both medically and psychologically from being in a trial, the transition from frequent contact with the investigator and staff, plus the benefits of treatment, may prove challenging.

Conclusion

Guidelines for early termination of a clinical trial should be established before any data review is undertaken.

Interim data analyses in conjunction with the totality of available evidence provides the necessary framework from which Data and Safety Monitoring Boards can make informed and prudent recommendations.

Controlled clinical trials should not be prematurely terminated for trivial reasons.

Controlled clinical trials should not be terminated prematurely on economic grounds, particularly if the information to be gained adds substantially to the knowledge base on the therapy of disease states.

Finally, continuation of a trial deemed to be futile is wasteful of resources and potentially unethical.

References:

1. Muth K, Yu E, Alston B, et al. The closeout process for a clinical trial terminated early for lagging enrollment and inadequate follow-up. Control Clin Trials. 2001;22:49-55.

2. Dixon DO, Lagakos SW. Should data and safety monitoring boards share confidential interim data? Control Clin Trials. 2000;21:1-6.

6. Pressel SL, Davis BR, Wright JT, et al. Operational aspects of terminating the doxazosin arm of the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). Control Clin Trials. 2001;22:29-41.



From the Departments of Medicine and Pharmacology, Medical College of Virginia of Virginia Commonwealth, University, Richmond, VA. J Clin Hypertens 4(3) :219-225, 2002. 2002 Le Jacq Communications, Inc.

Ann's NOTE: This paper was based on lessons learned in hypertension. But they clearly apply to all types of clinical trials.

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