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Comparison of futility monitoring guidelines using completed phase III oncology trials.

Publication ,  Journal Article
Zhang, Q; Freidlin, B; Korn, EL; Halabi, S; Mandrekar, S; Dignam, JJ
Published in: Clin Trials
February 2017

BACKGROUND: Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. PURPOSE: We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. METHODS: We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. RESULTS: For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials. CONCLUSION: The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.

Duke Scholars

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Published In

Clin Trials

DOI

EISSN

1740-7753

Publication Date

February 2017

Volume

14

Issue

1

Start / End Page

48 / 58

Location

England

Related Subject Headings

  • Statistics & Probability
  • Research Design
  • Neoplasms
  • Medical Futility
  • Humans
  • Clinical Trials, Phase III as Topic
  • Clinical Trials Data Monitoring Committees
  • 5203 Clinical and health psychology
  • 4905 Statistics
  • 3202 Clinical sciences
 

Citation

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Zhang, Q., Freidlin, B., Korn, E. L., Halabi, S., Mandrekar, S., & Dignam, J. J. (2017). Comparison of futility monitoring guidelines using completed phase III oncology trials. Clin Trials, 14(1), 48–58. https://doi.org/10.1177/1740774516666502
Zhang, Qiang, Boris Freidlin, Edward L. Korn, Susan Halabi, Sumithra Mandrekar, and James J. Dignam. “Comparison of futility monitoring guidelines using completed phase III oncology trials.Clin Trials 14, no. 1 (February 2017): 48–58. https://doi.org/10.1177/1740774516666502.
Zhang Q, Freidlin B, Korn EL, Halabi S, Mandrekar S, Dignam JJ. Comparison of futility monitoring guidelines using completed phase III oncology trials. Clin Trials. 2017 Feb;14(1):48–58.
Zhang, Qiang, et al. “Comparison of futility monitoring guidelines using completed phase III oncology trials.Clin Trials, vol. 14, no. 1, Feb. 2017, pp. 48–58. Pubmed, doi:10.1177/1740774516666502.
Zhang Q, Freidlin B, Korn EL, Halabi S, Mandrekar S, Dignam JJ. Comparison of futility monitoring guidelines using completed phase III oncology trials. Clin Trials. 2017 Feb;14(1):48–58.
Journal cover image

Published In

Clin Trials

DOI

EISSN

1740-7753

Publication Date

February 2017

Volume

14

Issue

1

Start / End Page

48 / 58

Location

England

Related Subject Headings

  • Statistics & Probability
  • Research Design
  • Neoplasms
  • Medical Futility
  • Humans
  • Clinical Trials, Phase III as Topic
  • Clinical Trials Data Monitoring Committees
  • 5203 Clinical and health psychology
  • 4905 Statistics
  • 3202 Clinical sciences