Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group

A. M. Stone, W. Bushnell, J. Denne, D. J. Sargent, O. Amit, C. Chen, R. Bailey-Iacona, J. Helterbrand, G. Williams

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Purpose: Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval. Patients and methods: These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions. Results: (1) In the assessment of PFS, there is a critical distinction between measurement error that results from random variation, which by itself tends to attenuate treatment effect, versus bias which increases the probability of a false negative or false positive finding. Investigator bias can be detected by auditing a random sample of patients by blinded, independent, central review (BICR). (2) ITT analyses generally resulted in smaller treatment effects (HRs closer to 1) than analyses that censor patients for potentially informative events (such as starting other anti-cancer therapy). (3) Interval censored analyses (ICA) are more robust to time-evaluation bias than the log-rank test. Conclusion: A sample based BICR audit may be employed in open or partially blinded trials and should not be required in true double-blind trials. Patients should be followed until progression even if they have discontinued treatment to be consistent with the ITT principle. ICAs should be a standard sensitivity analysis to assess time-evaluation bias. Implementation of these recommendations would standardize and in many cases simplify phase III oncology clinical trials that use a PFS primary end-point.

Original languageEnglish (US)
Pages (from-to)1763-1771
Number of pages9
JournalEuropean Journal of Cancer
Volume47
Issue number12
DOIs
StatePublished - Aug 2011

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Disease-Free Survival
Outcome Assessment (Health Care)
Clinical Trials
Research
Neoplasms
Phase III Clinical Trials
Therapeutics
Research Personnel
Pharmaceutical Research

Keywords

  • Bias
  • Progression
  • Randomised clinical trials
  • Solid tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group. / Stone, A. M.; Bushnell, W.; Denne, J.; Sargent, D. J.; Amit, O.; Chen, C.; Bailey-Iacona, R.; Helterbrand, J.; Williams, G.

In: European Journal of Cancer, Vol. 47, No. 12, 08.2011, p. 1763-1771.

Research output: Contribution to journalArticle

Stone, AM, Bushnell, W, Denne, J, Sargent, DJ, Amit, O, Chen, C, Bailey-Iacona, R, Helterbrand, J & Williams, G 2011, 'Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group', European Journal of Cancer, vol. 47, no. 12, pp. 1763-1771. https://doi.org/10.1016/j.ejca.2011.02.011
Stone, A. M. ; Bushnell, W. ; Denne, J. ; Sargent, D. J. ; Amit, O. ; Chen, C. ; Bailey-Iacona, R. ; Helterbrand, J. ; Williams, G. / Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group. In: European Journal of Cancer. 2011 ; Vol. 47, No. 12. pp. 1763-1771.
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