Exaggeration of PFS by blinded, independent, central review (BICR)

A Stone, V Gebski, R Davidson, R Bloomfield, J W Bartlett, A Sabin

Research output: Contribution to journalArticle

1 Citation (Scopus)
2 Downloads (Pure)

Abstract

Background Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are carried out and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. Methods We carried out a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. Results The Kaplan-Meier (KM) curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared with assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated KM curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. Conclusions In general, when there is a difference between local and BICR medians, the true BICR KM curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is carried out.

Original languageEnglish
Article numbermdy514
Pages (from-to)332-338
Number of pages7
JournalAnnals of Oncology
Volume30
Issue number2
Early online date23 Nov 2018
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

  • Bicr
  • Informative censoring
  • Kaplan-meier
  • Parp inhibitors
  • Progression-free survival

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Stone, A., Gebski, V., Davidson, R., Bloomfield, R., Bartlett, J. W., & Sabin, A. (2019). Exaggeration of PFS by blinded, independent, central review (BICR). Annals of Oncology, 30(2), 332-338. [mdy514]. https://doi.org/10.1093/annonc/mdy514

Exaggeration of PFS by blinded, independent, central review (BICR). / Stone, A; Gebski, V; Davidson, R; Bloomfield, R; Bartlett, J W; Sabin, A.

In: Annals of Oncology, Vol. 30, No. 2, mdy514, 01.02.2019, p. 332-338.

Research output: Contribution to journalArticle

Stone, A, Gebski, V, Davidson, R, Bloomfield, R, Bartlett, JW & Sabin, A 2019, 'Exaggeration of PFS by blinded, independent, central review (BICR)', Annals of Oncology, vol. 30, no. 2, mdy514, pp. 332-338. https://doi.org/10.1093/annonc/mdy514
Stone A, Gebski V, Davidson R, Bloomfield R, Bartlett JW, Sabin A. Exaggeration of PFS by blinded, independent, central review (BICR). Annals of Oncology. 2019 Feb 1;30(2):332-338. mdy514. https://doi.org/10.1093/annonc/mdy514
Stone, A ; Gebski, V ; Davidson, R ; Bloomfield, R ; Bartlett, J W ; Sabin, A. / Exaggeration of PFS by blinded, independent, central review (BICR). In: Annals of Oncology. 2019 ; Vol. 30, No. 2. pp. 332-338.
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abstract = "Background Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are carried out and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. Methods We carried out a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. Results The Kaplan-Meier (KM) curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared with assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated KM curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. Conclusions In general, when there is a difference between local and BICR medians, the true BICR KM curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is carried out.",
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author = "A Stone and V Gebski and R Davidson and R Bloomfield and Bartlett, {J W} and A Sabin",
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AU - Stone, A

AU - Gebski, V

AU - Davidson, R

AU - Bloomfield, R

AU - Bartlett, J W

AU - Sabin, A

N1 - © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are carried out and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. Methods We carried out a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. Results The Kaplan-Meier (KM) curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared with assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated KM curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. Conclusions In general, when there is a difference between local and BICR medians, the true BICR KM curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is carried out.

AB - Background Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are carried out and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. Methods We carried out a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. Results The Kaplan-Meier (KM) curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared with assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated KM curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. Conclusions In general, when there is a difference between local and BICR medians, the true BICR KM curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is carried out.

KW - Bicr

KW - Informative censoring

KW - Kaplan-meier

KW - Parp inhibitors

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DO - 10.1093/annonc/mdy514

M3 - Article

VL - 30

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JO - Annals of Oncology

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SN - 0923-7534

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