Design and Conduct of Oncology Cinical Trials:

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Presentation transcript:

Design and Conduct of Oncology Cinical Trials: A Session in Memory of Daniel J. Sargent (1970-2016) Marc Buyse IDDI, San Francisco I-BioStat, Universiteit Hasselt, Belgium SCT ICTMC Conference , Liverpool, UK May 8, 2017

Dan’s extraordinary contributions 313 peer-reviewed publications between 1995 and 2016

Number of peer-reviewed publications by year

Dan’s extraordinary contributions 313 peer-reviewed publications between 1995 and 2016 covering a wide range of applied topics (collaborative group trial reports, digestive cancers, biomarkers, quality of life, prognostic factors, etc.) as well as theoretical topics (Bayesian methods, clinical trial designs, MCMC algorithms, meta-analysis, multi-state models, surrogate endpoint evaluation, etc.)

Dan’s extraordinary contributions 313 peer-reviewed publications between 1995 and 2016 73 in J Clin Oncol 23 on surrogate endpoint evaluation 39 on trial designs

A new clinical trial design… Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

Classical phase II clinical trial design Assume we use the response rate (r) to test a new treatment. The treatment will be considered: insufficiently promising if r  r0 sufficiently promising if r  rA Null hypothesis: H0: r  r0 = 0.15 Alternative hypothesis: HA: r  rA = 0.3 Significance level:  = 0.05 Power : 1- = 0.8 Ref: Fleming T. Biometrics 1982; 38:143.

Classical phase II clinical trial design Fleming (1982) one-stage design: Using binomial distributions under H0 and HA, P( 12 responses among 48 patients  H0 true) = 0.048 P( 12 responses among 48 patients  HA true) = 0.819 Reject H0  12 48 patients # responses < 12 Reject HA Ref: Fleming T. Biometrics 1982; 38:143.

Classical phase II clinical trial design Ref: Fleming T. Biometrics 1982; 38:143.

A new clinical trial design… Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

A new clinical trial design… Sargent et al. (2001) question the clinical relevance of taking opposite decisions for 11 vs. 12 responses (r = 0.23 vs. 0.25) They suggest to control four probabilities Probability of false positive = P(RH0  H0 true) ,  Probability of true positive = P(RH0  HA true) ,  Probability of false negative = P(RHA  HA true),  Probability of true negative = P(RHA  H0 true),  Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

A new clinical trial design… Sargent et al. (2001) question the clinical relevance of taking opposite decisions for 11 vs. 12 responses (r = 0.23 vs. 0.25) They suggest to control four probabilities Probability of false positive = P(RH0  H0 true),  = 0.05 Probability of true positive = P(RH0  HA true),  = 0.8 Probability of false negative = P(RHA  HA true),  = 0.1 Probability of true negative = P(RHA  H0 true),  = 0.8 Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

A new clinical trial design… Sargent et al. (2001) one-stage design: Using binomial distributions under H0 and HA, P( 12 responses among 48 patients  H0 true) = 0.048 P( 12 responses among 48 patients  HA true) = 0.819 P(< 10 responses among 48 patients  HA true) = 0.057 P(< 10 responses among 48 patients  H0 true) = 0.826 Reject H0  12 = 10 or 11 48 patients # responses Do not conclude < 10 Reject HA Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

A new clinical trial design… Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

Classical phase II clinical trial design Simon (1989) two-stage minimax design: Reject H0  12 48 patients # responses  3 23 patients # responses < 12 Reject HA < 3 Reject HA Ref: Simon R. Controlled Clinical Trials 1989; 10:1.

A new clinical trial design… Sargent et al. (2001) two-stage minimax design: Reject H0  11 44 patients # responses = 9 or 10 Do not conclude  4 26 patients # responses < 9 Reject HA < 4 Reject HA Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

A new clinical trial design… Ref: Sargent DJ, Chan V, Goldberg RM. Controlled Clinical Trials 2001; 22:117.

Acknowledgments Qian Shi & Lindsay Renfro (Mayo Clinic) Mariella de Bausset (Fondation ARCAD) R code for Sargent design by elisabeth.coart@iddi.com

Dan as Mentor Courtesy Fondation ARCAD

Dan as Colleague Courtesy Fondation ARCAD

Dan as Friend and “Bon Vivant” Courtesy Fondation ARCAD