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

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

3. Number of peer-reviewed publications by year

4. 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.)

5. 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

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

7. 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.

8. 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.

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

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

11. 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.

12. 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.

13. 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.

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

15. 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.

16. 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.

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

18. Acknowledgments Qian Shi & Lindsay Renfro (Mayo Clinic)
Mariella de Bausset (Fondation ARCAD)
R code for Sargent design by

19. Dan as Mentor
Courtesy Fondation ARCAD

20. Dan as Colleague
Courtesy Fondation ARCAD

21. Dan as Friend and “Bon Vivant”
Courtesy Fondation ARCAD