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Designs for Phase II Clinical Trials

2. Overview. Introduction of clinical trialsSimon two-stage designs:Minimax designOptimal designCompromised/practical designs through graphical search. 3. Phase I trials (dose-finding trials): looking for the Most Tolerable Dose (MTD); small sample size (20-80) and short termPhase II trials

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Designs for Phase II Clinical Trials

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    1. 1 Designs for Phase II Clinical Trials May 30, 2006

    2. 2 Overview Introduction of clinical trials Simon two-stage designs: Minimax design Optimal design Compromised/practical designs through graphical search

    3. 3 Clinical Trials for Drug/Treatment Development

    4. 4 Phase II Trials P = efficacy level P <= Po ? unacceptable drug P >= P1 ? acceptable drug Type I error = accept an unacceptable drug Type II error = reject an acceptable drug

    5. 5 Two Stage Designs Let X be the number of responders

    6. 6 Important Operation Characteristics A 2-stage design (r1, n1, r, n) where n=n1+n2 Type I error rate a Type II error rate b Max sample size n Expected sample size EN

    7. 7 Calculation Let b(x;p,m) be the pmf of bin(p,m). Let B(x;p,m) be the cdf of bin(p,m). Ho: P=Po vs. H1:P=P1 Then P[accept Ho]= And EN=PETxn1+(1-PET)xn where PET=B(r1;Po,n1) the probability of stop after stage 1.

    8. 8 Simons 2-Stage Designs For fixed a, b The minimax design minimizes n The optimal design minimizes EN when P=Po (unacceptable low) Reference: Simon R. (1989) Controlled Clinical Trials

    9. 9 Practical Issues Po=0.1, P1=0.3 and (a,b)=(0.05,0.15) A (Simon) minimax design (2/18,5/27) n=27, EN=20.4 An (Simon) optimal design (1/11,6/35) n=35, EN=18.3 A good alternative design (1/13,5/28) n=28, EN=18.7

    10. 10 Alternative Designs Jung, Carey and Kim. (2001). Graphical Search for Two-Stage Designs for Phase II Clinical Trials, Controlled Clinical Trials Search good alternative designs between minimax and optimal designs

    11. 11 Graphical Search for Alternatives N = the affordable maximum number of patients for a study; n<=N For specified (Po,P1,a,b,N),

    12. 12 (Po,P1,a,b,N)=(0.4,0.6,0.05,0.1,60)

    13. 13 (Po,P1,a,b,N)=(0.1,0.3,0.05,0.15,35)

    14. 14

    15. 15 Software Graphical search for alternatives: http://biostat.hitchcock.org/BSR/Analytics/OptimalMinimax.asp

    16. 16 References Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 1989; 10:1-10 Jung S., Carey M. and Kim K. M. Graphical search for two-stage designs for phase II clinical trials. Controlled Clinical Trials 2001; 22:367-372

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