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The Orthopedic & Rehabilitation Device Advisory Panel Meeting (November 21, 2002)

The Orthopedic & Rehabilitation Device Advisory Panel Meeting (November 21, 2002). Statistical Issues for PMA P000054 (Recombinant human bone morphogenetic protein-2/ Absorbable collagen sponge device for orthopedic trauma, long -bone fractures) Chang S. Lao, Ph.D.

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The Orthopedic & Rehabilitation Device Advisory Panel Meeting (November 21, 2002)

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  1. The Orthopedic & Rehabilitation Device Advisory Panel Meeting(November 21, 2002) Statistical Issues for PMA P000054 (Recombinant human bone morphogenetic protein-2/ Absorbable collagen sponge device for orthopedic trauma, long -bone fractures) Chang S. Lao, Ph.D. Division of Biostatistics, OSB/CDRH/FDA

  2. Outline (Statistical Review) • 1. Pooling of multi-clinic data • (Meta-Analysis) • 2. Intra and inter-observer agreement (Reproducibility) • 3. Survival Analysis (time-specific) versus crude event (SI) probability

  3. Important considerations (pooling) High dose Center 1 Center 1 % No SI (Success) High dose High dose Control Center 1 High dose Control Control Center 2 High dose Center 2 Control Control Control Center 2 High dose Acceptable (Quantitative center by tr.interaction) Ideal (Parallel) Questionable (Qualitative int.)

  4. Hypothetical example of wrong pooling • Site 1Site 2Pooled • High Control Total High Control Total High Control Total • Outcome dose dose dose • Success10 40 50 60 40 100 70 80 150 • Failure20 80 100 30 20 50 50 100 150 • Total30 120 150 90 60 150 120 180 300 • Chi-square0 0 5.56 • p-value1 (NS) 1 (NS) 0.0186 (Sig.) • % Success33 33 67 67 58 45 • Invalid pooling by summing all observed cell numbers!

  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 -150 -100 -50 0 50 100 150 Estimated Differences (high dose - control) in % Success (Free of SI) and the exact 95% CI by regrouped investigator sites

  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 -150 -100 -50 0 50 100 150 Estimated Differences (high dose - control) in % Success (Free of SI) and the exact 95% confidence intervals (CI), CCRE patients

  7. Model Fixed effect Random effect Assumption Each center has the same clinical effect; consider within-center variability only Diverse nature in study design; methods among sites, heterogeneity; consider both within-center and between-center variability Statistical methods (Meta-analysis)

  8. Meta Analysis on difference of two proportions of success (high dose - SOC) • 30 regrouped investigator sites • FDA: excluded 3 regrouped sites with zero variances (for both regrouped investigator sites and CCRE study; use method of moments, DerSimonian & Laird, Stat. in Med., 1986)

  9. FDA results: Difference of two success (No SI) proportions, high dose – control,regrouped investigator sites • Model mean diff se p-value 95% CL • Fixed 0.1168 0.04 <0.01 (0.039, 0.194) • Random 0.1207 0.0818 NS (-0.04, 0.28) • 2 = 95.7 (26 d.f.), p<0.005, rejects the null hypothesis (between-center variance = 0) • random effect model is valid

  10. FDA results: Difference of two successproportions, high dose – control, CCRE • Model mean diff se p-value 95% CL • Fixed 0.097 0.042 <0.05 (0.014, 0.18) • Random 0.11 0.079 NS (- 0.05, 0.26) • 2 = 80 (26 d.f.), p<0.005, rejects the null hypothesis (between-center variance = 0) • random effect model is valid

  11. Reproducibility Study (intra-and-inter-observer agreement) • n = 60 patients from 10 US Trauma Centers • (different from PMA study; protocol #:C9612-11) • two teams (multiple raters), fracture union • Kappa 95% CL n • Inter-observer 0.87 (0.7, 1.0) 20 • Intra-observer (1) 0.50 (0.27, 0.74) 20 • Intra-observer (2) 0.49 (0.25, 0.73) 20

  12. Kappa Index for Agreement • Prof. Gary Koch (Biometrics 1977) • Kappa clinical interpretation • < 0 poor • 0 - 0.2 slight • 0.21 - 0.4 fair • 0.41 - 0.6 moderate • 0.61 - 0.8 substantial • 0.81 - 1.0 nearly perfect

  13. Problems of PMA (Kappa) Sample patient selection Random sample ? Representative? Masking? Time comparability? Multiple raters/Team

  14. Survival Analysis vs. crude SI event probability • Life-table analysis - Patient follow-up data • recently received • Fracture healing assessed by Investigator • Radiographic assessment of fracture union by independent radiology panel • CCRE study

  15. Survival Analysis in PMA • Without seeing the patient follow-up data and survival analyses, patients censored, lost, missing, and at risk of SI cannot be evaluated at time t • (Assumption: Censoring independent of treatment) • Crude SI event probability < time-specific cumulative SI event probability by survival analysis, unless ALL patients had completed the entire follow-up study, or ALL patients with SI

  16. Conclusion • Study Design • Heterogeneity among centers – random effect for combined analysis • Direct adding up all numbers and the corresponding analyses are not valid • Survival analysis is requireddue to patients censored, lost to follow-up • Questionable reproducibility studies

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