1 / 16

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.

greta
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related