1. Comparison of Bayesian and Frequentist Meta-Analytical Approaches for Analyzing Time to Event Data By Brenda Crowe (Joint work with Monica Bennett, Karen Price, James Stamey and John Seaman Jr) Midwest Biopharmaceutical Statistics Workshop 2014

2. 21 May 2014 MBSW 2

3. Outline Background/motivation Overview of results for rare events (mainly for binary data) Simulation study (time to event data) Methods, parameters Software Results Discussion, recommendations References 21 May 2014 MBSW 3

4. Meta-analysis (MA) refers to the combining of evidence from relevant studies using appropriate statistical methods to allow inferences to be made to the population of interest. (Definition from FDA’s 2013 white paper on meta-analysis http://www.fda.gov/downloads/Drugs/NewsEvents/UCM372069.pdf) http://www.fda.gov/downloads/Drugs/NewsEvents/UCM372069.pdf Definition 21 May 2014 MBSW 4

5. Lots of literature comparing MA methods for binary data E.g., Sweeting et al. (2004, 2006), Bradburn et al. (2007) Not much for time-to-event data, though anticipate problems similar to binary data Background/Motivation 21 May 2014 MBSW 5

6. December 2008 FDA issued a guidance for assessing cardiovascular (CV) risk in diabetes drugs. The guidance requires that the upper limit of the 2-sided 95% confidence interval for the risk ratio be less than 1.8 prior to submission and less than 1.3 after submission. This can be shown by performing a meta- analysis of phase 2 and 3 clinical trials and if these are insufficient, a large safety trial must be conducted. Background/Motivation 21 May 2014 MBSW 6

7. Used simulation study to compare the performance of several meta-analytic approaches in the survival analysis context. Considered two frequentist approaches and a Bayesian approach with and without informative prior. Background/Motivation: Our Research 21 May 2014 MBSW 7

8. Overview of statistical challenges and considerations for analysis of rare adverse events 21 May 2014 MBSW8 Mostly for Binary Data

9. Statistical Issues with Meta-analysis of Rare/Sparse Adverse Event Data Standard inferences for meta-analysis rely on large sample approximations. They may not be accurate and reliable when number of events is low. Zero events observed in one or both treatment arms for some studies Low power to detect heterogeneity (especially when the number of studies is modest) 21 May 2014 MBSW 9

10. Metrics and Methods MBSW 10

11. Metric Choices Binary outcomes risk difference (RD), arcsin risk difference* risk ratio (RR), odds ratio (OR) Time to event : hazard ratio, … * The arcsin link is not often used in clinical trials, but it is the asymptotically variance-stabilizing transformation for the binomial distribution. This link is studied by, for example, Rücker et al. (2009). 21 May 2014 MBSW 11

12. Behavior When Zero Events Occur in One or Both Arms of a Study Difference Metrics Risk difference is defined but its variance = 0 for total zero studies Arcsin difference and its variance are defined Relative Metrics Log odds ratio and log risk ratio are undefined (as are their variances) Hazard ratio and its variance are undefined Note: methods for combining studies have different properties for handling zero events 21 May 2014 MBSW 12

13. Common Binary Meta-analysis Methods Fixed Effect* Inverse variance (IV) Mantel Haenszel (MH) Peto Logistic Regression Exact stratified odds ratio Exact stratified risk difference (Tian et al., 2009) Random Effects* Inverse variance: Use a method to estimate the among-study variance such as method of moments (DerSimonian Laird [DSL]), anova (Hedges and Olkin) Mixed effects logistic regression Important: Stratify by study 21 May 2014 MBSW 13 *There are Bayesian versions of many of these methods. See, for example, Higgins and Spiegelhalter (2002). The paper includes some WinBugs code. See Deeks and Higgins (2010) for a concise overview of most of the non-Bayesian methods.

14. What do People do with Zero Cells Use a method that can handle zeros (e.g., MH risk difference, arcsin difference, Bayesian) Exclude studies with zero cells (more likely for relative metrics) Collapse ‘small’ studies with a similar randomization allocation ratio (Nissen, 2010) Use a continuity correction 21 May 2014 MBSW 14

15. Continuity Corrections (3 Ways) 1.Constant Add 0.5 (or some other fixed constant) to each cell 2.Treatment arm continuity correction Choose a proportionality constant k Add k / (Sample size for Opposite Treatment Arm) to each cell May be less biased in presence of severe imbalance 3.Empirical continuity correction Based on an empirical estimate of the pooled effect size using the non-zero event studies Sweeting et al, Stat in Med, 2004 and 2006 21 May 2014 MBSW 15

16. Which Method is Best? It depends on... Number of studies Sample size per trial and arm Event rate Amount of heterogeneity Note: None of the 2 major simulation studies (Bradburn et al., Sweeting et al.) assessed risk ratio. 21 May 2014 MBSW 16

17. Comparison of Binary Methods (Excludes RR Methods) for Sparse Data Alternative CCs perform better than the constant IV (OR and RD) and DSL (OR and RD) perform v. poorly Peto method performed well for very low event rates, but bias increases with greater group imbalance and larger treatment effect MH OR with no CC or alternative CC, logistic regression, exact stratified and Bayesian fixed effects perform fairly well (event rates >= 0.5% to 1% of the sample sizes studied in Sweeting and Bradburn) MH RD has low bias and low power for very sparse data See Sweeting, 2004 & 2006 and Bradburn, 2007 for further info

18. Simulation Study Meta-analytical approaches for analyzing time to event data

19. Overview of Methods 1.Standard Cox proportional hazards (CPH) 2.CPH with Firth correction term (penalized likelihood) 3.Bayesian CPH (with and without informative prior) All methods model two treatment arms and stratify by study 21 May 2014 MBSW 19

20. Cox Proportional Hazards The proportional hazards survival model for patient i in study j is i = 1, …, n s j = 1, …, s λ 0j (t) is the baseline hazard for study j x ij = 1 if patient i in study j is on treatment and x ij = 0 otherwise β is the log hazard ratio. 21 May 2014 MBSW 20

21. CPH with Firth Correction When events are rare the problem of monotone likelihood can be encountered. Estimates may not be available due to lack of convergence. Estimates may be imprecise and have large standard errors. Firth (1993) developed a penalization method used to reduce bias in maximum likelihood parameter estimates. Heinze and Schemper (2001) adapted the Firth method to be used with the Cox model. 21 May 2014 MBSW 21

22. Bayesian CPH Basic model assumes constant baseline hazard over time and specifies prior distributions for λ and β. 21 May 2014 MBSW 22

23. Study Designs for Simulation 3 phase 2 studies: n 0 = 50, n 1 = 150, duration = 90 days 3 phase 3 studies: n 0 = 250, n 1 = 500, duration = 1 year 1 outcome study: n 0 = 3500, n 1 = 3500, duration = 2 years Included in the 2 nd study grouping Included in the 1 st meta-analysis study grouping 21 May 2014 MBSW 23

24. Simulation Design/Parameters 21 May 2014 MBSW 24

25. Two study groupings 1.All phase 2 and 3 (with 4 analysis methods) 2.All 7 studies (with 3 analysis methods) Exponential distribution for data generation (constant hazard over time). 21 May 2014 25 MBSW Simulation Design/Parameters

26. 1.Diffuse priors Lambda0j ~gamma(0.01, 0.01) Beta~normal(0,1000) 2.More informative priors Used shape parameter for gamma prior = 0.01, 0.02 and 0.05 for corresponding event rates Rate parameter = 1 For log hazard ratio, for exp(beta) = 1.0, prior mean = 0 For exp(beta) = 1.3, prior mean was 0.25 and for exp(beta)=1.5, prior mean was 0.5 Used prior variance of 2 for each. Informative priors were only used for first study grouping. Bayesian Parameters 21 May 2014 MBSW 26

27. SAS 9.2 PROC PHREG proc phreg data=meta.gendata; strata=study; *use FIRTH option to perform Firth correction; model time*event(0) = treatment / firth; *use BAYES statement for Bayesian analysis; bayes seed=1 initial = NBI= NMC= coeffprior= plots= ; run; 21 May 2014 MBSW 27

28. R coxph{survival} coxph(Surv(time,event)~ treatment + strata(study), data=gendata) coxphf{coxphf} coxphf(Surv(time,event)~ treatment + strata(study), data=gendata) For the Bayesian methods WinBUGS or OpenBUGS can be used. The models for the Bayesian methods are based on the model in the “Leuk: survival analysis using Cox regression” example in WinBUGS. 21 May 2014 MBSW 28

29. Simulation Results

30. Standardized Bias Plots: Meta-analysis of Phase 2 and 3 Trials. 21 May 2014 MBSW 30 Firth gives best results (closest to zero bias line) in all situations.

31. 21 May 2014 31 MBSW 95% CI Coverage Plots : Meta- analysis of Phase 2 and 3 Trials Bayes with informative prior has overly high coverage in all scenarios (as do CPH and Firth, but they have less bad). Bayes with diffuse prior has lower coverage than desired, with exception of one scenario (lambda = 0.05), which may be because of the bias seen on previous slide

32. Proportion of Upper Bounds Less Than 1.8: Meta-analysis of All Phase 2 and 3 Studies 21 May 2014 MBSW 32 For true log HR = 0 and 0.262 (HR = 1, 1.3), higher proportions are better. For true HR = 1.8, lower are better. Firth does well/best in all situations.

33. 21 May 2014 33 MBSW Standardized Bias Plots : Meta-analysis of all Studies All methods have std. bias close to zero, with exception of Bayesian method, where drops to -0.1for HR = 1.8.

34. 21 May 2014 34 MBSW 95% CI Coverage Plots : Meta-analysis of all Studies Coverage in most scenarios is between 0.94 and 0.96. Exceptions are when true log HR = 0. E.g., Bayes and CPH have coverage = 0.935 when baseline event rate is 0.01.

35. Proportion of Upper Bounds less than 1.8: Meta-analysis of All Studies. 21 May 2014 MBSW 35 All methods perform well.

36. Concluding Remarks: Time to Event Data Based on the scenarios we studied, the Firth correction to the CPH is a good option for analyzing time-to-event data when the baseline event rate is low. For Bayesian method, informative prior reduces the bias of the estimated log HR. However a misspecified prior makes the situation worse (results not shown) With larger number of events there is not a big difference between the methods. 21 May 2014 MBSW 36

37. Concluding Remarks: Binary Data IV and DSL poor choices for rare events If need continuity correction, adding a constant to each cell is not the best choice Would Firth correction be good for binary data? 21 May 2014 MBSW 37

38. References 21 May 2014 MBSW 38 Bender, R., Augustin, T., & Blettner, M. (2005). Generating survival times to simulate Cox proportional hazards models. Stat Med, 24(11), 1713-1723. doi: 10.1002/sim.2059 Bennett, M. M., Crowe, B. J., Price, K. L., Stamey, J. D., & Seaman, J. W., Jr. (2013). Comparison of bayesian and frequentist meta-analytical approaches for analyzing time to event data. J Biopharm Stat, 23(1), 129-145. doi: 10.1080/10543406.2013.737210 Berlin, J. A., & Colditz, G. A. (1999). The role of meta-analysis in the regulatory process for foods, drugs, and devices. JAMA, 281(9), 830-834. Berry, S. M., Berry, D. A., Natarajan, K., Lin, C.-S., Hennekens, C. H., & Belder, R. (2004). Bayesian survival analysis with nonproportional hazards: metanalysis of combination pravastatin–aspirin. Journal of the American Statistical Association, 99(465), 36-44. Bradburn, M. J., Deeks, J. J., Berlin, J. A., & Russell Localio, A. (2007). Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Statistics in Medicine, 26(1), 53-77. doi: 10.1002/sim.2528 Crowe, B. J., Xia, H. A., Berlin, J. A., Watson, D. J., Shi, H., Lin, S. L.,... Hall, D. B. (2009). Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team. Clin Trials, 6(5), 430-440. doi: 10.1177/1740774509344101 Deeks, J. J., & Higgins, J. P. (2010). Statistical algorithms in Review Manager 5. http://tech.cochrane.org/revman/documentation/Statistical-methods-in-RevMan-5.pdf http://tech.cochrane.org/revman/documentation/Statistical-methods-in-RevMan-5.pdf Firth, D. (1993). Bias reduction of maximum likelihood estimates. Biometrika, 80(1), 27-38.

39. References 21 May 2014 MBSW 39 Heinze, G., & Ploner, M. (2002). SAS and SPLUS programs to perform Cox regression without convergence problems. Computer methods and programs in Biomedicine, 67(3), 217-223. Heinze, G., & Schemper, M. (2001). A solution to the problem of monotone likelihood in Cox regression. Biometrics, 57(1), 114-119. Higgins, J. P., & Spiegelhalter, D. J. (2002). Being sceptical about meta-analyses: a Bayesian perspective on magnesium trials in myocardial infarction. Int J Epidemiol, 31(1), 96-104. International Conference on Harmonisation (ICH). (1998). E9: Statistical Principles for Clinical Trials. International Conference on Harmonization Guidelines. http://www.ich.org/products/guidelines/efficacy/article/efficacy- guidelines.htmlhttp://www.ich.org/products/guidelines/efficacy/article/efficacy- guidelines.html Mantel, N., & Haenszel, W. (1959). Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute, 22(4), 719-748. Nissen, S. E., & Wolski, K. (2010). Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Archives of Internal Medicine, 170(14), 1191-1201. doi: 10.1001/archinternmed.2010.207 O'Neill, R. T. (1988). Assessment of safety Biopharmaceutical Statistics for Drug Development: Marcel Dekker. Proschan, M. A., Lan, K. K., & Wittes, J. T. (2006). Statistical Methods for Monitoring Clinical Trials. New York: Springer. Rucker, G., & Schumacher, M. (2008). Simpson's paradox visualized: the example of the rosiglitazone meta- analysis. BMC Med Res Methodol, 8, 34. doi: 10.1186/1471-2288-8-34 Sutton, A. J., & Abrams, K. R. (2001). Bayesian methods in meta-analysis and evidence synthesis. Statistical Methods in Medical Research, 10(4), 277-303. Sutton, A. J., Cooper, N. J., Lambert, P. C., Jones, D. R., Abrams, K. R., & Sweeting, M. J. (2002). Meta-analysis of rare and adverse event data.

40. References 21 May 2014 MBSW 40 Sweeting, M. J., Sutton, A. J., & Lambert, P. C. (2004). What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med, 23(9), 1351-1375. doi: 10.1002/sim.1761 Sweeting, M. J., Sutton, A. J., & Lambert, P. C. (2006). Correction. Statistics in Medicine, 25, 2700. Tian, L., Cai, T., Pfeffer, M. A., Piankov, N., Cremieux, P.-Y., & Wei, L. (2009). Exact and efficient inference procedure for meta-analysis and its application to the analysis of independent 2× 2 tables with all available data but without artificial continuity correction. Biostatistics, 10(2), 275-281. United States Food and Drug and Administration. (2008). Guidance for Industry: Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/%20Guidances/UCM071627.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/%20Guidances/UCM071627.pdf Warn, D., Thompson, S., & Spiegelhalter, D. (2002). Bayesian random effects meta ‐ analysis of trials with binary outcomes: methods for the absolute risk difference and relative risk scales. Statistics in Medicine, 21(11), 1601- 1623.

41. 21 May 2014 41 MBSW The End Duffy Lake, BC