Jonathan Rabinowitz (1), Nomi Werbeloff (1), Stephen Levine (2)

1. EXAMINING THE RELIABILITY AND USEFULLNESS OF INTERIM ANALYSIS DATA: CASE OF ANTIPSYCHOTIC DRUG TRIALS Jonathan Rabinowitz (1), Nomi Werbeloff (1), Stephen Levine (2) (1) Bar Ilan University, Ramat Gan, Israel (2) Haifa University

3. What is NEWMEDS? NEWMEDS is an international consortium of scientists that has launched one of the largest ever research academic-industry collaboration projects to find new methods for the development of drugs for schizophrenia and depression. EFPIA companies: H Lundbeck A/S, Abbott,AstraZeneca AB, Eli Lilly and Company Ltd, Janssen Pharmaceutica NV, Novartis Pharma AG, Orion Corporation, Pfizer Limited, F. Hoffmann-La Roche AG, Institut de Recherches Servier Universities: King’s College London (UK), Karolinska Institutet (Sweden), The University of Cambridge (UK), Central Institute of Mental Health (Germany), CSIC (Spain), The University of Manchester (UK), Bar Ilan University (Israel) SME‘s Psynova Neurotech Ltd (UK), deCODE genetics (Iceland), GABO:mi (Germany)

4. Who supports NEWMEDS? NEWMEDS is funded by the Innovative Medicines Initiative (IMI), a unique large scale public-private partnership between the European Union (represented by the European Commission) and the pharmaceutical industry (represented by the European Federation of Pharmaceutical Industries and Associations, EFPIA). IMI aims to put Europe at the forefront of biopharmaceutical innovation and to support more efficient discovery and development of better medicines for patients. www.imi.europa.eu

5. The Consortium

6. Key data for NEWMEDS Start date: 1 September 2009 Runtime: 5 years Structure: 11 Workpackages Clusters: System based animal models (A) Translational Technology (B) Patient Stratification (C)

7. Schizophrenia Database Data from: Astra Zeneca, Janssen, Lilly, Lundbeck, Pfizer 64 Industry sponsored studies 34 placebo controlled 30 active comparator 25,900 patients 16,105 study drug 7,119 active comparator 2,676 placebo 1 NIMH sponsored study CATIE 1,493 patients 1 European Union sponsored study EUFEST 498 patients

8. Depression Database Data from: Astra Zeneca, Lundbeck, Pfizer and Lilly                    39 placebo controlled Industry sponsored studies                                            12,217 patients 8,260 active drug                                              3,957 placebo

9. Methodological question Interim analyses yield effect size information that assist in deciding about potential sample size adjustments. To what extent are the results of the first cohort of patients to be enrolled similar to the results of the subsequently enrolled patients? In the rush to complete studies quality may decline reducing effect sizes over time. Method: Studies split at midpoint of enrolment. Results: Difference in placebo vs. active treatment difference in effect size (Cohen’s d) between cohorts: Mean Median Antipsychotic trials -0.01 -0.03 Antidepressant trials 0.05 0.04 Overall the first and second cohorts enrolled yielded similar results.

10. Effect size differences placebo vs. antipsychotic treatment in first and second cohort of patients enrolled ordered by difference: >Negative difference greater effect first cohort, positive greater effect second cohort >9 trials differences were positive, in 4 differences were negative, where first cohort showed more difference these differences were small (less than -.08). >In 7 of the 20 studies the first cohort well outperformed the second cohort (from -12 to -.44). Effect size differences placebo vs. active treatment in first and second cohort of patients enrolled ordered by difference

11. Effect size differences placebo vs. antidepressant treatment in first and second cohort of patients enrolled ordered by difference: >In 22 trials the differences were positive, in 17 the differences were negative. >In 12 studies these differences were small (less than .08 in favor of either cohorts). Effect size differences placebo vs. active treatment in first and second cohort of patients enrolled ordered by difference

12. Using first cohort results to re-estimate sample size -Repower study, as if designing a new study. Ignores the fact that first cohort results are fixed. -Repower second cohort based on conditional probability Makes use of the fact that first cohort results are fixed. Effect size differences placebo vs. active treatment in first and second cohort of patients enrolled ordered by difference

13. Sample size needed for second cohort estimated using formula for adding z scores. 1. Convert Cohen’s d to z = (d*sqrt(n))/2 2. Z needed for second cohort=(1.96*SQRT(n1^2+n2^2)-n1*z)/n1 (Based on formula for to sum weighted z scores.) 3. Compute P of z p=(1-NORMSDIST(z))*2 4. Compute sample size using d at time 1 and the p value from previous step. (a) Using power software. (b) Resampling-bootstrapping (sample sizes increased until obtaining needed p value). Effect size differences placebo vs. active treatment in first and second cohort of patients enrolled ordered by difference

15. Conclusion Results suggest that earlier cohorts in studies of antipsychotic and antidepressant medications can reliably serve to estimate trial effects in interim analyses and to efficiently adjust sample size calculations using conditional probability.