1. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Multi-Clinic and Multi-National Trials: A regulatory perspective Charles Anello Sc.D. Deputy Director, Office Of Biostatistics Office of Pharmacovigelence and Statistical Sciences Center for Drug Evaluation and Research anello@cder.fda.gov

2. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Acknowledgements I would like to express my appreciation to Robert T. ONeill, Satya Dubey, Jim Hung, Robert Temple and John Lawrence for their helpful suggestions in the preparation of this talk.

3. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Disclaimer The views expressed are those of the author and do not necessarily represent those of the Food and Drug Administration.

4. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Topics uMotivation uRegulatory Context uChanging Context uSome statistical Issues uMulti-national studies uAn example uConclusions

5. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Motivation uUniversity Group Diabetes Program uCoronary Drug Project uHow did multi-clinic and multi-national trials become so common?

6. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Regulatory Context Kefauver-Harris Amendments to FD &C Act. uThe need to establish efficacy based on substantial evidence uAdequately powered studies are needed to detect clinically meaningful drug effects u As the focus shifted to modest effects the need for large enough studies to establish efficacy led to the increase use of multi-clinic or multi-investigator trials.

7. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Changing Context uFormat and Content Guidance uICH E9 uEvidence Document uEmergence of a global pharmaceutical industry and the multi-national Trial

8. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Format and Content Guidance uResults for individual studies should be presented uSuggests test for interaction between treatments and centers uNo guidance on how this test is to be conducted or the significance level to be used

9. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Format and Content Guidance uExtreme or opposite results need to be discussed uDemographic, baseline and results presented by center uGraphic displays by center on key characteristics and findings uSpecial attentions is given to age, gender, ethnicity (or region).

10. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Why the emphasis on interaction? uThe review of a clinical trial as several aspects: 1.Are the treatment groups comparable 2.Are the potential sources of bias that may account for the findings 3.Is the treatment effect consistent across the centers

11. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Why the emphasis on interaction? uThe review function as a detective aspect uThe review function as a quality control aspect uThe goal of the review is to establish efficacy and safety and provide information to physicians in the product label about how and for whom the drug works uIf subgroups (e.g., clinics) show different results( i.e., interaction) this could impact the label

12. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD ICH E9 uSuggests multi-clinic trials are needed to speed up the time needed to conduct trials uProvide a basis for generalization uStress the need to implement the common protocol in a similar manner in all clinics across all regions uOffers advice how to approach the analysis

13. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD ICH E9 uTest main effect first, if significant uTest interaction as an exploratory analysis uIf there are a large number of centers, it is less important to consider interaction.

14. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Evidence Document uWhen only one multi-clinic trial is available for establishing substantial evidence of efficacy and safety uThe results need to be statistically very persuasive uInternally consistent

15. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Evidence Document uNo single site, clinic provides an unusually large fraction of patients uNo single site, clinic is responsible for a disproportionate favorable effect uEstimated effects are consistent across clinics uMultiple endpoints are consistent uResults highly statistically significant p<<.05 (eg..001)

16. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Lack of consistency in statistical advice? uIn an ANOVA situation the Format and Content document suggest one tests first for interaction but doesnt say how to do it. uICH E9 suggests one test main effects first only they are significant does one examine interaction uEvidence document focuses on the need for internal consistency but leaves open how consistency is to be established. No advice on statistical approach

17. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Looking at Interaction uThere is no consistent approach uSome advocate fixed effect models uSome advocate random effect models uSome advocated mixed effect models uAnd so on.

18. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Some statistical Issues uAre centers fixed or random uIf an ANOVA is used would one use the type II or type III sums of squares uOther approaches

19. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Are Centers Fixed or Random?

20. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Centers fixed or Random uThe decision to call centers fixed or random has implications for the analysis Arguments in support of fixed effects: 1.only approach for single center 2. gives precise answer to well defined question 3.only realistic approach with few centers, 4.definition of center is arbitrary Senn (1998)

21. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Centers fixed or Random uIn support of the Random effect model 1. approximate answer to difficult question 2. affect more general 3. wider confidence interval Senn (1998)

22. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Are Centers Fixed or Random? There are other opinions Fleiss(1988) favored fixed effect model with a test for interaction Grizzle(1988) questioned the fixed effect model and preferred the random effect model Senn(1993) remained open minded on this issue

23. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Are Centers Fixed or Random? uThe random effect model incorporates interaction into the error term. uThe fixed effect model allows one to explore interaction if it exists uBoth approaches can be justified at some level.

24. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Are Centers Fixed or Randon uIn order to label a product correctly one needs to be sure the effect is consistent across all relevant subgroups uFrom my perspective the fixed effect model seems more relevant. u Whereas the random effect model may answer a question it may answer a different question? uIt may give the right answer to the wrong question. Kimbell(1965) would have called this a type III error

25. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD What is the correct Sums of Squares in an ANOVA analysis uThe choice is between the type II and typeIII SS for SAS GLM uMany authors support the type II SS which involves weighting by center size uFDA has been alleged to favor the type III SS uWhile I can not speak for all FDA I think the current view within CDER is with those supporting the type II SS

26. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Much Discussion about variation between centers uIs to be expected but difficult to detect uIs it quantitative (i.e., same direction only magnitude differs) very common uIs it qualitative (i.e., treatment shows benefit in some centers, Placebo shows benefit in others) less common uQualitative interaction is of concern but not found very often and hard to establish Peto(1982)

27. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Expected Center Variation uFor fixed sample size as the number of centers increases so does the chances of reversal uIt has been shown that with as few as six centers there is better than a 50% chance of having at least one center where the placebo effect would exceed the treatment effect. ONeill et. al.(1998)

28. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Multi-national Differences Temple (SCT 2003) discussed the interpretation of international differences in clinical trail results I will focus on a single international trial in which a subgroup( country or region) appeared to show a result different from the overall finding of the study

29. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Multi-national Multi clinic Trials uMERIT-HF Trial a multi-national trial of mortality in patients with chronic heart failure. uWhen the regions of US versus Europe was examined by a post hoc analysis differences were observed although not quite at the qualitative difference uone group showed a benefit another did not.

30. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD MERIT-HF Trial uMetoprolol succinate extended release (Toprol XL) the MERIT-HF Trial uPlacebo controlled, multi-national 3991 patient trial in NYHA Class II_III CHF,treated added to ACEI, digitalis and other Rx uEndpoints: all cause mortality and all cause mortality plus hospitalization

31. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD MERIT-HF Trial uThe differences occurred in the mortality findings. The combined endpoint showed a consistent finding whereas the mortality endpoint showed a 50% reduction in the Non US population compared to a 5% excess in the US population. With a post hoc p-value of.003.

32. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD MERIT-HF Trial uThe regions were not a pre-specified subset uApproval was not an issue the study showed a benefit for mortality plus hospitalization uThe agencys internal debate focused on full disclosure this apparent unexplained qualitative interaction in a component of composite endpoint. uWhether regions matter in this instance is an open question. Temple(2003)

33. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Summary uMulti-clinic trials are an important aspect of drug development and regulatory review uMulti-clinic multi-national trials are becoming more important uFrom a regulatory perspective consistency in results are important uIf interaction occur, they need to be identified and understood uInteractions may have implications for the product label and public health

34. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Summary uSome statistical tools for dealing with these interaction exist, but may have limited utility due to low power uThe fixed effect model may be more useful when there are not to many clinics and the sample sizes are large and approximately equal size and it is reasonable to assume a constant effect across the clinics uThe random effect model may be more useful when there are large number of clinics with few observations per clinic and one can not address the question of center by treatment interaction. uWhen an ANOVA is appropriate, the type II sums of squares is often the Sums of squares of choice

35. FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Summary uQuantitative and Qualitative interactions happen although Qualitative interaction is rare uObserved clinic or regional differences need to be noted, explained if possible and reported but not necessarily believed. uThe potential for regional differences, may have implications for study design and the way DSMBs monitor trials.