FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Multi-Clinic and Multi-National Trials: A regulatory perspective Charles Anello.

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ASA-Industry Workshop,Sept.17-19,2000 Bethesda, MD

Multi-Clinic and Multi-National Trials: Multi-Clinic and Multi-National Trials: A regulatory perspectiveA regulatory perspective

Charles Anello Sc.D.Charles Anello Sc.D.

Deputy Director, Office Of BiostatisticsDeputy Director, Office Of Biostatistics

Office of Pharmacovigelence and Statistical SciencesOffice of Pharmacovigelence and Statistical Sciences

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

[email protected]@cder.fda.gov

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AcknowledgementsAcknowledgements

I would like to express my appreciation to I would like to express my appreciation to Robert T. O’Neill, Satya Dubey, Jim Hung, Robert T. O’Neill, Satya Dubey, Jim Hung, Robert Temple and John Lawrence for their Robert Temple and John Lawrence for their helpful suggestions in the preparation of helpful suggestions in the preparation of this talk.this talk.

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DisclaimerDisclaimer

The views expressed are those of the author The views expressed are those of the author and do not necessarily represent those of the and do not necessarily represent those of the Food and Drug Administration. Food and Drug Administration.

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TopicsTopics

MotivationMotivation Regulatory ContextRegulatory Context Changing ContextChanging Context Some statistical IssuesSome statistical Issues Multi-national studiesMulti-national studies An exampleAn example ConclusionsConclusions

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MotivationMotivation

University Group Diabetes ProgramUniversity Group Diabetes Program Coronary Drug ProjectCoronary Drug Project How did multi-clinic and multi-national How did multi-clinic and multi-national

trials become so common?trials become so common?

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Regulatory ContextRegulatory Context

Kefauver-Harris Amendments to FD &C Act.Kefauver-Harris Amendments to FD &C Act.

The need to establish efficacy based on substantial The need to establish efficacy based on substantial evidenceevidence

Adequately powered studies are needed to detect Adequately powered studies are needed to detect clinically meaningful drug effectsclinically meaningful drug effects

As the focus shifted to modest effects the need for large As the focus shifted to modest effects the need for large enough studies to establish efficacy led to the increase enough studies to establish efficacy led to the increase use of multi-clinic or multi-investigator trials.use of multi-clinic or multi-investigator trials.

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Changing ContextChanging Context

Format and Content GuidanceFormat and Content Guidance ICH E9ICH E9 Evidence DocumentEvidence Document Emergence of a global pharmaceutical Emergence of a global pharmaceutical

industry and the multi-nationalindustry and the multi-national TrialTrial

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Format and Content GuidanceFormat and Content Guidance

Results for individual studies should be Results for individual studies should be presentedpresented

Suggests test for interaction between Suggests test for interaction between treatments and centerstreatments and centers

No guidance on how this test is to be No guidance on how this test is to be conducted or the significance level to be conducted or the significance level to be usedused

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Format and Content GuidanceFormat and Content Guidance

Extreme or opposite results need to be Extreme or opposite results need to be discusseddiscussed

Demographic , baseline and results Demographic , baseline and results presented by centerpresented by center

Graphic displays by center on key Graphic displays by center on key characteristics and findingscharacteristics and findings

Special attentions is given to age, gender, Special attentions is given to age, gender, ethnicity (or region).ethnicity (or region).

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Why the emphasis on interaction?Why the emphasis on interaction?

The review of a clinical trial as several The review of a clinical trial as several aspects:aspects:

1.1. Are the treatment groups comparableAre the treatment groups comparable

2.2. Are the potential sources of bias that may Are the potential sources of bias that may account for the findingsaccount for the findings

3.3. Is the treatment effect consistent across the Is the treatment effect consistent across the centerscenters

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Why the emphasis on interaction?Why the emphasis on interaction?

The review function as a detective aspectThe review function as a detective aspect The review function as a quality control aspectThe review function as a quality control aspect The goal of the review is to establish efficacy and The goal of the review is to establish efficacy and

safety and provide information to physicians in safety and provide information to physicians in the product label about how and for whom the the product label about how and for whom the drug worksdrug works

If subgroups (e.g., clinics) show different If subgroups (e.g., clinics) show different results( i.e., interaction) this could impact the labelresults( i.e., interaction) this could impact the label

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ICH E9ICH E9

Suggests multi-clinic trials are needed to Suggests multi-clinic trials are needed to speed up the time needed to conduct trialsspeed up the time needed to conduct trials

Provide a basis for generalizationProvide a basis for generalization Stress the need to implement the common Stress the need to implement the common

protocol in a similar manner in all clinics protocol in a similar manner in all clinics across all regionsacross all regions

Offers advice how to approach the analysisOffers advice how to approach the analysis

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ICH E9ICH E9

Test main effect first , if significantTest main effect first , if significant Test interaction as an exploratory analysisTest interaction as an exploratory analysis If there are a large number of centers, it is If there are a large number of centers, it is

less important to consider interaction.less important to consider interaction.

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Evidence DocumentEvidence Document

When only one multi-clinic trial is available When only one multi-clinic trial is available for establishing substantial evidence of for establishing substantial evidence of efficacy and safetyefficacy and safety

The results need to be statistically very The results need to be statistically very persuasivepersuasive

Internally consistentInternally consistent

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Evidence DocumentEvidence Document

No single site, clinic provides an unusually large No single site, clinic provides an unusually large fraction of patientsfraction of patients

No single site, clinic is responsible for a No single site, clinic is responsible for a disproportionate favorable effectdisproportionate favorable effect

Estimated effects are consistent across clinicsEstimated effects are consistent across clinics Multiple endpoints are consistentMultiple endpoints are consistent Results highly statistically significant p<<.05 Results highly statistically significant p<<.05

(eg. .001)(eg. .001)

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Lack of consistency in statistical Lack of consistency in statistical advice?advice?

In an ANOVA situation the Format and Content In an ANOVA situation the Format and Content document suggest one tests first for interaction but document suggest one tests first for interaction but doesn’t say how to do it.doesn’t say how to do it.

ICH E9 suggests one test main effects first only ICH E9 suggests one test main effects first only they are significant does one examine interactionthey are significant does one examine interaction

Evidence document focuses on the need for Evidence document focuses on the need for internal consistency but leaves open how internal consistency but leaves open how consistency is to be established. No advice on consistency is to be established. No advice on statistical approachstatistical approach

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Looking at InteractionLooking at Interaction

There is no consistent approachThere is no consistent approach Some advocate fixed effect modelsSome advocate fixed effect models Some advocate random effect modelsSome advocate random effect models Some advocated mixed effect modelsSome advocated mixed effect models And so on.And so on.

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Some statistical IssuesSome statistical Issues

Are centers fixed or randomAre centers fixed or random If an ANOVA is used would one use the If an ANOVA is used would one use the

type II or type III sums of squarestype II or type III sums of squares Other approachesOther approaches

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Are Centers Fixed or Random?Are Centers Fixed or Random?

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Centers fixed or RandomCenters fixed or Random

The decision to call centers fixed or random has The decision to call centers fixed or random has implications for the analysisimplications for the analysis

Arguments in support of fixed effects:Arguments in support of fixed effects:

1.1. only approach for single centeronly approach for single center

2.2. gives precise answer to well defined questiongives precise answer to well defined question

3.3. only realistic approach with few centers,only realistic approach with few centers,

4.4. definition of center is arbitrarydefinition of center is arbitrary

Senn (1998)Senn (1998)

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Centers fixed or RandomCenters fixed or Random

In support of the Random effect modelIn support of the Random effect model

1.1. approximate answer to difficult question approximate answer to difficult question

2.2. affect more generalaffect more general

3.3. wider confidence intervalwider confidence interval

Senn (1998)Senn (1998)

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There are other opinionsThere are other opinionsFleiss(1988) favored fixed effect model with a Fleiss(1988) favored fixed effect model with a

test for interactiontest for interactionGrizzle(1988) questioned the fixed effect Grizzle(1988) questioned the fixed effect

model and preferred the random effect model and preferred the random effect modelmodel

Senn(1993) remained open minded on this Senn(1993) remained open minded on this issueissue

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The random effect model incorporates The random effect model incorporates interaction into the error term.interaction into the error term.

The fixed effect model allows one to The fixed effect model allows one to explore interaction if it existsexplore interaction if it exists

Both approaches can be justified at some Both approaches can be justified at some level.level.

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Are Centers Fixed or RandonAre Centers Fixed or Randon

In order to label a product correctly one needs to be sure In order to label a product correctly one needs to be sure the effect is consistent across all relevant subgroupsthe effect is consistent across all relevant subgroups

From my perspective the fixed effect model seems more From my perspective the fixed effect model seems more relevant.relevant.

Whereas the random effect model may answer a question Whereas the random effect model may answer a question it may answer a different question?it may answer a different question?

It may give the right answer to the wrong questionIt may give the right answer to the wrong question..

Kimbell(1965) would have called this a “Kimbell(1965) would have called this a “type III errortype III error””

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What is the correct Sums of Squares What is the correct Sums of Squares in an ANOVA analysisin an ANOVA analysis

The choice is between the type II and typeIII SS The choice is between the type II and typeIII SS for SAS GLMfor SAS GLM

Many authors support the type II SS which Many authors support the type II SS which involves weighting by center sizeinvolves weighting by center size

FDA has been alleged to favor the type III SSFDA has been alleged to favor the type III SS While I can not speak for all FDA I think the While I can not speak for all FDA I think the

current view within CDER is with those current view within CDER is with those supporting the type II SSsupporting the type II SS

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Much Discussion about variation Much Discussion about variation between centersbetween centers

Is to be expected but difficult to detectIs to be expected but difficult to detect Is it quantitative (i.e., same direction only Is it quantitative (i.e., same direction only

magnitude differs) very commonmagnitude differs) very common Is it qualitative (i.e., treatment shows benefit in Is it qualitative (i.e., treatment shows benefit in

some centers , Placebo shows benefit in others) some centers , Placebo shows benefit in others) less commonless common

Qualitative interaction is of concern but not found Qualitative interaction is of concern but not found very often and hard to establishvery often and hard to establish

Peto(1982)Peto(1982)

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Expected Center VariationExpected Center Variation

For fixed sample size as the number of centers For fixed sample size as the number of centers increases so does the chances of reversalincreases so does the chances of reversal

It has been shown that with as few as six centers It has been shown that with as few as six centers there is better than a 50% chance of having at there is better than a 50% chance of having at least one center where the placebo effect would least one center where the placebo effect would exceed the treatment effect.exceed the treatment effect.

O’Neill et. al.(1998) O’Neill et. al.(1998)

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Multi-national DifferencesMulti-national Differences

Temple (SCT 2003) discussed the Temple (SCT 2003) discussed the interpretation of international differences in interpretation of international differences in clinical trail resultsclinical trail results

I will focus on a single international trial in I will focus on a single international trial in which a subgroup( country or region) which a subgroup( country or region) appeared to show a result different from the appeared to show a result different from the overall finding of the studyoverall finding of the study

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Multi-national Multi clinic TrialsMulti-national Multi clinic Trials

MERIT-HF Trial a multi-national trial of MERIT-HF Trial a multi-national trial of mortality in patients with chronic heart mortality in patients with chronic heart failure.failure.

When the regions of US versus Europe was When the regions of US versus Europe was examined by a post hoc analysis differences examined by a post hoc analysis differences were observed although not quite at the were observed although not quite at the “qualitative difference” “qualitative difference”

one group showed a benefit another did not.one group showed a benefit another did not.

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MERIT-HF TrialMERIT-HF Trial

Metoprolol succinate extended release Metoprolol succinate extended release (Toprol XL) the MERIT-HF Trial(Toprol XL) the MERIT-HF Trial

Placebo controlled, multi-national 3991 Placebo controlled, multi-national 3991 patient trial in NYHA Class II_III patient trial in NYHA Class II_III CHF ,treated added to ACEI, digitalis and CHF ,treated added to ACEI, digitalis and other Rxother Rx

Endpoints: all cause mortality and all cause Endpoints: all cause mortality and all cause mortality plus hospitalizationmortality plus hospitalization

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The differences occurred in the mortality The differences occurred in the mortality findings. The combined endpoint showed a findings. The combined endpoint showed a consistent finding whereas the mortality consistent finding whereas the mortality endpoint showed a 50% reduction in the endpoint showed a 50% reduction in the Non US population compared to a 5% Non US population compared to a 5% excess in the US population. With a post excess in the US population. With a post hoc p-value of .003.hoc p-value of .003.

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The regions were not a pre-specified subsetThe regions were not a pre-specified subset Approval was not an issue the study showed a Approval was not an issue the study showed a

benefit for mortality plus hospitalizationbenefit for mortality plus hospitalization The agency’s internal debate focused on “full The agency’s internal debate focused on “full

disclosure” this apparent unexplained qualitative disclosure” this apparent unexplained qualitative interaction in a component of composite endpoint.interaction in a component of composite endpoint.

Whether regions matter in this instance is an open Whether regions matter in this instance is an open question.question.

Temple(2003)Temple(2003)

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SummarySummary

Multi-clinic trials are an important aspect of drug Multi-clinic trials are an important aspect of drug development and regulatory reviewdevelopment and regulatory review

Multi-clinic multi-national trials are becoming Multi-clinic multi-national trials are becoming more importantmore important

From a regulatory perspective consistency in From a regulatory perspective consistency in results are importantresults are important

If interaction occur, they need to be identified and If interaction occur, they need to be identified and understoodunderstood

Interactions may have implications for the product Interactions may have implications for the product label and public healthlabel and public health

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SummarySummary

Some statistical tools for dealing with these interaction Some statistical tools for dealing with these interaction exist, but may have limited utility due to low powerexist, but may have limited utility due to low power

The fixed effect model may be more useful when there are The fixed effect model may be more useful when there are not to many clinics and the sample sizes are large and not to many clinics and the sample sizes are large and approximately equal size and it is reasonable to assume a approximately equal size and it is reasonable to assume a constant effect across the clinicsconstant effect across the clinics

The random effect model may be more useful when there The random effect model may be more useful when there are large number of clinics with few observations per are large number of clinics with few observations per clinic and one can not address the question of center by clinic and one can not address the question of center by treatment interaction.treatment interaction.

When an ANOVA is appropriate, the type II sums of When an ANOVA is appropriate, the type II sums of squares is often the Sums of squares of choicesquares is often the Sums of squares of choice

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SummarySummary

Quantitative and Qualitative interactions happen Quantitative and Qualitative interactions happen although Qualitative interaction is rare although Qualitative interaction is rare

Observed clinic or regional differences need to be Observed clinic or regional differences need to be noted, explained if possible and reported but not noted, explained if possible and reported but not necessarily believed.necessarily believed.

The potential for regional differences, may have The potential for regional differences, may have implications for study design and the way DSMBs implications for study design and the way DSMBs monitor trials.monitor trials.

FDA\ CDER\OPASS\OB ASA-Industry Workshop,Sept.17- 19,2000 Bethesda, MD Multi-Clinic and Multi-National Trials: A regulatory perspective Charles Anello.

Documents

md multiclinic

md format

analysis slide

label slide

md disclaimer

md acknowledgements

multinational trial

multinational trials