Multi-regional Clinical TrialsMulti-regional Clinical TrialsWhy be concerned ?Why be concerned ?

A Regulatory Perspective on A Regulatory Perspective on IssuesIssues

Robert T. O’Neill Ph.D.Robert T. O’Neill Ph.D.Director , Office of BiostatisticsDirector , Office of Biostatistics

Office of Translational Sciences, CDEROffice of Translational Sciences, CDER

To be presented at the 17th Annual Harvard Schering-Plough Workshop: Global Trials, Challenges and Opportunities ; May 28 and 29, 2009

OutlineOutline Why now - Increasing use of this study design - some Why now - Increasing use of this study design - some

FDA experienceFDA experience What guidance , if any, on the the multi-regional What guidance , if any, on the the multi-regional

study- its design, analysis, reporting, and study- its design, analysis, reporting, and interpretationinterpretation

What are some concerns: quality, training, data What are some concerns: quality, training, data collection and management (bio)collection and management (bio)

Trial is only as good as the investigators: who are Trial is only as good as the investigators: who are they - training of investigators regarding protocol they - training of investigators regarding protocol and its complianceand its compliance

Implementation - time to increase our attention to Implementation - time to increase our attention to planning and analysisplanning and analysis

Proposal for way forwardProposal for way forward

Why nowWhy now Increasing use of this design in most medical areasIncreasing use of this design in most medical areas A Summary of two FDA studies on the use and regulatory impactA Summary of two FDA studies on the use and regulatory impact Increasing experience raises many questionsIncreasing experience raises many questions

ValidityValidity QualityQuality DesignDesign MonitoringMonitoring Single large study - relevanceSingle large study - relevance

Sparsity of written literature or FDA guidance on the issues that Sparsity of written literature or FDA guidance on the issues that are raising concernare raising concern It is time to address them - solutions will not be easy or It is time to address them - solutions will not be easy or

simplesimple ICH E5 actually expresses a position on the designICH E5 actually expresses a position on the design

Increasing emphasis on quality of clinical trials, cost and Increasing emphasis on quality of clinical trials, cost and streamlining - Critical Pathstreamlining - Critical Path

This is not just a This is not just a regulatory or drug regulatory or drug

development concerndevelopment concern

Modernize the clinical trial process

Defining QualityDefining Quality

Acceptable control of variationAcceptable control of variation Sources of variationSources of variation

Trial conduct problemsTrial conduct problems Poor record keepingPoor record keeping Flawed proceduresFlawed procedures

Quality is ? - metrics of acceptable Quality is ? - metrics of acceptable variationvariation

Coordinator

Region 1 Region 2 Region 3

Site 1 Site 2 Site 9 Site 10 Site 11 Site 12 Site 13Site 7 Site 8Site 3 Site 4 Site 5 Site 6

Sources of measurement error variability that can contribute to variability in estimates of

treatment effect / responseAuditing strategy vs. quality assurance strategy

Investigator

What does this have to do with What does this have to do with the training of clinical the training of clinical

investigators ?investigators ?

No requirement to be trained in clinical trialsNo requirement to be trained in clinical trials No requirement to be trained nor certified in ‘Good No requirement to be trained nor certified in ‘Good

Clinical Practices’Clinical Practices’ Is a requirement to have a license to practice Is a requirement to have a license to practice

medicinemedicine Investigators often are the measurement Investigators often are the measurement

instrument of treatment response and they instrument of treatment response and they implement the protocolimplement the protocol

Impact they have on the conduct of the studyImpact they have on the conduct of the study Whose responsibility - sponsor, monitor, Whose responsibility - sponsor, monitor,

investigator ?investigator ?

The regulatory review process The regulatory review process often serves as the end product often serves as the end product

auditaudit

FDA evaluates the study report and the FDA evaluates the study report and the conduct and key metrics of qualityconduct and key metrics of quality

FDA evaluates statistical displays of key FDA evaluates statistical displays of key sources of variation, bias and uncertaintysources of variation, bias and uncertainty

Regional and site outcomes evaluated: Regional and site outcomes evaluated: Dropouts, differences in response rates, Dropouts, differences in response rates, outcomes, covariates, exposures, follow-upoutcomes, covariates, exposures, follow-up

Individucal patient profiles nested within Individucal patient profiles nested within sitessites - which sites and which patient - which sites and which patient records to audit records to audit

Some Experience withSome Experience with statistical reviews of NDA’s statistical reviews of NDA’s

and Clinical Studiesand Clinical Studies Summary of review of 7 years of Summary of review of 7 years of

clinical studies involving foreign clinical studies involving foreign clinical data in NDA’sclinical data in NDA’s

21 NDA submissions whose decisions 21 NDA submissions whose decisions depended upon analysis and depended upon analysis and interpretation of treatment effects in interpretation of treatment effects in multi-regional trialsmulti-regional trials

John Lawrence evaluation of large John Lawrence evaluation of large cardiovascular outcome studiescardiovascular outcome studies

Of 1,926 clinical trials analyzed by OB during FY01-Of 1,926 clinical trials analyzed by OB during FY01-FY07:FY07:

41% were domestic; 50% foreign-domestic; and 9% 41% were domestic; 50% foreign-domestic; and 9% foreign.foreign.

Of all subjects enrolled in these trials:Of all subjects enrolled in these trials:30% were U.S.; 63% domestic-foreign; and 7% 30% were U.S.; 63% domestic-foreign; and 7%

foreign.foreign.

Of 1,926 trials analyzed by OB Statisticians during Of 1,926 trials analyzed by OB Statisticians during FY01-FY07:FY01-FY07:

Trend toward increasing numbers Trend toward increasing numbers in participation of non-U.S. centers and subjects in in participation of non-U.S. centers and subjects in

trial.trial.

Regulatory Regulatory consequencesconsequences

Non approvalsNon approvals 4 of 22 not approved because of 4 of 22 not approved because of

regional heterogeneityregional heterogeneity 9 of 22 approvable but more 9 of 22 approvable but more

information needed - regional information needed - regional heterogeneityheterogeneity

Need another studyNeed another study Labeling limitations or information - MeritLabeling limitations or information - Merit

Study Undertaken by FDA Study Undertaken by FDA statisticians to evaluate statisticians to evaluate possibility of systematic possibility of systematic

regional differencesregional differences Major cardiovascular outcome studies Major cardiovascular outcome studies

evaluated over the last 10 yearsevaluated over the last 10 years Overall study result statistically Overall study result statistically

positive, ie. demonstrated overall positive, ie. demonstrated overall effecteffect

Region never pre-specified as a factor Region never pre-specified as a factor to be evaluated statisticallyto be evaluated statistically

16 independent studies16 independent studies

difference of log-hazard ratios

Study % US

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5

31145227394451964373884974107411912313291417159016

Estimates and confidence intervals for difference between US and Non-US treatment effects for each study

J. Lawrence

In 13 of 16 , US log hazard above 0

An Example: Toprol -XLTaken from the Current Drug Label ; “Clinical

Trials”

MERIT-HF was a double-blind, placebo-controlled study of Toprol-XL conducted in 14 countries including the US. It randomized 3991 patients (1990 to Toprol-XL) with ejection fraction </= 0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event), and (2) all-cause mortality.

The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p=0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p=0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class. The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup and women, overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

A figureFrom the label

Interpretation - Interpretation - ExtrapolationExtrapolation

Impact on composite endpointImpact on composite endpoint Impact on components of composite Impact on components of composite

endpoints by region / subgroupendpoints by region / subgroup Which factor (s) most important to Which factor (s) most important to

evaluate relationship of treatment evaluate relationship of treatment effectseffects Site/center/clinic, Country , RegionSite/center/clinic, Country , Region

Wedel, DeMets, Deedwania, Fagerberg, et al. Challenges of subgroup analyses in multinational clinical trials: Experiences from the MERIT-HF trial. Amer. Heart J 2001; 142: 502-11

Version: 3 July 2008

Antiepileptic Drugs and Suicidality: Statistical Review

Mark Levenson, Ph.D.Statistical Safety Reviewer

Quantitative Safety and Pharmacoepidemiology Group Division of Biometrics 6/CDER/FDA

Joint Meeting of Peripheral and Central Nervous System Drugs Advisory Committee and Psychopharmacologic Drugs Advisory

Committee

July 10, 2008

Suicidal Behavior or Ideation Odds Ratio Estimates by Location

Odds Ratio

0.1 0.3 1 3.2 10

Overall

Non-North Am erican

North Am erican

1.80 (1.24, 2.66) [104/27863 38/16029]

4.53 (1.86, 13.18) [36/11022 5/6088]

1.38 (0.90, 2.13) [68/16841 33/9941]

Location OR (95% CI) [Sample Sizes]*

*[Treat. Events /Treat. n Plac. Events /Placebo n]

Risk lower in N A

Rates are higher in North Rates are higher in North America sitesAmerica sites

Rates are higher in North Rates are higher in North America sitesAmerica sites

Guidance on the topicsGuidance on the topics

ICH E3 -Multicenter studies - ICH E3 -Multicenter studies - reportingreporting

ICH E9 - Multicenter studies - ICH E9 - Multicenter studies - Planning and AnalysisPlanning and Analysis

ICH E5 - Multiregional clinical trials - ICH E5 - Multiregional clinical trials - global drug development - bridgingglobal drug development - bridging

Literature - Literature -

Modernizing the statistical Modernizing the statistical planning of a multi-regional planning of a multi-regional

study with more realistic study with more realistic objectivesobjectives

Some ideas and work of Dr. Hung Some ideas and work of Dr. Hung Modern planning should rely more Modern planning should rely more

on simulations of a variety of on simulations of a variety of assumptions for known or assumptions for known or expected sources of variability expected sources of variability and heterogeneity - scenario and heterogeneity - scenario planningplanning

Region I Region kBridging

Global

Multi-regional trial

Global Trial ConsiderationGlobal Trial Consideration

K geographical regionsK geographical regions

nnhh: sample size of region h : sample size of region h

N = N = n nhh

yyhh | | hh N( N( h h , , 22/n/nh h ))

hh ( ( , , 2 2 )) Effect sizes vary

but are all positiveHung,

2007

Question: Is meaningful, i.e., interpretable for all regions? (Interaction ?)

If not, only h is applicable to region h. Then, the study will require a sufficient sample size for each region.

Hung, 2007

If is interpretable for each region, estimate by Y rhyh , ( rh=nh/N )

22

2 1)(

)(

hrNYVar

YE

Hung, 2007

Should plan N to detect = > 0 at level & power 1-, assuming 0

1

222

)(

hrzz

N

1

222

)(

hrzz

N

Hung, 2007

If, instead, = 0 is assumed for planning sample size, then the resulting sample size N0 may be too low. How low?

22

20 )(1 hrzzNN

1

1)(

)|Pr(5.0

22

0 hrNzzz

P

Hung, 2007

Sample Size Ratio N/N0

0.000

2.000

4.000

6.000

8.000

0.3 0.5 0.7 0.9 1.1 1.3 1.5

delta

sigma_delta/sigma = 0.2 sigma_delta/sigma = 0.5

=0.025, =0.1, K=5, (r1 r2 r3 r4 r5)=(.2 .1 .4 .1 .2) Hung, 2007

Studies will be underpowered for Studies will be underpowered for effect sizes and could fail because effect sizes and could fail because

of it - increase sizeof it - increase size

Clinical endpoints that may Clinical endpoints that may be impacted by regional be impacted by regional

differencesdifferences

Difficulty with diagnosis , with ascertaining Difficulty with diagnosis , with ascertaining progression or resolution of conditionprogression or resolution of condition Anti-bacterial drugs for hospital- acquired Anti-bacterial drugs for hospital- acquired

pneumonia (HAP) and ventilator-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP)pneumonia (VAP)

Creation of composite endpoints whose components Creation of composite endpoints whose components are evaluated differentlyare evaluated differently

Antibiotic resistance, clinical practice Antibiotic resistance, clinical practice Patient reported outcomes, symptomatic conditionsPatient reported outcomes, symptomatic conditions Safety outcomes (how ascertained or defined - Safety outcomes (how ascertained or defined -

suicides)suicides)

Non-inferiority trials vs. Non-inferiority trials vs. Superiority trialsSuperiority trials

Impact of heterogeneity Impact of heterogeneity

Timing of outcome measurementTiming of outcome measurement Investigator trainingInvestigator training Differential sensitivity and Differential sensitivity and

specificityspecificity

Reasons for concern when Reasons for concern when extrapolatingextrapolating

Regional differences in observed treatment effects Regional differences in observed treatment effects within the same study (not always clear what is within the same study (not always clear what is responsible, chance ?)responsible, chance ?)

Differences in results of separate independent studies , Differences in results of separate independent studies , each done in different regionseach done in different regions

What (bridging data) can explain the differences ?What (bridging data) can explain the differences ? information gained prior to the studiesinformation gained prior to the studies information gained after studies completedinformation gained after studies completed A new studyA new study

The Way ForwardThe Way ForwardSome Recommendations to Some Recommendations to

considerconsider

For every multi-regional study, create a common template for For every multi-regional study, create a common template for planning for homogeneity/heterogeneity of regional planning for homogeneity/heterogeneity of regional differences and exploring sample sizing according to differences and exploring sample sizing according to assumptions of dropouts, follow-up, compliance, event assumptions of dropouts, follow-up, compliance, event ascertainment by investigator, degree of internal consistencyascertainment by investigator, degree of internal consistency

Enhance all study reports with section that discusses process Enhance all study reports with section that discusses process of quality assurance, data management, quality of data of quality assurance, data management, quality of data collected, monitoring strategies, important descriptors and collected, monitoring strategies, important descriptors and outcomes by region/countryoutcomes by region/country

Improve the statistical analysis plan to specifically address Improve the statistical analysis plan to specifically address strategies and interpretation of heterogeneity, power, strategies and interpretation of heterogeneity, power, internal consistency of by region resultsinternal consistency of by region results

Address the training / certification of investigators and quality Address the training / certification of investigators and quality checkschecks

Auditing strategies, metrics of qualityAuditing strategies, metrics of quality Update the study report for a MRCT to include new issuesUpdate the study report for a MRCT to include new issues