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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 - Why now - Increasing use of this study design - some FDA experiencesome FDA 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 / response
Auditing 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
311
452
273
94
45
196
437
388
49
7410
7411
912
313
2914
1715
9016
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 -XL
Taken 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 figure
From 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 , RegionWedel, 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
2
0 )(1 hrzzN
N
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 Creation of composite endpoints whose components are evaluated differentlycomponents are 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 Differences in results of separate independent studies , each done in different regionsstudies , each 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 every multi-regional study, create a common template for planning for homogeneity/heterogeneity of regional for 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 ascertainment by investigator, degree of internal consistencyconsistency
Enhance all study reports with section that discusses Enhance all study reports with section that discusses process of quality assurance, data management, quality of process of quality assurance, data management, quality of data collected, monitoring strategies, important descriptors data collected, monitoring strategies, important descriptors and outcomes by region/countryand outcomes 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 Address the training / certification of investigators and quality checksquality checks
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