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An Overview of Issues Surrounding Multi-Regional Clinical Trials
Bruce BinkowitzMerck & Co. [email protected]
May 28, 2009
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IntroductionIntroduction
• As of early 2008, there As of early 2008, there were were 50,62950,629 clinical clinical trials ongoing globally trials ongoing globally
• up by 1.3% over 2007up by 1.3% over 2007Bio-IT World “Clinical Trials in new Europe”, by Al Doig, Jan-Feb issue 2009Bio-IT World “Clinical Trials in new Europe”, by Al Doig, Jan-Feb issue 2009Further reading: European clinical Trial Site Options: An Insider’s Analysis by PAvle Vukojevic, Further reading: European clinical Trial Site Options: An Insider’s Analysis by PAvle Vukojevic,
Nov2008 www.InsightPhrarmReports.comNov2008 www.InsightPhrarmReports.com
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Global Trials: Challenges and Opportunities
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Guidances, Literature and the NewsGuidances, Literature and the News• Globalization of clinical trials is a reality.• Clinical trials across multiple regions of the
world have become common practice. • Multi-regional trials (MRCT) have benefits
but also come with a set of challenges.
• FDA/PhRMA Workshop: Challenges & Opportunities of Multi-regional Clinical Trials, Bethesda, MD October 29-30, 2007
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Guidances, Literature and the NewsGuidances, Literature and the News• FDA/PhRMA Workshop: Challenges &
Opportunities of Multiregional Clinical Trials, Bethesda, MD October 29-30, 2007
• The focus of the workshop was to cover the opportunities and challenges presented by these trials.
• The workshop brought together representatives from industry, regulatory agencies and academia, who shared their experiences, perspectives and expertise
• This is not a new issue, but it is now more This is not a new issue, but it is now more important and public than ever.important and public than ever.
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Guidances, Literature and the NewsGuidances, Literature and the News• ICH E5 guideline was adopted in 1998 (update
2006) with the purpose to facilitate the registration of medicinal products among different geographic regions by recommending a framework for evaluating the impact of ethnic factors upon the efficacy or safety of a product.
• ICH E3 mentions reporting results by investigator site and suggests examining interactions and outliers.
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Guidances, Literature and the NewsGuidances, Literature and the News• ICH E9 discusses multi-center studies – but can
this be extrapolated to multi-regional studies?
• EMEA REFLECTION PAPER ON THE EXTRAPOLATION OF RESULTS FROM CLINICAL STUDIES CONDUCTED OUTSIDE EUROPE TO THE EU-POPULATION (2009): (2009): the aim of this reflection paper is to highlight some current experience from pivotal clinical studies conducted outside the EU region and to discuss how different factors (in particular extrinsic factors) may complicate the evaluation of foreign data in a European perspective.
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Guidances, Literature and the NewsGuidances, Literature and the News• Basic Principles on Global Clinical Trials. (PFSB/ELD)
Notification No.0928010 dated Sept. 28, 2007. (Japan Guidance)
• Kawai N, Chuang-Stein C, Komiyama O and Li Y. An approach to rationalize partitioning sample size into individual regions in a multiregional trial. Drug Information Journal 2007; 42: 139-147.
• Hui Quan, Peng-Liang Zhao, Ji Zhang, Martin Roessner and Kyo Aizawa Sample size considerations for Japanese patients in a multi-regional trial based on MHLW guidance, accepted for publication in Pharmaceutical Statistics
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Guidances, Literature and the NewsGuidances, Literature and the News
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Guidances, Literature and the NewsGuidances, Literature and the News
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Guidances, Literature and the NewsGuidances, Literature and the News
Drug Information Journal:
• 1998 DIJ Vol 32, supplemental issue: Current Status of Clinical Trials in the Asia Pacific Region
• 2003 DIJ Vol 37, supplemental issue: Global New Drug Development and the International Conference on Harmonzation in Asia
• 2009 DIJ (Vol. 43.) “Good Regulatory Science in Asia/Pacific: Parts 1 & 2”
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Guidances, Literature and the NewsGuidances, Literature and the NewsThe Wall Street JournalThe Wall Street Journal (12/1/08, Wang, et al.) reports: (12/1/08, Wang, et al.) reports:• Western pharmaceutical companies are facing Western pharmaceutical companies are facing
intensifying scrutiny over the conduct of clinical intensifying scrutiny over the conduct of clinical trials in developing countries -- an increasingly trials in developing countries -- an increasingly important source of patients to test new drugs. important source of patients to test new drugs.
• Among the benefits of conducting trials in lower-Among the benefits of conducting trials in lower-income countries are the decreased cost and faster income countries are the decreased cost and faster patient recruitment. patient recruitment.
• Moreover, in countries where access to medical Moreover, in countries where access to medical care is poor, people are often desperate to care is poor, people are often desperate to participate in trials.participate in trials.
• But, one concern is that "locals who carry out the But, one concern is that "locals who carry out the work may feel pressure to cut corners to boost work may feel pressure to cut corners to boost enrollment or reconcile questionable data”.enrollment or reconcile questionable data”.
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Guidances, Literature and the NewsGuidances, Literature and the News• FDA/PhRMA Workshop:
Challenges & Opportunities of Multiregional Clinical Trials, Bethesda, MD October 29-30, 2007
• PhRMA MRCT Cross-Functional Key Issues Team
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MRCT Cross-Functional Key Issues Team• Created under the auspices of the PhRMA Created under the auspices of the PhRMA
Biostatistical and Data Management Technical Biostatistical and Data Management Technical Group (BDMTG) and the PhRMA Clinical Group (BDMTG) and the PhRMA Clinical Leadership Committee (CLC)Leadership Committee (CLC)
• A broad, ground level focusA broad, ground level focus• Resource to BDMTG, CLC as well as SGD, Resource to BDMTG, CLC as well as SGD,
CRTG, RACCCRTG, RACC• Multi-functional and worldwide in Multi-functional and worldwide in
compositioncomposition• StatisticsStatistics• EpidemiologyEpidemiology• Data ManagementData Management• Regulatory AffairsRegulatory Affairs• Clinical ResearchClinical Research
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Simultaneous Global DevelopmentSimultaneous Global Development
• ICH E-5 (February, 1998, clarifying ICH E-5 (February, 1998, clarifying document June, 2006)document June, 2006)
• MHLW guidance (September, 2007)MHLW guidance (September, 2007)• FDA/PhRMA MRCT Workshop FDA/PhRMA MRCT Workshop
(November, 2007)(November, 2007)• Tripartite Health Ministers Agreement Tripartite Health Ministers Agreement
(China, Korea, and Japan) and the East (China, Korea, and Japan) and the East Asia Pharmaceutical Regulatory Asia Pharmaceutical Regulatory Symposium (EAPRS: Tokyo April, 2008)Symposium (EAPRS: Tokyo April, 2008)
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MRCT Cross-Functional Key Issues TeamMRCT Cross-Functional Key Issues Team
• ScopeScope: : Identify and address issues Identify and address issues directly relevant to the efficient directly relevant to the efficient conduct of MRCT and the generation conduct of MRCT and the generation of data readily acceptable to of data readily acceptable to regulatory authorities. Such issues regulatory authorities. Such issues can fall into 5 broad categories (no can fall into 5 broad categories (no implied hierarchy here):implied hierarchy here):
• SStatisticaltatistical• CClinicallinical• OOperationalperational• RRegulatoryegulatory• EEthicalthical
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MRCT Cross-Functional Key Issues TeamMRCT Cross-Functional Key Issues Team• 2009 objective: get the word out, get
involved, get informed, begin work on issues.• 2009 DIA, SCT, JSM, FDA/Industry Workshop,
Harvard-SP, MRCT Conference in Korea (June 2009 http://www.apec-ahc.org/), special issue of Pharm. Stats Journal in 2010
• Collect case studies and examples of MRCTs• Develop a Survey of PhRMA• 2010 and beyond: Workstreams leading to
publications and presentations• Broad Objective: Data driven.• All suggestions welcome!
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MRCT Cross-Functional Key Issues TeamMRCT Cross-Functional Key Issues Team
• Underlying theme of all issues goes to Underlying theme of all issues goes to quality and integrity of a trial.quality and integrity of a trial.
• Clinical Trialists need to be acutely Clinical Trialists need to be acutely aware of the quality and integrity of the aware of the quality and integrity of the trial. . Not just the quality and integrity Not just the quality and integrity of the data.of the data.
• Design a MRCT trial keeping the 5 Design a MRCT trial keeping the 5 areas of impact areas of impact SCORESCORE in mind. in mind.
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Areas of Impact: Areas of Impact: EthicalEthical
• Adequacy of protection of research subjects Adequacy of protection of research subjects (e.g. NEJM (e.g. NEJM Glickman, et.al.)Glickman, et.al.)
• Informed Consent (e.g. Informed Consent (e.g. Annas in NEJM, 14May2009Annas in NEJM, 14May2009))• Integrity of research conductIntegrity of research conduct
• Ease of accessEase of access• Transparency of the researchTransparency of the research• Quality of the review that permits the conduct of the Quality of the review that permits the conduct of the
researchresearch• Local Ethics Committees, IRB’s, etc.Local Ethics Committees, IRB’s, etc.
• Data collection/privacyData collection/privacy• Above true in generalAbove true in general
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Areas of Impact: Areas of Impact: EthicalEthical
• Need to conduct a MRCT according to Need to conduct a MRCT according to Good Clinical Practice StandardsGood Clinical Practice Standards
• Relevant country and local statutes Relevant country and local statutes regarding:regarding:• Regs regarding ethical committee reviewsRegs regarding ethical committee reviews• Informed consentInformed consent• Withdrawn consentWithdrawn consent• Protection of human patients participating Protection of human patients participating
in biomedical research.in biomedical research.
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MRCT Areas of Impact: MRCT Areas of Impact: ClinicalClinical
From the EU Reflection Paper
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MRCT Areas of Impact: MRCT Areas of Impact: ClinicalClinicalExtrinsic versus Intrinsic factorsExtrinsic versus Intrinsic factors• Lack of quality data showing the Lack of quality data showing the
comparabiilty of PK/PD relationships comparabiilty of PK/PD relationships among different ethnic/racial groups, or among different ethnic/racial groups, or among “regions”.among “regions”.
• ““A Review and Assessment of Potential A Review and Assessment of Potential Sources of Ethnic Differences in Drug Sources of Ethnic Differences in Drug Responsiveness”, Thorir D. Bjornsson, Responsiveness”, Thorir D. Bjornsson, et.al. 2003:43:943-967, The Journal of et.al. 2003:43:943-967, The Journal of Clinical Pharmacology. “An extensive Clinical Pharmacology. “An extensive review of the world literature on ethnic review of the world literature on ethnic differences in drug disposition and differences in drug disposition and responsiveness.”, the PhRMA CPTG responsiveness.”, the PhRMA CPTG group.group.
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MRCT Areas of Impact: MRCT Areas of Impact: ClinicalClinical• Medical practiceMedical practice
• Differences in standard of care with markedly Differences in standard of care with markedly varied medical practice, including disease varied medical practice, including disease defintionsdefintions
• Differences in access to the regional Differences in access to the regional healthcare systemhealthcare system
• Differences in criteria for hospitalization and Differences in criteria for hospitalization and treatmenttreatment
• Concomitant medicationsConcomitant medications• Differences in diet, smoking, alcoholDifferences in diet, smoking, alcohol
• Placebo responsesPlacebo responses• Cultural differencesCultural differences
• AE reporting and evaluationAE reporting and evaluation• Endpoints PRO (i.e. more subjective Endpoints PRO (i.e. more subjective
endpoints).endpoints).
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MRCT Areas of Impact: MRCT Areas of Impact: ClinicalClinicalExample from the EU Reflection Paper - Antithrombotic Agents “The main factors that complicated the extrapolation of data between different geographical areas (North America versus Europe, China versus Europe, Eastern versus Western Europe) were differences in medical practice, such as co-medications, rate of revascularization and duration to treatment start.”
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Areas of Impact: Areas of Impact: OperationalOperational
• Challenges when moving from phase II to Challenges when moving from phase II to phase III to post-marketing (e.g. expanding phase III to post-marketing (e.g. expanding # of sites, regions. What about flexible # of sites, regions. What about flexible designsdesigns?)?)
• Language and translationsLanguage and translations• Local versus regional versus central labsLocal versus regional versus central labs
• ShippingShipping• Normal rangesNormal ranges• Quality Control, assay validationQuality Control, assay validation
• SOPs and Manuals, including Global Clinical SOPs and Manuals, including Global Clinical SOPs, data handling SOPs, operational SOPs SOPs, data handling SOPs, operational SOPs (translations, training, “help desk”)(translations, training, “help desk”)
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Areas of Impact: Areas of Impact: OperationalOperational
• Technological standards / Technological standards / telecommunication bandwidthtelecommunication bandwidth
• Multi-regional trial versus multiple Multi-regional trial versus multiple regional trialsregional trials
• Enrollment, access to the appropriate Enrollment, access to the appropriate patient populationpatient population
• Drug Supply, IVRS, RandomizationDrug Supply, IVRS, Randomization• Trial Quality and IntegrityTrial Quality and Integrity
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Areas of Impact: Areas of Impact: Operational
• Trial Quality and Integrity is this, and more:Trial Quality and Integrity is this, and more:• Investigator trainingInvestigator training• Quality AssuranceQuality Assurance• Data management and data qualityData management and data quality• Who’s looking at the data for a MRCT? Sponsor? Who’s looking at the data for a MRCT? Sponsor?
CRO? (QC of on-site monitoring, AE reporting)CRO? (QC of on-site monitoring, AE reporting)• Plan in the protocol for sources of heterogeneity – Plan in the protocol for sources of heterogeneity –
adjust the sample size as needed.adjust the sample size as needed.• Metrics: how do we measure quality and Metrics: how do we measure quality and
integrity? Is QA separate from QC, e.g. the integrity? Is QA separate from QC, e.g. the quality assurance audits of the QC activities quality assurance audits of the QC activities to ensure compliance to GCP, company to ensure compliance to GCP, company policies,etcpolicies,etc
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Areas of Impact: Areas of Impact: RegulatoryRegulatory• Dealing with differing (and possibly opposing) Dealing with differing (and possibly opposing)
regulatory requirementsregulatory requirements• Including differing primary and secondary Including differing primary and secondary
endpoint requirementsendpoint requirements• Divergence in the requirements for the control Divergence in the requirements for the control
arm, in clinical studies EU vs. US vs. Asia.arm, in clinical studies EU vs. US vs. Asia.• Obtaining agreement from differing health Obtaining agreement from differing health
authoritiesauthorities• Level of evidence neededLevel of evidence needed
• Based on the studiesBased on the studies• Based on the health authority resources Based on the health authority resources
(reliance on other health authorities)(reliance on other health authorities)
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Areas of Impact: Areas of Impact: RegulatoryRegulatory
• Handling different regulatory review and approval times when trying to orchestrate a simultaneous global submission.
• Managing and responding to requests across multiple agencies
• Determining the acceptability of MRCT data
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Areas of Impact: Areas of Impact: RegulatoryRegulatoryIllustrative ExampleIllustrative Example
• On April 5, 2006, Health Canada adopted the following two International Conference on Harmonisation (ICH) guidances:• ICH S7B: The Non-Clinical Evaluation of the Potential for Delayed
Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals
• ICH E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs
• On November 30, 2006, Health Canada adopted the following regional guidance documents to support the interpretation and implementation of the ICH guidances:• Health Canada Question and Answer Document Regarding the ICH
S7B and E14 Guidances• Guide for the Analysis and Review of QT/QTc Interval Data
(comments until June 10, 2009)• QT/QTc Interval Prolongation: Guidance for Product Monograph
Content
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Areas of Impact: Areas of Impact: StatisticalStatistical
• Importance of Importance of predefining the definition predefining the definition of regionof region
• Lab data – local, regional, Lab data – local, regional, centralcentral
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Areas of Impact: Areas of Impact: StatisticalStatistical
• Impact of regional differences on Impact of regional differences on power estimation / sample sizepower estimation / sample size
• Methods for subgroup analysisMethods for subgroup analysis• Randomization issues (and drug Randomization issues (and drug
supply) / stratificationsupply) / stratification• How to describe/present data by How to describe/present data by
regionregion
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Areas of Impact: Areas of Impact: StatisticalStatistical• Adaptive/flexible designs in a MRCT settingAdaptive/flexible designs in a MRCT setting• Imbalances in region sizes (planned and Imbalances in region sizes (planned and
unplanned)unplanned)• Use of placebo / placebo effectsUse of placebo / placebo effects• Acceptability of non-inferiority vs. Acceptability of non-inferiority vs.
superiority studies – regional acceptability? superiority studies – regional acceptability? Lack of consensus of the non-inferiority Lack of consensus of the non-inferiority margins? Differences in Health Authority margins? Differences in Health Authority preferences.preferences.
• Drug approved in countries with different Drug approved in countries with different dosing regimens – can you still use MRCT? dosing regimens – can you still use MRCT? Or multiple trials in different regions? Or multiple trials in different regions?
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Areas of Impact: Areas of Impact: StatisticalStatistical
• Multi-regional trial versus multiple Multi-regional trial versus multiple regional trials – a single pivotal regional trials – a single pivotal trial? Prep for ISE? Subgroups? trial? Prep for ISE? Subgroups? Pooling/meta-analysis/integration Pooling/meta-analysis/integration of efficacy data.of efficacy data.
• Define consistency of treatment Define consistency of treatment effect (not just by a statistical effect (not just by a statistical interaction test) interaction test)
• Fixed versus random effectsFixed versus random effects
Brief ExamplesBrief Examplesof MRCT Issuesof MRCT Issues
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EverestEverest
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EVERESTEVEREST
• In EVEREST, patients hospitalized for acute heart failure (HF) with systolic dysfunction on standard therapy were randomized to tolvaptan or placebo.
• The EVEREST program demonstrated that the oral vasopressin antagonist, tolvaptan, added to standard therapy, improved some, but not all, HF signs and symptoms during hospitalization over placebo; it showed no effect on long-term mortality or HF-related morbidity
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EVEREST post-hoc analysis:EVEREST post-hoc analysis:
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EVEREST post-hoc analysis EVEREST post-hoc analysis author’s summary:author’s summary:
• The publication yields data demonstrating that despite efforts to select for a fairly homogenous study population (i.e. a protocol), important differences in etiology, severity, management, and outcomes existed.
• The etiology and management of HF may vary by region and is difficult to control.
• Future AHFS trials should take these continental and regional differences into consideration and possibly stratify randomization based on continent or region when appropriate and analyze the data separately.
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Statistical Issues: MHLW guidanceStatistical Issues: MHLW guidance• The Japanese regulatory authority: Ministry of Health, Labour
and Welfare (MHLW), ‘Basic Principles on Global Clinical Trials’ guidance
• Provides basic concepts for planning and implementing MRCTs using a Q&A format
• One point specifically addresses a need to determine the number of Japanese patients.
• Does not recommend any single method for determining sample sizes to establish the consistency of treatment effects for the entire group versus the Japanese group
• BUT, it does provide two methods as examples.• Kawai et al. discuss sample size consideration for Method 2.• Quan et.al. discuss sample size considerations for Method 1.
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Example for A Placebo-controlled Study Using Quantitative Measurements
• Method 1Method 1• DDallall: difference in entire population: difference in entire population
• DDJJ: difference in subgroup of patients enrolled from Japan: difference in subgroup of patients enrolled from Japan
• P(DP(DJJ / D/ Dallall > >ππ) ≥ 80%, for example ) ≥ 80%, for example ππ = 0.5 = 0.5
DJ ( >πDall )
Dall
Efficacy0
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Example for A Placebo-controlled Study Example for A Placebo-controlled Study Using Quantitative MeasurementsUsing Quantitative Measurements
• Method 2Method 2• DDallall: difference in entire population: difference in entire population
• DD1 1 ,, DD2 2 ,, DD3 3 : differences in subgroup of region 1, 2, 3, : differences in subgroup of region 1, 2, 3,
respectively, in the case of three regionsrespectively, in the case of three regions
• P(DP(D11 >0, D >0, D22 >0, D >0, D33 >0 | D >0 | Dallall>0) ≥ say, 80%>0) ≥ say, 80%
D1
Efficacy0
D3
D2
Dall
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MethodMethod Method 1Method 1 Method 2Method 2
StatisticsStatistics Point estimatePoint estimate Point estimatePoint estimate
CriterionCriterion DDJJ / D/ Dallall > >ππ DD11 >0, D >0, D22 >0, D >0, D33 >0 >0
(3 region example)(3 region example)
when Dwhen Dallall>0>0
PropertiesProperties Focuses on Japan. Prob. of Focuses on Japan. Prob. of
meeting requirement meeting requirement
increases as % Japanese increases as % Japanese
pts increasespts increases
Treats regions symmetrically. Treats regions symmetrically. Prob. of meeting requirement Prob. of meeting requirement
reaches maximum when regions reaches maximum when regions have equal sample sizehave equal sample size
RemainingRemaining
IssuesIssues
Value of πValue of π Definition of region. Number of Definition of region. Number of regions.regions.
Is Japan the only interesting Is Japan the only interesting region? Dregion? DJJ>0 | D>0 | Dallall>0>0
Slides on methods 1,2 courtesy of Y. Song of Merck
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MLHW Consistency in Trends MLHW Consistency in Trends ApproachApproach
• Overall sample size determined to Overall sample size determined to provide 80% or 90% power at 1-provide 80% or 90% power at 1-sided 0.025 levelsided 0.025 level
• Sample size in the smallest region Sample size in the smallest region determined by ensuring the determined by ensuring the probability of observing consistent probability of observing consistent trends (in point estimates) across trends (in point estimates) across all concerned regions is 80% (90%)all concerned regions is 80% (90%)
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Conditional ConsistencyConditional Consistency• Sample size in the smallest region needs Sample size in the smallest region needs
to ensure the probability of observing to ensure the probability of observing consistent trends (in point estimates) consistent trends (in point estimates) across all concerned regions is 80% across all concerned regions is 80% (90%) (90%) conditional on the overall conditional on the overall treatment effect is significanttreatment effect is significant• A less conservative approach: smaller A less conservative approach: smaller
sample size requirement for the smallest sample size requirement for the smallest regionregion
• (Simple) Simulation is usually needed for (Simple) Simulation is usually needed for computationcomputation
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SummarySummary• When thinking of designing and When thinking of designing and
conducting a clinical trial, those conducting a clinical trial, those responsible for the conduct of the trial responsible for the conduct of the trial must consider the ethical, clinical, must consider the ethical, clinical, operational, regulatory and statistical operational, regulatory and statistical issues.issues.
• This is never more true than when This is never more true than when planning, conducting, analyzing and planning, conducting, analyzing and interpreting a trial that covers multiple interpreting a trial that covers multiple regions.regions.
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The PhRMA Cross-FunctionalThe PhRMA Cross-FunctionalKey Issues Membership:Key Issues Membership:
Ibia, Ekopimo Merck
Binkowitz, Bruce Merck
Saillot, Jean-Louis Schering-Plough
Tanaka, Yoko X1 Eli Lilly & Co
Menjoge, Shailendra Boehringer Ingelheim
Fedorov, Valerie V GlaxoSmithKline
Ouyang, S. Peter Celgene
Ferreira, Irene Amgen
Langley, Michael Eli Lilly & Co
Quan, Hui Sanofi-Aventis
Rabbia, Michael Roche
Ohishi, Masahiko Merck
Gallo, Paul Novartis
Ikeda, Kimitoshi Novartis
Chen, Joshua Merck
Cindy, Girman Merck
Talerico, Steven D Schering-Plough
Lee, Andy Pfizer
Field, Belinda Pfizer
Li, Gang J&JPRD
Houck, Tonya Pfizer
Schiff, Kenneth Hoffman LaRoche
Battles, Mary Ann Amgen
Luo, Xiaolong Celgene
Thank You!Thank You!
QuestionsQuestions??
