Transcript Slide 1

An Overview of Issues Surrounding
Multi-Regional Clinical Trials
Bruce Binkowitz
Merck & Co.
[email protected]
May 28, 2009
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Introduction
• As of early 2008, there
were 50,629 clinical
trials ongoing globally
• up by 1.3% over 2007
Bio-IT World “Clinical Trials in new Europe”, by Al Doig, Jan-Feb issue 2009
Further reading: European clinical Trial Site Options: An Insider’s Analysis by PAvle Vukojevic, Nov2008
www.InsightPhrarmReports.com
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Global Trials: Challenges and Opportunities
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Guidances, 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 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
important and public than ever.
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Guidances, 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 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):
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 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 News
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Guidances, Literature and the News
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Guidances, 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 News
The Wall Street Journal (12/1/08, Wang, et al.) reports:
• Western pharmaceutical companies are facing
intensifying scrutiny over the conduct of clinical trials
in developing countries -- an increasingly important
source of patients to test new drugs.
• Among the benefits of conducting trials in lower-income
countries are the decreased cost and faster patient
recruitment.
• Moreover, in countries where access to medical care is
poor, people are often desperate to participate in trials.
• But, one concern is that "locals who carry out the work
may feel pressure to cut corners to boost enrollment or
reconcile questionable data”.
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Guidances, 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
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Created under the auspices of the PhRMA
Biostatistical and Data Management Technical Group
(BDMTG) and the PhRMA Clinical Leadership
Committee (CLC)
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A broad, ground level focus
Resource to BDMTG, CLC as well as SGD,
CRTG, RACC
Multi-functional and worldwide in composition
Statistics
Epidemiology
Data Management
Regulatory Affairs
Clinical Research
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Simultaneous Global Development
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ICH E-5 (February, 1998, clarifying
document June, 2006)
MHLW guidance (September, 2007)
FDA/PhRMA MRCT Workshop
(November, 2007)
Tripartite Health Ministers Agreement
(China, Korea, and Japan) and the East
Asia Pharmaceutical Regulatory
Symposium (EAPRS: Tokyo April, 2008)
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MRCT Cross-Functional Key Issues Team
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Scope: Identify and address issues
directly relevant to the efficient conduct
of MRCT and the generation of data
readily acceptable to regulatory
authorities. Such issues can fall into 5
broad categories (no implied hierarchy
here):
• Statistical
• Clinical
• Operational
• Regulatory
• Ethical
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MRCT 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 Team
• Underlying theme of all issues goes to
quality and integrity of a trial.
• Clinical Trialists need to be acutely
aware of the quality and integrity of
the trial. Not just the quality and
integrity of the data.
• Design a MRCT trial keeping the 5
areas of impact SCORE in mind.
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Areas of Impact: Ethical
• Adequacy of protection of research subjects (e.g.
NEJM Glickman, et.al.)
• Informed Consent (e.g. Annas in NEJM, 14May2009)
• Integrity of research conduct
• Ease of access
• Transparency of the research
• Quality of the review that permits the conduct of the
research
• Local Ethics Committees, IRB’s, etc.
• Data collection/privacy
• Above true in general
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Areas of Impact: Ethical
• Need to conduct a MRCT according to Good
Clinical Practice Standards
• Relevant country and local statutes
regarding:
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Regs regarding ethical committee reviews
Informed consent
Withdrawn consent
Protection of human patients participating in
biomedical research.
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MRCT Areas of Impact: Clinical
From the EU Reflection Paper
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MRCT Areas of Impact: Clinical
Extrinsic versus Intrinsic factors
• Lack of quality data showing the
comparabiilty of PK/PD relationships among
different ethnic/racial groups, or among
“regions”.
• “A Review and Assessment of Potential
Sources of Ethnic Differences in Drug
Responsiveness”, Thorir D. Bjornsson, et.al.
2003:43:943-967, The Journal of Clinical
Pharmacology. “An extensive review of the
world literature on ethnic differences in
drug disposition and responsiveness.”, the
PhRMA CPTG group.
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MRCT Areas of Impact: Clinical
• Medical practice
• Differences in standard of care with markedly
varied medical practice, including disease
defintions
• Differences in access to the regional
healthcare system
• Differences in criteria for hospitalization and
treatment
• Concomitant medications
• Differences in diet, smoking, alcohol
• Placebo responses
• Cultural differences
• AE reporting and evaluation
• Endpoints PRO (i.e. more subjective endpoints).
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MRCT Areas of Impact: Clinical
Example 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: Operational
• Challenges when moving from phase II to
phase III to post-marketing (e.g. expanding #
of sites, regions. What about flexible designs?)
• Language and translations
• Local versus regional versus central labs
• Shipping
• Normal ranges
• Quality Control, assay validation
• SOPs and Manuals, including Global Clinical
SOPs, data handling SOPs, operational SOPs
(translations, training, “help desk”)
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Areas of Impact: Operational
• Technological standards /
telecommunication bandwidth
• Multi-regional trial versus multiple
regional trials
• Enrollment, access to the appropriate
patient population
• Drug Supply, IVRS, Randomization
• Trial Quality and Integrity
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Areas of Impact: Operational
• Trial Quality and Integrity is this, and more:
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Investigator training
Quality Assurance
Data management and data quality
Who’s looking at the data for a MRCT? Sponsor?
CRO? (QC of on-site monitoring, AE reporting)
• Plan in the protocol for sources of heterogeneity –
adjust the sample size as needed.
• Metrics: how do we measure quality and
integrity? Is QA separate from QC, e.g. the
quality assurance audits of the QC activities to
ensure compliance to GCP, company policies,etc
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Areas of Impact: Regulatory
• Dealing with differing (and possibly opposing)
regulatory requirements
• Including differing primary and secondary endpoint
requirements
• Divergence in the requirements for the control
arm, in clinical studies EU vs. US vs. Asia.
• Obtaining agreement from differing health
authorities
• Level of evidence needed
• Based on the studies
• Based on the health authority resources (reliance
on other health authorities)
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Areas of Impact: Regulatory
• 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: Regulatory
Illustrative 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: Statistical
• Importance of predefining
the definition of region
• Lab data – local, regional, central
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Areas of Impact: Statistical
• Impact of regional differences on
power estimation / sample size
• Methods for subgroup analysis
• Randomization issues (and drug
supply) / stratification
• How to describe/present data by
region
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Areas of Impact: Statistical
• Adaptive/flexible designs in a MRCT setting
• Imbalances in region sizes (planned and
unplanned)
• Use of placebo / placebo effects
• Acceptability of non-inferiority vs. superiority
studies – regional acceptability? Lack of
consensus of the non-inferiority margins?
Differences in Health Authority preferences.
• Drug approved in countries with different
dosing regimens – can you still use MRCT? Or
multiple trials in different regions?
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Areas of Impact: Statistical
• Multi-regional trial versus multiple
regional trials – a single pivotal trial?
Prep for ISE? Subgroups?
Pooling/meta-analysis/integration of
efficacy data.
• Define consistency of treatment
effect (not just by a statistical
interaction test)
• Fixed versus random effects
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Brief Examples
of MRCT Issues
Everest
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EVEREST
• 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:
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EVEREST post-hoc analysis
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 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 1
• Dall: difference in entire population
• DJ: difference in subgroup of patients enrolled from Japan
• P(DJ / Dall >π) ≥ 80%, for example π = 0.5
DJ ( >πDall )
Dall
0
Efficacy
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Example for A Placebo-controlled Study
Using Quantitative Measurements
• Method 2
• Dall: difference in entire population
• D1 , D2 , D3 : differences in subgroup of region 1, 2, 3,
respectively, in the case of three regions
• P(D1 >0, D2 >0, D3 >0 | Dall>0) ≥ say, 80%
Dall
D1
D2
D3
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Efficacy
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Method
Method 1
Method 2
Statistics
Point estimate
Point estimate
Criterion
DJ / Dall >π
D1 >0, D2 >0, D3 >0
(3 region example)
when Dall>0
Properties
Focuses on Japan. Prob. of
meeting requirement
increases as % Japanese
Treats regions symmetrically.
Prob. of meeting requirement
reaches maximum when regions
have equal sample size
pts increases
Remaining
Issues
Value of π
Definition of region. Number of
regions.
Is Japan the only interesting
region? DJ>0 | Dall>0
Slides on methods 1,2 courtesy of Y. Song of Merck
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MLHW Consistency in Trends
Approach
• Overall sample size determined to
provide 80% or 90% power at 1sided 0.025 level
• Sample size in the smallest region
determined by ensuring the
probability of observing consistent
trends (in point estimates) across
all concerned regions is 80% (90%)
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Conditional Consistency
• Sample size in the smallest region needs to
ensure the probability of observing
consistent trends (in point estimates)
across all concerned regions is 80% (90%)
conditional on the overall treatment
effect is significant
• A less conservative approach: smaller sample
size requirement for the smallest region
• (Simple) Simulation is usually needed for
computation
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Summary
• When thinking of designing and
conducting a clinical trial, those
responsible for the conduct of the trial
must consider the ethical, clinical,
operational, regulatory and statistical
issues.
• This is never more true than when
planning, conducting, analyzing and
interpreting a trial that covers multiple
regions.
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The PhRMA Cross-Functional
Key Issues Membership:
Ibia, Ekopimo
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Ikeda, Kimitoshi
Novartis
Binkowitz, Bruce
Merck
Chen, Joshua
Merck
Saillot, Jean-Louis
Schering-Plough
Cindy, Girman
Merck
Tanaka, Yoko X1
Eli Lilly & Co
Talerico, Steven D
Schering-Plough
Menjoge, Shailendra
Boehringer Ingelheim
Fedorov, Valerie V
GlaxoSmithKline
Lee, Andy
Pfizer
Ouyang, S. Peter
Celgene
Field, Belinda
Pfizer
Ferreira, Irene
Amgen
Li, Gang
J&JPRD
Langley, Michael
Eli Lilly & Co
Houck, Tonya
Pfizer
Quan, Hui
Sanofi-Aventis
Schiff, Kenneth
Hoffman LaRoche
Rabbia, Michael
Roche
Battles, Mary Ann
Amgen
Ohishi, Masahiko
Merck
Luo, Xiaolong
Celgene
Gallo, Paul
Novartis
Merck
Thank You!
Questions?