Transcript Qualification of clinical sites

Challenges and Opportunities on
Multi-regional Clinical Trials Including
Asian Countries
Dejun Tang, Novartis Pharma, China
PSI Webinar • July 16, 2015
Outline
 Introduction
 Regulatory requirements
 Opportunities and challenges
• Regulatory
• Trial design
• Sample size
• Statistical analysis
• Operational
 Summary and discussion
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Introduction
 Multiregional trials are widely conducted
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Introduction
 Multiregional trials are widely conducted
 Increasing number of global trials including Asia
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Introduction
 Multiregional trials are widely conducted
 Increasing number of global trials including Asia
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Introduction
 Multiregional trials are widely conducted
 Increasing number of global trials including Asia
 However, there are many challenges on trial design and
execution for such trials
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Relevant Guidance in ICH E5 Q & A
 The multiregional trial would have to satisfy requirements
of the region where the application is to be filed
 A multiregional study should be designed with sufficient
number of subjects so that there is adequate power to
have a reasonable likelihood of showing an effect in each
region of interest
 It is critical to provide efficacy and safety results by region
 Although Japan is the only ICH member in Asia, it is a
good practice to follow ICH-GCP when conducting clinical
trials including Asian countries
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Proposed ICH E17
 This topic was endorsed by ICH in June 2014
• It is proposed to provide guidance on general principles of
planning/designing Multi-Regional Clinical Trial (MRCT)
 Statement: Regulatory agencies are currently facing some
challenges in evaluating data from MRCTs for drug
approval and it was deemed necessary to developed a
harmonized international Guideline to promote conducting
MRCT appropriately, especially focusing on scientific
issues in planning/designing MRCTs. This new Guideline
will complement the guidance on MRCTs provided in ICH
E5(R1) Guideline and facilitate MRCT data acceptance by
multiple regulatory agencies.
 Expected timeline: 2017
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
CFDA IMCT Guidance
 CFDA Guidance on International Multi-center Clinical
Trials (IMCT)
• Published on January 30, 2015
• Tentative implemented on March 1, 2015
 In general, most of its items are in-line with ICH and
scientifically sound
 Some items are controversial
• Sample size requirements
• Trend analysis for
- Asian vs non-Asian
- Chinese vs non-Chinese (actually China vs non-China)
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| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Challenge – Different Regulatory Focuses
 Requirements are different from EU and US
Sample size, Mainland
China population
Safety, dose, data
quality
Standalone report
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Challenge – Region or Country
Taiwan
Hong Kong
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Challenge – Region or Country
• What is a
region?
Taiwan
Hong Kong
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Other Regulatory Challenges
Lack of detailed guidance
documents
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Other Regulatory Challenges
Lack of detailed guidance
documents
No formal health authority
consultation in many countries
14 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Other Regulatory Challenges
Lack of detailed guidance
documents
No formal health authority
consultation in many countries
Inconsistency among reviewers and
countries
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Other Regulatory Challenges
Lack of detailed guidance
documents
No formal health authority
consultation in many countries
Inconsistency among reviewers and
countries
Competency of independent external
consultants
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Study Design Challenges
Background
• Inclusion /
exclusion
criteria (TW)
• Sensitivity to
diseases
(symptoms,
reactions)
• Epidemiology
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Study Design Challenges
Background
• Inclusion /
exclusion
criteria (TW)
• Sensitivity to
diseases
(symptoms,
reactions)
• Epidemiology
Enrollment
• Sample size
determination
(will present
more details
later)
18 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Study Design Challenges
Background
• Inclusion /
exclusion
criteria (TW)
• Sensitivity to
diseases
(symptoms,
reactions)
• Epidemiology
Enrollment
Data
• Sample size
determination
(will present
more details
later)
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• CRF design
• Systems for
data
collection
• Data
standards
Sample Size Consideration
 For MRCTs, how to allocate the sample size for each
region/country should be carefully considered
 Currently there is no agreed rules on sample size
allocation for regions/countries
 Here we present the sample size requirements from
China and its possible impacts
 PMDA in Japan has some recommendations on sample
size based on efficacy and we won’t discuss here
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Sample Size Requirements in China
Provisions for Drug Registration (SFDA order NO. 28),
Chapter IV Application and Approval of New Drugs, Article 26:
The number of cases in the clinical study of a
drug should be decided in accordance with
the objective of the clinical trials and shall
meet both the statistical requirements and the
minimal cases required by this Regulation for
a clinical study.
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Simplified Version of Requirements in China
Sample size for Phase III trials
 Chemical products
• New drug – 300
• Marketed drug – 100 pairs
 Biological products
• 300 treated
 Both have to meet statistical requirements as well
 Our interpretations
• Statistical requirements likely for efficacy evaluations
• Minimum number requirements likely from safety considerations
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Discussions on Sample Size in China
For global trials including China as a country
 It could lead to a huge overall sample size to keep
comparable same sizes cross the regions
 Or it may have very unbalanced sample sizes for
different regions due to predominate Chinese patients
 It could make this type of trials less attractive, or even
not feasible to conduct
 Shall we take intrinsic and extrinsic ethnic factors into
the consideration (or at least in Asia)?
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Newly Issued IMCT Guidance from CFDA
Sample size should be reasonably distributed among
different countries/centers. In addition to satisfying the
statistics requirements of the trial, sample size is also
required to satisfy the needs for subgroup evaluation
with fully consideration of the epidemiological
characteristics of disease, the representativeness of
the sample selected and other relevant factors for
appropriate patients numbers distribution among
different countries and regions.
 Does it mean that the things are getting changed for
MRCTs in China?
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Challenges for Statistical Analysis
Subgroup analysis (small center / region)
Heterogeneity
Innovative methods
Multi-dimensional safety assessments
Meta-analysis
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Trend Analysis in CFDA’s IMCT Guidance
Statistical method to evaluate if there is a trend consistency
between a subgroup result and the overall results should be
established in advance. The difference between subgroups
should be compared for primary and key second endpoints.
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Trend Analysis in CFDA’s IMCT Guidance
Statistical method to evaluate if there is a trend consistency
between a subgroup result and the overall results should be
established in advance. The difference between subgroups
should be compared for primary and key second endpoints.
For safety signals in the overall population, consistency
tests among subgroups (country/center) should be done.
The reason, severity and acceptability should be analyzed
for any differences found.
27 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Trend Analysis in CFDA’s IMCT Guidance
Statistical method to evaluate if there is a trend consistency
between a subgroup result and the overall results should be
established in advance. The difference between subgroups
should be compared for primary and key second endpoints.
For safety signals in the overall population, consistency
tests among subgroups (country/center) should be done.
The reason, severity and acceptability should be analyzed
for any differences found.
Comparison between Chinese vs non-Chinese and Asian vs
non-Asian should be done if using data for China registration
application.
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Other Operational Challenges
 Long time for CTA approval in China
 Languages and translations of documents
 Qualification of clinical sites
 Data integrity
• Different understanding for data quality
 Quality control and compliance
 DMC / Interim analysis
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Other Operational Challenges
 Long time for CTA approval in China
 Languages and translations of documents
 Qualification of clinical sites
 Data integrity
• Different understanding for data quality
 Quality control and compliance
 DMC / Interim analysis
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Other Operational Challenges
 Long time for CTA approval in China
 Languages and translations of documents
 Qualification of clinical sites
 Data integrity
• Different understanding for data quality
 Quality control and compliance
 DMC / Interim analysis
31 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Other Operational Challenges
 Long time for CTA approval in China
 Languages and translations of documents
 Qualification of clinical sites
 Data integrity
• Different understanding for data quality
 Quality control and compliance
 DMC / Interim analysis
32 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Other Operational Challenges
 Long time for CTA approval in China
 Languages and translations of documents
 Qualification of clinical sites
 Data integrity
• Different understanding for data quality
 Quality control and compliance
 DMC / Interim analysis
33 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Other Operational Challenges
 Long time for CTA approval in China
 Languages and translations of documents
 Qualification of clinical sites
 Data integrity
• Different understanding for data quality
 Quality control and compliance
 DMC / Interim analysis
34 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Opportunities
 Health authority collaborations
 Scientific-based sample size determination
 Enhanced drug development environment
• Government / Academia / Industry
 Maximizing the use of advanced technology
• Drug research, IT, Statistics
 Knowledge and experience sharing
 “Big data” implication
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Summary and Discussion
 Many challenges to conduct clinical trials including
Asian countries
 Careful consideration and planning is essential
 Sample size for each region/country is one of the most
controversial issues
 Many questions have been addressed, but a lot more
are still remaining
 More collaborations among all parties involved would
make progress faster!
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