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Dejun Tang, Novartis Pharma, China
PSI Webinar • July 16, 2015
Challenges and Opportunities on Multi-regional Clinical Trials Including Asian Countries
Outline
Introduction
Regulatory requirements
Opportunities and challenges• Regulatory
• Trial design
• Sample size
• Statistical analysis
• Operational
Summary and discussion
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities2
Introduction
Multiregional trials are widely conducted
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities3
Introduction
Multiregional trials are widely conducted
Increasing number of global trials including Asia
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities4
Introduction
Multiregional trials are widely conducted
Increasing number of global trials including Asia
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities5
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities6
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities7
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 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities8
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)
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities9
Challenge – Different Regulatory Focuses
Requirements are different from EU and US
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities10
Sample size, Mainland China population
Safety, dose, data quality
Standalone report
Challenge – Region or Country
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities11
Taiwan
Hong Kong
Challenge – Region or Country
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities12
Taiwan
Hong Kong
• What is a region?
Other Regulatory Challenges
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities13
Lack of detailed guidance documents
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities14
Lack of detailed guidance documents
No formal health authority consultation in many countries
Other Regulatory Challenges
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities15
Lack of detailed guidance documents
No formal health authority consultation in many countries
Inconsistency among reviewers and countries
Other Regulatory Challenges
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities16
Lack of detailed guidance documents
No formal health authority consultation in many countries
Inconsistency among reviewers and countries
Competency of independent external consultants
Other Regulatory Challenges
Study Design Challenges
Background
• Inclusion / exclusion criteria (TW)
• Sensitivity to diseases (symptoms, reactions)
• Epidemiology
17 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
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
• Sample size determination (will present more details later)
Data
• CRF design• Systems for
data collection
• Data standards
19 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities
Study Design Challenges
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities20
Sample Size Requirements in China
Provisions for Drug Registration (SFDA order NO. 28),
Chapter IV Application and Approval of New Drugs, Article 26:
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities21
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.
Simplified Version of Requirements in ChinaSample 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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities22
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)?
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities23
Newly Issued IMCT Guidance from CFDA
Does it mean that the things are getting changed for MRCTs in China?
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities24
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.
Challenges for Statistical Analysis
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities25
Subgroup analysis (small center / region)
Heterogeneity
Innovative methods
Multi-dimensional safety assessments
Meta-analysis
Trend Analysis in CFDA’s IMCT Guidance
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities26
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.
Trend Analysis in CFDA’s IMCT Guidance
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities27
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.
Trend Analysis in CFDA’s IMCT Guidance
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities28
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.
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities29
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities30
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities31
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities32
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities33
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities34
Other Operational Challenges
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
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities35
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!
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities36
Thank you for your attention!
| PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities37
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