dejun tang, novartis pharma, china psi webinar july 16, 2015 challenges and opportunities on...

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


Introduction


Increasing number of global trials including Asia


Introduction




Introduction



However, there are many challenges on trial design and execution for such trials


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


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)


Challenge – Different Regulatory Focuses

Requirements are different from EU and US


Sample size, Mainland China population

Safety, dose, data quality

Standalone report

Challenge – Region or Country


Taiwan

Hong Kong

Challenge – Region or Country


Taiwan

Hong Kong

• What is a region?

Other Regulatory Challenges


Lack of detailed guidance documents



No formal health authority consultation in many countries





Inconsistency among reviewers and countries





Inconsistency among reviewers and countries

Competency of independent external consultants


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



• Epidemiology

Enrollment

• Sample size determination (will present more details later)



Background



• Epidemiology

Enrollment

• Sample size determination (will present more details later)

Data

• 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


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.

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


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)?


Newly Issued IMCT Guidance from CFDA

Does it mean that the things are getting changed for MRCTs in China?


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


Subgroup analysis (small center / region)

Heterogeneity

Innovative methods

Multi-dimensional safety assessments

Meta-analysis

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.




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





Data integrity






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


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!


Thank you for your attention!


dejun tang, novartis pharma, china psi webinar july 16, 2015 challenges and opportunities on...

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