Clinical Trials Conduct and Protocol Compliance in Asia

Clinical Trials Conduct and Protocol Compliance in Asia

James M. Pusey MD, MBA

New Zealander

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“‟Pharma Valley”

Shanghai, Cincinnati & Philadelphia

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James Pusey Profile

o Serial Global & China CEO

o Eternal Optimist

o No Sales Pitch Today!!

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® ®

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Globalization & Population Trends

Has Asia Pacific taken a higher share of pivotal Phase II & III

Global Clinical Trials?

Registered 1572 Investigators*

6

Country 2009 2013 % Change

Argentina 364 329 -10%

Brazil 371 343 -8%

China 186 177 -5%

UK 875 964 +10%

Hungary 439 488 +11%

Japan 521 658 +26%

Ukraine 466 514 +10%

Circa 60% of 1572 Investigators in USA, & 20% in Europe (no

change)

Several researchers report declines in Asia/Pacific Phase II & III trials

“Globalization” of Clinical Trials has not yet matched population trends

* Tufts Center for the Study of Drug Development (CSDD)

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China Case Study

• Healthcare Priorities

• Conducting China Trials

• Improving Data Quality

Healthcare Priorities

Where we are today, Clinical Trials and Disease Prevalence in China

Healthcare Priorities

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• 30% of World’s smokers live in

China

• 60% of male Chinese doctors

smoke

Smoker Presence

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Non-Small Cell Lung Cancer

o High smoking rates

o +ve EGFR rates higher vs ROW

o Only 50% of patients have routine EGFR

o Late presentations

o Many competing trials

o Clinics have administrative overload

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Country Prevalence # Pts million Pediatric thousands

USA 6.4% 17.0 5,000

Australia 6.5% 1.3 430

NZ 6.6% 0.3 85

China 2.1 – ??6.4% 27- ??83 9,000- ??27,000

Thailand 6.5% 4.2 1,400

S Korea 6.4% 3.1 1,000

Prevalence is converging due to ↑ spirometry & education; KOLs

& ICF management is key

Prevalence of Asthma

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Causes of Death 1. Cancer2. Stroke3. Heart Attacks4. COPD5. Trauma & Poison

Ministry of Health Priorities 2007 -2022

1. Hypertension2. Diabetes 3. Heart disease 4. Malignant tumor5. Chronic respiratory disease

Government COPD Initiatives1. Risk factors

• Smoking cessation• Reduction of air pollution

2. Early Intervention with Rx3. Development of effective and

affordable medication

China Deaths & COPD Example

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Conducting China Trials

Protocol Compliance in China

Hospital Admissions Area EU

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Hospital Admissions Area - China

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Resourcing Sites

o Trial funding

Access difficulties …. Institutions receive $$ not clinic

Considered income & not resource building

o Site staff availability & “dedication”

Dedicated research personnel rare

Motivation highly variable due to workload

Inexperience in clinical trials

High workload

• > 70 patients per clinician per session

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Site Number (2 Year study) 20 sites in Mainland China

FTE during start up & closeout 0.5 per site

FTE during recruitment 1.0 per site

Service Cost $108,108

Product Manager Cost $144,963

Pass through cost $4,425

Total Cost for 100% of sites $2,395,623

Total Cost for 50% of sites $1,270,293

Cost of Providing CRCs in China (from SMO)

o More cost effective than Study Nurses or Managers

o Managed independently of Trial Staff

o Can focus on larger site databases >1,000 pts

o Accelerate study start-up

o Increase recruitment (randomization) significantly

o Improved SD administration & data quality

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Protocol Compliance in China

o Protocol design

Healthcare priorities are different to West

Clinical care ≠ to US & Europe clinical care

Different screening & Rx approaches

o Healthcare culture at sites

Inter-disciplinary & Institutional care constraints

Resourcing at sites

Inexperience in clinical trials: rural > urban

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Large cities e.g. Beijing,

Shanghai, Guangzhou,

Wuhan, and Hong Kong

17 cities have the best

centers including HKG

Many Cities > 20 Million

Strategically place trial

centers to cover best sites

for recruitment and data

quality (i.e., urban areas)

Circa 2,500 CFDA certified

sites including HKG

Deciding on a Footprint in China: Urban Trial Centers

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Success Factors & Site Compliance

o Address clinical practice during protocol development (KOL Steering Committee) Take into account healthcare priorities

o Establish close CRA & independent CRC relationships at sites (ensuring protocol compliance) Very high site visit frequency Pro-active site issue identification & resolution Constant education of site staff (SDV, GCP, ICH

etc) Providing resource (CRCs from independent SMO)

• Improves patient recruitment

• Quality of source documentation

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Latest Approaches to Improve Data

Quality

Risk Based Monitoring improves

Quality, but does not directly lower

cost

Risk

Protocol

• TA

• Safety profile

• Endpoints

• Population

• Vendors

Dynamic

• Turnover

• Recruitment

• SAE

• Deviations

• Site errors

• Queries

• Entry lag

• Misconduct

• Fraud

Site

• Experience

• CRA

seniority

• Location

• CRCs

• Focus

Risk Assessment and Plan Development

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Centralized Data Analytics

• Individual patient data

• Across patient data

• Across site & study data

Central Monitoring

Site Management

Associate (SMA)

Study Site

Project Team

• On-going Risk Assessment & Iterative Operational Strategy

On-Site Monitoring (CRA)

• SDV

• Patient & Site triggers & alerts24

Central Monitoring

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Regulatory &

Safety

• Regulatory Documents

• Status of IRB/EC

• Informed Consents

• CTA Initial/ Amendments

• Safety Events Reporting

Site Performance

• Training

• Motivation

• Activation

• Availability

• Retention

• Identification of new staff

• Metrics Analysis (data entry lag, query resolution)

Enrollment

• Rates

• Eligibility

• Randomize

• IMP Inventory, dispensation

Data

• EDC System

• Data entry review

• Scales completion

• Sample collection and shipment

• Adjudication Documents

Site Management Associate (SMA)Central Monitoring Activities

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Central Monitoring DashboardExample

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China is the largest patient event HealthCare

Market in the World

Case Study Summary

o Global systems & processes are increasing in China

o Investigator & site staff sophistication is increasing

But inadequate resources threaten data quality

o Technical & therapeutic expertise

Use of risk based monitoring techniques to spot sites at risk

o Administrative resources at site: CRCs & quality control staff

Improves SDV and supports sites at risk

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Takeaways for Asia Clinical Trials

o Protocol design

Healthcare priorities are different to West

Clinical care ≠ to US & Europe clinical care

Different screening & Rx approaches

o Healthcare culture at sites

Inter-disciplinary & institutional care constraints

Resourcing at sites

Inexperience in clinical trials: Rural > Urban

o Immense clinical trial markets remain

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谢谢Thank You