Jiyao Wang, MD, MSc, AGAF

Zhong Shan Hospital, Fudan University

Center of EBM, Fudan University

How Clinical Research Promoted by Health Industries Can Contribute to Improve The

Quality of Care? The Experience in China

Bench To Bedside : Interdependence

Bench To Bedside

The 3T’s

Dougherty, D. et al. JAMA 2008;299:2319-2321

The Innovation Interface •Basic/clinical science •Technology focus •Public health

•Policy/ Culture

Category of Clinical Research For product development

Discovery

Phase III

Phase II

Phase I

Preclinical

Toxicology

Time(years) Regulatory Filing

Phase IV

Launched by pharmaceutical company

Launched by investigators

Efficacy & safety

in selected population Effectiveness & safety

in real clinical practice

Long term

Clinical outcome

What, Exactly, is IMCT ?

• Include a larger number of participants

• Different geographic locations

• The possibility of inclusion of a wider range of population groups with different

– genetic

– environmental

– and ethnic or cultural backgrounds

Current Status of IMCT

• Globalization of clinical trials is a reality

• Clinical trials across multiple regions of the world have become common practice

• China is an increasingly important source of patients to test new drugs – As of April 28, 2015, there were 18,9109 clinical

trials globally

– Up to 6040 in mainland China

Source: www.clinicaltrial.gov Search date: 2015-4-28

Current status of clinical trials Source: www.clinicaltrial.gov

Search date: 2015-4-28

18,9109

Source: www.clinicaltrial.gov Search date: 2015-4-28

Registry on clinicaltrial.gov

Open studies of IMCT

Mainland 6040 527

Hong Kong 1059 46

Taiwan 3917 201

Current status of IMCT in China

Type Ongoing multi-center clinical trials in our hospital

Phase I 3

Phase II 8

Phase III 24

Phase IV 13

IMCT 25

Sponsor: Large pharmaceutical companies in Europe and America

What we are doing

Clinical Practice Research

Ethical

Simultaneous Global Development

IMCT , Areas of Impact

Regulatory

• Key opinion leaders

• Principle investigators

• Doctors

• Hospital teams

Impact of Clinical Research Promoted by Health Industries

Key opinion leader

• Organize professional activities

• Write and promote guidelines

• Practice new evidence in the specialty

• Become the primary investigators for the clinical trials

• Impact on the quality of care of medical practice

– The standard of care

–Healthcare system

Benefits of participation for the key opinion leader in the country for his/her expertise

development in his/her speciality

• More access to acquire resources

– More patients

– More facilities, both from hospitals and pharmacies

• Newer information to be caught

• More experience in the design, management and evaluation for the whole protocol

• Be familiar with GCPs

• Know the responsibilities as the “PI”

• Establish excellent communication with external sites

• Establish excellent communication with international colleagues

• Build an international research reputation

Benefits of participation : principle investigators

• As a local PI, I have participated a lot of clinical trials (phase II and III) lunched by pharmaceutical companies (such as Searl company, Astrazeneca, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Roch, etc) since 1992.

• I am familiar with GCP, established SOPs and became member of local ethics committee.

• I have been invited to participate the international multicenter clinical trials organized by famous experts in the world.

• I have organized multicenter clinical trial within China in order to get more evidence for improving quality of health care.

1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The

Netherlands; 2Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China; 3Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China; 4Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China; 5Cerrahpasa Medical Faculty, Istanbul, Turkey; 6National Institute of Infectious Disease, Bucharest, Romania; 7University of Ankara, Medical School, Ankara, Turkey; 8Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; 9Department of Gastroenterology, Fundeni Cinical Institute, Bucharest, Romania; 10Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland; 11Department of Internal Medicine, Fundeni Cinical Institute, Bucharest, Romania; 12Department of Gastroenterology, Yuksek Ihsitas Hospital, Ankara, Turkey; 13Department of Infectious Diseases, Silesian Medical University, Katowice, Poland; 14Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands; and 15Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada.

• (AASLD 2014 presentation and published in Hepatology 2015;61:1512-1522)

Genetic study of peginterferon treatment in chronic hepatitis B

To identify genetic polymorphisms associated with response to interferon therapy in chronic Hepatitis B patients

Need to conduct clinical trial according to Good Clinical Practice(GCP) Standards

•GCP is a standard for the design, conduct, monitoring, analyses, and reporting of clinical trials

•The practice of GCP were standard in all Member Sites, before 2002, only a minority of hospital in China had previously were familiar with the obligations of the different parties of GCP

•IMCT introduced GCP principles to ensure that trials are conducted in accordance with high standards of ethics and science

Benefits of participation: Doctors (1)

Drive the Quality care of patients •IMCT helps doctors ensure continuous quality improvement of diseases treatment by aligning clinical care with evidence-based guidelines •More access to acquire resources

– More patients – More facilities, both from hospitals and pharmacies

•Newer information to be caught •More experience in the design, management and evaluation for the whole protocol

Benefits of participation: Doctors (2)

• Access to the most up-to-date research and scientific publications

• Professional education opportunities, such as workshops and webinars

• Clinical tools and resources • Patient education resources • A competitive advantage in the healthcare marketplace • National and local recognition for hospital team program

achievement • Quality improvement, broaden knowledge of short- and

long-term benefits and risks • Established ethical committee in Hospital level

Benefits of participation: the hospital team

Improve China clinical trial design and research level(1)

• Investigator training

• Plan in the protocol : SOPs and Manuals, including Global Clinical SOPs, data handling SOPs, operational SOPs

• Adaptive/flexible designs setting

IMCT Areas of Impact：Research

Improve China clinical trial design and research level(2) • Quality Assurance • eCRF • Electronic Data Capture (for use in clinical trials) • Data management and data quality • power estimation / sample size • Methods for subgroup analysis; Randomization issues / stratification • How to describe/present data

•Somewhat Structured

•SOPs not available

•Less Experienced

•Well organized and Structured

•SOPs and Processes in place

•Experienced team

The quality of clinical research changed:

2003-2015

IMCT Areas of Impact：Ethical

• Informed Consent

• Local Ethics Committees, IRB’s

• Integrity of research conduct

• Data collection/privacy

Pros and Cons for patients in terms of participation of IMCT

• Pros

– Patients will be benefited from free new effective medications already on the market in Europe and America

– Patients will be benefited from tailored follow-up , and will decrease cost

– More convenient for a clinic (saving time, good doctors and nurses)

– Cost saving

• Cons

– Information not balanced, misunderstood

– Under-treatment if control arm is not well designed, like placebo

– Safety concern for the very new treatments

– Impact on activities of daily living?

– Some are worried about privacy, asynchronous communication can be more efficient.

• 1) access to treatment 2) improved care when participating to a clinical trial but 3) exposure to safety issues or to no treatement (in case of placebo controlled trial) : how does the

On 12/1/2002, ‘Drug Registration Regulation’ was issued by CFDA, the first regulation for approval of an international multi-center trial, then , international multi-center clinical trial showed an increasing trend in China. On 30/1/2015 , China Food and Drug Administration(CFDA) issued ‘International multi-center clinical trial Guideline’ as a framework for good management in trials of medicines in China

IMCT Areas of Impact: Regulatory

Encountered problems of IMCT in China today

Compared with developed countries, there is a gap

• Less IMCT: For example, Cancer Patients, enrolled in one of a clinical trial

– >90% , USA

– About 9% , China

• Among the ongoing IMCL in mainland China, the majority IMCL are industry-sponsored trial ( IST), while investigator-initiated clinical trial ( IIT) were viewed as of higher academic value

Types of Ongoing IMCT

• Therapeutic : >90% • Prevention

• Early detection/diagnostic

• Disease Management

• Correlative

• Population-based studies:

• Epidemiological

• Observational

• Quality-of-life

Rare disease research, diagnosis or treatment compared to marketed drugs and other new uses

Areas not covered

Need MORE Investigator-initiated clinical trial

A report including combined data from approx. 1140

studies shows that industry-sponsored clinical trials

are significantly more likely to reach conclusions in

favor of the industry vs non-industry studies- possibly

publication bias or selection of an inappropriate

comparator to the drug being evaluated

J. E. Bekelman, Y. Li and C. P. Gross J. Am. Med. Assoc. 289, 454–465; 2003

We has done much to promote national multi-center clinical trials • Investigator Initiated Trials (IITs)

• Investigator Initiated Studies (IISs)

• Investigator Sponsored Trials (ISTs)

• Investigator Initiated Research (IIR)

• Non Registration trials (NRTs)

• Non Sponsored Trials

What are Today’s Challenges?

• Each participating site needs to be visited numerous times, making this a large, and time-consuming administrative activity, not only for the monitor, but also for the physicians involved. Monitoring is associated with high costs

Investigator-initiated China regional multi-center clinical trial in China

• With Limited funds:

– How to protect the enthusiasm and commitment of the physicians and attract them to involve.

– Time-consuming, in some cases even to the extent that they declared not to participate in these kind of studies again in the future.

How to improve

• A well designed protocol – Background to evaluate the feasibility of the new

treatment and control arm, based on the best clinical practice guideline

– Ethical committee fully consider the safety for all the participants

– Mostly understanding and fully consent to attend by the participants and their family

– Reimbursement should be prepared and easily got accessed

• Independent supports from large pharmaceutical companies

Quality Assurement

• Team building including investigators, nurses, CRC(clinical research coordinator), CRA(clinical research associate),statistician

• Timely audit for the projects, both inside hospital and outside hospital

• supplements including office, network, and storage space

• Central study pharmacy inside hospital is promoting

Conflict of Interest (COI)

• COI issues are real

– Focus on financial only

– Tone: non – collaborative

– Unintended consequences – effecting collaborative efforts

• Debate needs broader view: goal - improve public health

• Alternative position

– Include all types of conflicts

– Improve public health is a primary interest

– Checks and balances in place

– Collaboration/ cooperation/ learning /teaching

• Clinical trial is a good clinical practice

• Only the medical team with good practice can start a good clinical trial

• Increasing realization that institutions can’t go it alone

• Collaborative efforts in complex systems, Sharing the rewards

• Focus on unmet medical need/public health value

Future : Integration/Collaboration

unknown Known Action

Knowing-doing gap Knowledge gap

The bridge between bench and bed

Improve quality of care Clinical Research

Thank you!

Trials are short; real-clinical practice has no time limit