Transcript Slide 1

Globalization of Clinical Trials –
Promise and Reality
Zvi Ladin, Ph.D.
Principal
Boston MedTech Advisors
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Outline
• Ethical principles
• Historical perspective
• Registration requirements
• FDA acceptance of foreign clinical data
• Global trends in conduct of clinical trials
• Global opportunities
• Global challenges
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Ethics (Example #1)
• New ‘block buster’ drug being
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developed
• BIG profits?
Need to quickly test it
Some questions regarding
side effects
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Could be serious
Need large number of
patients for testing
Too costly (and too risky?) to
study in developed countries
• Solution
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Go to Africa
Paint as ‘humanitarian effort’
• Voilà – a ‘blockbuster’ movie
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In the News (Example #2)
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Federal Indictment
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Synthes, Medical Device
Maker, Accused of Improper
Marketing
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A medical device maker, Synthes Inc., and
four of its executives were indicted Tuesday
on federal charges that they improperly
promoted a bone filler for purposes not
approved by the Food and Drug
Administration, including encouraging its
use in what prosecutors called
“unauthorized” human trials.
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Norian - $28M
Synthes (parent company) - $8M
Executives indicted:
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By BARRY MEIER
Published: June 16, 2009
Criminal misdemeanor
Shipping unapproved medical device
Possible prison sentence of 1 year
Possible fines:
Michael B Huggins, President, Synthes
Spinal Division
Thomas E Higgins, Senior VP, Global
Strategy
Richard E Bohner, VP Operations
John J Walsh, Regulatory Affairs Executive
Unauthorized trial of using bone filler in
spinal procedures
Patient population:
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~200 patients treated
3 patients died
“They put their profits ahead of responsible business practices and the truth,”
Michael L. Levy, the United States attorney, said in a statement.
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Understanding the Regulator
• Global ethical / legal framework
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Nuremberg trials
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Helsinki Declaration
• Local implementation
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Culture
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Language
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Infrastructure
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Economic pressures
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Protection and Improvement of Public Health
Information Supply
Information Demand
• Clear new drugs /
• Treat large populations
technologies
expeditiously
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• Low incidence
Quick studies
• High severity
• Limited populations
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Adverse events
• Lead to….
• Limited duration
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Complications
Limited Information
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Public outcry
• Adverse events
(severity, incidence)
Where patients come first
VIOXX® (rofecoxib)
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Developing a Legal Framework
• 1947 – Nuremberg Code
• 1964 – Declaration of Helsinki adopted – World Medical Assoc
USA
Europe
• 1966, NEJM – Henry Beecher, MD
• 1960’s – Patient consent – FDC
• 1970’s – IRB review of clinical
• Maurice Pappworth, MD
protocols
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1972 – NIH established OPRR (Office
for Protection from Research Risks)
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Risks and benefits of research
• 1981 – FDA requires written
patient consent
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1967 – Human Guinea
Pigs
• 1960’s – Patient consent
• 1970’s – MDD
• Competent Authorities
• Notified Bodies
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1998 Office of Inspector General (OIG) Report –
Clinical Research’s Shifting Environment
• Funding – from public to private
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NIH
industry
• Nature – from single site to multi-center
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Limited information to local IRB
• Size and numbers
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1998 OIG Report – Revamping the IRB
• Overwhelmed Local IRB
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Time and expertise limiting review
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New ethical issues (e.g. genetic screening)
• Evaluating IRB Effectiveness
• Conflict of Interest Inside the IRB
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Part of the organization that gains from research
• Limited Training of IRB Members and
Researchers
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2004 – Clinical Trial Outcry (or Example #3)
• GlaxoSmithKline (GSK) Paroxetine treatment of depression in
children
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Attorney General of NY sued company
Allegation
• Company selectively published positive partial results
• Off-label promotion of drug by company
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Settlement
• GSK published all study results on Web
• 150 Scientists and organizations signed the Ottawa statement
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Mandatory trial registration
• International Committee of Medical Journal Editors (ICJME) of 12
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leading medical journals – no publication of unregistered studies
Ministerial Summit on Health Research in Mexico
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WHO
52 Countries
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Global Goals
Only 25% of Americans think that
the pharmaceutical industry is
doing a “good job” – similar to
reputation of….tobacco industry
[Godlee, F. BMJ 2005(330):1224, 1229]
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Restoring Public Trust
Patient
• Full disclosure
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Procedure
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Alternatives
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Risk / Benefits
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Beneficiaries
• Financial
interests
Regulators
• Study approval
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National regulatory
authority
Local committee
• IRB
• Helsinki committee
• Complete and
comprehensive
information submittal
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Community
• Clinical
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Disclosure
Conferences
Publications
• Public
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Registries
Patient groups
Related studies
Device safety
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Clinical Trial Registration
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US FDA requirement – ClinicalTrials.gov
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Established under FDAMA (1997)
First version – February 29, 2000
Initially mandated for only drug treatment
of life threatening diseases
Expanded to include all US trials
October 2003 – 1000th study registered
Registration for non-life threatening
treatments – RECOMMENDED!
June 2009
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WHO International Registry
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50,000 daily visitors
40 million monthly ‘hits’
Established 2004
Date
US
Registration
WHO
Registration
2003
(October)
1000
0
2004
13,000
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2006 (June)
>40,000
12,000
2009
(June 18)
74,734
50 states
167 countries
> 72,000
(June 2008)
Enforcement
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FDA (limited to life-threatening
treatments)
WHO (none)
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WHO Clinical Trial Registry
• http://www.who.int/ictrp/en/
• Major components of trial including:
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Contact information
• Sponsor / source of support
• Countries
• Interventions
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Key inclusion / exclusion criteria
Study type
Sample size
Recruitment status
Outcomes
• No requirement to report results
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Time-To-Market
New technologies must demonstrate
enhanced outcomes and cost
effectiveness to be covered.
Cost
Effectiveness
Outcomes
Outcomes
Efficacy
Efficacy
Efficacy
Safety
Safety
Safety
1980’s
1990’s
2000’s
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Time-To-Market Acceptance
Time-To-’Market Acceptance’ is Increasing
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FDA Acceptance of Foreign Data (IND)
• Final Rule Published (effective October 27, 2008)
• 21 CFR Part 312
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Non-IND foreign clinical studies
• Previous Requirement
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Adherence to ethical principles stated in 1989 Helsinki
Declaration (World Medical Association)
• Current Requirement – GCP
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Includes review and approval by independent ethical
committee (IEC)
Non-compliant studies
• Have to be submitted
• Cannot be accepted as support
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FDA Acceptance of Foreign Data (PMA)
• 21 Section 814.15 (last amended December 2, 1986)
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Valid data
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Conformance with Helsinki Declaration or local
laws and regulations
• Whichever accords greater protection to the human
subjects
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If data is sole basis for submission:
• Data applicable to US population and medical practice
• Competent clinical investigators
• Data can be audited and validated by FDA
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Economic Drivers
Increase regulation
Move studies to:
• Increase
• Less regulated countries
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Costs
• Faster study initiation
• Clinical environment
• Lower regulatory
overhead
• Patient recruitment
Time
• Longer
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Time
• Investigators
• Monitors
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Effort
• Less expensive cost of
living
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Lower costs
• However…..
• Higher
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Remember Murphy*!
• Poor infrastructure
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Clinical complications
• Simple problems could become significant, severe and….expensive
• Poor regulatory infrastructure
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May limit acceptability of data
• Poor study control
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May jeopardize collection of data
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May disqualify patients
• Hence….
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Regulatory submission denial
*Anything that can go wrong…will!
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Global Trends in Clinical Trials Conduct
Observation (Cause?)
Observation (Effect?)
• 1980’s – increased
• Migration of clinical trials
regulation in US (FDA)
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to Europe
FDA acceptance of
European clinical data
• European Union Clinical
• Migration of clinical trials
Trial Directive (2001)
to India, Russia and China
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Tassignon JP. The globalization of clinical trials.
Applied Clinical Trials (2006)
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Density of Actively Recruiting Clinical Sites of
Biopharmaceutical Clinical Trials Worldwide (4/2007)
Ref: Trends in the globalization of clinical trials, Fabio A. Thiers, Anthony J. Sinskey & Ernst R. Berndt
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
US Registry
Density is in per country inhabitant (in millions; based on 2005 population censuses); darker orange/red
denotes a higher density. The trial density and average relative annual growth rate in percent is shown for
selected countries. The countries in grey had no actively recruiting biopharmaceutical clinical trial sites as of
12 April 2007.
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Shifting Environment –
Regional Distribution of Trial Types
North America
[%]
Trial Type
Western Europe
[%]
Oceania
[%]
4/2007
4/2008
4/2007
4/2008
4/2007
4/2008
Early
62.4
23.9
21.1
18.4
4.2
24.6
Confirmatory
55.6
61.0
23.9
59.9
3.8
65.0
PostMarketing
52.7
15.2
33.0
21.7
2.3
10.3
Trial Type
Eastern Europe
[%]
Latin America
[%]
Asia
[%]
(4/2007 to 4/2008)
Middle East
[%]
increased
compliance in
2008?
Africa
[%]
4/2007 4/2007 4/2007 4/2008 4/2007 4/2008 4/2007 4/2008 4/2007 4/2008
Early
6.7
21.4
2.5
70.8
1.7
12.2
0.7
17.3
0.7
17.9
Confirmatory
7.4
67.5
3.9
13.4
3.6
72.3
0.9
65.4
0.9
67.3
PostMarketing
4.6
11.2
2.8
9.9
2.9
15.5
0.9
17.4
0.8
14.9
Ref: Trends in the globalization of clinical trials, Fabio A. Thiers, Anthony J. Sinskey & Ernst R. Berndt
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
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Economic-Based Distribution of Clinical Trials
Global Distribution of
Clinical Trials
Latin America
(WHO Database – 10/2008)
• Streamlined laws make Latin
America attractive to
sponsors
• October 2008 – 20% growth
in the number of international
clinical trials over four years
• 3.1% of all active trials
in low-income countries
• 6.8% of all active trials
in low – middle-income
countries
• 90.6% of all active trials
Country
Open Trials
Brazil
323
in OECD countries
Mexico
292
Colombia
107
(Organization of Economic CoOperation and Development)
Ghersi D and Pang t. The Lancet; (2008) 372(9649):1531-1532
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Global Trends
• Harmonization
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Global Harmonization Task Force (GHTF)
• Harmonize medical device regulations world-wide
• Founding members (1992)
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Regulatory authorities from Australia, Canada, EU, Japan and
US
• Five task forces, including one focused on clinical
investigations
• EU (March 2009) – European requirement for proof of
clinical effectiveness (in addition to safety)
• Global acceptance (and requirement) of GCP
compliance
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New FDA rule
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Global Opportunities
• Potential Advantages of Foreign Clinical Studies
(advertisement by an Indian CRO)
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Diverse population
• Genetically
• Culturally
• Socio-economically
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Large numbers of target patients
• Quicker studies
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Regulatory approval
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Medical infrastructure
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Language
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Costs
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Global Challenges – I
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Regulatory Approval
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Economic / social progress leads to increased regulation
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India – consideration of registration requirement linked to regulatory oversight
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India + China – Association of journal editors established policies on trial registration
Medical Infrastructure
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Addressing adverse events
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Access to healthcare system
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Access to specialists
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Addressing complications
Training investigators
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Global Challenges – II
• Language
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Translation
• Communication with patients, investigators
Validated questionnaires (e.g. QOL)
• Culture
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Patient – clinician relationship
Collecting medical history (family, personal)
Medical tests
• Geography
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Time
Distance
• Support
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Global Limitations
• Review clinical plan with target regulators
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In trial country
In target market
• Applicability of Clinical Data
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Will target market accept trial data?
• Regulators?
• Clinical market?
Ethics
and
Profitability
• Validity of ‘Pooling’ Data
• Cost Information
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Will it have any bearing on target market?
• Cost – Effectiveness Analysis
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Is reimbursement an issue?
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Ethical Dilemmas (to ponder)
• Patient Enrollment
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Monetary incentive
Clinician / patient trust (pressure?)
Full disclosure (risks, benefits, incentives)
• Study Conduct
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Payment to investigators
Patient access to healthcare
Information dissemination to patients
Protocol requirements (tests, travel)
• Post-study
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Availability of treatment
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Contact
Zvi Ladin, Ph.D
Principal
Boston MedTech Advisors, Inc.
990 Washington Street
Dedham, MA 02026
Ph 781.407.0900
Fax 781.407.0901
[email protected]
www.bmtadvisors.com
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