Roadmap to Emerging Regions: Clinical Trials in Developing
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Transcript Roadmap to Emerging Regions: Clinical Trials in Developing
Roadmap to Emerging Regions: Clinical Trials in
Developing Countries
International Clinical Trials Conference
New York, 26 February 2009
Written By:
Cristiana Spontoni
Partner
Squire, Sanders & Dempsey L.L.P.
Brussels
Presented by:
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
Michael A. Swit, Esq.
Vice President
The Weinberg Group Inc.
San Diego, California
US and EU Data on Trials in Emerging Regions
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
The Global Landscape
69,175 clinical trials are being carried out in 161 countries1
Majority of trials
are conducted in
the U.S. and
Western Europe
Increasingly being
conducted in Central &
Eastern Europe, Latin
America and Asia
Trials increasingly outsourced to Clinical Research Organizations
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Globalization of Trials: European Data
According to the EMEA, around one quarter of
patients recruited in pivotal trials submitted in
MAAs to EMEA between 2005 and 2008 were
recruited in:
• Latin America
• Asia
• CIS
• Africa
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Recurrent Themes in Global Trials
• Good central coordination but flexibility to local
requirements/habits/culture (eg, CTA templates)
• Sound use of resources: CRO, PIs, Sites: how
much should be delegated and how much should
be kept under control (eg, negotiating/entering
CTAs, filing for regulatory approvals)
• All the more true in emerging economies…
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Advantages and Challenges
Squire, Sanders & Dempsey L.L.P.
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Advantages Of Emerging Economies
• Limited costs: drugs, hospitalisation, travel and
other general expenses, basic support services
• Higher number of patients, especially naive
patients (i.e., patients who never received a
treatment)
• Large patient populations with diseases of both
developed and developing countries (e.g.,
HIV/AIDS)
• Multi-ethnic/multiracial populations
• Wide spectrum for diseases
• Potential new markets (e.g., China)
• Competent/motivated PIs
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Clinical Trials in Emerging Regions
• Conducting trials in emerging regions poses a
number of challenges:
– Different treatments and standard of care
– Differing levels of clinical research experience and
sophistication
– Different capabilities of CROs in the region
• Requires greater direct management efforts
• Many apparent similarities in challenges requiring
different responses
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Challenges of Conducting These
Clinical Trials
•
Regulatory
– Trial Designs
– Regulatory Authorities and IRB/ECs
– Translation requirements
– Import/Export licenses
•
Legal
– Contracts/Clinical Trial Agreements
– Insurance requirements
– Intellectual property issues
•
Other
– CRO Partnering
– Site/Investigator Identification
– Adherence to Good Clinical Practice
– Assuring the Ethical Conduct of the Trial
– Quality Control issues
– Cultural and infrastructure considerations
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An ordinary day in an ordinary global trial
-- Some real life experiences --
Squire, Sanders & Dempsey L.L.P.
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Practical Challenge: Control of
Temperature
• “Control of storage and transportation
temperatures is essential in
maintaining the quality of medicines
and in helping to protect patients from
sub-standard or ineffective medicines
that may result from inadequate
control” (J. Taylor, Quality and Standards Manager, MHRA)
• Increased risks for biotech products,
vaccines, blood products, semi-solids,
chemically unstable at certain
temperatures, and of course, study drugs.
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Let’s Get a Fridge!
• Sponsor wants to perform a study at site x
• Site x does not have a way of keeping Study Drug at
appropriate controlled temperature
• Let’s get a fridge there!
OK BUT…
• Can sponsor sell/donate the fridge?
– To whom? Under what circumstances? Do we need a
written contract? Do we need to get prior authorizations?
From whom?
• What if Site is a public hospital?
• What if we are talking about very expensive medical
devices?
• Can the fridge be imported in country x?
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Legal Challenge: Study in 21
Jurisdictions in the EMEA Region
• Can a CTA be entered by a non-local Sponsor?
Answer:
- Yes, BUT -- in one jurisdiction, still need to go
through local entity or mediator
- Yes BUT -- in Israel, sites often will object to
contracting with a non-Israeli entity
- Yes BUT -- certain regulatory procedures will
have to be performed by local entities either
because it is required by law (e.g., Ukraine) or
because -- that’s the way we do things
here (Middle East)
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Legal Challenge 2: What’s the Right
Price?
• Sponsor sells x vials of Study Drug to a non EU
European country
• Custom authorities google name of Study Drug
and find its price in the US: 10,000 USD
• Custom authorities apply a custom duty
considering that value of the Study Drug
• Should Sponsor pay?
• What’s the practice in other countries?
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Ethical Challenge: Unusable Data
• Violations result in unusable data: in requesting
marketing authorisation, a company submits a file
to the EMEA, which includes the description of
the trial performed. In examining the file, the
EMEA evaluates the respect of GCP, the granting
of informed consent and the approval by ECs.
– Illustrates just how important compliance with GCP
will be
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The Emerging European Jurisdictions and Their Rules
Squire, Sanders & Dempsey L.L.P.
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The Rules in Emerging EU
Jurisdictions
• Estonia, Hungary, Latvia, Lithuania, Czech
Republic, Slovakia, Slovenia, Poland, Bulgaria,
Romania, Malta, Cyprus: now all EU countries
• Directive 2001/20/EC on clinical trials applies:
- GCP standards
- Uniform regulatory requirements
- BUT: local challenges still remain
• Highly educated and competent investigators
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The EU Directive on Clinical Trials
• Same rules (in principle!) across 27
jurisdictions
• Commercial + Non-commercial trials
• Phases I,II,III,IV
• All trials except “non-interventional” trials
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The Sponsor
• Industry, Government, Research Council,
University, …
• Does not need to be EU-based but must appoint
EU-based representative that bears civil and
criminal liability as EU-based sponsors
• Sponsor can delegate (NOT transfer!) sponsor
responsibilities to third parties (e.g., CROs)
BUT sponsor bears ultimate responsibility
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Protection of Trial Subjects
• Informed consent
• Special consideration for children and
incapacitated adults
• Data protection:
– Directive 95/46/EC regulates strictly any
processing or transfer of data outside the EU
– Medical data qualifies as “sensitive”
– The US is considered not a “safe place” for the
purpose of data protection
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Commencement of Trials in the EU
Sponsor applies for EUDRACT number
Application to EC
Favorable
Opinion of
EC
Notification to CA
•
60 days max 1 x clock
stop for info.
•
60+30+90 days max
•
No Time Limit
(exception)
CA no grounds
for
non-acceptance
Explicit
authorization
required only
in certain
cases
Separate procedures
but can run in parallel
One opinion per MS
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Conduct of a Trial – Reporting
Obligations
• Substantial amendments to be notified to ECs and
CAs (35 days max)
• Safety measures adopted to protect safety of subjects
• Notification of trial end (90 days or 15 if early
termination)
• Notification of SUSARs
– fatal or life threatening: 7 days
– other SUSARs: 15 days
– annual reporting
• Notification of Serious Adverse Events
Guidance on reporting and standard forms
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IMPs – Investigational Medicinal
Products
• Manufacture/importation authorisation
• Authorisation holder must have QP at disposal:
check compliance with EU GMPs or standards
that are “at least equivalent”
• IMPs must be supplied free of charge
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Suspension of Trials - Infringements
• CAs can suspend or prohibit trials if:
– conditions for granting authorisation for trial
conduct are not met anymore
– doubts about safety/scientific validity
• Must consult with sponsor/investigator except in
cases of “imminent risk”
• CA will inform other CAs, EMEA and European
Commission
• You may have duty to inform FDA as well
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Inspections on GCP/GMP Compliance
• Before, during or after completion of a trial
• As part of marketing authorisation process or
follow-up to it
• At: trial sites, IMP manufacturing site, any
laboratory used in the trial, or at sponsor’s
premises
• Conducted by CAs
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GCP Violations = Unusable Data
•
Drugs reviewed by the EMEA can be granted a marketing
authorization only if they are based on clinical trials
conducted in compliance with the Declaration of Helsinki
•
In requesting marketing authorisation, a company submits a
file to the EMEA, which includes the description of the trial
performed. In examining the file, the EMEA evaluates the
respect of GCP, the granting of informed consent and the
approval by ECs.
•
When problems are identified, namely regarding ethical
aspects, the EMEA can advise the Commission to refuse the
marketing authorisation or can advise the withdrawal of
marketing authorisation already delivered by Member States.
This information is also made public.
•
However, the EMEA intervention happens after the clinical
trial is finalised and presented in the file and not before or
during the trial.
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Inconsistent Approach/Interpretation
An example…
• Question: can sponsor be non-EU based?
• EU law answer: yes, if it appoints a EU-based
representative
– Answer in BG, Czech Rep., Estonia, Latvia,
Lithuania, Malta, Romania, Slovakia, Slovenia: yes,
if it appoints an EU representative
– Answer in Cyprus: NO!
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EU Rules on Trials Conducted in Third Countries
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EU Rules on Trials in Third Countries
• Financial penalties apply in case of failure to
comply with clinical trials requirements
• Sites in third countries can be inspected by the
competent authorities of Member States. The
EMEA has a system of GCP inspections in third
countries since 2006 which has led to an
increasing number of inspections in Latin
America, Africa and Asia
• Inspections concentrate primarily on: informed
consent and appropriate EC (IRB) approvals
• EU assisting on GCP capacity
building/inspections a number of countries - in
last EMEA GCP Inspectors’ WG
workprogramme: Croatia, Macedonia, Turkey
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Increased Regulatory Scrutiny
• A European Commission paper of 2002 indicated
that:
– The regulatory framework for clinical trials is
expected to adapt to the globalization.
– the budget and number of international/national
GCP inspectors is expected to increase
– more information on all these clinical trials should
be available through an international database
– the key role of IRBs and of capacity building in this
area
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Increased Regulatory Scrutiny …
• Opinion 17 of the European group on ethics
in science and new technologies to the
European Commission: “Ethical aspects of
clinical research in developing countries”
(February 2003)
• 2006-2008: Series of Parliamentary
Questions on trials in poor countries
• On 5 December, the EMEA issued a strategy
paper on: “Acceptance of clinical trials
conducted in third countries for evaluation in
Marketing Authorisations”
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EMEA Action Plan: Watch This Space!
Three-year-s action plan includes:
• Clarify application of ethical standards
• Consider issues driving recruitment of subjects in
third countries
• Consider tools to respond to non-compliance/step
up GCP inspections
• Training of EMEA/sponsors/experts
• Increased transparency: EPAR should include a
clear description of the assessment of ethical
standards of trials in emerging economies
• Promote capacity building also through EU
funding instruments
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Wrap-Up
• Clear opportunities ahead of sponsors in
emerging regions
• Require strong central coordination and resource
management
• But, also must understand need for flexibility in
approach and understanding of local specificities
• Beware of compliance pitfalls no matter where
you conduct your trial!
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Thanks!!
Cristiana Spontoni, Partner
T: 011.322.627.11.05
E: [email protected]
www.ssd.com
Roadmap to Emerging Regions:
Sponsor Experiences in Central Europe and Asia
Carlos F. Peza
February 26, 2009
Recent Experiences in Emerging Regions
Phase IV trial in Oncology conducted in
5 countries (France, Germany, Greece, Italy, Slovenia)
250 sites
8,448 valid subjects (3,719 valid controls)
Field period from November 2005 to October 2008
Cross-Sectional Survey on Tobacco Prevalence in Indonesia
Inclusion criteria similar to control inclusion criteria in European
study
11 sites
1,500 valid subjects
Field period from January to October 2007
Research was financially supported by Philip Morris International
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Slovenia
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Why Slovenia?
Small number of sites provided access to almost every
subject in the country who was suffering from the target
condition
Regulatory Agency and Central Ethics Committee are
among the most efficient in Europe
Highly educated and motivated Investigators
Local CROs charged competitive fees for their services
Relatively few challenges for study start up and conduct
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Specifics of Slovenian Situation
Small country, well reachable
Centralized healthcare system with developed referral network
Approximately 100 clinical trials are performed annually
Laws and regulations for conducting clinical trials are based on
EU Clinical Trials Directive (2001/20/EC)
Agency for Medicinal Products and Medical Devices (JAZMP) is
the competent authority for clinical trial authorization
EC approval given at the national level by the National Medical
Ethics Committee
National Cancer Registry
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Overcoming the Challenges in Slovenia
Challenge: Identifying and vetting the appropriate
CRO
Identify the strength and weaknesses of potential vendors
Understand how you will have to supplement for the potential
weaknesses
Our approach:
Vetted international and national CROs
Decided on National/Local CRO
Identified its strengths
Worked with them to shore up their potential weaknesses
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Overcoming the Challenges in Slovenia
Challenge: Obtaining ethics approval for a controversially
funded study
Our approach:
Recruited Principal Investigator wisely
Provided him with the information needed to fully understand and promote
the study
Became invested in the study
Good reputation, leadership skills, and willing to act as a key advocate of the
study
Set the stage with Ethics Committee
Identified, recruited and developed good working relationship with Key
Opinion Leaders in order to understand local considerations
Understood the potential concerns of the members
Addressed these during the submission
Gained support of stakeholders and who demonstrated this support to EC
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Overcoming the Challenges in Slovenia
Challenge: Achieving potential subject recruitment
Our approach:
Developed Principal Investigator and sub-investigators as key
promoters and coordinators
Coordination and promoting activities of different sites
Coordinating and promoting study within site
Developed investigator network where subjects were identified
in the periphery and “treated” in the central location
Motivated site team
Actively recognize the role of each site member
CRA partnership with sites
Kept site team informed and involv
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Slovenian Participation in the Study
1 Local/National CRO
16 Sites
1 Country Principal Investigator, 24
investigators/subinvestigators, more than 20 study nurses
Comparably high recruitment rate
First patient in: April 2007
1,391 valid subjects (721 valid controls)
16% of total study subjects recruited within one year
Recruitment rate stable over the year (no holiday gaps)
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Our Experience in Slovenia
Excellent experience in Slovenia
High subject recruitment rate
Qualified and motivated medical professionals
Uniformed regulatory issues as in Western Europe
EU Clinical Trials Directive, ICH and GCP already
implemented
Relatively lower CRO costs to conduct the trial
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Indonesia
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Indonesian Smoking Prevalence Study
Originally intended to conduct a series of studies to
understand the relative risks of smoking for a several
disease end point
Planned to conduct several case-control studies for each of
the disease endpoints
In planning the studies, it was determined that there did
not exist valid epidemiological data to be able to guide
the design of the studies
A pilot study of patients in hospitals to be used in the
case-control studies was conducted
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Specifics of the Indonesian Situation
Large Country
Very few trials being conducted, but numbers are growing.
Government and investigators receptive to industry knowledge
GCP implemented into national laws and guidelines governing
clinical trials
ECs to be established at institutional, regional/provincial, and
national levels according to need
National Agency for Drug and Food Control is competent
authority for clinical trial authorization
Lack of population-based registries
Hospital based-cancer registries in 13 cities
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Indonesian Smoking Prevalence Study
Cross-sectional study on the smoking prevalence of Indonesian
male hospital patients
Study performed to regulated standards of a clinical trial
11 hospital sites in Jakarta, Solo, Surabaya, Padang
1 Principal Investigator, 22 investigators/subinvestigators, 60
CRA/interviewers
More than 18,000 medical records evaluated
1,533 valid subjects recruited
38 week field period
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Overcoming the Challenges in Indonesia
Challenge: Designing a clinical trial to account for the
specifics of the region
Cultural issues
Inclusion/Exclusion Criteria
Trial Length and approval timings
Infrastructure issues
Investigator and Staff Training
Our approach:
Trial designed to account:
Differences in medical practice (disease diagnosis, investigator-patient relationship)
Translation of study/regulatory documents
Validation of measurement scales (patient questionnaire)
Understood need to apply “partnership approach” to build
supportive relationships
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Overcoming the Challenges in Indonesia
Challenge: Identifying and vetting the appropriate
CRO partner
No local CROs
Only a handful of Regional CROs working in Indonesia
Our approach:
Decided on one regional CRO
Worked on setting clear expectations on how the study should
be conducted
Task distribution (assigning of responsibility)
Which SOPs were going to be used
Increased communication
Thorough training of CRO staff and co-monitoring visits
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Overcoming the Challenges in Indonesia
Challenge: Investigators and Staff experience
Lack of clinical trial experience
Gaps between concept and reality in the field
Our Approach:
Incorporation of GCP, ethical practices, clinical management training into
Investigator Meetings, CRA/interviewer training, monitor training
Special emphasis on informed consent process
The training methods paralleled the expected performance of the
study team
Site based CRAs conducting SDVs during patient recruitment process
Increased site monitoring
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Overcoming the Challenges in Indonesia
Challenge: Local infrastructure and sites constraints
Lack computerized central patient database systems
Lack of secure storage space
Difficult internet and phone access
Understaffing
Our approach:
Site auditing prior to contract signature
Financial investments made into resources and personnel
Regular monitoring
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Overcoming the Challenges in Indonesia
Challenge: Cultural Complexities
Hierarchical social structure impacts recruitment
Investigator
Site
Patient
Our approach:
Build trust and cultivate relationships
Principal Investigator
Key Opinion leaders
Involve hospital administration in site selection and start up
activities
Train and inform on “foreign” practices and international
expectations
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Our Experience in Indonesia
Untapped potential
Large patient pool
Many potential sites
Government and Investigators very eager to bring more
clinical research into the country
Need for capacity building
Limited infrastructure
Continued need to help local authorities adjust their
regulatory environment to allow high quality clinical
research
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Approaches to Consider
Advance preparation and strategy development
Thorough knowledge of local processes and operations
Design trial with an implementable protocol
Upfront dialogue and partnership-oriented approaches
Identify a CRO that is suitable for you
Know your limitations and how much you are willing to concede to your
vendors
Audit CRO, site and monitors
GCP training before start of the study
Close monitoring during the study
What is your plan B?
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Questions?
Carlos F. Peza
Consultant
The Weinberg Group Inc.
One Embarcadero, Suite 500
San Francisco, CA 94111
P +1 415.293.1031
[email protected]
About Your Speaker
Carlos Peza is a Consultant at The Weinberg Group. He recently served as
Project Manager for a large international Phase IV oncology trial. The study was
carried out in more than 250 sites in five European countries and enrolled more
than 8,500 valid subjects.
Mr. Peza also managed a cross-sectional study on smoking prevalence in
Indonesia. The study field period took place over a period of 38 weeks in 2007
in 11 sites in Indonesia. More than 18,600 medical records were reviewed and
valid data was collected from more than 1,500 subjects.
His main tasks in these studies were interacting with international, national, and
regional CROs to assure comprehensive management of the studies. In addition,
he managed the development and implementation of the data collection
instruments and all interview-related project components, including the
development of a computerized questionnaire instrument for the European
study, translation of the data collection instruments into the appropriate country
languages, as well as the training and monitoring of interviewers.
Through his experience at The Weinberg Group, Mr. Peza has developed a
significant knowledge of protocol design, questionnaire design, data collection
methods, survey quality, coverage error, and interviewer effects.