Roadmap to Emerging Regions: Clinical Trials in
Developing Countries
International Clinical Trials Conference
New York, 26 February 2009
Written By:
Cristiana Spontoni
Squire, Sanders & Dempsey L.L.P.
Presented by:
Squire, Sanders & Dempsey L.L.P.
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.
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
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
• Africa
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…
Advantages and Challenges
Squire, Sanders & Dempsey L.L.P.
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
• Large patient populations with diseases of both
developed and developing countries (e.g.,
• Multi-ethnic/multiracial populations
• Wide spectrum for diseases
• Potential new markets (e.g., China)
• Competent/motivated PIs
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
– Different capabilities of CROs in the region
• Requires greater direct management efforts
• Many apparent similarities in challenges requiring
different responses
Challenges of Conducting These
Clinical Trials
– Trial Designs
– Regulatory Authorities and IRB/ECs
– Translation requirements
– Import/Export licenses
– Contracts/Clinical Trial Agreements
– Insurance requirements
– Intellectual property issues
– CRO Partnering
– Site/Investigator Identification
– Adherence to Good Clinical Practice
– Assuring the Ethical Conduct of the Trial
– Quality Control issues
– Cultural and infrastructure considerations
An ordinary day in an ordinary global trial
-- Some real life experiences --
Squire, Sanders & Dempsey L.L.P.
Practical Challenge: Control of
• “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.
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!
• 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
• Can the fridge be imported in country x?
Legal Challenge: Study in 21
Jurisdictions in the EMEA Region
• Can a CTA be entered by a non-local Sponsor?
- 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)
Legal Challenge 2: What’s the Right
• 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?
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
The Emerging European Jurisdictions and Their Rules
Squire, Sanders & Dempsey L.L.P.
The Rules in Emerging EU
• 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
The EU Directive on Clinical Trials
• Same rules (in principle!) across 27
• Commercial + Non-commercial trials
• Phases I,II,III,IV
• All trials except “non-interventional” trials
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
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
Commencement of Trials in the EU
Sponsor applies for EUDRACT number
Application to EC
Opinion of
Notification to CA
60 days max 1 x clock
stop for info.
60+30+90 days max
No Time Limit
CA no grounds
required only
in certain
Separate procedures
but can run in parallel
One opinion per MS
Conduct of a Trial – Reporting
• 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
• 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
IMPs – Investigational Medicinal
• 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
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
• You may have duty to inform FDA as well
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
• Conducted by CAs
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.
Inconsistent Approach/Interpretation
An example…
• Question: can sponsor be non-EU based?
• EU law answer: yes, if it appoints a EU-based
– Answer in BG, Czech Rep., Estonia, Latvia,
Lithuania, Malta, Romania, Slovakia, Slovenia: yes,
if it appoints an EU representative
– Answer in Cyprus: NO!
EU Rules on Trials Conducted in Third Countries
Squire, Sanders & Dempsey L.L.P.
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
Increased Regulatory Scrutiny
• A European Commission paper of 2002 indicated
– 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
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”
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
• Clear opportunities ahead of sponsors in
emerging regions
• Require strong central coordination and resource
• 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!
Cristiana Spontoni, Partner
T: 011.322.627.11.05
E: [email protected]
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
 11 sites
 1,500 valid subjects
 Field period from January to October 2007
 Research was financially supported by Philip Morris International
Why Slovenia?
 Small number of sites provided access to almost every
subject in the country who was suffering from the target
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
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
Overcoming the Challenges in Slovenia
 Challenge: Identifying and vetting the appropriate
 Identify the strength and weaknesses of potential vendors
 Understand how you will have to supplement for the potential
 Our approach:
 Vetted international and national CROs
 Decided on National/Local CRO
 Identified its strengths
 Worked with them to shore up their potential weaknesses
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
 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
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
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)
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
 Relatively lower CRO costs to conduct the trial
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
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
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
More than 18,000 medical records evaluated
1,533 valid subjects recruited
38 week field period
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
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
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
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
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
 Train and inform on “foreign” practices and international
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
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
Audit CRO, site and monitors
GCP training before start of the study
Close monitoring during the study
What is your plan B?
Carlos F. Peza
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.

Roadmap to Emerging Regions: Clinical Trials in …