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Roadmap to Emerging Regions: Clinical Trials in Developing Countries

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Roadmap to Emerging Regions: Clinical Trials in Developing Countries International Clinical Trials Conference New York, 26 February 2009 Written By: – PowerPoint PPT presentation

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Title: Roadmap to Emerging Regions: Clinical Trials in Developing Countries


1
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 Michael A. Swit,
Esq. Vice President The Weinberg Group Inc. San
Diego, California
2
US and EU Data on Trials in Emerging Regions
3
The Global Landscape
69,175 clinical trials are being carried out in
161 countries1
  • Increasingly being conducted in Central Eastern
    Europe, Latin America and Asia

Majority of trials are conducted in the U.S. and
Western Europe
Trials increasingly outsourced to Clinical
Research Organizations
4
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

5
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

6
Advantages and Challenges
7
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

8
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

9
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

10
An ordinary day in an ordinary global trial--
Some real life experiences --
11
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.

12
Lets 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
  • Lets 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?

13
(No Transcript)
14
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 -- thats the way we do things here 
    (Middle East)?

15
Legal Challenge 2 Whats 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?
  • Whats the practice in other countries?

16
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

17
The Emerging European Jurisdictions and Their
Rules
18
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

19
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

20
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

21
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

22
Commencement of Trials in the EU
Sponsor applies for EUDRACT number
Application to EC
Notification to CA
CA no grounds for non-acceptance Explicit
authorization required only in certain cases
Favorable Opinion of EC
  • 60 days max 1 x clock stop for info.
  • 603090 days max
  • No Time Limit (exception)

Separate procedures but can run in parallel
One opinion per MS
23
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

24
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

25
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

26
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 sponsors
    premises
  • Conducted by CAs

27
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.

28
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!

29
EU Rules on Trials Conducted in Third Countries
30
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

31
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

32
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

33
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

34
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!

35
Thanks!!
  • Cristiana Spontoni, Partner
  • T 011.322.627.11.05 
  • E cspontoni_at_ssd.com

36
Roadmap to Emerging Regions Sponsor Experiences
in Central Europe and AsiaCarlos F.
PezaFebruary 26, 2009
37
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

38
Slovenia
39
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

40
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

41
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

42
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

43
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

44
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)

45
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

46
Indonesia
47
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

48
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

49
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/subinve
    stigators, 60 CRA/interviewers
  • More than 18,000 medical records evaluated
  • 1,533 valid subjects recruited
  • 38 week field period

50
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

51
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

52
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

53
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

54
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

55
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

56
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?

57
Questions?
  • Carlos F. Peza
  • Consultant
  • The Weinberg Group Inc.
  • One Embarcadero, Suite 500
  • San Francisco, CA 94111
  • P 1 415.293.1031
  • carlos.peza_at_weinberggroup.com

58
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.
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