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Clinical Trials in Low Resource Settings

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Title: Clinical Trials in Low Resource Settings


1
Clinical Trials in Low Resource Settings
  • Ian Magrath

www.inctr.org
2
Outline
Questions
Propositions
Addressing the Problems Role of Clinical Trials
Problems faced in developing countries
Infrastructure knowledge transfer
Who pays? sponsorships
Conclusions
INCTR Strategies
3
Propositions -1
Interventions that are evidence-based are
important everywhere Where resources are
limited, wasted time, money and expertise, or
actual harm to people, have particularly
significant socioeconomic implications
4
Propositions - 2
In spite of existing obstacles, the conduct of
Phase II-IV clinical trials in developing
countries is essential, and would improve
standards of care whilst creating a foundation of
data on which continuing improvements in the
outcome of health interventions can occur i.e.,
sustainability
5
Propositions - 3
Drug development is not the highest priority in
low resource settings, and phase I clinical
trials initiated by international pharmaceutical
companies should address the additional ethical
issues that are created (benefit to study
population)
6
Propositions - 4
Evidence collected in high income countries is
directed towards their own problems in the
context of their populations, environments and
available resources. Not all of this can be
assumed to be generalizable and there will be
inevitable gaps
7
Questions - 1
What are the advantages and disadvantages of
clinical research versus the use of clinical
guidelines in improving care (early detection and
treatment) in developing countries?
8
Questions - 2
How can clinical research be promoted and the
necessary infrastructure built in countries with
limited resources?
9
The Problem a Vicious Cycle
Many Patients With Advanced Disease and Many
Potential Patients
High Mortality Rate
Limited Resources
POOR ACCESS
Unmet need for terminal care
LOW CAPACITY
10
Quantitative Limitations
  • Limited numbers of cancer specialists (but some
    centers of excellence) number of patients
    overwhelming
  • Few specialized facilities limitations in drugs
    and equipment (availability, cost and
    maintenance)
  • Public and academic salaries low many seek some
    or full-time private practice, often out of
    necessity
  • Bright students go or sent for training overseas
    many are permanently lost

11
Qualitative Limitations
  • Cancer often not considered by primary health
    personnel, or fatalistic attitude inhibits
    referral
  • Training often of poor quality and ceases after
    medical school (little or no continuing
    education)
  • Medicine often eminence-based, not evidence-based
  • Minimal discipline in implementation of
    interventions since limited supervision and
    accountability no incentive to follow up or
    record outcome
  • Nursing, pharmacy, blood banks etc. often
    inadequate and non-medical staff generally
    ineffectively utilized (no specialist nurses, for
    example)

12
Factors Limiting Access
  • Poverty and ignorance delay seeking help
  • Primary (and secondary) care suboptimal lack of
    focus and knowledge about cancer leads to
    misdiagnosis and misinformation
  • Few centers average journey long (cost)
  • Result late diagnosis advanced disease

13
Limitations in Resources for Cancer Therapy
  • In Dec 2004, there were approximately 2500
    radiotherapy centers and 3700 machines for cancer
    therapy (enough for 1.85 million patients per
    year compared to 3 million who need it.
    Maldistribution gt20 countries have none. (DIRAC)
  • In 2000 the USA accounted for 60 of anti-cancer
    drug sales, Europe, 19 and Japan, 16. The rest
    of the world, 5. (IMS)

14
Leakage of Talent to the USA
30 of Mexicans with PhDs are in the USA
All India Institute of Medical Science 56 of
medical graduates emigrated from 1956-80, 49 in
the 1990s
The 1million Indians in the USA account for 0.1
of India's population but the equivalent of 10
of India's total income
15
Nurses who joined the UK register from countries
from which recruitment is banned (2004-5)
Source Annual Report, 2005, Nursing and
Midwifery Council, UK
  • South Africa 933
  • Nigeria 466
  • West Indies 352
  • Zimbabwe 311
  • Ghana 272
  • Pakistan 205
  • Zambia 162
  • Mauritius 102
  • Kenya 99
  • Botswana 91
  • Nepal 73
  • Swaziland 69
  • Malawi 52
  • Sri Lanka 47
  • Lesotho 43
  • Sierra Leone 24

Initial Registrants 33,257 Overseas (non-EU)
11,477 India 3,690 Philippines 2,521 Nigeria
466
Total 3301
16
The Solution Build Capacity
Education Screening
Prevention
Lower Mortality Rate
Fewer Patients with More Limited Disease and
Fewer Potential Patients
Less Limited Resources
Less need and greater capacity for terminal care
GREATER CAPACITY
IMPROVED ACCESS
17
Capacity Building
  • Improve quality of existing human, and to the
    extent possible, material resources
  • This will require training, at least of the
    national and regional leaders in scientific
    medicine
  • Expand by training more graduates in health
    related disciplines and creating centers for
    specialist training
  • Lessen loss to academic medicine by improving
    professional and economic circumstances outside
    assistance essential

18
Why do Clinical Trials in Low Resource Settings?
  1. An ability to conduct research is essential to
    the development of a high quality, sustainable,
    health system
  2. Scientifically trained physicians are more able
    to learn from existing sources of information
    the literature, web-based information, meetings
    etc.

19
Why do Clinical Trials in Low Resource Settings?
  1. To accumulate data that allows the efficacy and
    cost-benefit ratio (efficiency) of any feasible
    interventions in the natural history of a disease
    to be assessed
  2. Because evidence is context sensitive
    therefore, what applies in one population or
    environment does not necessarily apply in another

20
Why do Clinical Trials in Low Resource Settings?
  1. The questions (hypotheses) that need to be
    addressed to improve care in low resource
    settings frequently differ from those that are
    given highest priority in high resource settings
  2. More than half of all cancer is in developing
    countries this represents a valuable, but
    largely untapped source of potentially unique
    knowledge of value to all

21
In Addition, Clinical Trials Can
  • Simultaneously provide effective prevention or
    treatment
  • Provide a focus for training and education
  • Improve clinical care quality assurance needs
    (monitoring and audits) detect problems, provide
    supervision instill good practices
  • Provide improved professional circumstances and
    new career opportunities with added incentives
    to improve results

22
Phase II/III Clinical Trials can Improve Care
  • Clinical research demands high standards of care
    and expertise in the disease in question
  • Accurate diagnosis
  • Appropriate treatment (or early detection) design
  • Discipline in adhering to protocol good
    supportive care
  • Documentation of results (follow up essential)
  • Quality assurance of care and data
  • Studies must be designed with available resources
    and study populations in mind
  • Performing clinical trials will help to identify
    infrastructural inadequacies, stimulate the
    search for solutions and increase precision and
    discipline
  • Ethical principles must be adhered to

23
Examples of Clinical Trials that Result in
Improved Care
  • Comparison of relative toxicity, cost or
    scheduling of standard regimens optimization
    studies
  • Identification of risk factors in a local
    context, or characterization of disease or its
    epidemiology (generally one arm studies)
  • Early detection studies, particularly using
    direct visualization techniques and simple
    treatment strategies of early lesions

24
Value of Inter-Institutional Clinical Projects
  • Improved access of patients and professionals to
    the local (few) and international experts
  • Increased communication and hence learning among
    all participants (community of practice)
  • Greater acceptability of quality control
    potentially healthy competition among
    participating institutions
  • May identify problems that are specific to
    populations, regions or institutions

25
High Priority Clinical Trials in Low Resource
Settings
  • Questions of national or local importance
  • Treatment of high priority diseases high
    incidence with a known effective intervention
    (may be uncommon in the affluent world (e.g.
    hepatoma, bilharzial bladder cancer) Preventable
    or curable
  • Study of toxicity, efficacy and practicality of
    therapies developed in high income countries
  • Impact of resource sparing modifications
    (detection methods, e.g., VIA, VILI, altered drug
    regimens or X-ray fields, simpler surgery)
  • Standard therapies associated with evaluation of
    risk factors, characterization or epidemiology

26
Developing Necessary Infrastructure
  • Will nearly always require international
    collaboration ideally, direct participation
  • To provide the necessary propositional and
    procedural knowledge
  • To provide training and education
  • To monitor conformity to protocol, quality of
    data and confirm results of the intervention
  • To encourage inter-departmental and
    inter-institutional collaboration

27
Benefits to All
  • Translational and clinical research will be more
    rapidly accomplished if a larger number of
    patients were accessible (applies particularly to
    uncommon cancers or stages of cancer)
  • Developing countries provide unique opportunities
    for understanding the epidemiology and
    pathogenesis of cancer and exploring the efficacy
    of low cost or resource sparing interventions
  • Research in developing countries may be relevant
    to minority populations in affluent countries

28
Obstacles to Research in Developing Countries
  • Little or no research training of physicians
    promotion generally based on seniority
  • Protocols often viewed as guidelines which can be
    modified at will
  • Limited research infrastructure
  • Concept of data quality rudimentary
  • Published data often unreliable
  • Lack of professional or financial rewards lack
    of incentive to perform research
  • Can be seen as limiting freedom
  • Follow up often poor

29
Knowledge Transfer The Standard Model
  • High level meetings in developing countries (with
    predominantly Western faculty)
  • Utility depends on content, but audience
    unselected and no outcome measures
  • Training in Western institutions
  • Benefits the West more than low and middle income
    countries, although has created some excellent
    leaders in developing countries
  • Provision of written guidelines
  • Essential, assuming based on relevant evidence,
    but limited or no assessment of use or value

30
Communicating Information
Sender information put in language that
recipient understands
Recipient must have sufficient experience for
information to be meaningful
Information of no value unless acted upon
31
Standard Model Guidelines
  • Many organizations develop best practice
    guidelines
  • May be created with minimal knowledge of local
    resources and populations (feasibility?)
  • Based on information derived, for the most part,
    from high income countries (applicability?)
  • Read only by a small fraction of practitioners
    and not necessarily used as written (utility?)
  • Usually no measures of use, performance or
    outcome (i.e. evidence of utility)
  • May be used by non-specialists with the potential
    for serious harm

32
Applicability of Guidelines
  • The pattern of disease differs incidence and
    stage distribution (different priorities re
    cancers to be studied)
  • Cancer biology may differ e.g., bilharzial
    associated bladder cancer (different approaches
    to prevention or treatment), genetic lesions may
    differ
  • Resources and facilities differ differences in
    staff expertise, and availability or access to
    products
  • Patients differ - illiteracy and poverty impact
    upon adherence to treatment, genetic and
    environmental factors (pharmacogenetics,
    comorbidities, malnutrition, hygiene) may change
    outcome

33
Clinical Trials Actively Build Capacity
  • Training/continuing education can be accomplished
    in the context of clinical trials for health
    professionals
  • Infrastructure is developed, with additional
    staff, improved use of IT etc. that should impact
    on non-research clinical care
  • Trials foster collaboration and communication,
    both nationally and internationally
  • Quality assurance provides an assessment of
    effectiveness of educational methods

34
Comparison of Guidelines and Clinical Trials
Research
Guidelines
  • Designed for a specific population in the context
    of available resource
  • Usually entails collaboration and mutual learning
  • Associated with quality assurance and ethical
    review
  • Identifies deficiencies
  • Associated with outcome measures
  • Generates new information
  • Based on available evidence usually from a
    high resource context
  • Rarely entails collaboration or learning
  • Rarely any quality control and no ethical review
  • No identification of deficiencies
  • No outcome measures
  • No new information

35
Dialogue the Importance of Mutual Understanding
The Sage, the person of wisdom, for whom
knowledge is sacred is the fount of knowledge
Sage
  1. LISTEN Chinese character includes those for
    heart, eye and ear
  2. LEADS TO deeper understanding and a sense of
    shared meaning

Listen
Dialogue from Greek dia across, logos word,
36
Advantages and Opportunities re Cooperative
Trials in LRS
  • Improved access of patients and professionals to
    the limited number of experts involved in conduct
    of the trial
  • Increased communication and hence learning among
    all participants
  • Instills good habits of clinical care, and a
    research perspective in junior staff that extends
    beyond the trial in question
  • Provides a local data base that can be built upon
    a step towards sustainability

37
Cooperative Groups in Low Resource Settings -
Foreign
  • Can join existing groups based in affluent
    countries but
  • Trials will not address locally important
    problems
  • Patients may not be comparable to those entered
    in a western setting
  • Limited opportunities to play a role in
    identifying or designing studies
  • Resources provided to group members in the
    wealthy country may not be available
  • Regulatory issues can create problems

38
Cooperative Groups in Low Resource Settings -
Local
  • Can develop own groups but
  • May lack appropriate leadership
  • Inter-institutional rivalries may exist
  • Entrenched views of senior members of
    institutions (lack of academic mindset) may limit
    studies that can be done
  • Will usually have limited infrastructure and
    ability to monitor quality
  • Therefore will usually require outside assistance

39
Cooperative Groups in Low Resource Settings
  • Most cooperative groups in developing countries
    are in more advanced countries such as Latin
    America
  • GATLA, GATHEM for hematological neoplasms
  • Some relationships between US or European Groups
    have been established
  • Collaboration with external organizations or
    institutions who support the development of local
    groups increasing (e.g., INCTR)

40
Who Pays for Research?
  • The consumer especially when combined with
    appropriate therapy
  • Out-of-pocket expenses, private or national
    insurance
  • The institution where research is supported by
    grants, and/or institution is academic
    (education)
  • Charitable organizations/NGOs which provide
    funds for disciplined patient treatment,
    professional education or research (not for
    individuals)
  • Government or Governmental Organizations
    particularly when health/economic (closely
    linked) or international political benefit may
    result from the research or training
  • The Pharmaceutical industry drug development

41
Pharma Sponsored Trials
  • If international pharmaceutical sponsor,
    ultimately directed to increased drug sales
    (initial incentives, e.g., donations of drugs or
    funds may be valuable)
  • Post-trial local price and availability are
    issues that should be addressed in drug
    development trials
  • Is it sufficient for only high income patients in
    the country to benefit?
  • Need to avoid charges of exploitation esp.
    phase I
  • Can help to improve infrastructure and provide
    additional revenue for hospitals
  • Patients can benefit if trials address important
    local problems as well as special ethical
    considerations

42
Local Pharma Industry
  • Local pharmaceutical industries are growing
  • Local drugs much less expensive Indian drugs
    now used widely in Asia and Africa government
    subsidies
  • Increasing local development pipe-line with
    increased local needs for clinical trials,
    including phase I studies
  • May push international pharmaceutical companies
    out of the huge market in developing countries
    (at least for generics) 55 or so of all cancer
    and climbing

43
Sponsorship by NGOs
  • Most cancer societies not involved in patient
    care, but may support salaries or provide grants
  • Some professional societies may sponsor studies
  • SIOP Wilms, hepatoblastoma
  • INCTR dedicated to cancer in developing
    countries support NCI, grants, Pharma
  • Clinical trials used to both immediately improve
    patient care and as a focus for capacity building

44
INCTRs Network
Offices and Branches
Collaborating Units
45
Tenets of the Network
  • Focused on small number of centers in countries
    interested in clinical research and training
    programs
  • Includes active participation in identification
    and design of projects
  • Works with other organizations with overlapping
    interests
  • Once studies running effectively, add additional
    centers use participating centers to provide
    training for others in the country or region
  • Modern capabilities re IT for training,
    consultation, review of diagnostic images etc.
    gradually being enhanced

46
Active Clinical Projects
  • Reasons for late presentation of retinoblastoma
    16 centers in 11 countries
  • Survey of breast cancer management - 4 countries
  • Cx Cancer screening (with IARC) 2 countries, 4
    sites
  • Treatment of advanced cervical cancer (with Eli
    Lilly) 10 centers in 10 countries (accrual
    complete)
  • Treatment and study of ALL in India - 4 Indian
    centers
  • Treatment and study of Burkitts Lymphoma in
    Africa - 4 centers in 3 countries (expanded
    access in Tanzania)
  • Palliative care provision and training 4
    countries
  • Expansion of care for leukemia (Philippines)

47
Projects in Planning Phase
  • Treatment of locally advanced retinoblastoma
    (Philippines, Turkey)
  • Treatment of breast cancer (with IAEA)
  • Cervical cancer screening and treatment
  • Palliative care in Nicaragua (PACT)
  • Cancer control in Cameroon
  • Cancer control in Uzbekistan

48
ALL study 1048 Patients
Acute Lymphoblastic Leukemia
MUMBAI (652)
DELHI
  • DELHI (232)

CHENNAI (168)
49
Improvement over time with MCP 841 at TMH

50
Research Projects
PROJECTS
INCTR Programs, Branches, Associate Members,
Partners
Scientific Review
Ethical Review
Disease Specific Strategy Groups
Implementation
51
Strategy Groups
International groups identify and implement
disease specific activities in prevention,
treatment, education
Cx Cancer, August 2004
Implementation Meeting, African BL, Tanzania,
August 2004
52
Clinical Trials Workshops
  • Provide basic information on clinical trials in
    cancer prevention and treatment
  • Associated with training of data managers
  • Supported by pharmaceutical industry
  • Held in China and Brazil to date

53
Educational Meetings
Workshops and training courses
Jordan, Iraqi Ped Onc Workshop, April 2004
Nurses Oncology Training, Cairo, October 2003
Includes courses in GCP
54
Expert Visits
Experts spend time in centers to teach, learn,
and in some cases help establish programs
Can be supplemented by electives for trainees and
long term stays where feasible MERGES WITH
TWINNING PROGRAMS
Stuart Brown, Palliative Care, Nepal, August 2003
55
Strategies
  • Will need to develop training courses in both
    clinical science (oncology) and infrastructure
    required for trials management, including CTOs
  • Accreditation of individuals and institutions
    would be valuable
  • Continuing education essential
  • A system of monitoring will need to be put in
    place

56
Expanding Access
  • Create centers in appropriate institutions that
    can participate in projects that encompass
    research, service provision and the simultaneous
    provision of training and education to provide a
    FOCUS
  • Develop a plan for creating satellite centers
    such that KSD and research are expanded within
    the country in a coordinated fashion
  • Maximize in-country training utilize where
    necessary training in established centers in
    other developing countries of similar SES

57
Maximizing IT - 2006
  • Telesynergy or internet-based lectures, focused
    meetings and training courses
  • Use of PORTAL for Staff Workspaces
  • Use of PORTAL for discussions, surveys free
    contributions

58
Communication Tools
Newsletter NETWORK
NETWORK Workspace
Admin. Workspace
Education Site
Members Forum
Annual Meet. Workspace
59
Strategy for Sustainability
  • In country training with hands-on experience
    long term collaborative research projects with
    immediate benefits to patients
  • Clinical trials of locally relevant approaches to
    screening and treatment provide improved care as
    well as professional education
  • Development of training centers that will expand
    the workforce and increase access to care in the
    country or region
  • Education and training built around projects
  • Training in scientific methodology enhanced
    professional experience independence
  • Information collected provides a foundation on
    which to build future endeavors

60
Evidence Based Cancer Control Multiple Benefits
  • INCTR is working with Cochrane Cancer Network and
    other partners to
  • Catalogue available evidence from developing
    countries
  • Develop a training program for secondary review
    (and therefore, disease experts)
  • Create a data base of secondary reviews
  • Identify gaps in knowledge and promote clinical
    trials to fill them

61
Secondary Research
  • Knowledge of existing literature is essential in
    order to decide which questions are worth
    answering (the art of science)
  • Training in the evaluation of published research
    provides an understanding of the scientific
    method in a clinical context
  • Thus, an important part of education in the
    conduct of clinical trials and sustainability

62
Summary and Conclusions
  • Clinical trials essential in developing
    countries
  • Outcomes of interventions may differ from those
    in affluent populations new evidence base
    required
  • Best interventions may differ from rich countries
    because of toxicity, cost or limited access
    (expertise, materials)
  • Clinical trials can be a focus for building
    capacity, and can lead to immediate patient
    benefits while building a foundation of data on
    which to make further progress
  • Collaboration between governments, corporations
    and NGOs (including academia) should be mutually
    beneficial and benefit patients everywhere
  • Scientific training is best done via hands-on
    training in both primary and secondary research
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