Clinical Trials in Low Resource Settings

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Clinical Trials in Low Resource Settings

• Ian Magrath

www.inctr.org
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Outline
Questions
Propositions
Addressing the Problems Role of Clinical Trials
Problems faced in developing countries
Infrastructure knowledge transfer
Who pays? sponsorships
Conclusions
INCTR Strategies
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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
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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
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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)
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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
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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?
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Questions - 2
How can clinical research be promoted and the
necessary infrastructure built in countries with
limited resources?
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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
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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

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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)

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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

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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)

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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
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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
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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
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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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
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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

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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

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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

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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

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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,
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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

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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

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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

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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)

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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

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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

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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

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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

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INCTRs Network
Offices and Branches
Collaborating Units
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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

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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)

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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

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

• DELHI (232)

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

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Research Projects
PROJECTS
INCTR Programs, Branches, Associate Members,
Partners
Scientific Review
Ethical Review
Disease Specific Strategy Groups
Implementation
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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
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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

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Educational Meetings
Workshops and training courses
Jordan, Iraqi Ped Onc Workshop, April 2004
Nurses Oncology Training, Cairo, October 2003
Includes courses in GCP
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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
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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

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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

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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

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Communication Tools
Newsletter NETWORK
NETWORK Workspace
Admin. Workspace
Education Site
Members Forum
Annual Meet. Workspace
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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

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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

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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

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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