Evidence Based Interventions

1
Evidence Based Interventions Cancer Control in
Context
Ian Magrath www.inctr.org
2
What is Evidence?

• Information that can be used to support or refute
  the truth of a statement or assertion
• Pigs can fly
• Vincristine is an effective drug in the treatment
  of Burkitts lymphoma

3
Why do we need it?

• Because without it we cannot practice scientific
  medicine we might resort to cupping or bleeding
• When major procedures or treatments are used for
  serious illness, the potential for harm, or no
  benefit (with a fatal consequence) is such that
  knowledge of utility is essential
• Practicing what was taught means that even if
  the teacher was knowledgeable and up-to-date,
  his/her students will soon be practicing
  antiquated medicine unless they stay abreast of
  new data
• Continuous creation and assessment of evidence
  and continuing education are therefore essential

4
How is Evidence Obtained?

• Observation of natural phenomena or
  experimentation
• E.g., no pig has been observed to fly by a
  reliable witness (observation)
• Pigs that fall off cliffs (or are pushed) are
  unable to fly (observation or experiment)
• Most patients with Burkitts lymphoma treated
  with vincristine have a response
• (experiment in this case, a clinical trial)

5
Evidence Based Medicine

• Convert clinical information needs into
  answerable questions (hypotheses)
• Identify best evidence to answer them
• Clinical trials
• Appraise evidence for validity and utility
• Usually, results of multiple trials
• Apply results of appraisal in clinical practice
• Evaluate clinical performance
• Use of intervention, not its outcome is measured

6
Cautions

• Evidence is context sensitive
• Pigs can fly (or at least float) in a space
  capsule
• Clinical interventions can have different results
  in different populations
• In cancer, the tumor differs (e.g., Egyptian
  bladder cancer), the population differs (drugs
  handled differently) or medical care differs
  (discipline with which protocol followed,
  facilities, support measures)
• New information may make older evidence obsolete
  (better treatment or support)

7
Analysis and Evaluation

• Evidence must be of high quality
• Expectations must be built into a clinical trial
• Demonstration of activity what level?
• Comparison of approaches equivalent? Different
  to what degree?
• Heterogeneity always present, and patterns may
  differ in different populations
• Are small but significant differences
  reproducible?
• Will results be the same in African versus US
  populations

8
Randomization and Meta-analysis

• Large randomized trials needed to show small
  differences reproducibility may depend upon
  patient population
• Meta-analyses of multiple studies probably most
  valuable, but demonstrate variability in results
  of different trials
• All studies are averaging results for
  populations Bill Gates alone significantly
  raises the average income of the USA

9
Ethics in Practice

• Research can only be undertaken in an ethical
  context that protects the rights of the patient
• Medical practice is much less regulated
• To what extent should there be national
  standards versus individual physician choice?
• How can this be enforced (cost of treatment)?
• Who would decide on standards and what ought to
  be the consequences of failure to abide

10
Obstacles to EB Cancer Control in Low Resource
Settings

• There is a paucity of evidence from low and
  middle income countries
• Few population based cancer registries
• Few clinical trials
• Evidence is used from high income countries
• May not always apply (populations and diseases or
  disease subtypes may differ)
• Interventions may not be feasible (too expensive,
  no available expertise)
• There are rather few studies of the quality of
  application, or outcome, of interventions
  evaluated in high income countries in the
  different contexts of low and middle income
  countries

11
Contextual Differences

• Differences in resources
• Human, material, financial
• Differences in population genetics
• Impact of environmental risk factors and
  metabolism of drugs (efficacy and toxicity)
• Differences in tumors themselves
• Incidence and frequency may influence priority
  or cost effectiveness of an intervention
• Molecular profile from differences in causal
  factors many influence efficacy of treatment

12
Conclusions

• Literature must be particularly carefully
  appraised if evidence is to be used in different
  contexts
• Interventions may need to be retested, or tested
  in modified form in different contexts
• Interventions may be less effective in low
  resource settings
• Outcome measures always valuable since changes
  may occur over time (e.g., in skill or staff,
  availability or cost of interventions, or even
  disease)
• Better approaches (more effective, less toxic or
  less expensive) should continuously be sought
  (need for clinical research)

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Poverty the Grim Reality
World lt1 per day gt1 billion lt2 per day gt2.7
billion)
World Development Indicators 2005
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Education (98-01)
15
Health Expenditure Per Cap
3039
5274
2489
12
World Development Indicators 2005
16
Physicians, Nurses per 1000
9.37
10.24
World Health Report 2006
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Disease Burden and Resources
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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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Cancer Registration I-VIII
Fraction of World Population
149 5 60 11 1
Number of registries does not accurately reflect
population coverage (e.g., African registries
cover approx 7 million of the 888 million people
20
Cx Cancer Publications
Bhutan India Nepal Pakistan Sri Lanka TOTAL
Prevention 0 0 0 0 0 0
HPV related 0 23 0 0 0 23
HIV related 0 4 0 0 0 4
Screening 0 24 4 3 0 31
Treatment 0 39 1 0 0 40
Palliative care 0 0 0 0 0 0
Sub-totals 0 210 5 7 0 223
Indexed from Medline, Embase, Conference
proceedings 2001 - 2006
21
Crude Incidence of Cancer (Males)
Globocan 2002
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Crude Rates by Regions
More affluent regions have higher actual
incidence and mortality rates and higher
incidence mortality ratios
23
Age-Standardized Rates
Differences in incidence not solely due to
differences in the age structure of populations
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Age-Specific Incidence
Breast Cancer
25
Relative Importance of Predisposing Factors

• Tobacco (approximately 30 in affluent countries)
  
• Diet (approximately 30 in affluent countries) -
  high fat, low fibre diets, alcohol
• Infections (overall, 20, more in developing
  countries)
• Other pollutants, ultraviolet light, asbestos
  and other occupational exposures (especially in
  developing countries)
• Familial predisposition (usually involving DNA
  repair genes), associated with 4 of cancer.
  Modified by environmental factors

26
Progression of Tobacco Epidemic in Various
Countries
27
World Food Consumption
3000
2000
3800
2400
Calories per person per day
UN Food and Agricultural Organization
28
Infectious Agents and Cancer

• Viruses
• HPV, HBV, EBV, HTLV-1, HIV, HHV-8
• Bacteria
• Helicobacter pylori, Borrelia
• Protozoans
• Malaria?
• Fungi
• Aflotoxins
• Worms
• Trematodes (flukes)

Chronic infections more common in developing
countries
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Some Cancers Associated with Infection/Infestation

• Cervix, anus, penis, others HPV
• Hepatocellular Carcinoma HBV, HCV
• Stomach, lymphoma H.pylori
• Bladder, bowel, liver Shistosomes, Clonorchis
• Kaposis Sarcoma HHV8
• Lymphomas EBV, HHV8, HTLV1

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Prevention Feasibility and Cost Effectiveness

• Approaches to prevention in USA cytopathology,
  mammography, PSA, colonoscopy (diagnostic skills,
  action)

Crude Incidence Nigeria USA
Breast (F) 20.6 143.8
Cervix Uteri (F) 16.7 9.0
Prostate (M) 10.3 168.9
Colon (M) 3.3 60
GNI per cap (2004) 430 41,440
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Implications

• Differences in resources and cultural contexts
  may alter the feasibility or efficacy of
  interventions validated in high income countries
• e.g., mammography, colonoscopy
• Differences in cancer patterns change priorities
  for cancer control
• Infection control more important in developing
  countries

32
Caution Future Trends

• Attention must be paid to trends in cancer
  patterns relating to socioeconomic status
• Tobacco control must be high on the list of
  priorities, even though this is a much less
  important risk factor at present many measures
  may be easier to take prior to the height of the
  epidemic
• Consideration may be given to diet before this
  becomes a major problem too

33
Some Problems in the Use of Evidence for Cancer
Control

• Multiple disciplines are involved, and may be
  address only the evidence with which they are
  familiar
• Most interventions are based on western evidence
  transmitted by western experts
• Western experts often assume that western
  approaches are optimal
• Western experts often unfamiliar with the
  problems of developing countries

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Multiverses Potentially Unhealthy Divides
Government
Epidemiology and Public Health
Health Service Provision
Gov. Agencies
Charities
Universities
Prof. Societies
Health Service Administration
Clinical and Basic Research
Academies
Corporations
Task ensure coordinated efforts integration
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Some Approaches to Transfer of Evidence

• Passive hope that the necessary professionals
  have access to the available literature, and the
  knowledge and skills to make use of new
  information (works well in high income countries)
• Active engage in an active process of
  knowledge/evidence transfer

36
The Standard Model

• High level meetings in developing countries (with
  western faculty)
• No outcome measures, content often irrelevant
• Training in Western institutions
• Benefits the West more than low and middle income
  countries
• Provision of written guidelines
• Need appropriate skills and knowledge to apply
• Rarely is there assessment of use or value

37
Major Congresses

• Leading experts want to discuss their latest
  advances, not necessarily the most relevant
  information to the country in question
• Little or no attention is paid to differences in
  resources
• Even professionals practicing in high income
  countries prefer to dazzle their erstwhile
  colleagues with their achievements (e.g., bone
  marrow transplantation)

38
Standard Model Training

• Best people from developing countries trained in
  institutions in high income countries
• Many do not return, or return temporarily
• Some high income countries recruit from
  developing countries
• Net benefits accrue to wealthy countries

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Nurses who joined the UK register from countries
from which recruitment is banned (2004-5)
Source Annual Report, 20005, 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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Standard Model Guidelines

• Many well meaning persons or organizations
  develop best practice guidelines
• Often 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
  usually the more knowledgable (utility?)
• Require basic or advanced KSD for effective use
• No measures of degree of adherence or of outcome
  made value in new context remains unknown!

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Limitations of Guidelines
Even if comprehension is perfect, health workers
modify their practices to incorporate none, some
or all of the guidelines. Hence, correct
knowledge often does not predict correct
performance.
Rowe et al., Lancet 3661026, 2005 In the context
of low resource settings
42
Limitations of Guidelines

• Dissemination of written guidelines without
  additional interventions is generally ineffective
• Supervision and audit is generally quite
  effective
• Computer based training may be less expensive
  than and as effective as traditional methods

Rowe et al., Lancet 3661026, 2005 In the context
of low resource settings
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Conclusion

• While guidelines are inherent to the concept of
  evidence based medicine, and, in the standard
  model, emerge from the collection and analysis of
  evidence, it is essential to recognize that
  evidence is context sensitive
• In many cases, guidelines are premature they may
  be replaced by the conduct of collaborative
  research studies
• There is a need for active assistance in
  translating evidence into action (practice)

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Alternate Model

• In country training with hands-on experience
  establishment of long term collaborative
  research projects with immediate benefits
• Clinical trials with surveillance and outcome
• Education and training built around projects
• Training in scientific methodology enhanced
  professional experience independence of mind
• Information collected provides a foundation on
  which to build future endeavors

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International NGO or Institution
FUNDING
Visiting Experts
External Training
E-learning?
Government or Local NGO
Local project service provision and training
Education of other primary health care workers
or trainees
Dissemination to other centers
Dissemination to Health Care System
46
Research in Developing Countries

• Is essential to the creation of a more relevant
  evidence base
• Leads to a more analytical approach to all
  aspects of health care
• Will allow advantage to be taken of unique
  scientific opportunities
• Will lead to greater independence of developing
  countries from high income countries

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Clinical Trials in Low RS

• Controlled or even single arm studies in
  prevention and treatment designed to address
  questions of importance in low resource settings
  (NB., clinical trials does not refer solely to
  drug development) can
• Provide effective prevention or treatment
• Provide a focus for training and education
• Give added incentives to improve outcome
  (especially if multi-centered)
• Builds on the evidence base for low resource
  settings
• Provides (potentially) improved professional
  circumstances and new career opportunities
• Necessary monitoring and audits provide
  assessment of performance and effective
  supervision

48
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 (all
  subject to it) potentially healthy competition
• May identify problems that are specific to
  populations, regions or institutions

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Comparison of Treatment Guidelines and Clinical
Trials
Research
Guidelines

• Designed for a specific population in the context
  of available resources
• Usually entails collaboration and mutual learning
• Associated with quality assurance and ethical
  review
• Identifies deficiencies
• Associated with outcome measures
• Generates new contextually relevant information
  builds the evidence base

• Based on available evidence may be from a
  different population and with different resources
  
• Rarely entails collaboration or learning (except
  by rote)
• No quality control or ethical review (lack of
  resources!)
• May be modified such that validity questionable
• No outcome measures
• No new information generated

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Obstacles to Research in Developing Countries

• Little or no research training
• Protocols often viewed as guidelines which can be
  modified at will
• Limited research infrastructure
• Concept of data quality rudimentary
• Published data often unreliable
• Research often considered a luxury rather than a
  necessity

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General Strategy

• Create a center in an appropriate institution
  that can participate in research, provide
  services and also serve as a training center
• Develop a coordinated approach to training in
  association with expanding access
• Maximize in-country training, with second choice
  training in good centers in other developing
  countries

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On-site Collaboration

• In low income settings, there is no substitute
  for well trained persons (local or visitors)
  on-site in introducing interventions
• Transfer of KSD is maximally efficient
• Local circumstances are automatically taken into
  consideration
• Unrecognized local problems may be identified
• Not always easy to accomplish

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Conclusions

• There is a need for a review of existing evidence
  for cancer control in developing countries
• Approaches to cancer control must take into
  consideration the local context
• It should be possible to implement interventions,
  while studying their outcome and developing a
  firmer and larger foundation of evidence relevant
  to developing countries