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Ethical Aspects of Research Involving
Human Subjects- The Challenges of ERC/
IRB in reviewing protocols involving research
on highly infectious diseases
Prof Elizabeth Anne Bukusi
Deputy Director(Research & Training)
Kenya Medical Research Institute
Recent highly infectious epidemics
EBOLA
SARS
MDR/XDR TB
Emerging
infections
HIV/AIDS
HIN9
HINI
Concerns
 High mortality and morbidity
 Very short timescale for decision making
 Some are Highly contagious
 Global susceptibility
 Threat to global security and economy
But some special features A case may also be a risk factor
- Person with infection can also be source of infection
 People may be immune
- Having had an infection or disease could result to resistance to an
infection (immunity)
 A case may be a source without being recognized
- Asymptomatic/sub-clinical infections
 There is sometimes a need for urgency
- Epidemics may spread fast and require control measures
 Preventive measures (usually) have a good scientific evidence
Challenges in reviewing infectious
diseases protocols
Infectious Diseases spread quickly, with
Infectious Diseases spread quickly, with
high mortality, crossing borders/
high mortality, crossing borders
Information and expertise may be limited
Need to make the correct decision quickly
sometimes with little information and time
Uncertainty over the safety and
effectiveness of the trial productespecially in epidemic situation
Chain of Transmission
Reservoir
Person-toperson
transmission
Portal
of exit
Susceptible
host
Agent
Portal
of
entry
Reservoir and source of infection
 Reservoir of infection
 Ecological niche where the infectious agent survives and
multiplies
 Person, animal, arthropod, soil, or substance
 Source
 Human
 Animal
 Environment
Transmission routes
Direct transmission
Indirect transmission
Mucous to mucous membrane
Waterborne
Across placenta
Airborne
Transplants, blood
Foodborne
Skin to skin
Vectorborne
Sneezes, cough
Objects/Fomites
Possible outcomes after exposure to an
infectious agent
Exposure
No infection
Death
Clinical infection
Immunity
Subclinical infection
Carriage
Carriage
Non-immunity
Dynamics of disease and infectiousness
Latent period
Infectious period
Incubation period
Infection
Clinical disease
Onset of
symptoms
Non-infectious period
Recovery
Resolution
of symptoms
Time
Relationships between time periods
Transmission
Second patient
Latent period
Infectious period
Incubation period
First patient
Transmission
Latent period
Incubation period
Infection
Clinical disease
Infectious period
Clinical disease
Serial interval
or generation time
Time
Disease occurrence in populations
 Sporadic
 Occasional cases occurring at irregular intervals
 Endemic
 Continuous occurrence at an expected frequency over a certain
period of time and in a certain geographical location
 Epidemic or outbreak
 Occurrence in a community or region of cases of an illness with
a frequency clearly in excess of normal expectancy
 Pandemic
 Epidemic involves several countries or continents, affecting a
large population
What causes incidence to increase?
Reservoir
Person-toperson
transmission
Portal
of exit
Susceptible
host
Agent
Portal
of
entry
Factors influencing disease transmission
Climate change
Megacities
Pollution
Vector proliferation
Environment
Vector resistance
Vectors
Animals
Food production
Infectivity
Agent
Intensive farming
Antibiotics
Pathogenicity
Virulence
Immunogenicity
Population growth
Migration
Behaviour
Antigenic stability
Reproductive rate
•
Potential of an infectious disease to spread in a
population
•
Dependent on 4 factors:
–
Probability of transmission in a contact between
an infected individual and a susceptible one
–
Frequency of contacts in the population contact patterns in a society
–
–
Duration of infectiousness
Proportion of the population/contacts that are
already immune, not susceptible
Basic reproductive rate (R0)
Basic formula for the actual value: R0 = β * κ * D
 β - risk of transmission per contact (i.e. attack rate)
 Condoms, face masks, hand washing  β ↓
 κ - average number of contacts per time unit
 Isolation, closing schools, public campaigns  κ ↓
 D - duration of infectiousness measured by the same time units
as κ
 Specific for an infectious disease
 Early diagnosis and treatment, screening, contact tracing  D
↓
Ethical issues
 Vulnerability
 Confidentiality
 Beneficence
 Choice of control
 Study design
 Informed consent
 Standard of care
 Compensation
 Oversight and regulation
 Post trial access
Vulnerability
Vulnerability
 Participants from developing countries are especially
vulnerable due to their
 poverty,
 underdevelopment
 high disease burden
Confidentiality
Quarantine – identification may lead to
 Lack of confidentiality by
 Invasion of privacy
 exposure of sensitive personal
information
 Could lead to negative social
outcomes like job loss or loss of
insurance coverage
Confidentiality
 ERC Role in protection of Confidentiality
 Ensure subjects are protected from unwarranted and
unwanted disclosure.
 Prohibit disclosures in cases
 Ensure Identifiable subject information is not disclosed
without their consent
 Limit what information is recorded in subjects medical
records to avoid breach of confidentiality
 This is a against a back drop of community or social
concern especially over infectious agents with public
health impact.
Risk/Benefit Analysis
 What is the risk in relation to the benefits?
 What is the risk among subjects most likely to
benefit from participating in the trial ?
 What is the relevance of the trial on the
population?
 Is there compelling need to use the selected
Population, will they benefit the most?
Benefit vs. Risk
 ERC considerations:
 Severity of the disease, risk of infection, and subjects’
vulnerability and potential adverse events and
outcomes
 Evidence that animal and lab tests have demonstrated
safety
 Compelling need to use selected participants Potential
benefits of the intervention
Benefits, risks
 Does address how benefits and risk will be shared
 Did the community have a say on inclusion or exclusion
of subjects?
Equipoise and choice of
control
 Does the selected control best establishes the value of
the candidate intervention and has documented positive
outcomes for the condition ?
 If no effective intervention exists, a placebo may be
appropriate, with good informed consent.
 A licensed and effective intervention is by default the
comparator of choice for the control group.
 Any exception should be fully justified to, and carefully
reviewed by, relevant ethics committees
ERC community
considerations
 Ensure that the community is well informed before the
trial.
 Justification for segregating and providing differential
treatment
 Understanding of social and cultural practices that may
promote or inhibit trial implementation
 Good community practices not standard and not always
well documented
Study design
 Trials should be design to involve those at risk of
exposure and those who stand to benefit the most
 The type of infectious disease, its route of transmission
and infectiousness, what is known about it , and any
known treatment or support determine the kind of
study design that is most appropriate
Informed consent
 The value of informed consent may be diminished in highly
infectious diseases due to morbidity.
Informed consent
 Challenges further heightened by social-economic
factors e.g. lack of education and poverty in developing
countries
 Voluntary participation / and especially where proxy
consent is required
 Language and translation of concepts may be a
challenge
 Improved medical care provided during trial may
constitute inducement
Standard of care
 Should be defined prior to the
trial’s initiation through
stakeholders consultation and
agreement
 Consensus between ERC’s
where North- South
collaborations are engaged in
approval would be desirable
Compensation
 Reimbursement/compensation
should not constitute
inducement
 The local ERC should provide
guidance on the appropriate
compensation depending on the
context of the trial
 The protocols need to provide
indemnity incase of injuries in
the course of the trial
 Local indemnity cover is not
easily available
Oversight and regulation
 Clinical trials often involve
multiple institutions, which
lead to a complex process
of ethical and regulatory
review
 The capacity of National
and local regulatory and
ethical review bodies
especially in developing
countries should
continually improve their
processes
Study Monitoring/ Audits
 Monitoring of studies often
included in the design – for
quality control
 DSMB included to ensure
safety and for clear stopping
rule decisions
 Local ERC review of ongoing
SAE – capacity may be a
challenge
 ERC oversight for actual
conduct may also be a
challenge do to resources
 For multi site trials, efforts
should be made to enable
ERCs share information and
concerns, and a mechanism
by which to resolve
difference
 ERCs must ensure sponsors
have provisions for
monitoring and maintenance
of safety and efficacy records
of the intervention
Post Trial Access
 ERCs need to ensure
that provision is made
for the trial community to
benefit from early
access to any product of
the trial, infrastructure
and knowledge brought
by the trial
Post trial access
 While the ERCs ensure the protocol includes information to
ensure that products which are valuable for treatment/
prevention are not only available but affordable and in the
quantities needed to tackle the outbreak at its epicenter.
 Enforcement of such agreements are challenging – both
follow up and implementation
 The investigators have the burden/ responsibility of follow up
 No clear mechanisms for research to policy and best
practices in a rapid manner except for some with strong
advocacy groups.
Thank- you
 Anderson RM & May RM, Infectious Diseases of Humans:
Dynamics and Control, 11th ed. 2006
 Giesecke J, Modern Infectious Disease Epidemiology,
2nd ed. 2002
 Barreto ML, Teixeira MG, Carmo EH. Infectious diseases
epidemiology. J Epidemiol Community Health 2006; 60; 192195
 Heymann D, Control of Communicable Diseases Manual, 19th
ed. 2008
 McNeill, WH. Plagues and Peoples, 3rd ed. 1998
 Everlyn Ombati , Timothy Kipkoskei and KEMRI SERU team.