Interventions can be classified into two broad categories: (1) preventive
interventions are those that prevent disease from occurring and thus reduce
the incidence (new cases) of disease, and (2) therapeutic interventions are
those that treat, mitigate, or postpone the effects of disease, once it is
under way, and thus reduce the case fatality rate or reduce the disability
or morbidity associated with a disease. Some interventions may have both
effects.
2.1. Preventive interventions
2.1.1. Vaccines
Vaccines are administered to individuals, usually before they have
encountered the infectious agent against which the vaccine is
targeted, in order to protect them when they are naturally exposed
to the agent. Many are among the most cost-effective interventions,
because, after a single dose or a series of doses of the vaccine, an
individual may acquire long-term protection against the agent. They
work by inducing a variety of immune mechanisms, through the humoral
and/or cellular immune systems. The immunological responses and
associated immunological memory induced by vaccination confer
protection from later infections, though a booster vaccination may
be necessary if the interval between the original vaccination and
exposure to the agent is long. Most vaccines have to be administered
before the infectious agent is encountered naturally, and thus field
trials of such vaccines will involve the enrolment of healthy
individuals and often involve infants or very young children—though
the vaccine may be given at a later age if the age of natural
infection is at later ages, for example, for most sexually
transmitted infections (STIs), or if a new infectious agent, to
which no one has been previously exposed, enters a community such as
a new strain of influenza.
Not all vaccines are targeted at persons without previous exposure to
the infectious agent. For example, there is substantial research to
develop vaccines against parasitic diseases. The mode of action of
some of these vaccines is to prevent parasitic proliferation within
the host after invasion (and hence curtailment of disease), and some
vaccines against vector-borne diseases are even targeted to prevent
replication of the forms of the infection in the vector, so that
onward transmission to humans is prevented.
For infectious diseases that affect both high-income countries (HICs)
and LMICs, the first trials of new vaccines are usually conducted in
HICs. This is because currently most new vaccines are developed and
produced in HICs (though this situation is changing), and it is
generally accepted that at least early clinical studies should be
conducted in the country of vaccine manufacture. However, the
results of trials in HICs may not be directly applicable to LMICs
for a variety of reasons such as differing prevalences of other
infections or of nutritional deficiencies, which might interfere
with the mode of action of the vaccine. Thus, there will often be a
need for further trials of the vaccine in LMICs, even if efficacy
has been established in HICs. In addition, there has been increased
focus in recent years on the development of vaccines against
infectious agents that only, or almost only, occur in LMICs, such as
malaria or visceral leishmaniasis, or where the overwhelming disease
burden is in such countries, such as tuberculosis (TB) or HIV
infection. For vaccines against these agents, the first major field
trials to assess efficacy are likely to be conducted in LMICs.
2.1.2. Nutritional interventions
Food and nutrition are major determinants of human health and
disease. Particularly in low-income countries and deprived
populations in middle-income countries, under-nutrition remains a
major cause of disease. Severe malnutrition, such as kwashiorkor or
marasmus, is life-threatening, but milder forms of malnutrition are
major risk factors that adversely influence the susceptibility to,
and the outcome of, many infectious and other diseases, as well as
cognitive development. In addition to calorie and protein
deficiencies, specific deficiencies in micronutrients, such as iron,
folate, zinc, iodine, and vitamin A, may be important determinants
of severe diseases. Trials to address these problems may involve the
regular provision of high-protein/calorie diets or supplementation
to individuals with specific micronutrients, involving repeated
visits to the same persons over several years, the frequency of
administration depending on the nature of the supplement(s). Other
trials, often with the intervention being applied at a community
level, may involve food fortification (for example, iron, iodine,
vitamin D) and experiments to change agricultural practices or
eating or food preparation habits to increase the intake of
particular micronutrients.
2.1.3. Maternal and neonatal interventions
A mother’s health and well-being during pregnancy and around the time
of delivery, including access to appropriate care, are critical
determinants of maternal mortality and neonatal and child health in
the early years of life, and possibly for much longer. Preventive
interventions before or during pregnancy include family planning,
treatment of infections, such as syphilis and malaria, good
nutrition, including micronutrients, good antenatal monitoring and
care, and access to skilled care at the time of delivery and
post-partum. Trials of maternal interventions may involve both
community-based studies, with the early identification of
pregnancies and the instigation of preventive interventions to avoid
pregnancy complications, or may be hospital- or health centre-based,
directed at improving the performance of the health system in caring
for women during and after pregnancy and at the time of birth.
Interventions directed to the neonate are also important, such as
exclusive breastfeeding and care practices, such as ‘kangaroo mother
care’, a method of care of preterm infants, involving infants being
carried, usually by the mother, with skin-to-skin contact.
2.1.4. Education and behaviour change
Some interventions directed at preventing disease are based solely
upon changing human behaviour (for example, anti-smoking campaigns
or campaigns to promote breastfeeding). Nearly all health
interventions must have an associated educational component for
their effective deployment, but the extent of educational effort
required ranges from the provision of simple information (for
example, when and where a clinic for immunization will be held) to
efforts at increasing understanding (for example, of the importance
of male circumcision for the prevention of HIV) and to attempts to
change lifestyles (for example, diet or sexual habits). Education to
increase knowledge and impart new skills may be necessary but is
rarely sufficient to induce behaviour change. Individuals must also
have the capacity, willingness, and motivation to act on the
knowledge and to use the skills. The design and implementation of an
educational intervention, and other ‘complex’ interventions (Craig et al.,
2008), will usually need to be researched through careful
investigations in the community, using the kinds of methods
discussed in Chapters 9 and 15.
Examples of educational components of disease control programmes
include:
- ◆
educating children or mothers about the causes of the
disease, such as diarrhoea, and how to prevent it
- ◆
promoting adherence to long-term treatment such as for
HIV infection or TB
- ◆
developing effective participation in programmes
that:
- ●
need broad coverage to maximize the effects of
immunization or drug distribution
- ●
require people to recognize disease symptoms for
early treatment
- ●
necessitate active co-operation in home
improvements or insecticide programmes
- ●
involve direct action and responsibility in
deploying vector, or intermediate host, traps
- ●
need community efforts for environmental
improvements such as developing and maintaining
improved water supplies or better disposal methods
for faeces.
Organizing trials of behaviour change interventions are among the
most challenging, and there are few examples illustrating the design
of replicable interventions that achieve lasting behavioural change
in the context of a trial. For example, changing tobacco smoking
behaviour at a population level required decades of concerted,
multifaceted campaigns. However, attempts to reduce diarrhoeal
diseases and respiratory infections through the promotion of
hand-washing with soap have produced encouraging results.
2.1.5. Environmental alterations
Alterations to the environment directed at reducing the transmission
of infections are central to the control of many infectious
diseases, particularly those that are transmitted through water,
such as cholera, or through the faecal–oral route such as many
gastrointestinal infections. Environmental interventions to reduce
human faecal and urine contamination include latrine construction,
provision of sewage systems, clean water supplies, and protected
food storage. Other environmental interventions tackle indoor or
outdoor air pollution or involve the disposal of contaminants such
as pesticides or heavy metals. Many of these interventions require
substantial educational efforts and lifestyle changes. They are also
interventions that typically have to be applied to whole
communities, rather than to individuals in a community, so that, in
trials, the unit of randomization is the community or, in some
instances, the household.
2.1.6. Vector and intermediate host control
Some major communicable diseases in developing countries depend on
vector and intermediate hosts for their transmission. For different
infections, the vectors include mosquitoes, tsetse flies, triatomine
bugs, sandflies, ticks, and snails. There are a wide variety of
control measures to reduce transmission of these infections through
attacking the vectors or the reservoirs of infection. Most
interventions require a good understanding of the vector or
intermediate host, its life cycle, and the environmental conditions
that it requires to propagate infections. Control measures may
include the application of insecticides or larvicides, new or
improved selective biological agents against disease vectors,
engineering techniques for reducing vector habitats, community
involvement in eliminating vector breeding sites and in deploying
traps, housing and screening improvement for reducing human–vector
contact, and strategies involving combinations of methods with, for
example, the objective of reducing or delaying insecticide
resistance. For many of these methods, intermediate process
indicators, such as reduction in vector density, can be used for the
assessment of impact, but it is often also necessary to determine
the impact of the measures on the health status of the population.
For example, for malaria, many different approaches to vector
control have been used, based upon attacking the mosquito in various
stages of its life cycle. These include control of breeding sites to
reduce vector density by drainage and waterway engineering and
application of specific larvicides and biological agents; the use of
mosquito netting, screens, and repellents for personal protection
from bites; aerosol distribution of insecticides to reduce adult
mosquito densities; and different approaches to killing adult
mosquitoes, through either spraying residual insecticides, such as
with dichlorodiphenyltrichloroethane (DDT), on the internal walls of
houses where mosquitoes rest after a blood meal or through the use
of insecticide-treated bed-nets (ITNs) that kill and/or repel
mosquitoes seeking a blood meal. These different approaches require
quite different study designs. Residual insecticide on the walls of
houses offers relatively little direct protection to those in the
treated household, as the mosquitoes take up the insecticide while
resting after a blood meal. The protection is to
those in other households whom these mosquitoes would have bitten
for their next blood meal. To reduce transmission in high
transmission areas, virtually all households in the neighbourhood
must be sprayed. The higher the intensity of transmission, the more
difficult it is to achieve sufficient coverage. The use of ITNs,
developed as an intervention against malaria over the last two
decades, leads to reductions in transmission, clinical disease, and
overall childhood mortality. Trials of these kinds of intervention
often involve communities, rather than individuals, as the unit of
randomization. These trials are especially challenging to design,
because some vectors, such as mosquitoes, may have a flight range
that may lead to the ‘contamination’ of intervention communities,
with vectors coming in from outside of the community.
2.1.7. Drugs for the prevention of disease
Drugs or other interventions may be used for the prevention of
infection (prophylaxis) or disease consequent on infection. An
example of the former would be isoniazid prophylaxis to HIV-infected
individuals to reduce their risk of TB, and of the latter, the
treatment of HIV-infected individuals with antiretroviral drugs to
slow the progression of their disease. Sometimes, the use of drugs
for prophylaxis or to reduce disease progression does not involve
individual diagnosis, but community or group diagnosis is needed to
identify groups that should receive the treatment. For example, mass
administration of anti-helminthic treatment to schoolchildren is
sometimes administered in this way. Whether requiring specific
diagnosis or not, therapeutic or preventive agents are usually taken
on an individual basis, though sometimes agents can be distributed
to everyone in a community through the water supply (for example,
fluoride against dental caries) or in food (for example,
historically, diethylcarbamazine for filariasis and chloroquine for
malaria in medicated salt). Mass treatment of school-age children in
areas highly endemic for the infection with an anti-schistosomal
drug every year or two may be sufficient to virtually eliminate
serious disease consequences of infection with Schistosoma
mansoni.
Prophylaxis may be aimed at preventing or limiting infection,
particularly in those at high risk for a limited period of time (for
example, anti-malarials taken by those who are temporarily visiting
malaria-endemic areas). The value of such an approach is limited by
the duration of action of the agent (which determines the frequency
with which it must be taken), by adverse reactions, and sometimes by
the role of the intervention in stimulating the development of
drug-resistant organisms. For some purposes, prophylaxis may be used
by permanent residents of endemic areas (for example, anti-malarials
in pregnancy).
Drugs also may be used prophylactically for treatment of preclinical
infection (for example, during the incubation period before the
onset of symptoms, as for the gambiense type of
trypanosomiasis) or for treatment of subclinical infection (for
example, ivermectin against onchocerciasis, and praziquantel against
schistosomiasis).
Strategies for the use of such interventions include the mass
treatment of entire populations or the targeted treatment of
identifiable subgroups (such as school-age children) in areas where
the infection is highly prevalent. Generally, such treatment is
applied for the benefit of the individuals treated, but the
objective may also be to reduce the transmission of the agent in the
community more generally. When the prevalence is very high and the
treatment is cheap, treating all those in a defined population may
be more cost-effective than screening the whole population and then
treating only those found infected.
2.1.8. Injury prevention
Injuries are major causes of death and disability, especially in
LMICs. They disproportionately affect the young and have a large
economic impact on society. For children and young people, road
traffic accidents, drowning, fires, poisoning, interpersonal
violence, and war are leading global causes of serious injuries, but
often these are not considered ‘health problems’ and are not
sufficiently integrated into public health thinking. Yet there are
many potential interventions that might lead to reductions in deaths
and disabilities from injuries, such as traffic calming or
infrastructural changes to separate pedestrians from fast-moving
vehicles to reduce motor vehicle injuries, and improving the
security of water sources to reduce drowning accidents; there is
great need for more trials of interventions directed at reducing
injuries.
2.2. Therapeutic interventions
2.2.1. Treatment of infectious diseases
The mechanism of action of a drug used for disease control will
influence the design of field trials to evaluate its impact. Most
drugs employed against infectious disease are used to kill or
inhibit the replication or spread of the pathogen in the host.
Strategies for disease control that use such agents may involve case
detection (which requires an appropriate case definition and a
diagnostic method), followed by treatment that is designed to reduce
morbidity and mortality. Often, the public health success of this
approach depends critically upon case finding, and, for diseases
such as TB and leprosy, it depends also on case holding, i.e. being
able to follow and treat each patient at regular intervals over
sufficient time to eliminate the agent from the individual. Case
finding and treatment may also reduce transmission of an agent if
cases are the main reservoirs of infection, if case detection
methods locate a high proportion of prevalent cases, and if the
treatment is sufficiently effective.
2.2.2. Surgical and radiation treatment
RCTs of surgical and radiation treatments are usually done as
clinical trials; field trials of these interventions are relatively
uncommon. However, procedures, such as cataract extraction or simple
inguinal hernia repair, are examples of where field trials have been
usefully undertaken. In general, the only distinctive feature that
may set these apart, in terms of study design, from other field
trials is the issue of ‘blinding’ (see Chapter 11, Section 4). For some forms
of surgery, ‘sham’ operations have been used in clinical studies and
perhaps could be considered in field trials. In general, however,
randomized trials of these procedures will have to be conducted
without blinding.
2.2.3. Diagnostics to guide therapy
The efficient treatment of most diseases requires first that they be
accurately diagnosed. Often the diagnosis is made on the basis of
clinical symptoms and signs, but the imprecision of this method for
many conditions is increasingly recognized. There is an urgent need
for new, or improved, sensitive and specific diagnostic tests for
many infectious and chronic diseases, that are both simple to use
and cheap. For example, intervention strategies that depend upon
case finding and treatment usually require suitable diagnostic
tests. Specific studies may be necessary to measure the specificity,
sensitivity, and predictive values of different diagnostic tests, as
these properties will impact on the likely effectiveness of a case
finding and treatment intervention. For example, the development and
widespread introduction of rapid diagnostic tests for malaria, to
replace microscopy or the presumptive treatment of fever, has been
an important innovation in malaria control and has also focused
attention on the need for improved diagnostic methods and
appropriate treatment of non-malarial fevers.
Field trials to evaluate the performance characteristics of
diagnostics are not discussed specifically in this book, other than
in the context that they may be incorporated as part of an
intervention strategy to improve the control of a specific disease.
The design of studies to evaluate the properties of diagnostics has
been discussed elsewhere (Peeling et al., 2010).
2.2.4. Control of chronic diseases
Chronic conditions may have an infectious aetiology (for example,
HIV, TB) or may have environmental or other causes (for example,
cardiovascular diseases and many cancers). Many chronic diseases,
once diagnosed, may not be curable, but they can be controlled by a
combination of education/behaviour change interventions, plus
regular, often daily, use of pharmaceuticals. The nature of the
clinical care required is often more complicated than required for
acute conditions, such as diarrhoea and pneumonia, which, once
diagnosed, usually require a single course of treatment.
Interventions for chronic disease often must include screening of
communities to identify cases; assessment of each case for the stage
of the disease and possible attendant complications that are likely
to require a variety of laboratory tests; and developing a long-term
treatment and assessment plan. The treatment of such conditions
often requires long-term monitoring, with a dependence on reliable
laboratory results and a system to track the clinical and laboratory
findings within a single individual over time. Trials of such
interventions must often be conducted over several years, or even
decades, to completely assess treatment efficacy.
2.3. Other forms of intervention
2.3.1. Legislation, legal action, taxation, and subsidies
Enforcement of anti-pollution laws, food labelling, and legal
restrictions have an important role to play in public health.
Behaviour may be strongly influenced by legal restrictions, and
increasing prices through taxation have been shown to be effective
in reducing tobacco and alcohol consumption, for example. However,
it is difficult to design randomized trials of such interventions,
because the interventions usually have to be implemented at the
national level, making it very difficult to identify a suitable
control group.
There has been increasing interest recently in providing various
types of subsidies to individuals to change their health-related
behaviour (often known as conditional cash transfers). Examples
include incentives for children to remain in school, or to health
care providers to provide services of at least a certain minimum
quality (performance incentives). Some of these interventions have
been evaluated through RCTs, and there is further scope for using
such approaches.
2.3.2. Health systems interventions
Increasing recognition of the importance of interventions that
operate at health systems level, such as policy implementation,
financing, educational reform, and strengthening of leadership,
management, and governance, has led to a variety of health sector
training programmes, organization changes, decentralization and
devolution, and various incentives and personnel policies. Most of
these efforts have been introduced on a system-wide basis, with
little thought about the value of rigorous assessment. But, with
adequate planning, rigorous evaluation of these kinds of
interventions should be possible through randomized trials,
especially by making use of the ‘stepped wedge’ approach of a phased
introduction of measures in different communities over a period of
time (Brown and
Lilford, 2006). Many health systems research studies may
be considered as implementation research, and most could be
considered as complex interventions, as discussed in Sections 2.3.3 and 2.3.4.
2.3.3. Implementation research
Within the context of field trials, implementation research does not
aim to develop new interventions but focuses on optimizing the
delivery of existing interventions that have previously been shown
to be efficacious when implemented well. Implementation research
explores the challenges of how best to implement research findings
in the real world and how to contextualize interventions for
specific settings. Hence, an example of an implementation research
trial was one where a comparison was made of the costs and
effectiveness of health workers delivering antiretroviral therapy to
patients who attend a central clinic or hospital, compared with lay
workers delivering the antiretrovirals to patients in their homes
and only referring them to the clinic if they reported problems on a
screening questionnaire (Jaffar et al., 2009).
A general reference on implementation research is Werner
(2004).
2.3.4. Complex interventions
The design of a trial to evaluate the efficacy of a new vaccine or
drug is relatively straightforward, in the sense that there are many
past examples of such evaluations to draw upon when planning a new
study. However, the evaluation of some interventions, such as the
deployment of a new procedure in the health service or in public
health practice, may involve consideration of several interacting
components, including, for example, educational components and
behavioural change. Such interventions pose special problems for
evaluation, and these kinds of intervention have been called
‘complex’. Many of the extra problems relate to the difficulty of
standardizing the design and delivery of the interventions, their
sensitivity to features of the local context, the organizational and
logistical difficulty of applying experimental methods to service or
policy change, and the length and complexity of the causal chains
linking intervention with outcome.
In 2000, the UK Medical Research Council published a
Framework for development and evaluation of RCTs for
complex interventions to improve health to help
researchers and research funders to recognize and adopt appropriate
methods. These guidelines were updated and revised subsequently and
can be downloaded from the Internet (<http://www.mrc.ac.uk/documents/pdf/complex-interventions-guidance>).
Box 2.1 is reproduced from the guidelines and summarizes the
steps in developing and evaluating trials involving complex
interventions.
The development–evaluation–implementation process.
