Managerial Epidemiology: Assignment Week 4
Chapter 8
Experimental Study
Designs
Learning Objectives (abridged)
• State how study designs compare with respect
to validity of causal inference
• Distinguish between a controlled experiment
and a quasi-experiment
• Describe the scope of intervention studies
• Define the term controlled clinical trials and give
examples
• Explain the phases in testing a new drug or
vaccine
Learning Objectives (abridged)
• Discuss blinding and crossover in
clinical trials.
• Define what is meant by community
trials.
• Discuss ethical aspects of
experimentation with human subjects.
True Experimental Studies
• Most convincing for conferring
evidence of associations between
risk factors and outcomes
• Manipulation of study factor and
randomization of subjects
• An example is a randomized clinical
trial.
Women’s Health Initiative
• Hormone Replacement Therapy (HRT)
– Epidemiologic studies had shown that HRT
use had significant benefits against coronary
heart disease.
– Clinical trials had failed to demonstrate any
benefit.
– Large body of epidemiologic research had
observed that women who took HRT had
elevated risks of breast cancer.
Women’s Health Initiative
• Hormone Replacement Therapy (HRT)
– To resolve the question of risks versus benefits of
HRT, a clinical trial was conducted.
– Demonstrated that:
• the epidemiologic findings on cancer were
generally accurate
• the benefits on cardiovascular disease had
been overestimated
– Results
• Use of HRT decreased 40%-80% after the trial
was stopped
Quasi-
Experiment/Community Trial
• Ranked immediately below
controlled experiments in rigor
• Investigator is unable to randomly
allocate subjects to the conditions.
• There may be contamination across
the conditions of the study.
Intervention Studies
• An investigation involving intentional
change in some aspect of the status
of subjects
• Used to test efficacy of preventive or
therapeutic measures
• Manipulation of the study factor and
randomization of study subjects
Intervention Studies
• Two categories:
– Clinical trials (focus on the individual)
– Community trial or community
intervention (focus on the group or
community.
• NOTE: Controlled clinical trials may
be conducted both at the individual
and community levels.
Clinical Trials: Definition
• A research activity that involves the
administration of a test regimen to
humans to evaluate its efficacy and safety
• Wide variation in usage:
– The first use of the term was for studies in
humans without any control treatment
– Now denotes a rigorously designed and
executed experiment involving RANDOM
ALLOCATION of test and control treatments
Characteristics of Clinical Trials
• Carefully designed and rigidly enforced
protocol
• Tightly controlled in terms of eligibility,
delivery of the intervention, and monitoring
out outcomes
• Duration ranges from days to years
• Participation is generally restricted to a
highly selected group of individuals.
Characteristics of Clinical Trials
• Once subjects agree to participate,
they are randomly assigned to one of
the study groups, e.g., intervention or
control (placebo)
History of Clinical Trials
• In 1537, Ambroise Paré applied
experimental treatment for battlefield
wounds.
• East India Shipping Company (1600)
found that lemon juice protected against
scurvy.
• James Lind (1747) used the concurrently
treated control group method.
History of Clinical Trials
• Edward Jenner’s efforts to develop a
smallpox vaccine in the late 18th century
• Most recent historical developments
include the use of multicenter trials.
– Instrumental in the development of
treatments for infectious diseases and
recently in chronic diseases that are of
noninfectious origin
Prophylactic and Therapeutic
Trials
• A prophylactic trial evaluates the
effectiveness of a substance that is used
to prevent disease; it can also involve a
prevention program.
• A therapeutic trial involves the study of
curative drugs or a new surgical procedure
to improve the patient’s health.
Outcomes of Clinical Trials
• Referred to as clinical end points
• May include rates of disease, death, or
recovery
• The outcome of interest is measured in
the intervention and control arms of the
trial to evaluate efficacy--these must be
measured in a comparable manner.
Examples of Clinical Trials
• Medical Research Council Vitamin
Study—studied role of folic acid in
preventing neural tube defects.
• South Bronx, NY, STD Program—
evaluated effectiveness of education
efforts to prevent spread of sexually
transmitted diseases (STDs).
Blinding (Masking)
• To maintain the integrity of a study and
reduce the potential for bias, the
investigator may utilize one of two popular
approaches:
–Single-blind design: subject unaware of
group assignment
–Double-blind design: Neither subject nor
experimenter is aware of group
assignment
Phases of Clinical Trials
• Before a vaccine, drug, or treatment can
be licensed for general use, it must go
through several stages of development.
• This lengthy process requires balance to:
– protect the public from a potentially
deleterious vaccine
– satisfy the urgent needs for new vaccines
Stages in the Development of A
Vaccination Program • Pre-licensing evaluation of vaccine
– Phase I trials: Safety of adult volunteers
– Phase II trials: Immunogenicity and reactogenicity in the target population.
– Phase III trials: protective efficacy
• Post-licensing evaluation
– Safety and efficacy of vaccine
– Disease surveillance
– Serologic surveillance
– Measurement of vaccine coverage
Phase IV Trials
• There can be more than three phases in a
clinical trial.
• Phase IV trials involve post-marketing
research to gather more information about
risks and benefits of a drug.
Randomization
• Method of choice for assigning subjects to
the treatment or control conditions of a
clinical trial.
• Non-random assignment may cause
mixing of the effects of the intervention
with differences (e.g., demographic)
among the participants of the trial.
Crossover Designs • Any change of treatment for a patient in a
clinical trial involving a switch of study
treatments
• In planned crossovers a protocol is
developed in advance, and the patient
may serve as his or her own control.
• Unplanned crossovers exist for various
reasons, such as patient’s request to change treatment.
Ethical Aspects of Human
Experimentation • Benefits must outweigh risks.
• Ethical issues: – Informed consent
– Withholding treatment known to be effective
– Protective the interests of the individual patient
– Monitoring for side effects
– Deciding when to withdraw a patient
Reporting the Results of
Clinical Trials
• The CONSORT Statement is a
protocol that guides the reporting of
randomized trials by providing a 22-
item checklist and a flowchart.
Summary of Clinical Trials
• Strengths:
– Provide the greatest control over:
• the amount of exposure
• the timing and frequency of exposure
• the period of observation
– Ability to randomize reduces the likelihood
that groups will differ significantly.
Summary of Clinical Trials
(cont’d)
• Limitations:
– Artificial setting
– Limited scope of potential impact
– Adherence to protocol is difficult to
enforce
– Ethical dilemmas
Community Trials
• Community intervention trials determine the
potential benefit of new policies and programs
• Intervention: Any program or other planned
effort designed to produce changes in a target
population
• Community refers to a defined unit, e.g., a
county, state, or school district
Community Trials (cont’d)
• Start by determining eligible communities and
their willingness to participate
• Collect baseline measures of the problem to be
addressed in the intervention and control
communities
• Use a variety of measures, e.g., disease rates,
knowledge, attitudes, and practices
Community Trials (cont’d)
• Communities are randomized and followed over
time
• Outcomes of interest are measured
Examples of Community Trials
• North Karelia Project
• Minnesota Heart Health Program
• Stanford Five-City Project
• Pawtucket Heart Health Program
• Community Intervention Trial for Smoking
Cessation (COMMIT)
• Project Respect
Summary of Community Trials:
Advantages
• They represent the only way to estimate
directly the impact of change in behavior
or modifiable exposure on the incidence of
disease.
Summary of Community Trials:
Disadvantages
• They are inferior to clinical trials with respect to ability to control entrance into study, delivery of the intervention, and monitoring of outcomes.
• Fewer study units are capable of being randomized, which affects comparability.
• They are affected by population dynamics, secular trends, and nonintervention influences.
Four Stages of Evaluation
• Formative: Will all plans and procedures
work as conceived?
• Process: Is the program serving the
target group as planned?
• Impact: Has the program produced any
changes among the target group?
• Outcome: Did the program accomplish
its ultimate goal?
Overview of Quasi-Experimental
Study Designs
Type of Study Design Group(s) Pretest Intervention Posttest
Posttest only Intervention O X X
(has only one group)
Pretest/Posttest Intervention X X X
(has only one group)
Pretest/Posttest/Control Intervention X X X
(has two groups) Control X O X
Solomon Four-Group Intervention 1 X X X
(has four groups) Intervention 2 O X X
Control 1 X O X
Control 2 O O X
Note. O = not used; X = used.
Quasi-Experimental Designs
• Posttest only--observations are made only
after the program has been delivered.
• Pretest/Posttest--baseline and follow-up
observations are made.
• Pretest/Postest/Control--observations are
made in both intervention and control
groups before and after the program.
Quasi-Experimental Designs
(cont’d)
• Solomon Four-Group assignment:
– Used to overcome the Hawthorne Effect.
– Uses four equivalent groups, two
intervention and two control:
• Two are observed before and after intervention.
• Two are observed only after intervention.