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.