Chapter 8 Experimental Studies in Epidemiology - PowerPoint Presentation

Slide1

Chapter 8

Experimental Studies in Epidemiology

Slide2

Objectives

Discuss the role of randomization in controlled

trials

Discuss the role of blinding in controlled

trials

Identify the general strengths and weaknesses of controlled

trials

Identify the advantages to using a run-in design, a factorial design, a randomized matched pair design, or a group-randomized

design

Discuss some of the ethical issues associated with experimental

studies

Slide3

Epidemiologic

Experimental Studies

Resemble controlled experiments performed in scientific

research

Best reserved for relatively mature questions

Best for establishing cause-effect relationships and for evaluating the efficacy of prevention and therapeutic

interventions

Slide4

Experimental

Studies

Also called intervention studiesInvestigators

influence

the exposure of the study subjects

Two types of

experimental

trials

Controlled trials

Community trials

Slide5

Between-Group Design

The

strongest methodological design

is

a

between-group

design

, where

outcomes are compared between two or more groups of people receiving different levels of

the

intervention

Slide6

Within-Group Design

May be used where the outcome in a single group is compared before and after the assignment of an intervention

Strength – Individual

characteristics that might confound an association (e.g., gender, race, genetic susceptibility) are

controlled

Weakness – Susceptible

to confounding from time-related factors such as the media but may be adjusted for in

the

analysis

Slide7

Controlled

Trial

The unit of analysis is the individual A randomized controlled trial in a clinical setting is referred to as a clinical trial

Slide8

Community

Trial

The unit of analysis is the group or community An experimental epidemiologic study where one group

of

people,

or

one community,

receives an intervention and

another

does

not is a community trial

Slide9

Natural

Experiment

In some rare situations in nature, unplanned events produce a natural experiment

Levels of exposure to a presumed cause differ among a population in a way that is relatively unaffected by extraneous factors so that the situation resembles a planned experiment

Slide10

Example of Natural Experiment

Screening and treatment for prostate cancer in the Seattle-Puget Sound area differed considerably from that in Connecticut during 1987-90

Specifically, prostate-specific antigen testing was 5.39 (95% confidence interval: 4.76 to 6.11) times higher in Seattle than

in

Connecticut,

and the prostate biopsy rate was 2.20 (1.81 to 2.68) times higher than in Connecticut

Slide11

Example

of

Natural ExperimentTen-year cumulative incidences of radical prostatectomy and external beam radiation up to

1996

were

2.7% and 3.9% for those in Seattle

0.5% and 3.1% for those in Connecticut

Slide12

Example

of

Natural ExperimentDid mortality from prostate cancer from 1987 to 1997

differ

between Seattle and

Connecticut?

The adjusted rate ratio of prostate cancer mortality during the study period for

Seattle

vs.

Connecticut was 1.03 (0.95 to

1.11

)

In other words,

the

11-year

follow-up data showed no difference in prostate cancer mortality between the two areas, despite much more intensive screening and treatment

in

Seattle

Slide13

Experimental

Studies

Experimental studies may beBetween-group designs

Within-group designs

Slide14

Between

Group Design

When a comparison is made between outcomes observed in two or more groups of subjects that receive different levels of the intervention, we call this a between-group design

Slide15

Within

Group Design

When we compare the outcomes observed in a single group before and after the

intervention,

it is called a within-group design

Slide16

Random

Assignment

Random assignment makes intervention and control groups

look as similar as possible

Chance

is the only factor that determines group assignment

Neither the patient or the physician know in advance which prevention program or therapy will be assigned

Confounding and sample size

Slide17

Non-Randomized Study

Also called convenience sample

Concurrent

comparison group is allocated by a

non-random process

Assignment

Problems

Not effective at controlling unmeasured

confounding

variables

Measured

confounding

variables;

however, may be adjusted through analytic methods

Slide18

Advantages and disadvantages of randomized controlled clinical trials

Advantages

of randomization

Eliminates conscious bias due to physician or patient selection

Averages out unconscious bias due to unknown factors

Groups are “alike on average”

Disadvantages

of

randomization

Ethical issues

Interferes with the doctor-patient relationship

Slide19

Blinding

Three levels of blinding

Single blind – Subjects

Double blind – Investigators

Triple blind – Analyses

Slide20

Single-Blinded Study

In a

single-blinded

placebo-controlled

study, the subjects are blinded but investigators are aware of who is receiving the active treatment

Slide21

Double-Blinded Study

In a

double-blind

study

, neither

the subjects nor the investigators know who is receiving the active treatment

Slide22

Triple-Blinded Study

In a

triple-blind

study

, not

only are the treatment and research approaches kept a secret from the subjects and investigators, but the analyses are completed in a manner that is removed from the investigators

Slide23

Blinding

Patients

Why blind patients?

Patients try to get well/please physicians

Minimize potential bias from a

placebo

effect

A

placebo effect

is defined as the effect on patient outcomes (improved or worsened) that may occur due to the expectation by a patient (or provider) that a particular intervention will have

an

effect

Slide24

Chronic

Severe Itching Study

Forty-six patients randomly assigned to one of four groups

Treatment

Itching Score

Cyproheptadine HCI 27.6

Trimeprazine tartrate 34.6

Placebo 30.4

Nothing 49.6

Slide25

Blinding

Patients

To blind

patients,

use

a

placebo; for example,

Pill

of same size, color, shape as treatment

Sham

operation (anesthesia and incision) for angina relief (unethical)

Problems

In non-drug studies may be impossible/unethical

In drug studies if treatment has characteristic side effects

Slide26

Blinding

Patients

More subjective outcomes call for more serious consideration of placebo

For example, time

to death vs. pain relief

Placebos improve comparability of treatment groups in terms of compliance and follow-up

For example,

if patient perceives improvement

because of medication, more likely to remain in study

Slide27

Blinding physician or outcome assessing investigator

Best way to avoid unconscious bias is to blind

Physicians –

don’t know which patient is taking the placebo and which patient is taking the drug

Assessors –

of the outcome;

are not the treating doctors, and are not told which treatment was used

What if

physician

blinding is

not possible (e.g., surgery or radiation trial)?

Slide28

Problems w

ith Blinding

For non-drug

studies,

such as those involving behavior changes or surgery, it may be impossible or unethical to blind

It may also be problematic to blind in drug studies where a treatment has characteristic side effects

Slide29

Purpose o

f Experimental Studies

To identify clinical and public health approaches to solving public health problems (how to prevent or treat)

Slide30

Strengths of blinded randomized controlled clinical trials

Demonstrate cause-effect relationships

May produce a faster and cheaper answer than observational studies

Only appropriate approach for some research questions

Allow investigators to control the exposure levels as needed

Slide31

Weaknesses of blinded randomized controlled clinical trials

Often more costly in time and money

Many research questions are not suitable for experimental designs because of ethical barriers and because of rare outcomes

Many research questions are not suitable for blinding

Standardized interventions may be different from common practice

May have limited generalizability due to the use of volunteers, eligibility criteria, and loss to follow-up

Slide32

Early

History of Clinical Trials

1600 – East India Company

1747 – James Lind

1835 – P.C.A. Louis, Charite Hospital, Paris

Day bled after onset Died Lived % Surviving

1-3 12 12 50

4-6 12 22 65

7-9 3 16 84 .

Note: 1827 33,000,000 leeches imported to Paris

1837 7,000 leeches imported to Paris

Slide33

Designing

a Clinical Trial

Assembling study

cohort

Measuring baseline variables

Choosing

comparison group

Assuring compliance

Selecting

treatment

Selecting

patient

population

Selecting

outcome

(endpoint)

Ethical considerations

Slide34

Assembling

Study Cohort

Inclusion criteria

Broad vs.

specific – related to the extent

of generalization

Is

the outcome rare (e.g., CHD incidence)?

Then

recruit from populations at high risk

such

as males.

Slide35

Assembling

Study Cohort

Exclusion criteria

Define

exclusion criteria that will help

control

error.

Example

: An advanced cancer that may be fatal

before

the end of the follow-up period in

a

subject

entering

a

CHD-prevention

study

Exclude

those with difficulty

in

complying

Examples

: Alcoholics, psychotic patients, individuals planning to move out of state

Sample size

Slide36

Measuring

Baseline Variables

Characterize the

study cohort

Identifying information (name, address, ID#)

Demographics (age, race, gender, etc.)

Clinical

factors

The

first table of a final report of any randomized blinded trial typically compares the level of baseline characteristics in the two study groups

Slide37

Measuring

Baseline Variables

Consider measuring the outcome variable

Change (appropriate for within-group design)

To assure disease is or is not present at baseline (appropriate for

between-group

design)

Measure various predictors of outcomes (e.g., smoking habits) to allow for statistical adjustment

Be parsimonious (i.e., keep simple)

Slide38

Choosing Comparison Group

Not

contaminated by

treatment

Ideal – possible to blind, usually meaning placebo

used

Status

quo

vs.

new treatment

Slide39

Assuring

Compliance

Calling the day before clinical visitProviding reimbursement

Adhering to the intervention protocol

Drug or behavioral intervention should be well tolerated

Taking once a day vs. complex schedule

Measuring compliance (self-report, pill counts, urinary metabolite levels)

Slide40

Selecting

Treatment

What is the research objective?Are the therapies safe and active against the disease?

Is there evidence that one therapy is better than another?

Is the intervention likely to be implemented in a clinical practice?

Is the intervention “strong” enough to have a chance of producing a detectable effect?

Slide41

Selecting

Patient Population

Often a compromise between

The population most efficient for answering the clinical question

The population best for generalizing the study findings

For example, many CHD-prevention

trials do not include subjects over age 60 because such elderly subjects might already have extensive atheriosclerosis of their coronary arteries that would no longer be responsive to preventive efforts.

Slide42

Selecting

Outcomes (Endpoints

)Primary endpointFor example,

the primary endpoint for

most

phase

III clinical trials in HIV disease is

an

AIDS-defining

event

or

death

Major

AIDS-defining

events

are:

parasitic infections; fungal infections; bacterial infections; viral infections; neoplastic disease; HIV dementia; HIV wasting syndrome

Selection of the “best” endpoint is often complicated

Surrogate endpoint

Slide43

Phase

I

TrialUnblinded

, uncontrolled study with

typically

fewer than

30

patients

The

purpose of phase I trials is to determine the safety of a test

in

humans

Patients

in phase I trials often have advanced disease and have already tried

other

options

They

often undergo

intense

monitoring

Slide44

Phase

II

TrialRelatively

small (up to 50 people) randomized blinded trials that test

Tolerability

Safe dosage

Side effects

How the

body copes with the

drug

Also

evaluate which types of disease a treatment is effective against, further assess side effects and how they can be managed, and reveal the most effective

dosage

level

Slide45

Phase

III

TrialTypically

much larger and may involve thousands

of

patients

These

trials typically involve random assignment and are used to evaluate the efficacy of a

new

treatment

Different

dosages or methods of administration of the treatment are often part of

the

evaluation

Slide46

Phase

IV Trial

A large study conducted after the therapy has been approved by the FDA to assess the rate of serious side effects,

and explore further

therapeutic uses

Slide47

Selected special

types

ofrandomized designs

Basic randomized designs

Run-in designs

Factorial design

Randomization of matched pairs

Group randomization

Slide48

Run-In Design

All subjects in the cohort are placed on placebo (or treatment), followed for some period of time (usually a week or two), and then those who have remained in the study are randomly assigned to either the treatment or placebo arms of the study

A limitation of this study design is that the subjects in the cohort at the time of randomization may no longer reflect the population of interest

Slide49

Factorial

Design

Subjects are randomly assigned to one of four groups. The groups represent the different combinations of the two

interventions.

Slide50

Randomization o

f Matched Pairs

Improves covariate balance on potential confounding variables

Matched randomization provides more accurate estimates than

unmatched

randomization,

and may involve matching on several potential confounders

Slide51

Randomization o

f Matched Pairs

Subjects are matched in pairs according to some confounding factor (e.g., age, sex, race/ethnicity)

One subject is then randomly assigned the study group (e.g., a dietary program, a drug) and the other is assigned to the comparison control group

Slide52

Group

Randomization

Groups or naturally forming clusters are randomly assigned the intervention

Groups may involve

Practices

Schools

Hospitals

Communities

Individuals or patients within a cluster are likely to be more similar to each other compared to those in other clusters

Slide53

Summary o

f Ethical Principles

Benefits –

Maximize

good

Risks – Avoid doing harm

Subject – Respect for all persons

Society – Fairness to all

Is

consent necessary?

Is it necessary to disclose to the subject the fact that they will be determined by chance?

Should subjects be compensated for injury?

Who should be permitted (or encouraged) to participate in clinical research?

When and how should a clinical trial be

stopped

?

Slide54

Tuskegee

Syphilis Study

The Tuskegee study had nothing to do with medical experiments

No treatment was offered for syphilis

No new drugs were tested, nor

were

any efforts

made to establish the efficacy of older chemical treatments

Slide55

Summary o

f Ethical Principles

Competent investigators and good research design lead to a greater likelihood of benefits, protect subjects from harm, ensure that peoples’ time is not

wasted,

and their desire to participate in a meaningful activity not frustrated.

Source:

Levine and Labacqz