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Study Design in Clinical Research

Ronald A Thisted, PhD

Department of Health Studies

The University of Chicago

The employment of a method

presupposes that in a proposed inquiry

the use of the method is advantageous

to the solution.

Alfred E Cohn (1924)

Purposes in Medical Research

Journal of Clinical Investigation

Components of Research

Broad objectives

Background and significance

Specific aims / hypotheses

Preliminary results

Methods / design

Dissemination

Social contract / human subjects protection

Components of Research

Broad objectives

Background and significance

Specific aims / hypotheses

Preliminary results

Methods / design

Dissemination

Social contract / human subjects protection

Methods

A detailed

1) plan of action,

2) that will achieve the specific aims

Note that there is an intimate

connection between the aims and the

methodsmake the connection clear!

Research Methods and

Journalism

The Methods answer basic questions:

Who?

What?

When?

Where?

Why?

How?

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Tying Methods to Aims

The methods to be employed are those

which are appropriate to illuminating the

specific problems in question.

Alfred E Cohn (1924)

Purposes in Medical Research

Journal of Clinical Investigation

Methods and W5H

Who will be studied?

Who will be excluded? Why? How will they be studied?

Observation or manipulation?

Measurements:

What will be measured?

How will they be done?

Who will take them? Why?

When, and how often?

Where? Why?

How will the measurements be

used to test the hypotheses?

What will subjects know?

What do different possible

outcomes imply for hypotheses?

What statistical methods will be

used, and why?

How will procedures/tests

accomplish the specific aims?

How many subjects will be

studied? Why?

What obstacles might prevent

complete success?

How can they be minimized?

What might limit conclusions?

Method vs Design

Pharmacokinetics Absorption

Distribution

Elimination

Bioequivalence

Immunogenicity

Dose-escalation

Toxicity / safety

Efficacy

Risk

Case-control

Cohort

Randomized control

trial (RCT)

Crossover

Meta-analysis

Repeated measures

There are packages of approaches:

Method vs Design

Pharmacokinetics Absorption

Distribution

Elimination

Bioequivalence

Immunogenicity

Dose-escalation

Toxicity / safety

Efficacy

Risk

Case-control

Cohort

Randomized control

trial (RCT)

Crossover

Meta-analysis

Repeated measures

There are packages of approaches:

Design = A + B + N

Testing hypotheses

Fundamental idea:Worthwhile research hinges on comparing A to B rigorously

All statistical tests involve comparison

The appropriate statistical analysis depends on the design

The design implies how a comparison will be accomplished,

which implies how the results can be interpreted

The best design depends on the hypothesis being tested

As methods are developed, aims may be refined

And vice versa

Investigator responsibility

Understanding what the methodsselected can accomplish

Understanding the limits of the method Selecting an appropriate design

This can be done with collaborators,including biostatisticians, epidemiolo-gists, and others with specific methods.

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Some Design Examples

Randomized clinical trial

Case-control study

Prospective cohort study

CAST Cardiac Arrhythmia Suppression Trial

Hypotheses:

E, F, M will reduce death from cardiac arrest

One of E, F, or M will do this job best

Design: Randomized, double-blind, placebo-controlled trial, juried adjudication of events, n=1727

Advantage: fairest possible comparison of effects ofprescribing agents on outcome

Strengths: prospective, bias-limiting

Limitations: generalizability to broad pt pops

Issues: compliance and intent-to-treat

Echt, et al (1991) NEJM

CAST Results DES and Vaginal Adenocarcinoma

Hypothesis: A specific risk factor accounts forsudden increase in rare Ca

Design: case-control studyof 8 cases with 32matched controls

Advantage: well-suited to rare disease withlengthy exposure-outcome latency

Limitations: weak bias control, retrospective

Issues: ascertainment, no incidence info,selection

Herbst (1971) NEJM

Maternal Risk Factor #1

Maternal Smoking

Yes No

Cases 7 1

Controls 21 11

p=0.50

Maternal Risk Factor #2

DES given this pregnancy

Yes No

Cases 7 1

Controls 0 32

p

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Natural Hx of Prostate Ca Conservative management of localized PCa

Hypothesis:

Prognosis is affected by specific risk factors

Design: Prospective cohorts, pooled data, n=828

Advantage: allows long follow-up, broad population

Strengths: prospective

Limitations: bias control limited

Issues: selection, loss to follow-up

Chodak, et al (1994) NEJM

Results

Also: age