Study designs

S Kannan, D.M (Clinical Pharmacology)

Senior Resident
Department of Clinical Pharmacology
Seth GS Medical College & KEM hospital
 Making decisions

Books, teaching, scientific articles

We all read a number
of papers

Clues (symptoms, signs, tests)

Is one study better
than the other?

Diagnosis
 We are all in a bind
• Pressure on time
• Staying abreast of published literature
• Inverse relationship between knowledge of
contemporary care and time since
graduation
 What do we do?
• Compulsory hours per year of CME
• Failed to improve patient care
• Self directed learning
• Not easy to understand
• Scientific illiteracy is a major failing of
medical education
Study design depends on the research question:
the FINER Criteria, Hulley and Cummings, 1998

• F - Feasible

• I - Interesting

• N - Novel

• E - Ethical

• R - Relevant
 Two categories
No intervention Intervention

Observational Experimental

Random allocation
Comparison group
No Yes
No Yes

Descriptive Analytical Non Randomised

study study randomised controlled
controlled trial trial
Time

Cross sectional, case control. cohort

 Descriptive studies are the first
foray into research
• Describe the frequency, natural history
and determinants of a disease
• Case reports/case series/Surveillance
• Do not allow assessment of association
• Follow up with analytical and randomised
controlled studies
What should descriptive studies tell us

• Who has the disease?

• What is the condition or disease being
tested?
• Why did the condition arise?
• When is the condition common or rare?
• Where does or does not the disease
arise?
• So what?
 First report of AIDS
MMWR, June 5 1981
• Pneumocystis Pneumonia --- Los Angeles
• In the period October 1980-May 1981, 5 young men, all active
homosexuals, were treated for biopsy-confirmed Pneumocystis carinii
pneumonia at 3 different hospitals in Los Angeles, California. Two of the
patients died. All 5 patients had laboratory-confirmed previous or current
cytomegalovirus (CMV) infection and candidal mucosal infection. Case
reports of these patients follow.
• Patient 1: A previously healthy 33-year-old man developed P. carinii
pneumonia and oral mucosal candidiasis in March 1981 after a 2-month
history of fever associated with elevated liver enzymes, leukopenia, and
CMV viruria. The serum complement-fixation CMV titer in October 1980
was 256; in may 1981 it was 32.* The patient's condition deteriorated
despite courses of treatment with trimethoprim-sulfamethoxazole
(TMP/SMX), pentamidine, and acyclovir. He died May 3, and
postmortem examination showed residual P. carinii and CMV
pneumonia, but no evidence of neoplasia.
• Patient 2: A previously healthy 30-year-old man developed p. carinii
pneumonia in April 1981 after a 5-month history of fever each day and of
elevated liver-function tests, CMV viruria, and documented
seroconversion to CMV, i.e., an acute-phase titer of 16 and a
convalescent-phase titer of 28* in anticomplement i
Lipoatrophy/Lipodystrophy associated with
antitretroviral drugs
 Cross sectional study
Snapshot in time

• Disease and exposure at a particular time

• Difficult to judge a temporal relationship
• Prevalence study/frequency survey

In women with arthritis, obesity is more common

Obesity Arthritis due to load on the joints

Arthritis Obesity due to reduced mobility

 Cohort studies
Marching towards outcomes
• Military word
• Track people forward in time – from exposure
to outcome
• Compares the experience of a group
exposed to one factor to a group not exposed
to the factor
• Smokers Vs non smokers
– Lung cancer
– Oral cancer
– Heart disease
– Stroke
– COPD
 Cohort studies
Marching towards outcomes
• Enables calculation of incidence, relative
risks and attributable risks
• Selection bias
• Not good
– Rare events
– Events that take a long time to develop
• Loss to follow up
– Differential losses between groups can lead to
bias
– Alteration of exposure status over time
 Case Control study
Thinking backwards
• Start with the outcome and go back in time to
exposure
• Cause of AIDS
• Identified risk groups
– Gay men
– Blood transfusion recipients
– IV drug users
– Multiple sexual partners
– Not using condoms
• Results obtained quickly and at a low cost and effort
• Odds ratio
• Good for rare outcomes
 Case Control study
Thinking backwards

• Not good
– If the frequency of the exposure is low
• Affected by
– Selection of the case group
– Selection of the control group
– Recall bias
– Bias from those who gather data
– Confounders
 A research question
• Is paracetamol intake associated with an
increased risk of asthma?
Association between paracetamol use in infancy and asthma at 6-7 years of life
Lancet, 2008
Paracetamol and asthma:
Case control study
Weekly Vs less than weekly use of paracetamol

Eur Res J, 2008

Eur Res J, 2008
Meta-analysis for other pain killers

Eur Res J, 2008

 Is there a biological plausibility?
• Paracetamol reduces the amount of
glutathione in the lungs and this may
reduce its antioxidant defense
mechanisms
Barriers to valid evidence:
What Is The Truth Here?

IS THERE A BIAS?

WHAT ABOUT CONFOUNDERS?

 3 key study designs
Cohort study
Exposure Outcome

Case control study

Exposure Outcome

Cross sectional study

Exposure

Outcome

Time
 Nested case control study
• Within a cohort
• Compare characteristics between cases
and controls within a cohort
– Blood samples for inflammatory markers for
CRP between smokers and COPD cases Vs
smokers who did not develop COPD (controls)
 Non randomized controlled trial
• Comparison of 2 different cholecystectomy
surgical procedures in 2 units in the same
hospital
• Randomize alternate patients to the 2
interventions
• May overestimate the advantages of one
• Differences in the populations studied
 Randomized controlled studies
Gold standard

• Equal chance of being allocated to either of

the 2 groups
• Minimize the effects of chance or
coincidence
• Minimize biases
• Balance confounders
 Types of RCTs
• Parallel
• Cross over
• Factorial
 Aspirin and asthma:
Randomized double blind study

• 37,270 women
assigned to aspirin or
placebo
• 872 in he ASP group
and 963 in the
placebo group
developed asthma

Thorax, 2008
 Combination Therapy in BPH
Provides Dual Mechanism of Action

Alpha 5-reductase
blockade inhibition

Dynamic Static component

component and obstructive
and irritative symptoms
symptoms
Rationale for Combination Therapy

5ARIs Alpha1-adrenergic
blockers

Arrest disease Rapidly relieve

progression symptoms

Combination therapy: arrest disease progression

and rapidly relieve symptoms?
Medical Treatment Of Prostate Symptoms
Primary Research Question
• To Determine if Medical Therapy Prevents
or Delays the Clinical Progression of BPH
as defined by one of the following:
• Acute urinary retention (AUR)
• Renal insufficiency due to BPH (> 50% rise in
baseline serum creatinine & > 1.5 mg/dl)
• Recurrent UTI or urosepsis
• Incontinence (socially unacceptable)
• ≥ 4 - Point Rise in Baseline AUA Symptom
Score confirmed within 2 - 4 weeks
 Study Design: Overview
•Double-blind, placebo-controlled, multicenter, randomized
Average follow-up: 4.5 years

Randomized
N=3047
Entry Criteria
• Men 50 years of age
• AUA symptom score 8–30
• Qmax 4–15 ml/sec
• Voided volume 125 ml

Finasteride +
Doxazosin Finasteride Placebo
doxazosin
(n=756) (n=768) (n=737)
(n=786)

AUA=American Urological Association; Qmax=maximum urinary flow

Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
 Cumulative Incidence of BPH Progression
25
p < 0.0001 ; df = 3

20
Percent with Event

15

10

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Years from Randomization
Placebo Doxazosin Finasteride Combination
 Cross over trials
• Each patient serves as his own control.
• Each patient gets both drugs; the order in which
the patient gets each drug is randomized.
• Avoids between participant variation in
estimating the intervention effect.
• Requires a small sample size.
• Assumptions:
– The effects of intervention during the first period does
not carry over into the second period.
– Internal and external factors are constant over time.
 2 weeks 2 weeks 2 weeks 2 weeks 2 weeks

SFC WO TIO WO TIO + SFC

 Factorial design

• Used when there are two or more

interventions.
• Allows effects of one intervention to be
estimated at all the levels of the other
intervention.
• Allows the study of interactive effects of
two interventions
Effects of Tiotropium, PR and the
combination in COPD

Tiotropium Placebo
+ +
Pulmonary Pulmonary
rehabilitation rehabilitation

Tiotropium Placebo
 When is an RCT not appropriate?
• Aetiology or natural history of disease
– Placebo group in an RCT
• When it is unethical to randomise
• When the effect of an intervention is so
powerful that a trial is not necessary
 Cumulative Incidence of BPH Progression: Placebo
25

20
Percent with Event

15

10

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Years from Randomization
Placebo Doxazosin Finasteride Combination
Limitations/Drawbacks of RCTs
• Expensive and time consuming
• May not always apply to the general
population (poor external validity)
 Withdrawal designs
• Stopping ICS in a group of COPD patients
Vs continuing them raises the risk of
exacerbations
 Example of cholesterol and heart disease

• 500 patients admitted to a hospital with heart

attacks Descriptive study
• Compare the cholesterol levels of the patients
with heart attacks with those of their neighbours.
Case control study
• Follow up a group of patients with ‘high’
cholesterol vs ‘normal’ or ‘low’ cholesterol.
Cohort study
• Randomized treatment of a cholesterol lowering
drug with that of placebo using heart attacks as
an end point
Randomized controlled study
Hierarchy of evidence
Quality of evidence
Strength of recommendations

Randomized controlled trial

Cohort studies
Case control studies
Case reports/series
• Study of nutrient deficiencies in children
among a slum population of Mumbai
• Study of risk factors for glaucoma
• Efficacy and safety of Moxifloxacin, a
fourth generation quinolone in
Tuberculosis
• Change in mortality after introduction of
antiretroviral drugs among HIV infected
individuals