CLINICAL TRIALS (2)

CONTROLS FOR BIAS

Bias: deviation of results or inference from the truth otthe
processes leading to the above
The systematic tendency of any aspect of a clinical study
that leads to an estimate of a treatment effect that deviates
from is true value.
Control techniques to reduce bias:
Randomization
Blinding

A. RANDOMIZATION
Process of assigning subjects to a control or experimental
treatment group on a random basis.
Advantages:
Ensures equal chance at each treatment
Ensures subject samles are similar
Equal distribution of known and unknown factors that
can affect the outcome.
Provides sound statistical basis for evaluation and
comparison of treatment.

RANDOMIZATIONcont.
Disadvantages:

Participants studied may not represent general or study

population (generalizability of results)
Recruitment is difficult
Acceptability of randomization process
Some physicians will refuse
Some participants will refuse
Administrative complexity

TYPES OF RANDOMIZATION
Simple: Code assigns treatment
Block
-Block size chosen;
Can be permuted blocks (2,4,6,8,)
- # of patients assigned to each treatment is proportional
(1:1,(2:1,(3:1)
Systematic: random order in sequential assignments (e.g.(ABAB)

STRATIFICATION
Randomly assigning subjects to treatment groups according
to important prognostic factors measured at baseline, e.g.
Age (young vs elderly)
Severity of disease (HF Type I to IV)
Gender (male vs female)
Weight (normal weight range vs. obese)
Ensures even distribution among treatment groups

MASKING (BLINDING)
Withholding the identity of a subjects treatment
assignment from
Study(participants
Investigators
Sponsors

TREATMENT GROUPS
Fundamental(principles:
Groups must be alike in all important aspects and only
differ in the intervention each group receives!
In practical
terms, comparable treatment groups means alike on the
average
Usually consists of:
Experimental/Test Group
Control Group

EXPERIMENTAL/TEST GROUP
Group under study

Study objective drives the selection

Defined as to dosage form, route of administration, dosage
regimen, length of treatment, & type of dosing.
Provides critical information for the prescribing of the drug
in clinical practice

CONTROL GROUP
A group of people or set of items that serves as a standard or
reference for comparison with the experimental group
Characteristics: Similar to the experimental group in number
and and in specified ccharacteristics such as sex, age, annual
income, parity etc.
Does not receive the experimental treatment or
intervention.

TYPES OF CONTROL IN CLINICAL RESEARCHDESCRIPTION

1) Placebo Concurrent Control
Subjects randomly assigned to an experimental treatment or
placebo group (aka negative control).

Placebo group receives an inactive treatment that is

Identical appearing to the test drug

2) No Treatment Concurrent Control

Subjects randomly assigned to an experimental treatment or no
treatment groups.
Difference from above-patients and investigators are not blinded

TYPES OF CONTROL IN CLINICAL RESEARCHDESCRIPTION cont

3)Active Concurrent Control
Subjects randomly assigned to an experimental
treatment or active control groups.
Active control group, aka positive control.
4) Dose response Concurrent Control
Subjects randomly assigned to one of several fixed dose
groups, initially or raised doses gradually.
Intended comparison between dose groups always the
final dose;
Several variations, with or without placebo

TYPES OF CONTROLS IN CLINICAL RESEARCH

cont.
5) External Control (Historical Control)
Compares a group of subjects receiving the experimental treatment with a
group of subjects external to the study
Compares observations to results of earlier studies.
External controls can be subjects treated at an earlier time or during the same
time period but in another setting.
Least preferred ; difficult to find adequate historical control.

6) Baseline controlled Studies

Subjects status during treatment is compared with their
status before treatment.
Subject acts as his/her own control

TYPES OF MASKING / BLINDING

Open label
Treatment identity is known by the subject and investigator. No
attempt at masking
Single masked (or single blinded)
Withholds treatment identity from subject but not from
investigator
Double masked (or Double blinded)
Subjects of the study, investigators and sponsors are unaware of
each subjects assigned treatment identity.

TYPES OF MASKING /BLINDING cont

Triple masked (or triple blinded)
An extension of the double blind design where there is a
monitoring committee that reviews data but is unaware of
the identity of treatment and data is simply labeled A or
B.

VARIATIONS of BLINDING
Double dummy
Method to allow blinding when 2 treatments can not
be made identical, e.g.
Different test and comparator drug formulations
Different patterns of administration
Both active drug and indistinguishable placebo in
Each treatment arm