HAND BOOK OF BASIC QUANTITATIVE RESEARCH METHODS IN HEALTH CARE

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What study design is useful to answer the follow

I would like to know how many pregnant women
well as to determine if pregnant women with ges
induced hypertension

wing question?

n have hypertension in a tertiary care center as
stational diabetes are more at risk for pregnancy

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What study design is useful to answer the follow
I would like to know what conditions are associat

wing question?
ted with pregnancy induced hypertension

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What study design is useful to answer the follow

I would like to know the outcomes of pregnancy
induced hypertension is a cause for preterm labo

wing question?

induced hypertension and also if pregnancy
or and low birth weight

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What study design is useful to answer the follow

I would like to know if Magnesium Sulfate is usef
hypertension

wing question?
ful in the management of pregnancy induced

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What study design is useful to answer the follow

I would like to know how many people have preg
sulfate is useful in the management of pregnancy

wing question?

gnancy induced hypertension and if magnesium
y induced hypertension

Moving Ahead

These are just the very basic elements pertaining
We will work through the intricacies of each desi

g to study designs.
ign as separate modules

Cross sectional study

The important elements of a cross sectional study
1. Across a specified population
2. In a given geographical location(s)
3. In a specified time period

When do we do a cross sectional study?
We do a cross sectional study when

 We want to estimate the prevalence of the outcome or condition of interest in a
given population in a given period of time.

Examples:

a) What is the prevalence of gestational diabetes in population of pregnant women in
the state of Karnataka in 2011?

b) What is the prevalence of cardiac diseases in an urban population of pregnant
women aged 30 years and younger in the state of Andhra Pradesh in 2011?

c) What is the prevalence of low birth weight babies among elderly pregnant women
who delivered live babies at an advanced tertiary care center in the state of Andhra
Pradesh in 2011?

STOP. TAKE A MOMENT TO CONSIDER YOUR RESEARCH QUESTION.
IS A CROSS SECTIONAL DESIGN THE MOST APPROPRIATE DESIGN?
Is your research question focused on determining the proportion of subjects with a
certain condition?
Basic components of a cross sectional study

ITEM COMMENTS

Define the geographical location(s) of the Where is the study conducted? An example will
study be “The study was conducted in Guntur, a semi
Define the time period of the study rural district of the state of Andhra Pradesh in
India”

When is the study conducted? Describe the
relevant dates including periods of recruitment,

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Define the population of the study exposure, follow up and data collection
Describe the strategies used to identify the How is the population identified?
population for the study From outpatient clinics, hospitals, inpatient
wards, labour rooms, communities etc
What sampling strategy is used? Random selection of subjects, convenience
What is the sample frame? selection etc
Describe the strategies used to identify the A community, A village, District, etc
study subjects Identify subjects for the study from within the
population of interest
What sampling strategy, if any, is used? Random sampling, cluster sampling, systematic
What are the inclusion criteria? sampling
What are the exclusion criteria? Define each inclusion criteria
Define each exclusion criteria
Has informed consent been obtained? Procedure to collect written informed consent,
who collects the consent and when
Is informed consent verbal or written? Can be verbal or written. Written is more
Define the variables of interest preferred

How are the variables defined? Describe all variables- exposure, disease,
predictor, outcomes, potential confounders and
How are the variables ascertained? effect modifiers. Give diagnostic criteria if
Who and how many people ascertain the applicable
variables? Describe how the variables are measured and
Describe comparability of assessment ascertained
methods or assessors if there are more than 1
Describe standardization procedures for How are procedures and observers standardized
assessment methods
Describe in detail

Describe in detail

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Describe standardization training for assessors Describe in detail

Describe potential sources of bias Describe sources of bias and steps to minimize
bias

Describe the study size

Assumptions used to estimate the sample size

The sample size including specific subgroup Describe the inputs and assumptions used to
sample size if any estimate the sample size

Describe statistical analysis What software will be used, what variables will
be compare, what tests will be used

How are missing data dealt with

Describe groupings of quantitative variables
with justification

Describe all statistical methods including sub
group analysis and interactions, sensitivity
analyses, and adjustments for sampling
strategy

How are confounders dealt with?

Mention software package used for analysis

Ethics committee and IRB approval Ethics Committee Approval or IRB approval
before study starts

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Case Control Design

The important elements of a case control study
1. The outcome has already occurred
2. The case is a person with the condition of interest
3. The control is a person without the condition of interest

When do we do a case control study?
We do a case control study when

 We want to estimate the association of different factors with the condition of interest.
 The case control design is a retrospective study design that starts from the condition

of interest and then explores to see what factors were associated with the development of
that condition
Examples:
a) What are the risk factors associated with gestational diabetes ?
b) What are the risk factors associated with pre-eclampsia?
c) What are the risk factors associated with preterm labour?

STOP. TAKE A MOMENT TO CONSIDER YOUR RESEARCH QUESTION.
IS A CASE CONTROL DESIGN THE MOST APPROPRIATE DESIGN?
Is your study question focused on determining risk factors associated with a condition?

ITEM COMMENTS

Define the Case The case is a person with the condition of
interest

How is the case defined?

Describe the method(s) of ascertainment of the The ascertainment of the case is masked to the
case exposure factors of interest.

Where is the case selected from? A hospital, population, screening program etc

What are the inclusion criteria?

What are the exclusion criteria?

Define the control The control is a person without the condition of
interest

Journal of Fetal Radiology By AMMA ERF & KREST, Kochi

How is the control defined?

Describe the method(s) of ascertainment of the
case

Where is the case selected from? A hospital, family, neighbors, population etc

What are the inclusion criteria?

What are the exclusion criteria?

Establish that controls do not have the condition
of interest

Define the variables of interest

How are the variables defined? Describe all variables- exposure, disease,
predictor, outcomes, potential confounders and
effect modifiers. Give diagnostic criteria if
applicable

How are the variables ascertained? Describe how the variables are measured and
ascertained

Who and how many people ascertain the
variables?

Describe comparability of assessment methods or
assessors if there are more than 1

Describe standardization procedures for
assessment methods

Describe standardization training for assessors

Are cases and controls matched?

Describe the variables matched for and
justify selection

Describe potential sources of bias

Describe how bias is minimized

Describe the study size

Assumptions used to estimate the sample size

The sample size including specific subgroup

Journal of Fetal Radiology By AMMA ERF & KREST, Kochi

sample size if any
What is the ratio of case to control?
Describe statistical analysis
How are missing data dealt with
Describe groupings of quantitative variables with
justification
Describe all statistical methods including sub
group analysis and interactions, sensitivity
analyses, and comparisons between the cases and
controls
How are confounders dealt?
Mention software package used for analysis
Ethics committee and IRB approval

Journal of Fetal Radiology By AMMA ERF & KREST, Kochi

Cohort Study

The important elements of a cohort study
1. The exposure has already occurred
2. A cohort of people- with and without the exposure- are followed up over a period of time to
see who develops the condition(s) of interest
3. A cohort study helps in establishing causation

When do we do a cohort study?
We do a cohort study when

 We want to establish a causal link between the exposure of interest and the condition(s) of
interest.

 We want to establish multiple outcomes from a single exposure
Examples:
a) Is obesity a cause for gestational diabetes mellitus?
b) What are the maternal and fetal outcomes of tobacco smoking in pregnant women?

STOP. TAKE A MOMENT TO CONSIDER YOUR RESEARCH QUESTION.
IS A COHORT DESIGN THE MOST APPROPRIATE DESIGN?

Is your study focused on determining multiple outcomes associated with an exposure?
Is your study focused on determining what causes a condition of interest?

ITEM COMMENTS

Define the exposure The exposure or prognostic variable is the
variable of interest

How is the exposure defined?

Describe the method(s) of ascertainment of the Show evidence that these are standard and
exposure accepted methods of ascertaining the exposure

How often is exposure measured and at what A hospital, population, screening program etc
intervals

How are missing values or ascertainments dealt
with?

Define the non exposure Need to show evidence that it is possible to
correctly classify non exposure and minimize

Journal of Fetal Radiology By AMMA ERF & KREST, Kochi

misclassification

How is the non-exposure defined?

Describe the method(s) of ascertainment of the
non-exposure

Establish that exposure and non-exposure groups
do not overlap

Define study subjects

Describe the population from which the two The two groups should be selected from similar
groups are sourced populations that preferably differ only in the
exposure of interest

Establish that the subjects in the study do not
have the outcome of interest at time of
enrollment

Define the variables of interest

How are the variables defined? Describe all variables- exposure, disease,
predictor, outcomes, potential confounders
and effect modifiers. Give diagnostic criteria if
applicable

How are the variables ascertained? Describe how the variables are measured and
ascertained Assessment of outcome is blind to
exposure status

Who and how many people ascertain the
variables?

Describe comparability of assessment methods or
assessors if there are more than 1

Describe standardization procedures for
assessment methods

Describe standardization training for assessors

Describe the process of masking

Describe time period of ascertaining each variable How many times and at what intervals

Are the two groups matched?

Describe the variables matched for and justify

Journal of Fetal Radiology By AMMA ERF & KREST, Kochi

matching

Describe potential sources of bias

Describe potential sources of bias and how bias is
minimized

Describe the study size

Assumptions used to estimate the sample size

The sample size including specific subgroup
sample size if any

What is the ratio of exposure to non-exposure?

Describe statistical analysis

How are missing data dealt with? Loss to follow up, lack of all measures at all
intervals

Describe groupings of quantitative variables with
justification

Describe all statistical methods including sub
group analysis and interactions, sensitivity
analyses, and comparisons between the exposure
and non-exposure

How are confounders dealt?

Describe how causal links will be established

Mention software package used for analysis

Ethics committee and IRB approval

Journal of Fetal Radiology By AMMA ERF & KREST, Kochi

Clinical Trial Design

Trial- Phases

There are several phases a “new” drug goes through prior to becoming recommended practice.
Thus, a new drug does not enter the market straight away and is not prescribed without prior
testing.
There are several steps before the drug enters the market and some after the drug enters the
market.
The pre-phase I studies
A new compound or a new molecule is not immediately tested on humans.
There are several reasons for this. The mew compound or molecule may not, despite the best
intentions of the “creators”, behave as expected and may possibly lead to serious adverse
events. Therefore, the process of extensive testing of new drugs or therapeutic interventions starts
in animals in a lab setting.
Animal studies look at several things

1. We quantify or assess the course of the molecule (drug), over time, in various tissues and
organs -pharmacokinetics

2. We determine the effects of the molecule (drug) on the structure and function of cells,
tissues, organs, and organ systems – pharmacodynamics

3. We assess what happens to the molecule- how is it metabolized, what is it converted to,
how or how much is retained, how is it excreted, what are the effects of these conversions,
are these conversions/storage/excretions toxic or adverse event inducing changes.

4. We give the molecule in increasing doses till it kills at least 50% of the lab animals to
determine the lethal dosage (LD50 ). We examine the X% (usually 50%) that die at once.
Survivors are killed at various intervals thereafter and examined.

We will consider the new molecule for further testing if
 The lethal dose (LD50) of the new molecule is much higher than the dose required for the
desired pharmacodynamic effect (in other words, the molecule can do good at much lower
doses than when it becomes lethal)
 if other attributes that are tested are favourable- there are more beneficial changes than
toxic effects
 if the further development and testing of the molecule shows promise to provide an
affordable (or more profitable) drug

Further testing is done on humans based on the results of the animal studies that precede it.

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Phase I trials

In these trials, tiny or small doses of the compound or molecule is given to a few volunteers (variable
number, maybe 10-15) to see how the molecule behaves in healthy humans. This step focuses on
examining if the molecule or compound displays the same pharmacokinetics, the same metabolic
conversions and for any potential toxicity.

If the molecule behaves safely, the molecule is then given in increasing amounts (incremental
increases) to volunteers or subjects until the results (pharmacodynamic results) found in animals are
replicated in humans. This phase of the testing may be done on healthy subjects or on persons with
the serious forms of the disease or condition (who are not improving with any of the available
current interventions) that the molecule is expected to improve. These subjects undergo intense
monitoring for known and unknown side effects and a whole series of lab tests for a whole range of
values.

If the molecule or compound still looks promising, we move onto phase II trials

Phase II trials

In a phase II trial, the molecule or compound is administered to a larger group of participants
(maybe between 25-40) with the target condition of interest.

This phase is focused on

 To confirm the results of the previous pharmacokinetic and metabolic studies

 To determine and confirm the dose required to achieve the optimal or desired
pharmacodynamic effects

 To estimate the proportion of persons who respond and achieve the desired effects at the
set dose and the proportion of persons who do not respond and do not achieve the desired
effects at the set dose

 To look for known and hitherto unknown effects of the molecule (toxicity) on a larger
sample.

Phase III trials

Molecules or compounds that still look promising in phase II trials may be continued to phase III
trials.

It is important to consider that not all molecules in a phase II trial may continue to a phase III trial
even if they look promising. Issues of cost, development and return on investment play a role in
further progress.

Do all phase II “passed” molecules or compounds achieve success in a phase III study? A moot point
that may need further study. (Intuitively, it is unlikely a significant proportion will achieve success).

The phase III trial is a full-fledged randomized clinical trial with sufficient sample size and power to
either conclusively prove or refute the predicted benefits from the molecule.

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Phase IV studies

These are otherwise known as surveillance studies or post marketing studies. Needless to say, they
occur after a phase III study has proven benefits and the molecule or compound is now into the
realm of prescription and marketing.

Why do we need phase IV studies?

 We need to continue surveillance to look for rare, serious adverse events that may not have
shown up in the subjects studied earlier

 If we want to be 95% confident or sure of observing one adverse event that occurs once in X
subjects, we need to study at least 3X subjects.

 The sample size estimation for phase III trials are rarely so large and hence we need phase IV
studies.

 We can explore for potential interactions of the molecule with other drugs, diet, behaviours,
the distribution or determinants of its use (pharmacoepidemiology) and health economics-
measurement of cost effectiveness, cost utility (pharmacoeconomics).

 We can also explore for the effects of the drug in a wider spectrum of population that may
not be sampled as part of a phase III trial (the elderly, the young, vulnerable populations)
etc.

Take home messages

 There is a process of development before a molecule enters the market for prescription
towards a disease or condition

 The initial phase of testing is usually done on animals in captive conditions in a lab. Lives are
lost to look for solutions to human problems…so, if you have ever popped a pill, please do
attempt to be more humane towards animals.

 Studies pass through progressively larger numbers and strict protocols before they are
finally approved for marketing.

 Data on post marketing studies have to be considered before the drug/molecule/compound
is finally declared relatively safe for use.

Ideal or Pragmatic Clinical Trial?

We have looked at the various phases of trials that are done during the development of a molecule
into a drug or medicine. We have seen how these are tested on a larger population as part of a
randomized clinical trial (phase III trials). A randomized clinical trial (RCT) is considered the best
design to determine the efficacy or effectiveness of a new intervention.

Clinicians worldwide are aware that the strictly controlled environment of a RCT does not necessarily
translate to actual clinical practice. It may not be possible to monitor patients as intensely as done
during a trial, patients may or may not take the medicine as prescribed, and they may or may not
come for follow up, and may or may not report adverse events. In other words, the “effectiveness”

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or “efficacy” of an intervention with evidence from a well-designed RCT may or may not translate to
actual benefits in clinical practice.

Why does that happen?

Typically, these trials are designed and carried out adhering to a strict protocol that is designed to
tell us if the new intervention (drug) are taken faithfully by subjects (after prescription) will exhibit
their full pharmacodynamic properties, have an acceptable low risk of adverse events, and do more
good than harm. The RCT is done under a strictly controlled environment that is more ideal than
pragmatic. Thus, the RCT is designed to find out if the new drug can provide better than harm
under ideal conditions….it may not be able to provide an answer to the benefits accrued under less
than ideal conditions.

RCTs usually (an ideal RCT)

 Have strict exclusion and inclusion criteria. These criteria are usually defined with strict and narrow
parameters that limit inclusion to the high or moderate risk subjects. Subjects on the milder
spectrum of the condition may be excluded just by the parameters of the inclusion criteria. A
particular subgroup, with a different risk profile, may also be excluded just because it is difficult to
make assessments in those groups (example-studies on pregnant women often do not included
multiple pregnancy as a subgroup) or because those are relatively rarer.

 Enrol subjects who are committed to complete the course of medication. This may limit enrolment
to within a geographical radius that allows us to follow them up more intensely, where we could
possibly chase them down at their residence if they do not turn up.

 Exclude subjects who are later found not to meet the criteria for inclusion (after enrolment)

 Include subjects who show they can withstand or are more likely to withstand the new treatment,
thus the extremes of ages (elderly and young) and other vulnerable populations (undernourished or
the people with more severe forms of the condition for example) may be excluded from the scope of
the trial

 Subjects are assessed by experts and receive care under the supervision of experts

 They are carefully and intensely monitored by experts for compliance and health status

 Assessments may include sophisticated technology and techniques that help to identify adverse
events early

 Have monitors who intervene if compliance fails

 Have monitors who intervene if the treating doctors do not follow the protocol

 Look for adverse events focused on the research question- other adverse events may not be
reported unless serious

 Exclude subjects who stop complying

 Exclude subjects who do not follow up

 Stop follow up after the duration set by the trial.

What happens in a real life clinical practice?

In real life, a controlled environment does not always exist for clinical practice.

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The population with the disease may include the elderly, the young, other vulnerable populations,
and people with milder forms or very severe forms of the disease. The methods of assessment may
differ. Some clinicians may base their diagnosis on a clinical exam with little tech support, some may
base their diagnosis after a very detailed (maybe even an overkill) set of tests including sophisticated
scans. People may or may not comply with the medications. People may not comply with follow up
and may come at different durations than advised. There may be no one to monitor and point out
missed parameters to the treating physician or to the patient. The course, duration and outcomes of
the disease may not show the same improvement reported in the trial.

Clinicians become disappointed with the effect of the new medication and wonder if they were sold
a dud…and wonder about the integrity of the trial.

What do clinicians want?

Clinicians want to know how a drug or medicine will behave, when prescribed in a small practice (not
in the biggest of the institutes that have the most sophisticated diagnostic and therapeutic
support) to patients with a wide spectrum of disease that is often skewed towards the milder forms,
and who may or may not come for further follow up. Clinicians want to know what may be a safe
dose to get enough of the drug into the body to provide a beneficial effect with minimal or no side
effects.

An ideal RCT may or may not be able to answer that question.

What is needed to answer that question is a pragmatic trial focused on the real life management of
patients.

A pragmatic trial can be designed

 By setting less strict parameters or boundaries for the inclusion or exclusion of subjects

 Include all eligible subjects regardless of risk, potential compliance, responsiveness, or site of care

 Retain all admitted or enrolled subject in the analysis

 Leave the clinician and the patient to get on with the treatment without intense monitoring or
forcing the patient or the clinician to a precise regime

 Look at a broad range of events and include them in the analysis

 Charge adverse events to the intervention they were randomized to or received.

Characteristic Ideal RCT Pragmatic RCT

Condition of the Does the treatment Does the treatment work
trial work under under usual conditions?
ideal conditions?

Who is eligible? Very strict inclusion All persons with the target
and exclusion criteria disorder who consent to
participate

What happens to Excluded from the Included in the analysis
subjects found analysis

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ineligible at a later
date?

Administration of By experts under strict As in routine clinical care
intervention supervised conditions
and monitored

Follow up Intense, frequent visits As in routine clinical care

Compliance Closely monitored with Unobtrusive monitoring, no
strategies to improve compliance enhancing
or maintain strategies
compliance

Adherence to study Strict, monitored Little or no monitoring
protocol

Reporting adverse Restricted to study All adverse events
events question (s)

Duration of follow Stops when event of Continues till the end of trial
up interest occurs or death, whichever comes
first

Do the conclusions differ in an Ideal and a Pragmatic RCT?
We can conclude from a RCT that

1. Benefits are clearly greater than harm

2. Benefits are clearly not greater than harm

How does an ideal and pragmatic RCT differ in the ability to interpret these conclusions?

Type of Conclusion from the trial Benefit <= Harm
Trial Benefit > Harm

Ideal It works only if patients Abandon the treatment. It does not
and clinicians are work as well as hoped for
willing to walk the
extra mile to sustain
success

Pragmatic Clearly worthwhile to Cannot be sure why it failed – Is the
adopt the treatment as treatment really not good or most
it works under almost patients and clinicians did not follow
all conditions instructions and hence we could not
really evaluate the treatment.

Take Home messages

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 It is possible to do an ideal RCT or a pragmatic RCT. Both have certain advantages and
disadvantages.

 Both are not exactly in isolation from each other, there may be a certain overlap.

 The choice of the design (ideal or RCT) depends on the research question. Thus, your research
question determines the choice of an ideal RCT or a pragmatic RCT.

 We could choose to initially test the new treatment under strict conditions using an Ideal RCT design
and follow that up with a larger, simpler, pragmatic trial (if the strict trial shows benefits). However,
most trials stop at the ideal RCT stage….

 We could also do a simultaneous ideal-pragmatic design. We start with an ideal RCT design that
includes eligible subjects who meet a strict inclusion-exclusion criteria. They are randomized to the
intervention arms. Simultaneously, those found ineligible (as per the strict inclusion-exclusion
criteria) are included as a separate pragmatic arm and randomized to each intervention. The final
analysis can include an analysis of the ideal RCT plus an analysis of the larger group (ideal +
pragmatic). (Read more on this design at Banerjees SH, Raskob G, Hull RD. A new design to permit
the simultaneous performance of explanatory and management randomized clinical trials. Clin Res
1984; 32: 543 A)

SUPERIORITY AND INFERIORITY TRIALS

Clinicians like to have the answers to three questions before they use a new treatment for their
patients.

1. Is the new treatment better than existing treatments?

2. If the new treatment is not better than the existing treatment, is it at least as good as the
existing treatment?

3. Is the new treatment affordable, does it have fewer side effects or less severe side effects, is
it easily available?

These questions can be answered by a superiority or non-inferiority trial design.

A superiority RCT attempts to answer the question whether intervention X is superior to an
established effective therapy or a placebo (we will discuss effective established therapy later). The
margin of superiority is predetermined prior to the trial and is considered as the margin of
superiority to be considered as clinically significant.

Example- I will consider intervention Y to be superior to the established Intervention X if the results
with intervention Y are at least 15% better than intervention X for specified outcomes.

The margin of superiority is a clinical decision based on optimal benefits to the patients. We can
consider these as minimally important differences (MID) and have to incorporate these at the design
state of the trial. We will discuss about minimally important differences later.

Any intervention compared to a placebo has to pass through a superiority trial.

A non inferiority trial, on the other hand, checks to find if the intervention Y is at least as good as
intervention X. The margins of “as good as” are predetermined based on what is clinically significant.

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Intervention X maybe better (based on the predetermined margin) or worse (based on the
predetermined margin) that intervention Y. Essentially, we are checking to see if both interventions
are nearly similar and if the dissimilarity is clinically acceptable.

Example- Intervention Y is not inferior to intervention X; Intervention Y may give up to 5% different
results in either direction (up to 5% better or up to 5% worse) compared to intervention Y. Specify
the margins prior to the trial.

We can use a non-inferiority design to compare a new intervention against an established therapy.
This is most often used to compare a new similar class drug against a market competitor (the
interest in this instance is not necessarily to show superiority of drug but that the drug is not inferior
to the existing drug)

Take home messages

1. Clinical trials can explore if an intervention is superior to the existing intervention-
superiority trials

2. Clinical trials can explore if an intervention is not inferior to the existing intervention- non
inferiority trials

3. The margins of superiority or non-inferiority have to be set prior to the start of the trial.
These margins play a role in sample size determinations

4. Any placebo trial (placebos are used only in specific circumstances) has to be a superiority
trial. We do not want to show that the intervention is not inferior to a placebo.

5. More of the same, under different guises, need not always be good (though there may be
advantages as in generic drugs), so evaluate non inferiority trials carefully.

Allocate Intervention

A clinical trial compares the effects of an intervention to one or more other interventions. The
interventions are offered to groups of eligible, enrolled subjects and the effects compared across
groups (or individuals, organs). To minimize noise in the comparison, the experimental therapy is
given to everyone in the “experimental” group and to no one in the control group. Both groups are
treated similarly except for the intervention (as much as possible). The outcomes including adverse
events are measured and assessed similarly for the two groups.

How do we allocate subjects to the intervention arms?

There are several strategies that can be used to allocate individuals to the intervention arms. We can
toss a coin, we can use an “alternate approach (odd and even numbers), we can use days of the
week, we can use hours of the day…and several such approaches.

There are several concerns we would like to address while we allocate subjects. An important
consideration is that every subject in the trial has an equal, unbiased chance of receiving either
intervention. Neither the subject nor the investigator determine the intervention they receive. Once
eligibility is confirmed and the subject is enrolled into the trial, they should have an equal unbiased
chance of receiving any of the interventions under study.

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