RESEARCH DESIGNS

Although the randomized controlled trial is

the most frequently used study design for
clinical research, several other designs are
used in specific situations, such as
investigating rare outcome incidences,
studying equivalency/noninferiority between
drugs, or minimizing patient exposure to new
drugs with inadequate efficacy.
Variations of Controlled Clinical Trial
1. Non-inferiority Trial
2. N-of-1 Trial
3. Adaptive Clinical Trial
4. Stability Studies/In Vitro Studies
5. Bioequivalence Trials
6. Programmatic Research
NON-INFERIORITY (NI) TRIALS
seek to show that any difference between two
treatments is small enough to conclude the test
drug has "an effect not too much smaller than
the active control" or reference drug
NON-INFERIORITY (NI) TRIALS
Other randomized, controlled, clinical trials to determine
outcomes between comparative drugs

Superiority trials - the aim is to determine that one drug is

superior to the other
Equivalency trials - designed to determine if the new drug is
therapeutically similar to the control drug
NI TRIALS
is often considered when superiority of a test drug over a
reference drug (for instance standard of care) is not
anticipated
the objective is showing the test drug to be statistically
and clinically not inferior to the reference drug
NI TRIALS
considered when the use of a superiority trial would be
considered unethical
Superiority trial of Drug A vs. placebo
it is unethical to use a placebo when there is available
effective treatment that possesses an important benefit
such as preventing death or irreversible injury to the
patient
NI TRIALS - DESIGN
focuses on the mean difference in efficacy measures between
the test drug versus reference drug
NI margin - can show how much better the reference drug's
effect can be and still allow the test drug to be considered
non-inferior
correctly determining this margin is considered the
greatest challenge in the design and interpretation of NI
trials
NI TRIALS - STATISTICAL RATIONALE
the defining parameters for the null and alternative
hypotheses differ from those used with superiority trials
null hypothesis - reference drug is significantly different
from the test drug by at least the established NI margin
alternative hypothesis - reference drug is not significantly
different from the test drug by not exceeding the established
NI margin
NI TRIALS - STATISTICAL RATIONALE
Check also for:

Assay Sensitivity - the reference drug being used must have

an established effect over placebo in order to further
conclude the possible observed efficacy of a test drug when
compared to the reference drug.
NI TRIALS - STATISTICAL RATIONALE
Check also for:

Constancy Assumption - important parameters from

previously conducted studies must be made identical to
ensure the effectiveness of the reference and test drug being
observed in the present.
N-of-1 Trial
attempts to apply the principles of clinical trials, such as
randomization and blinding, to individual patients
useful when the beneficial effects of a particular treatment in
an individual patient are in doubt
advantageous if the treatment has a short half-life (allowing
multiple crossover periods without carryover effects) and is
being used for symptomatic relief of a chronic condition
N-of-1 Trial
attempts to apply the principles of clinical trials, such as
randomization and blinding, to individual patients
useful when the beneficial effects of a particular treatment in
an individual patient are in doubt
advantageous if the treatment has a short half-life (allowing
multiple crossover periods without carryover effects) and is
being used for symptomatic relief of a chronic condition
 N-of-1 Trial Case Study
Retrospective
Design Prospective
(most often)
Predefined methods Yes No
Clearly defined outcome
Yes No
measures
Randomization Yes No
Blinding Yes No
Multiple treatment
Yes Not usually
periods
ADAPTIVE CLINICAL TRIALS
provides enough flexibility to incorporate continuously emerging knowledge
generated as a trial is carried out
provides an opportunity to change some study methodology when they identify
things that may need to be done differently
different dose, different patients, or measuring different outcomes over a different period of time
staged protocol or group sequential trial
3+3 trial - three patients start at a specific dose, and if no toxicity is noted, a second group of three
patients are given a higher dose
fewer patients are allocated to a less-effective therapy
Stability Studies/In Vitro Studies
determine the stability of drugs in various preparations (e.g., ophthalmologic,
intravenous, topical, and oral) under various conditions
knowing the length of time a particular preparation is stable
Bioequivalence Trials
establish that the quality, safety, and efficacy of generic drugs are the same as the
brand name product
FDA regulations require that bioequivalence between the generic product and the
brand name product be demonstrated
conducted under standardized conditions in normal healthy adult volunteers

Bioequivalent products - products that are equivalent in rate and extent of absorption

in a bioequivalence trial, a 10% difference between products would be equivalent,

whereas, a 10% difference between the products in a superiority trial could easily
be deemed as meaning that there is a difference
Programmatic Research
focused on the impact and economic value of programs and services provided by
pharmacists in community and institutional settings
limited resources and budget constraints demand that only those services that improve patient care
in a cost-effective manner should be implemented
Observational Study Design
used in specific situations such as when large populations of patients must be
followed over extended periods of time
can be prospective, retrospective, or a single snapshot (or slice) in time
interpretation of results from these types of trials only allows associations to be
formed, rather than true cause-and-effect relationships

1. Cohort Studies
2. Case-control Studies
3. Cross-sectional Studies
 Exposure Outcome Study Study
Prospective Retrospective
Observational Known at Known at Determines Determines
Data Data
Study Design Beginning Beginning of Exposure Outcome
Collection Collection
of Study Study Status Occurrence

Cohort X X X

Case-control
X X X
(trohoc)

Cross-sectional X X X
Cohort Studies
Cohort - describe a group of individuals with a common characteristic or
experience
a specific exposure to a particular agent such as a vaccine, medication, procedure, or
environmental toxin
follow-up, incidence, and longitudinal studies
participants are grouped by their exposure and followed over time to determine
the incidence of symptoms, disease, or death
Two groups are usually compared
exposed
non-exposed
Cohort Studies
Categories:

1. prospective (looking forward in time)/concurrent

participants are monitored over time, groups the participants based on
current or past exposure and then follows these groups over time, observing
the various predetermined outcomes
2. retrospective(looking back in time)/historical/nonconcurrent
both the exposure and the outcome are already recorded in a database, uses
computerized data on patients that has been recorded over the natural course
of their health care
Cohort Studies
Categories:

3. ambidirectional (looking both forward and backward in time)

involves both prospective and retrospective components
Ex. Air Force Health Study looking at pilots involved in aerial spraying of
herbicides including Agent Orange during the Vietnam War. The
retrospective portion of the study observed the incidence of cancer and
mortality from time of exposure in the war through the 1980s while the
prospective component involves observing these men well into the future
Cohort Studies
Other terms describing cohort studies:

1. open or dynamic - participants may enter or leave based on changing

characteristics, such as smoking, alcohol consumption, occupation, specific
geographical location
2. fixed - identified by an unchangeable event such as having undergone a surgical
procedure or been exposed to a potential toxin like Agent Orange at a specific
time
exposures do not change or are considered fixed
Cohort Studies
Other terms describing cohort studies:

3. closed - involves an unchangeable event

has a specific starting and ending point that involves follow-up
participants attending a high school football game to determine if the nachos and spicy cheese
consumed at the game provided them discomfort such as gastritis throughout the remainder of the
evening until morning
Cohort Studies
used to investigate the cause of a disease or the benefits and safety risks of both
medication and procedures
simplest approach for studying disease incidence
disadvantages - expense and time consumption
attempts to establish a relationship between an exposure or risk factor and a
subsequent outcome - relative risk
risk of developing a disease or adverse event in those participants exposed to a specific variable
compared to those not exposed to that variable
Cohort Studies
no randomization process that occurs to ensure that each participant has an equal
opportunity to be in either the exposed or non-exposed group
a cohort study has no assurance of this similarity
Cohort Studies
two concerns arise:
selection bias - is a potential whenever the investigator is allowed to decide who is
brought into the study and who is not selected to participate
an investigator either knowingly or unknowingly selects from the general
population only the healthiest individuals to be assigned to the non-exposure
group while at the same time a mixture of healthy and unhealthy participants are
selected for the exposure group
confounder - is a variable related to one or more variables defined in the study
is common since they are the product of not using a randomization schedule
Cohort Studies
accurate measurement of the outcome is essential
surveillance bias is a potential problem when one group, generally the
exposed group is more intensely monitored for changes in the outcome
measure than the comparison group
blinding the investigator to reduce bias
information bias can occur if the same efforts to measure outcomes are not
made for both the exposed and non-exposed groups
Case-Controlled Studies
case-referent / case history / retrospective studies /trohoc
studies
seek to retrospectively identify potential risk factors of
diseases or outcomes
subjects (cases) with a particular characteristic or outcome of
interest (e.g., disease) are recruited, matched with, and
compared to a similar group of subjects (controls) who have
not experienced the characteristic or outcome
Case-Controlled Studies
data are collected retrospectively via patient interviews or by
reviewing subject data records, and the two groups are
compared to identify possible risk factors or contributors for
development of the disease or outcome of interest
Case-Controlled Studies
more useful when diseases have a rare prevalence or when
many years of exposure to the risk factor is required
predisposition to the disease of interest should be similar in
both cases and controls, except for exposure to the risk factor
under investigation; however, this is extremely difficult to
ensure - matching
both should undergo the same diagnostic evaluation to
determine presence or absence of the disease under
investigation
Case-Controlled Studies
Advantages:

relatively inexpensive and can be completed in a shorter

timeframe than cohorts
reduce the need for large sample sizes
Case-Controlled Studies
Disadvantages:

Historical data obtained from medical records may be inaccurate or

incomplete
equal distribution of patients' ability to recall events that have happened in
the past between the two groups may not be ensured
recall bias - patients with disease have probably contemplated factors they
believe may have contributed to disease development
Unblinded investigators who collect data also may question individuals
exposed to the disease more intensely than control subjects
Case-Controlled Studies
Disadvantages:

information about the exposure and outcome is collected

simultaneously, so it is difficult to sort out the temporal
relationship between the two
protopathic bias - difficulty to determine if the outcome preceded the exposure
Ex: Abnormal vaginal bleeding may be an early sign of uterine cancer. Vaginal
bleeding, however, may lead to prescribing hormonal therapies such as progesterone.
An investigator may later erroneously conclude that use of progesterone was
associated with development of uterine cancer, when in fact the cancer preceded use of
the progesterone in this case.
Case-Controlled Studies
Odds ratios - used to help interpret the results from
case-control studies
an estimate of relative risk
greater than one denotes increased risk, equal to one indicates no effect, and
less than one indicates a protective effect
Cross-Sectional Studies
prevalence surveys
can be thought of as a snapshot (or slice) of time because
data are collected and evaluated at a single point in time
hypothesis generating as opposed to hypothesis testing
not suited for testing the effectiveness of interventions
Cross-Sectional Studies
only an association can be drawn from the results, not a
cause-effect relationship
quick and easy to perform
useful for measuring current health status or setting priorities for
disease control
Ex. a survey of smokers is cross-sectional when the questionnaire is
administered once, even though the questions contained in the
survey may focus on smoking habits over the past 10 years
Cross-Sectional Studies
problems are errors in data collection and transient effects that
may influence observations
inaccuracies in data collection may go unnoticed because there are
no prior data for comparison