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Literature Evaluation
Types and Quality of
Medical Literature
Study Design
Types of Drug Resources- Tertiary
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Tertiary Sources
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Compendia (Facts and Comparisons, textbooks,
Micromedex, review and meta-analysis articles)
Advantages: convenient, easy to use, quick
access, compact information, general overviews
Disadvantages: incomplete, outdated, contains
most human bias, lack of expertise and evidence.
Types of Resources: Secondary
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Indexing and abstracting services (Medline)
Use: to locate primary drug literature
resources
Advantages: easy access to primary
resources
Disadvantage: cost, some only have indexing
or abstracting available
Types of Resources: Primary
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Articles in journals about original research or
case reports of actual drug trials/studies.
Advantages: Provides significant detail of
drug knowledge, research methodology,
scientific results allowing the reader to
evaluate the drug in the most non-biased and
scientifically based way.
Most current, most unbiased, used for
therapeutic decisions (actual research data).
Types of Literature Articles…
Tertiary Resource
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Review articles-- tertiary resource articles (not primary)
Purpose: to review a drug in a monograph form or in
a literature search format where many articles are
reviewed, clinical studies are looked at and
conclusions are made that reflect the “current
thinking” on a given subject or drug.
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Advantages: Excellent beginning resource to locate
information about a particular subject. Rapid access to large
amount of information.
Types of Literature Articles….
Tertiary Resource
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Systematic Review
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Summarizes scientific evidence—reviews multiple studies
One or more questions/hypotheses posed at start of review
Studies are collected to review, data is extracted and
combined/compared; Or, if data cannot be combined,
strength of evidence is assessed and used to evaluate
results.
Conclusions are made based on results and presence or
absence of supporting evidence.
Types of Literature Articles…
Tertiary Resource
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Meta-Analysis studies: tertiary resource information.
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A quantitative or statistical method of combining the results of
independent studies (usually drawn from published literature)
and synthesizing summaries and conclusions, statistically, which
may be used to evaluate therapeutic effectiveness, plan new
studies, etc.
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Used when measuring very small effects, to resolve conflict or
inconclusive results among studies, or to evaluate objectives not
posed at the beginning of the study.
Always has statistical evidence present.
Always a retrospective evaluation of collected data.
Types of Literature Articles in Medical
Journals
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Pharmacokinetic studies:
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To estimate:
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the drug’s pharmacokinetic parameters, such as volume
of distribution, metabolism, elimination.
bioavailability or bioequivalence of drugs or dosage
forms.
Drug interactions (food, drug, genetics)
Common in: phase I or II clinical trials
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animal or human studies (small #s, healthy volunteers,
not placebo controlled, not blinded, not randomized)
Types of Literature Articles in Medical
Journals...
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Pharmacodynamic Studies:
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To evaluate drug concentration-effect relationships (if drug conc.
Produce a therapeutic or toxic effect)
Can be animal or human studies (small #’s, healthy volunteers,
not blinded, not randomized, not placebo controlled)
Common place: Pre-clinical and phase I trials. Often combined
with pharmacokinetic studies.
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Types of Literature Articles…
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Pharmacoeconomic Studies
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Studies identifying cost effectiveness for a given dosage
regimen, disease state, or drug therapy
Provides additional information about the potential impact of
a drug’s clinical use.
Example: A Study comparing the cost effectiveness of
tricyclic antidepressants with the newer SSRI
antidepressants in regards to actual pill costs and overall
mental health care costs (hospitalizations, compliance with
medication, longer term side effects, etc.)
Common place: phase IV trials
Types of Literature Articles...
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Clinical Methodology Studies
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Development of new methods compared to the current
standards.
Example: A study to estimate the predictive performance of a
new instrument, sensitivity and specificity of a diagnostic test
or validation of a new drug dosing regimen.
Purpose: to look for more convenient, less expensive or less
invasive means of making measurements.
Types of Literature Articles...
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Pharmacoepidemiologic Studies
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These studies evaluate the use and effects of drugs in large
numbers of people. Used to assess drug use patterns and
to document clinical efficacy and toxicity of drugs.
Have led to the discovery of uncommon, but serious side
effects of drugs, leading to their withdrawal from the
marketplace.
Most common type of design: cohort, case-control.
Common place: phase IV trials
Types of Literature Articles….
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Quality of Life Studies
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performed to evaluate the functional effects, beneficial or
adverse effects that a drug or treatment regimen may have
on a patient and their quality of life.
Used to assess treatments that have minimal effects, to
evaluate a drug in a disease state where few effective
therapies exist, or to differentiate between drugs of the same
class.
Most often in phase IV trials.
Editorial Board
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Editorial boards are made up of people with expertise
to critique the type of manuscript submitted for
publication.
Editorial board members
– Advise the editor about the suitability of submitted
manuscripts
– Assist the editor in setting journal policy
Peer Review
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Experts in their field, asked to review, critique
manuscripts before approval for publication.
Most journals do not identify peer reviewers
for specific articles.
Peer reviewers may or may not be part of the
editorial board.
Peer Review
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How to tell if journal article has been peer
reviewed:
1. Look in “Guidelines for submitting
manuscripts”. This will tell you how many
copies of their manuscript they need to send
in, and will often indicate if peer review is
used. (If more than 2 copies, assume it is
peer reviewed)
Peer Review….
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2. Check either the bottom of the first page or
the last page of the published study. Some
journals will print the date they received a
manuscript, the date it was revised and the
date it was accepted for publication. The use
of peer review will often mean that 3 months
or more have lapsed from the time a
manuscript is received by the journal to the
time it is accepted for publication.
Peer Review….
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3. If the manuscript has been revised, it
usually means it has been peer reviewed and
the author has been asked to make changes.
4. Some journals will put a special symbol in
the side margins or at the end of those
articles that have been through the peer
review process.
Advertising in Journals
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The amount of advertising (ads for specific
drugs, books, equipment, etc) varies from
journal to journal, and ranges from none to
the majority of the contents.
Advertising does not in itself affect the quality
of a journal, but it does lower the cost of the
journal for its readership.
Controlled Circulation
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Several journals are distributed free of charge, with
their cost entirely absorbed by advertisers.
These journals focus on a specific target audience
(community practitioners, retail RPh, etc) and
distribution is targeted to these individuals. This
method of targeting is called “controlled circulation”.
Controlled circulation journals usually do not contain
comprehensive research or clinical studies.
They can provide topic overviews of interest as
review articles.
Citations
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Citations (references) indicate the author has
researched the subject and has used
previous published work as a guide to this
research.
Caution- Sometimes an author will cite his
own work from a previously written article on
the same/similar work-- can create bias and
lower the quality of the reference
Review of Clinical Trial Phases
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Phase I: to identify preferred route, safe
dosage range, toxicity, pharmacokinetics.
Uses healthy volunteers w/ no pre-existing
conditions. Uses low dosages.
Phase II: to evaluate efficacy in subjects with
proposed disease state; identify group most
likely to benefit from drug.
Review of Drug Trial Phases
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Phase III: Compare to current therapy,
multicenter studies, serve as basis for NDA,
large numbers of patients tested.
Phase IV: Post marketing surveillance
studies, to look for side effects, new
indications, new dosages, long term effects,
drug interactions in defined populations.
Drug Study Design
Purpose of a Study Design
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To answer a research question.
The research design determines what can be
concluded from a particular study and the
amount of inference required to interpret the
data.
Research design influences the selection of
the statistical procedures used to analyze
and interpret results.
Research Design
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Organized around three general concepts:
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Description
Analysis
Evaluation
2 basic types of medical research studies:
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Observational
Experimental
Hierarchy of Research Design
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Lowest levels of evidence:
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Higher levels of evidence:
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Descriptive
Cross Sectional
Case-Control
Cohort
Highest levels of evidence:
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Experimental (randomized controlled study)
Types of Medical Studies...
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Observational
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prospective (happening in present and future)
retrospective (looking backwards for data)
observing only, no direct intervention
Experimental
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always prospective
investigators of study have direct intervention
Observational Designs
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Descriptive (Case-Series, Case Report)
Study
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describes situation in group of patients, or
interesting or unique phenomena.
No comparison or control patient groups are used.
Example: 15 patients are described in whom resolution of
herpes zoster occurred following the initiation of Tagamet
therapy for peptic ulcer. All pts. began therapy with Tagamet
300 mg QID for peptic ulcer disease during the time they
were having acute episodes of herpes zoster. The zoster
resolved in 3 days
Descriptive (Case Series, Case Report)
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Advantages
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Relatively easy and inexpensive to perform
Provides preliminary information that could prove valuable
upon further study- raises questions that may prompt more
studies
Disadvantages
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Patients might not be representative of others with the
specific condition
Information provided is subject to many potential biases.
Observational Design- Cross
Sectional Study
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Sometimes called Prevalence or Survey
Study.
Used to determine the existence of specific
conditions or characteristics at one given
point in time. It identifies a sample population
and makes an assessment of outcome all at
the same time.
No controls used
Cross-Sectional Study
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Example: A study selects patients which have had an
adverse drug reaction to a glaucoma medicine. The
study looks for risk factors at the time the study
patients were selected.
Example: Study to determine whether serum
creatinine increases with age. SCr levels were
measured in 400 healthy subjects, between 18-70
y.o. The relationship between age and serum
creatinine were then analyzed. The analysis showed
the strength of the relationship or association and the
direction of the relationship or association.
Cross-Sectional Study Design
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Leads to the “Chicken and the Egg” dilemma
of which came first. Does the patient have
the ADR because of the risk factor or is the
risk factor a manifestation of the disease,
ADR, or a confounding factor?
Cross-Sectional Study Design
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Advantages
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Less time consuming to perform
Least expensive to perform
Easy to complete (sometimes survey form)
Appropriate for evaluating the current status of a
condition or characteristic.
Useful for measuring prevalence, association, and
estimating risk with odds ratios.
Cross Sectional Study Design
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Disadvantages:
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Bias may be introduced if the measured outcome
depends on chart review or recall information
(selection bias, subject bias, investigator bias)
Transient effects: If the condition being monitored
can change over time, the results can be
inaccurate or misleading.
Does not establish causation
No control group
Observational Design- Case
Control Study
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Case-Control Study
– Used to determine the possible factors influencing (risks), or
the causes of, an observed event or outcome. Since one is
looking back in time to identify the factors or causes of the
observed event or outcome, the design is always
retrospective.
– The “cases” are the patients who have the observed event or
outcome.
– The “controls” are similar to the cases, except that they do
NOT have the observed event or outcome. The factors that
are different between the cases and controls are then
examined in terms of the ability to influence the event or
outcome.
– Always 2 groups of patients: one group with outcome, one
group without outcome.
Case-Control Study
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Study Example:
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A study was conducted to evaluate the risk of leukemia
resulting from the use of cancer chemotherapy to treat
breast cancer. The patient files of 90 women with breast
cancer diagnosed from 1973 to 1985 who developed
leukemia were examined. Two to 3 additional patients with
breast cancer but without leukemia were matched to each
of the other 90 patients and examined. It was found that
leukemia was uncommon in patients with breast cancer,
although the risk of developing it was significantly enhanced
by the use of regional radiation.
Case-Control Study
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Always retrospective.
Control group used (without outcome)
Reports odds ratios and risk ratios
Outcome is known- you are looking for
factors influencing the development of the
outcome.
Measures risks.
Sometimes called Trohoc studies
Case-Control Study
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Advantages
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Relatively quick to perform
Generally inexpensive
Appropriate for studying rare diseases or
conditions which take several years to develop.
Case-Control Study
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Disadvantages
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Dependent upon accuracy and completeness of existing
records of past events.
Cannot evaluate cause and effect of measure incidence-only prevalence and association.
Easily biased by the retrospective nature.
Berkson’s Bias: Difficult to obtain “controls” which are truly
comparable to the “cases”
Protopathic Bias: A disease leads to exposure of risk factor
rather than visa versa.
Berkson’s Bias
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The more similar the case and control groups
are to each other, the more likely a difference
found between the groups will be due to the
variable being assessed instead of random
variation.
Example: A study who uses subjects drawn
from hospitalized populations whose
exposure to the risk factor may differ from a
population in the community.
Protopathic Bias
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A disease leads to exposure of the risk factor
rather than the exposure of the risk factor
leading to the disease.
Example: Vaginal bleeding may be an early
sign of uterine cancer. But vaginal bleeding
leads to the use of progesterone. A study
may say that progesterone caused cancer
but, maybe the cancer preceded the
progesterone use.
Terminology
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Prevalence rate: The proportion of existing
cases of a medical condition in the
population at risk at a specified point in time.
For example, the prevalence of hospitalizedacquired pneumonia is the number of cases
divided by the total number of patients
hospitalized at a particular point in time.
Terminology
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Incidence Rate: The ratio of the number of
new cases of a condition to the total number
of persons in the population at risk for the
condition during a specified period. For
example, the incidence of a condition
developing may be reported as the
percentage per person per year.
Terminology
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Odds Ratio: A relative measure of disease
occurrence that provides an estimate of the
relative risk. It is defined as the frequency
with which the event occurs divided by the
frequency with which it does not occur and is
usually calculated for case-control studies
where the incidence is not known.
Observational Design- Cohort
Studies
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Longitudinal study and observational in nature.
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Example: study looking for drug-drug interactions.
Cohort: group of patients who have not yet
experienced the outcome under study.
Cohort Study: characteristics of the cohort are
recorded over time as the investigator observes them
waiting for the outcome to occur.
Does use a control group
Cohort Study
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Prospective Cohort: follows or observes
patients both with and without certain
characteristics/features over time period to
determine what outcomes will be.
Retrospective (historical) Cohort: Patients
are followed both with and without certain
features but all information is collected from
the past (records, charts, billing claims etc)
Cohort Study
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Advantages of Cohort Study
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Usually a clear relationship between risk factors
and the outcomes can be determined.
Allows for uniform data collection and avoids
recall bias (prospective cohort).
Useful for measuring incidence, relative risk,
association and causation
Uses a control group -ranks higher for “levels of
evidence” in evidence base medicine)
Cohort Study
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Disadvantages of Cohort Study
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Exact causes of an outcome cannot be definitively
proven since only observations are being made
(no intervention)
Expensive if patients are followed over long
period of time
Drop out rate can be higher if study is over long
period of time.
Hawthorne Effect
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Subjects change their behavior while being
observed (if they know they are being
watched, they will perform differently)
This can increase compliance and increase
side effects.
Cohort Study Example
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In order to calculate the relationship between high
serum cholesterol concentrations and the risk of
developing heart disease, 1000 healthy men between
35-50 years were enrolled into a study. They were
divided into 2 groups- those with cholesterol <180
and those >180. Men were given medical checkups
yearly. At the end of 10 years, the results indicated
men with high cholesterol were 2x more likely to
develop heart disease.