DRUG LITERATURE EVALUATION

CONTROLLED CLINICAL TRIAL EVALUATION Validity of Clinical Trials

Term Meaning Application
Controlled Clinical Trial Internal Quality of the Strong design
● Premiere study design to measure and quantify Validity study design should translate
differences in effect of the intervention and control into reliable
● Consists of an investigational (intervention) group results
being directly compared to a control group (e.g. External Ability to apply Study results
standard therapy, placebo) Validity results to meaningful to
practice practitioners and
● Most robust method to measure and quantify
can be used for
differences in effects between a therapy under study
patient care
and the control group
METHODS - Study Design
TITLE
● Study questions dictate the study design
● Reflective of the work, unbiased, specific, and concise
● Controlled clinical trial - prospectively measures a
(usually ≲ 10 words) but not too general or detailed
difference in effect between two or more therapies
● Declarative sentences that tends to overemphasize
○ Groups are similar and treated identically with the
conclusions are not preferred
exception of the therapies under study
● RCT should be identified in the title
○ Parallel design - subjects in the study are assigned
● Should include key words that are both sensitive
to one of the groups and monitored
(easing the task of locating the appropriate articles) and
● Controlled clinical trial - most rigorous method of
specific (excluding those not being searched for)
establishing a cause-and-effect relationship between
treatment and outcome
ABSTRACT ○ Treatment is the cause and outcome is the effect
● Concise overview of the study or a synopsis of the ○ Effect is compared to the effect of other groups
major principles of the article ○ Magnitude of the difference in effect can be
● Includes information addressing the article objective, estimated
methods, results, conclusions
● Should be thorough, complete, and unbiased in METHODS - Patient Inclusion/Exclusion Criteria
wording selection The results of a controlled clinical trial should be
extrapolated to the patient type enrolled in the study
INTRODUCTION and readers must be aware of the limitations of
● Purposes of introduction: surrogate endpoints and subgroup analysis results.
1. Discussing the study rationale
2. Discussing the study purpose/objective Surrogate endpoint - a study measurement (lab value
● After formulating the objective, formulate: or physical assessment) that serves as a substitute
1. Research hypothesis - difference in the therapy marker for an actual clinical outcome (LDL levels for
under investigation and control cardiovascular events)
2. Null hypothesis - no difference between the two
groups Inclusion criteria: lists subject demographics that must
● Not all clinical trials includes hypotheses be present in order for the subject to be enrolled in the
trial
METHODS
● Design of the study is important for the results to be Exclusion criteria: characteristics that prevent a subject
valid from enrollment in the trial or necessitates withdrawal
● Includes: types of subjects enrolled, the comparative from the study
therapy description, outcome measures, and statistics

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● These are pertinent to the extrapolation of the study
results (applying study results to practice [external
validity])
● Ex: CONDOR (Celecoxib versus Omeprazole and
Diclofenac in patients with Osteoarthritis and
rheumatoid arthritis) trial
○ Subjects are either:
(1) at least 60 y/o; or
(2) 18-59 y/o with a history of gastroduodenal
ulceration or GI hemorrhage
○ Thus, results cannot be extrapolated to patients
less than 60 years since only those less than 60 years
with history of gastroduodenal ulcer were included
● Selection bias may be present
○ Occurs after subjects meet the inclusion and
exclusion criteria, but are not enrolled in the study
○ Investigators prevent them from being enrolled
because they may alter the results either positively
or negatively
○ Common form in the run-in phase (Lead-in phase)
● Run-in phase (Lead-in phase)
○ 2-4 weeks before being officially enrolled
○ Can identify subjects who may or may not adhere
to the therapy regimen, experience side effects from
the therapy, or did not meet prespecified criteria
○ They are excluded from participating even if they
met the original inclusion criteria
○ Produces a bias by selecting a group who do not
completely represent the population
METHODS - Intervention and Control Groups
Intervention group: consists of the therapy under
investigation (medication or procedure) Control group:
consist of no therapy (placebo), another therapy (active
control) or be compared to existing data (historical
data)
Both are to be as similar as possible in all respects
(average age, number of male/female, medication use,
disease states) other than the treatment received.
Any identified differences can be attributed to
intervention rather than other factors.
Controlled clinical trial - the word “control” indicates
another therapy is serving as the measuring point for
the effect of the intervention to be assessed.
METHODS - Institutional Review Board/Subject
Consent
Research projects that use human as study subjects
must be approved before investigators begin enrolling
subjects in the trial.
IRB - committee charged with ensuring the subjects are
protected and not exposed to unnecessary harm or
unethical medical procedures
Informed consent form: subject is presented with the
form to notify study procedures, their rights and
responsibilities of participating in the study,the risks,
benefits, compensation, voluntary participation, and
right to withdraw without penalty
METHODS - Blinding
● A technique in which subjects and/or investigators are
unaware of who is in the intervention or control group
● To reduce the influence of bias on measuring a
difference in effect between the intervention and
control
Types of Definition
Blinding
No blinding Investigators and subjects are aware
(open-label) of the assignment to the intervention
or control
Single Either investigators or subjects, but
not both, are aware of the assignment
Double Both investigators and subjects are
not aware of the assignment
Triple In addition to both investigators and
subjects not being aware, trial
personnel involved in data
interpretation are not aware of
subject assignment
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METHODS - Randomization
● An essential component of all controlled clinical trials
and a significant differentiator from other study designs
● All persons in a clinical trial who have an equal chance
to be in the intervention or control group
● Results are more dependable than nonrandomized
trials
METHODS - Endpoints
Primary endpoint - one effect caused by the
intervention and control
Secondary endpoints - routine and useful measure; not
considered to be the primary purpose of the study
The primary endpoint should be appropriate for the
study purpose and measured using valid techniques and
methods.
Composite endpoints - combination of endpoint
measures into one primary endpoint
● Consists of clinical outcomes directly related to
morbidity and mortality as opposed to a
pharmacological action (reduction in any incidence of
stroke/MI/CV-related death vs. lowering cholesterol
levels
● To measure an overall effect of therapy
METHODS - Follow-Up Schedule/Data
Collection/Adherence
Considerations:
1. study should be conducted for an appropriate
duration
2. data need to be consistently collected throughout the
entire trial
Monitoring of the trial results at predetermined
intervals is important throughout the duration of the
trial.
● the protocol for discontinuing the clinical trial early is
established prior to enrolling study subjects
● prior to the start of the study, data collection
methods are established
● investigators should ensure trial personnel are
properly trained and have sufficient resources to
complete data collection
● measuring the adherence of therapy
○ medication dosage unit counts
○ serum drug levels
○ regular follow-up communications (i.e., telephone
conversations)
● insufficient and/or inappropriate data collection
methods and nonadherence usually lead to biased
results
METHODS - Sample Size
● appropriate sample size is vital for the study results to
have any significant meaning; conducting a power
analysis is important to determine a suitable sample
size
Sample size (n) - refers to the number of subjects
randomized into a study and is of considerable
importance to the validity of the study results
● sample size should not be determined on the basis of
convenience, arbitrarily, or by the number of easily
recruited subjects
● dependent on the expected magnitude of difference
in the endpoint effect between the intervention and
control
○ large sample size is needed to detect a small
difference in effect between the intervention and
control outcome, while a smaller sample size is
needed to detect large differences between the two
groups
●regardless of the method selected to determine the
appropriate sample size, it must be calculated prior to
initiating the clinical trial
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METHODS - Statistical Analysis ○ continuous data are assessed via parametric statistics;
● means to analyze sample data and apply it to the common tests are Student’s t-test, analysis of variance
population (ANOVA), and analysis of covariance (ANCOVA)
● a biostatistician is consulted as one of the trial ○ Nonparametric tests are used for nominal and ordinal
investigators to perform the statistical analysis of the data; examples are chi-square (χ 2) and Mann-Whitney
trial results U test
● to collect sufficient evidence to reject H0 in favor of
accepting the research hypothesis (H1 ) (new Descriptive statistics
terminology may refer to this as failure to accept H0 ) ○ describe the characteristics of the sample (e.g.,
● appropriate tests are selected based on the type of average subject age, baseline endpoint values, number
data that will be collected and analyzed of subjects with another disease present) and the
results in some studies (e.g., X% had an adverse effect)
Type of Definition Examples ○ presented as measures of central tendency (e.g.,
Data mean [average], median, mode) and/or measure of
Nominal Categorical data; Yes/No; variability (e.g., range, standard deviation [SD],
data placed in alive/dead; colors variance)
one category, but of cars in a
not more than parking lot into Non-Parametric Test
one category, five categories of Chi-square test Comparison of nominal
mutually either red, white, data for independent
exclusive blue, black, or groups (2x2)
other
Fischer’s exact test Comparison of nominal
Ordinal Ranking, ordered Likert scale; visual data for 2 groups when
analog scale expected frequency is <5
Interval Data with Temperature in McNemar’s test Comparison of nominal
measurable equal degrees data for 2 matched or
distances Fahrenheit paired groups
between points,
Contingency table Comparison of nominal
but no absolute
analysis (R x C) data when there are >2
zero
groups or >2 possible
Ratio Data with Temperature in outcomes
measurable equal degrees Kelvin,
Cochran Mantel- Comparison of nominal
distances blood pressure,
Haenszel test data for multiple 2x2
between points cholesterol levels,
tables
and an absolute white blood
Wilcoxon Rank Sum test Comparison of
zero count
Mann-Whitney U test continuous data taken
from 2 independent
Inferential statistics (e.g., Student’s t-test, chi-square groups
test) Wilcoxon signed rank Comparison of
○ used to draw conclusions, based on the sample, for test continuous data taken
the application of the trial results to the population from 2 paired groups
○ used to determine if a statistical difference is present Kruskal Wallis test Comparison of
between the intervention and control groups continuous data taken
○ p-value is calculated based on trial results and from >3 independent
statistical tests; afterward, the p-value is compared to groups
the alpha (α)-value established prior to the beginning of Friedman’s test Comparison of
the trial continuous data taken
○ selection of the statistical test depends on the data from >3 paired groups
being parametric (i.e., normal distribution) versus
nonparametric

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 Parametric Test
Student’s T-test Comparison of continuous
data taken from 2
independent groups
Paired T-test Matched/paired groups
1 – Way ANOVA Comparison of continuous
data taken from >3
independent groups
Repeated measures For paired / matched
groups
2 – Way ANOVA Similar to 1 – way ANOVA,
but can be made for >2
factors
Other Tests
Pearson Regression Determines if a linear
correlation between 2
groups when data is
normally distributed
Spearman Regression Determines if a linear
correlation between 2
groups when data is NOT
normally distributed
Multivariate Regression Determines relationship
of variable with single
dependent continuous
variable
Logistic Regression Determines relationship
of multiple variable with
single dependent
dichotomous variable
● Type I error (alpha error)
- H0 is falsely rejected and H1 is falsely accepted ○ Due
to chance
● Type II error (beta error)
- H0 is falsely accepted and H1 is falsely rejected ○ due
to either by chance or small sample size
RESULTS
● contains primary and secondary endpoint results and
other useful information (patient demographics,
dropout information, and safety information)
RESULTS - Subject Demographics
● describes the subjects actually enrolled and
randomized in the clinical trial
● usually presented in a table of demographic
information
● includes average age, gender ratio, disease states,
and/or drug therapy use among the study participants
at the time of enrollment
● patient baseline demographic data need to be
compared between treatment groups to ensure the
groups are as similar as possible
RESULTS - Subject Dropouts/Adherence
● After the baseline subject information, data regarding
the follow-up (i.e., subject dropout or attrition) and
adherence should be presented
● DROPOUT/Loss to follow-up - subjects randomized in
a clinical trial did not complete the entire duration
○ lack of desire to continue, subject relocation
(e.g., moving to another city), difficulty finding
transportation to clinic visits, subject protocol
violation, side effects, and death
● not all subjects will be compliant with the therapy
● investigators need to report the number of subjects
and major reasons for discontinuing the study,
adherence rates, and the techniques of assessing the
data
● attrition rates of 60% among both groups of a clinical
trial, although not ideal, is much less concerning than a
study where attrition rates are 10% in one group and
50% in another
○ indicator of significant medication safety
considerations
● intention-to-treat (ITT) principle - study results are
analyzed using data collected from all randomized
subjects, regardless of whether they completed the
entire study duration
○ mimics real-life application of an intervention
into practice because, similar to real life, all
subjects in a clinical trial may not complete
therapy as prescribed
● Per protocol (PP) principle - analyzing data only from
subjects completing the trial per the protocol
○ determining the effects of the intervention in
subjects who followed the study protocol and
completed the entire course of therapy
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RESULTS - Endpoints/Safety
● Primary endpoint results - presented clearly and
completely, using transparent and unbiased methods ○
investigators need to explain the results and present
probability values (i.e., p-values)
● Secondary endpoint results - presented in a fashion
similar to the primary endpoints
● Surrogate endpoints - a measure of the efficacy of a
treatment can be defined as laboratory values (e.g.,
HDL-C/LDL-C), symptoms (e.g., pain), or clinical
parameters (e.g., blood pressure) that are employed as
a substitute for a clinical endpoint (e.g., morbidity,
mortality)
○ convenience (easily and readily assessable)
○ well-established relationship between the
surrogate and clinical outcomes (e.g.,
hemoglobin A1C and risk/severity of diabetes)
○ determination of clinical benefit as a result of
changes in the surrogate endpoint
RESULTS - Subgroup Analysis
● Investigators often analyze the results of subsets of
the study subjects, as divided into various groups that
often include gender, age, and presence of diseases or
other complicating factors (i.e., diabetes versus no
diabetes)
DISCUSSION/CONCLUSION
● to evaluate and/or interpret the results of the clinical
trial
● begin with a summary of the key findings of the study
● the trial may be discussed in comparison to other
trials assessing the intervention or the disease state
under investigation
● it can contain biased wording
● most commonly cited criticisms of clinical trials by
clinicians is the lack of external validity of the trials ●
study strengths and limitations should be addressed
DISCUSSION/CONCLUSION - Result Interpretation
STATISTICAL SIGNIFICANCE VS. CLINICAL DIFFERENCE
● Interpreting the p-values correctly is crucial in
evaluating a controlled clinical trial; not all statistically
significant p-values are clinically important. The
magnitude of difference in effect between the
intervention and control cannot be determined solely
with the p-value.
CONFIDENCE INTERVAL
● The use of 95% CI can assist the reader in assessing
the magnitude of difference in effect between the
intervention and control to apply to the population.
No Difference Does Not Indicate Equivalency
● H0 is not written to state the intervention and control
are the same, but stated as no difference in the effect
(i.e., endpoint measurement) between the intervention
and control
● Nonstatistically significant results do not equate to
the intervention and control being the same or equal
BIBLIOGRAPHY
● provides documentation to support the information
provided in the manuscript or acknowledgment for the
work of other authors
● Readers should scan the references listed in the
bibliography to determine if the authors used material
from reputable sources
ACKNOWLEDGEMENTS
● list of individuals/groups contributing to the clinical
trial, but who do not meet the requirements for
authorship
FUNDING
Controlled clinical trial investigators and authors should
disclose any funding sources and potential conflicts of
interest.
● pharmaceutical companies, government agencies
(e.g., National Institutes of Health [NIH]), national
organizations (e.g., American Heart Association),
university grants (e.g., faculty development grants), and
private donation.
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