this is all about randomized clinical trial

1. Introduction to Literature
evaluation
Controlled Clinical Trial (CCT)

2. Objectives of CCT
• Describe special characteristics of a controlled clinical trial
• Prepare a null hypothesis (H0) based upon the clinical trial
objective(s) and endpoint(s).
• Differentiate between the types of data, measures of central
tendency, and measures of variability.
• Differentiate between Type I and Type II errors.
• Interpret p-values and 95% confidence interval (CI); discuss whether
to reject or fail-to-reject the H0 by using these clinical trial results.
• Calculate and interpret relative risk (RR), relative risk reduction (RRR),
absolute risk reduction (ARR), and number needed to treat (NNT).
• State whether a statistical significance and clinical difference are
present using the clinical trial results.
4/3/2024 2

3. 4/3/2024 3

4. Why it is important to evaluate the literature?
• The practice of medicine and pharmacy are dynamic, and drug facts
acquired during formal education cannot sustain a health care
provider in future practice.
• Changes include new medications, dosage formulations and uses
approved by the FDA, revised drug safety information (i.e., ADEs, drug
interactions), and updated disease state therapeutic guidelines.
• During 2016, greater than 37 new molecular entities/biological agents
were approved by the FDA, and
• over 3,000 published articles classified as human practice guidelines were
added to the NLM database.
4/3/2024 4

5. • Practitioners need to efficiently locate, critically analyze, and
effectively communicate data from the primary literature in daily
activities of patient care and the medication use process.
• Therefore, skills, such as drug literature evaluation, are necessary to
prepare the health care provider for practice.
4/3/2024 5

6. • Multiple resources are available for practitioners to provide answers
to questions, care for patients, make decisions, and solve problems.
• But, practitioners need to recognize both the advantages and
limitations of the information resources.
• Advantages include ready access and electronic formats.
• Potential disadvantages include biases, costs, and lag time (i.e., lack of current
content) that hinder the usefulness of some references.
• In addition, misinterpretation of the information can lead to improper patient
care.
• Almost 25% of medical students had trouble interpretation of the medical
literature
4/3/2024 6

7. SO what?
• Pharmacy practitioners are repeatedly relied upon to clarify, explain,
defend, and/ or refute information
• Because have skills in efficiently locating and critically analyzing drug
information to appropriately formulate and efficiently communicate a
response.
• Due to the important contribution pharmacy practitioners have in
patient care,
• they need to have skill in identifying the strengths and limitations of the
biomedical literature.
4/3/2024 7

8. Biomedical/Pharmacy Literature
4/3/2024 8

9. • Clinical trials are one particular type of primary literature that can be
a reliable source of new information to change health care practices.
• A controlled clinical trial is the premier study design to measure and
quantify differences in effect of the intervention versus control.
• New information may either counter or serve as the root for altering
existing practice regimens; as a result, practitioners need to critique
clinical trials.
• Proper interpretation of clinical trials is vital to providing appropriate
health care.
4/3/2024 9

10. • In general, a CCT consists of an investigational (intervention) group
being directly compared to a control group (e.g., standard therapy,
placebo).
• The goal of the clinical trial is to measure and quantify the difference
in effect (e.g., efficacy, safety) between the investigational and control
groups.
4/3/2024 10

11. Approach to Evaluating Research Studies (True
Experiments)
• A checklist for pertinent information
• Answering the questions contained in a checklist can allow readers to
determine the strengths and limitations of a clinical trial.
4/3/2024 11

12. Format and Content Of Controlled Clinical Trials
4/3/2024 12

13. TITLE
• Title should be
• reflective of the work, unbiased, specific, and
• concise (i.e., usually ≤ 10 words or 40 characters), but not too general or
detailed.
• Declarative sentences, which tend to overemphasize a conclusion, are
not preferred for scientific articles
• It should not be phrased as a question and
• RCTs should be identified in the title; however, depending on the
journal, the study design must be included in the title.
• It should include key words that are both sensitive and specific that
allow easier electronic retrieval of the article.
4/3/2024 13

14. Example of study title:
• “Improved bronchodilation with levalbuterol compared with racemic
albuterol in patients with asthma.”
VS
• “Comparison of levalbuterol and racemic albuterol bronchodilation in
patients with asthma: a randomized clinical trial.”
4/3/2024 14

15. ABSTRACT
• A concise overview of the study or a synopsis of the major principles
of the article.
• Its primary use is to obtain an immediate overview of the article to
determine if the entire article should be read.
• Usually contain less than or equal to 500 words.
• The structured abstract includes the following sections:
• objective, research design, clinical setting, participants, interventions, main
outcome measurements, results, and conclusions
• It should be consistent with the manuscript and should not present
biased and/or inaccurate information.
4/3/2024 15

16. INTRODUCTION
• The introduction section serves two specific purposes:
• discussing the study rationale and study purpose.
• The study investigators may state that
• due to the lack of data to answer a question or because available data are
conflicting regarding an issue.
• The investigators should explain how the clinical trial will overcome
the shortcomings of the prior research, if applicable.
• The study objective is often stated within the last paragraph, if not
the last sentence, of this section.
4/3/2024 16

17. • Once the clinical trial objective is determined, the investigators need
to formulate a research and null hypothesis.
• A research hypothesis (also known as the alternative hypothesis) states that
there is a difference between the therapy under investigation and the control,
while
• The null hypothesis (H0) states that there is no difference between these two
groups
• Readers should recognize that not all clinical trials will include the
specific research and null hypotheses in the introduction section.
• it does not necessarily indicate that the paper contains incorrect information.
4/3/2024 17

18. METHODS
• The methods section should include
• the trial design, participants, interventions, outcomes, sample size,
randomization sequence generation, allocation concealment
mechanisms (e.g., mechanisms used to generate random
allocation sequence), blinding, and statistical methods.
• Poor study design leads to reduced study internal validity,
thus resulting in limited external study validity.
4/3/2024 18

19. • The two comparator groups are similar and treated identically with
the exception of the interventions that are being investigated.
• The subjects in the study are assigned to one of the groups and
monitored.
• This study type, called parallel design, is the primary study design
encountered in the literature.
• Example:
• simvastatin plus ezetimibe (cause) to simvastatin plus placebo in patients with
familial hypercholesterolemia.
4/3/2024 19

20. 4/3/2024 20

21. 4/3/2024 21

22. INTERNAL VERSUS EXTERNAL VALIDITY OF CLINICAL TRIALS
4/3/2024 22

23. Patient Inclusion/Exclusion Criteria
• Inclusion criteria lists subject demographics that must be present in
order for the subject to be enrolled into the trial, while
• Exclusion criteria are characteristics that prevent a subject from
enrollment into the trial or necessitates withdrawal from the study, if
they are later determined to be present.
• The inclusion/exclusion criteria are pertinent to the extrapolation of
the study results (i.e., applying the study results to practice [external
validity]).
4/3/2024 23

24. • During the process of selecting subjects to be included into a study,
need to be conscious of the potential for a selection bias that may be
present.
• Selection bias occurs after subjects meet the inclusion and exclusion
criteria, but are not enrolled into the study.
4/3/2024 24

25. • One common form of a selection bias is requiring the subjects to
complete a run-in phase (also called lead-in phase) before being
officially enrolled in the study.
• This phase is usually short in duration (usually 2 to 4 weeks) in which
the subjects may take a placebo or the therapy being investigated.
• Typical reasons include identifying subjects that may or may not adhere with
the therapy regimen, experience side effects from the therapy, or did not
meet prespecified criteria.
• Afterwards, these identified subjects are excluded from participating
in the study.
4/3/2024 25

26. Intervention and Control Groups
• The intervention group consists of the therapy under investigation (e.g.,
medication, procedure).
• The control group can consist of no therapy (e.g., placebo), another
therapy (a.k.a. active control) (e.g., drug, exercise), or compared to existing
data (i.e., historical data).
• Historical controls are described as data that have been collected prior to
the beginning of a clinical trial.
• Then, assess a new therapy in these patients and compare the research results to
historical data (obtained from prior research)
• Denying therapy that has been documented to reduce morbidity and/or
mortality to patients with selected diseases may be unethical.
• These studies would not include a placebo as the control, but instead may use active
control (i.e., standard therapy).
• Example: Patients with cancer
4/3/2024 26

27. Institutional Review Board (IRB)/Subject Consent
• The IRB is the committee charged with ensuring that the study
subjects are protected and not exposed to unnecessary harm or
unethical medical procedures, including vulnerable populations (e.g.,
pediatrics, pregnant women, impaired persons.
• Another primary responsibility of the IRB is to approve the informed
consent form.
• IRB provides investigators with suggestions on how to write the form
in language that laypersons can comprehend.
4/3/2024 27

28. Blinding
• Blinding is a technique in which subjects and/ or the investigators are
unaware of who is in the intervention or control group.
• Blinding techniques are to reduce possible bias (defined as
“differences between the true value and that actually obtained [are]
due to all causes other than sampling variability”).
• Patients knowing they are taking a placebo to reduce depression symptoms
are likely to report no change or worsening of the disease.
4/3/2024 28

29. Four types of blinding can be used in a clinical trial
(e.g., surgery versus medication)
the gold-standard blinding technique and is most commonly used in clinical trials.
4/3/2024 29

30. • Double-dummy methods are included in clinical trials when two
therapies being compared are not the same (e.g., different routes of
administration, different formulations).
• Double dummy is a method of blinding where both treatment groups
may receive placebo.
• E.g., Once-daily oral contraceptive tablet vs. intramuscular
contraceptive agent administered every 3 months
intramuscular placebo to those patients randomized to once-daily oral
contraceptives vs. once-daily placebo tablet to those patients randomized to
the intramuscular contraceptive.
4/3/2024 30

31. Randomization
• Is a distinguishing study attribute that separates controlled clinical
trials from other study designs (e.g., case-control, cohort).
• All persons in a clinical trial have an equal chance to be in the
intervention or control group.
4/3/2024 31

32. Subject Eligibility
• Subjects are eligible for randomization after meeting the trial
inclusion criteria.
• Randomization minimizes bias by lowering the potential for an
imbalance of risk factors or prognostic variations between the
intervention and control groups.
• Measuring differences in the effect between the intervention and
control groups requires the groups to be as similar in as many
characteristics as possible (e.g., age, gender, severity of illness) so that
outside factors (i.e., confounders) do not influence the results.
4/3/2024 32

33. Randomization Techniques
• Various methods are available that include random number tables and
computer programs.
• It should not allow the subjects or investigators to know in advance to
which group the subject will be assigned.
• Specific randomization methods include from simple (i.e., coin toss) to
more advanced techniques (i.e., stratification).
• Simple randomization is an easy technique to implement and includes
• assigning subjects according to some criteria (e.g., day of the week, subject birthday,
or subject medical record number).
• A random number table can be considered useful since the table allows for
each study subject to have equal opportunity to be assigned to either
group.
4/3/2024 33

34. Stratification
• Selected factors are identified (e.g., age, smoking, presence of other
disease states) and
• used in determining which group the subjects will be assigned so all subjects with
any specific factor have an equal chance of being in each group.
• Since these patient factors can affect the outcome being measured,
stratified randomization is a technique that enables these
factors to be comparable between the study groups.
• For example, the risk of developing a venous thrombosis is greater in
cancer patients who are immobilized and/or receiving hormonal therapy
• ensure a similar number of patients with these two risk factors are assigned in each
of the two study groups.
• e.g., low-molecular-weight heparin versus unfractionated heparin gp.
4/3/2024 34

35. Blocked randomization process
• Block randomization allows for a balance of groups between the
intervention and control.
• For instance, if there are 4 patients in each group, the group will be
balanced every time the 4th patient is enrolled in the study.
• There are 6 ways in which 4 patients can be allocated to a group so
that two subjects get two As and two Bs.
• The allocation sequence could look like this: (1) AABB; (2) ABAB; (3) ABBA; (4)
BBAA; (5) BABA; and (6) BAAB.
• Block randomization is helpful when interim analyses are planned
because it ensures an equal balance between groups.
4/3/2024 35

36. • The disadvantage to this allocation is that the person who is responsible for
treatment allocation can predict every 4th sample.
• To counter this effect, the allocator may hide the block size from the
executor and use randomly mixed block sizes (e.g., 2, 4, 6).
• Although the majority of trials have an equal allocation of subjects, there
are times when an unequal allocation (e.g., 2:1 ratio of treatment to
control) is used.
• Investigators should provide an explanation of the rational for unequal allocation of
study subjects in the groups.
4/3/2024 36

37. Endpoints
• All trials specify one effect caused by the intervention and control.
• The primary endpoint should be appropriate for the study purpose
and measured using valid techniques and methods.
• Secondary endpoints are important, but not considered to be the
primary purpose of the study.
• Composite endpoint: Investigators may combine a group of endpoint
measures into one primary endpoint.
• The rationale is to measure an overall effect of therapy, since one specific
outcome cannot be deemed to be the most important for the study subjects
• Debate: The results of the individual components of the composite
should be reported separately and analyzed.
• A final type of endpoint that may be seen is a surrogate endpoint.
4/3/2024 37

38. Follow-Up Schedule/Data Collection/Adherence
• The length of the study (i.e., follow-up time) should be an ideal
representation to answer the question being researched.
• E.g., Statins usually exert the maximum cholesterol lowering effect
after approximately 6 weeks of stable dosing.
• Subject monitoring is required during the clinical investigation.
• Interim analyses of the study results may indicate that the
intervention produces either a favorable outcome or increased risk
over the control before the established duration of the study has
been completed.
4/3/2024 38

39. • Prior to the start of the study, data collection methods are
established.
• Trial personnel are properly trained and that they have sufficient
resources to complete data collection.
• Another issue is measuring the adherence of therapy in the study
participants.
• This includes medication dosage unit counts, serum drug levels, or regular
follow-up communications (i.e., telephone conversations).
4/3/2024 39

40. Sample Size
• Conducting a power analysis is important to determine a suitable
sample size.
• Power is the ability of a study to detect statistically significant
differences between treatment groups, when such a difference truly
does exist.
• Does the number of patients used in the analysis meet the sample
size required to meet power?
• If so, one should feel confident that enough patients are included to show a
difference if one exists.
• Power set at 80% is considered appropriate for most studies.
• Power of 80% means the study has an 80% chance of seeing a difference
between treatment groups, if a difference really exists.
• It is of considerable importance to the validity of the study results.
4/3/2024 40

41. • The sample size should not be determined on the basis of
convenience, arbitrarily, or by the number of easily recruited subjects.
• The number of subjects to enroll is dependent on
• the expected magnitude of difference in the endpoint effect between the
intervention and control.
• The expected magnitude of difference in effect between groups is
estimated based on the results of previously conducted trials or other
research results.
• Researchers use various procedures, from table/charts to manual
calculations, in estimating the necessary sample size for a particular
trial.
4/3/2024 41

42. https://openepi.com/
4/3/2024 42

43. Statistical Analysis
• To analyze sample data and apply it to the population
• The purpose is to collect sufficient evidence to reject the null
hypothesis (H0) in favor of accepting the research hypothesis (H1)
(new terminology may refer to this as failure to accept the null
hypothesis).
• The selection of statistical tests is dependent on the type of data.
• There are four types of data:
• nominal, ordinal, interval, and ratio (the latter two are usually referred
collectively as continuous).
4/3/2024 43

44. TYPES OF DATA
• the 0 point does not mean an absence of value. E.g., 0 Celsius
e.g., no money, no behavior, none correct
4/3/2024 44

45. • The type of data collected also dictates the use of inferential or
descriptive statistical methods.
• Data Presentation Methods
While SD measures the deviation of the individual values from the mean of the sample, SEM measures the deviation of the individual
sample means from the mean of the population.
4/3/2024 45

46. • The selection of the statistical test depends on the data being
parametric (i.e., normal distribution) versus nonparametric.
• Typically, continuous data are assessed via parametric statistics;
common tests are
• Student's t-test, analysis of variance (ANOVA), and analysis of covariance
(ANCOVA).
• Nonparametric tests are used for nominal and ordinal data; examples
are
• chi square (χ2) and Mann-Whitney U test
4/3/2024 46

47. Type I and II Errors/Power Analysis
• Before the trial begins, the investigators develop a
• null hypothesis (H0; no difference between the groups) and
• research hypothesis (H1; a difference is present between the groups).
• If a difference is present, this could actually be due to
• the intervention or happen by random chance (error).
• Two types of errors are possible in hypothesis testing
• A Type I error can occur when the H0 is falsely rejected and the H1 is
falsely accepted.
• Also known as a false-positive finding.
• A Type II error can occur when H0 is falsely accepted and the H1 is
falsely rejected.
• Also known as a false-negative finding.
4/3/2024 47

48. TYPE I AND II ERRORs POSSIBILITIES
4/3/2024 48

49. 4/3/2024 49

50. RESULTS
• This section contains primary and secondary endpoint results and
other useful information, which includes patient demographics,
dropout information, and safety information.
• This section is to be critically appraised to verify if the study objective
was met, based upon the data, but also to evaluate the other types of
outcomes that may have occurred.
Subject Demographics
• The first type of information provided in the results section
4/3/2024 50

51. Subject Dropouts/Adherence
• Not all subjects randomized in a clinical trial will complete the entire
duration, at which time they are then termed a study dropout or lost
to follow-up.
• As a result, the investigators need to report
• the number of subjects and
• major reasons for discontinuing the study,
• adherence rates, and
• the techniques of assessing the data to draw appropriate conclusions about
the intervention under study and subsequent trial results.
4/3/2024 51

52. • Dropout data can be very revealing about the overall tolerability of a
medication.
• Disproportionate attrition rates among both groups can be an
indicator of significant medication safety considerations, particularly if
safety endpoints were not a primary endpoint of the study.
• Frequently, the study results will be analyzed using data collected
from
• all randomized subjects, regardless of whether they completed the entire
study duration (i.e., results from dropouts are not discarded, but are
considered to be treatment failures).
• This technique is referred to as the intention-to-treat (ITT) principle.
4/3/2024 52

53. • The advantage of the ITT analysis is that this analysis better 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.
• However, a concern with the ITT analysis is that data from subjects
discontinuing a trial early may bias the analysis.
4/3/2024 53

54. • Per-protocol [PP]) procedure refers to analyzing data only from
subjects completing the trial per the protocol.
• The advantage of this technique is for determining the effects of the
intervention in subjects that followed the study protocol and
completed the entire course of therapy.
• The ITT analysis can be thought of as a worst-case scenario model,
whereas the PP analysis can be thought of as a best-case scenario
model.
4/3/2024 54

55. • The ITT analysis is typically favored by clinicians or readers of studies
when analyzing results due to the desire to determine
• whether statistically and clinically significant differences are present between
the two groups.
• Such results are much stronger than demonstrating statistical or
clinical significance under best-case scenario conditions as patients in
the greater population are not completely adherent to prescriber
instructions.
4/3/2024 55

56. • Optimally, study investigators will present both ITT and PP results; the
desire is to see no significant differences between the ITT and PP results.
• If a significant difference exists, this can be an indirect indicator of differences in
attrition rates between treatment arms.
• Furthermore, clinical trials including only the PP results are to be
scrutinized more because
• results from all subjects are not assessed that could result in an overestimation of
treatment effects in favor of a treatment arm with high attrition rates.
• An example of analyzing study data according to ITT and PP methods
• E.g., Caffeine for treatment of Parkinson disease. Doi: 10.1212/WNL.0b013e318263570d
4/3/2024 56

57. Endpoints/Safety
• A critical component of the results section is the primary endpoint
results.
• These results can be displayed as tables, graphs, or other illustrations.
• Results of secondary endpoints should follow and are presented in a
fashion similar to the primary endpoints.
• Safety assessments or tolerability of all therapies should be included
in the results section.
• One issue to consider in evaluating the results in some clinical trials is
whether medication dosing titration is allowed in the methods.
4/3/2024 57

58. Surrogate Endpoints
• Described as “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., BP) that are employed as a substitute for a
clinical endpoint (e.g., morbidity, mortality).”
• Primary reason that surrogate endpoints are selected for clinical trials
is to quickly measure an effect at a lower overall cost.
4/3/2024 58

59. Subgroup Analysis
• Reasons to analyze the results in these subgroups vary but usually
relate to providing additional information in these specific patient
types as opposed to the overall trial results from all randomized
subjects.
• E.g., ≤65 years and >65 years
• Subgroup analyses can be helpful in determining future research
targets, but, unless powered appropriately, should not be used as a
basis for therapeutic decision making.
4/3/2024 59

60. Ancillary versus Adjunctive Therapies
• Ancillary therapy, in which subjects can take another therapy that
can distort or confound interpretation of the results.
• Needs to be assessed and included in the study evaluation.
• Adjunctive therapy: which all participants receive as treatment, while
• ancillary therapy may not be equally distributed between the intervention
and control groups.
• E.g., Effect of cinnamon extract Vs placebo on glycemic markers in
patients with diabetes.
• all subjects were taking an adjunctive sulfonylurea agent each day.
• Ancillary therapy would occur if patients were allowed to take any
other agent that could alter blood glucose levels
4/3/2024 60

61. DISCUSSION/CONCLUSION
• The primary purpose of the discussion/conclusion is
• to evaluate and/or interpret the results of the clinical trial.
• Should begin with a summary of the key findings of the study.
• Potential explanations of the study results should be addressed, in
addition to discussing internal and external validity of outcomes.
• Interpret the trial results in comparison with results of other similarly
designed studies.
• This is also where clinical trial limitations are identified and discussed.
4/3/2024 61

62. • Also address the clinical importance of the results and how these
results should be used in practice.
• All of this information should allow the reader to understand the
application of the clinical trial results in practice.
• The discussion section should also address future concerns and
unanswered questions.
4/3/2024 62

63. • The conclusion section should provide an overall research
recommendation to the readers.
• The investigators’ conclusion should focus on the primary endpoint
results, especially if no statistically significant differences between the
intervention and control groups were observed, rather than
favorable, secondary endpoint results.
• The conclusions should be aligned with the results of the trial
4/3/2024 63

64. Clinical Trial Result Interpretation
Statistical Significance versus Clinical Difference
• Not all statistically significant p-values are clinically important.
• The p-value is compared to the alpha (α) value established prior to
the beginning of the clinical trial (a priori).
• A p-value for the primary endpoint that is less than the α value
indicates
• the H0 is rejected and a statistically significant difference is declared between
the intervention and control groups.
• The H0 is accepted (failed to be rejected) with a p-value equal to or
greater than the α value and
• no statistically significant difference is declared.
4/3/2024 64

65. • Lower p-values indicate a lower probability that chance alone could be the reason
a difference in effect was measured between the intervention and control.
4/3/2024 65

66. Example
• A study compared the efficacy of oral mesalamine (n=28 patients)
with topical mesalamine (n=31 patients) for the treatment of distal
ulcerative colitis. Following 2 weeks of therapy with either agents, the
clinical response rate was 43% with oral mesalamine vs 58% with
topical mesalamine (P = 0.003).
• Is this therapy difference statistically different?
4/3/2024 66

67. Assessing Clinical Difference
• Two critical items needed are the p-value and actual study results
used to calculate the p-value.
• A fundamental first step of determining clinical difference in a given
trial begins with determining if statistical significance exists (i.e., p < a
priori alpha value)
• The second step in assessing clinical differences is evaluating the
results used to calculate the p-value.
• The reader must analyze the magnitude of endpoint difference
between the intervention and control results.
4/3/2024 67

68. Confidence Intervals (CIs)
• Many clinical trials include 95% confidence intervals (CIs) with the
study results.
• CIs provide data that address the size of effect (e.g., mean reduction
in DBP) of the intervention by presenting a range that likely covers the
true but unknown value.
• E.g., mean reduction in DBP with an ACE inhibitor was −11.3 mmHg (95% CI,
−8.2 to −14.4 mmHg) in subjects with a mean baseline DBP of 99 mmHg.
• The use of a CI can assist in judging the clinical usefulness of the study
result.
4/3/2024 68

69. Interpreting Risks and Number Needed to Treat
• Another technique to critique and interpret clinical trial results is to
calculate the measures of association:
• relative risk (RR), relative risk reduction (RRR), absolute risk reduction (ARR),
and number needed to treat (NNT).
• PRESENTING NOMINAL DATA STUDY RESULTS
4/3/2024 69

70. Example
The trial had a median follow-up time period of 5.4 years.
• Calculate RR? 0.70
• Calculate RRR? 30%
• Calculate ARR? 3.3%
• Calculate NNT? 30
Group Died (Yes) Died (No) Total
Simvastatin 182 (A) 2039 (B) 2221
Placebo 256 (C) 1967 (D) 2223
4/3/2024 70

71. • Relative risk (RR) is calculated as the proportion of the intervention
group experiencing the outcome divided by the proportion of the
control group with the event.
• The RR equaled to 1 indicates no difference between the intervention and
control.
• RR < 1 signifies the intervention lowered the risk of the outcome compared to
the control (i.e., protective effect).
• RR > 1 indicates the intervention increased the risk of the outcome; a greater
proportion of the intervention group had the outcome compared to control.
4/3/2024 71

72. • Relative risk reduction (RRR) indicates the relative change in the outcome
rate between the intervention and control groups.
• The RRR was calculated as (1 − RR × 100).
• E.g., The risk of experiencing death was 30% lower by treating with simvastatin
instead of placebo.
• Absolute risk reduction (ARR) refers to the difference in the outcome rate
between the intervention and control groups.
• A higher proportion of subjects taking placebo died (n = 256 of 2,223 or
11.5%) compared to those taking simvastatin (182 of 2,221 or 8.2%).
• The ARR for death associated with simvastatin was 3.3% (ARR = 11.5% −
8.2%); thus,
• 3.3% of the subjects receiving simvastatin were spared death compared to placebo.
4/3/2024 72

73. • The NNT of this study equals 30 (NNT = 1/0.033),
• meaning 30 subjects need to be treated for a median of 5.4 years with
simvastatin instead of placebo to prevent one case of death.
4/3/2024 73

74. MEASURES OF ASSOCIATION DESCRIPTION AND FORMULAS
4/3/2024 74

75. Absolute Risk Increase (ARI), NNH: Number needed to harm: 1/ARI
4/3/2024 75

76. • CIs can also be calculated for nominal endpoints presented as RR or
hazard ratio (HR).
• The same formula for RR is used to calculate HR, which refers to
whether the hazard of the adverse event (e.g., MI, hospitalization) is
lowered or increased with the intervention compared to the control.
4/3/2024 76

77. No Difference Does Not Indicate Equivalency
• Non-statistically significant results do not equate to the intervention
and control being the same or equal.
• A difference in effect between the intervention and control groups
may be present but either by chance or by a small trial sample size,
the difference in effect was not detected.
• Usually (but not all of the time) clinical trials in which the H0 is
accepted have too small of a sample size.
4/3/2024 77

78. Assessing the Clinical Relevance of the Results
• All controlled clinical trial results need to be assessed to determine
the clinical relevance (i.e., meaningfulness) of the intervention versus
control.
• Small treatment effects and/or differences may be statistically
different, but really not mean much clinically.
• Not all clinical trials reporting non-statistically significant results are
completely devoid of clinical importance.
• The overall effect of the intervention and control need to be assessed.
4/3/2024 78

79. • The clinical trial methods need to be reviewed for the ability to
replicate these into every day patient care.
• Another issue to consider is the demand on the actual patient.
• At times investigators offer incentives (e.g., monetary compensation,
free medical care) for the subjects to strictly follow the study protocol
(i.e., more motivated to be compliant).
• But in practice, real patients may not be as eager to follow an
intricate schedule.
4/3/2024 79

80. BIBLIOGRAPHY
• Any material that the author uses in the manuscript should be appropriately
cited.
• References included in the manuscript should be recent (e.g., outdated articles
should not be used unless the results of the article are pertinent to the
manuscript) and complete.
• Determine if the authors used material from reputable sources.
• In addition, authors should refrain from extensively citing only their own work.
• At minimum, the information in the reference section should be sufficient to lead
the reader to locating the same article.
• request weblinks and/or the direct-object identifier (DOI) be included at the end of the
citation.
• PubMed identification number (PubMed ID)
• In the event that the full content is not freely available (e.g., subscription only),
the most accurate URL to lead the person to the content should be used.
4/3/2024 80

81. ACKNOWLEDGMENTS
• Individuals contributing to the clinical trial can be recognized in this
section.
• Medical writers or editors also may be listed if their contributions
significantly strengthened the clarity of the content.
• A collaboration or group may receive recognition in the
acknowledgment section.
• Financial support and conflicts of interest, which can help the reader
identify or reconcile sources of bias.
4/3/2024 81

82. FUNDING
• Controlled clinical trial investigators and authors should disclose any
funding sources and potential conflicts of interest.
• Various funding sources are available that include
• 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 donations.
4/3/2024 82

83. Conflicts of interest (COI)
• A set of conditions in which professional judgment concerning a primary
interest (such as a patient's welfare) tends to be unduly influenced by a
secondary interest (such as financial gain)” that may result in potential
bias.
• COI arise because the industry may be prompted to publish articles as a
means of making their product appear better for a disease state in relation
to the standard of care.
• The role of the funding source in the design of the study, collection and
analysis of data, and the interpretation of study results should be included.
• Further, the investigators made the decision about publication of the data
and the role the investigators had in writing, editing, and approving the
manuscript.
4/3/2024 83

84. Thank You!
4/3/2024 84