Study design
Standard of care
 Controlled clinical trial - prospectively
measures a difference in effect between two or
more therapies
 Cause – treatment under study (investigational/
intervention group)
 Effect – consequence of giving the treatment
Patient Inclusion/ Exclusion Criteria
Inclusion criteria
 Subject demographics that must be present to
be enrolled into the trial
 Include subjects to the common types of
patients in practice
Exclusion criteria
 Characteristics that prevent enrolment into the
trial or necessitate withdrawal from the study if
they are later determined to be present
 Standard types of patients disqualified:
 Pregnant and lactating females
 Subjects with severe conditions
Patient Inclusion/ Exclusion Criteria
 Study participants features should reflect the
disease under investigation
 Existence of complex and/or extensive
comorbid conditions in the study patients may
not allow accurate measurements of different
in effect between the groups
Intervention and Control Groups
 Intervention group – consists of new therapy
under investigation
 Control group – consists of no therapy, another
therapy, or compared to existing data
Institutional Review Board/ Subject Consent
 IRB – committee charged with ensuring the
subjects are protected and not exposed to
necessary harm or unethical medical procedure,
in particular vulnerable population (geria and
pedia)
Elements of Research Ethics
1. Informed consent
2. Risk, benefits, and safety
3. Termination of study
4. Community care
5. Privacy and confidentiality
6. Disclosure of research results
7.
8. Compensation for research participants
9. Participant groups that require special
consideration
10. Absence of direct benefit
Principles of Ethical Clinical Research
1. Value
 Poses a clinically, scientifically, or socially
valuable question that will contribute to
generalizable knowledge about health or
be useful to improving to health
 Responsive to health needs and priorities
2. Validity
 Study has an appropriate and feasible
design and end points, rigorous
methods, and feasible strategy to
ensure valid and interpretable data
3. Fair subject selection
4. Favourable risk-benefit ratio
5. Independent review
 Independent evaluation of adherence
to ethical guidelines in the design,
conduct, and analysis of research
6. Informed consents
 clear processes for providing adequate
information to and promoting the
voluntary enrolment of subjects
7. Respect for enrolled participants
 Study attends to and shows respects for
the rights and welfare of participants
both during and at the conclusion of
research
Blinding
 A technique in which subjects and/or the
investigators are unaware of who is in the
intervention or control group
 Reduce the influence of bias on measuring a
difference in effect between the intervention
and control
 Specific blinding type – dictated by the effect
being measured during the trial
Methods
1. Appropriate study design used
2. Inclusion and exclusion criteria represented
an appropriate patient population for the
study
 3. Sample size large enough to detect a
statistically significant difference between
treatment groups
4. Study sample representative of the patient
population to which the study results were
intended to be generalized
5. Study controlled; controls appropriate
6. Outcome variables relevant, clearly defined,
objective, and clinically and biologically
significant
7. Methodology used to measure outcome
variables described in detail
Randomization
 An essential component of all controlled clinical
trials and a significant differentiator from other
study designs
 All persons in a clinical trial have an equal
chance to be in the intervention or control
group
 Subjects are eligible for randomization after
meeting the inclusion criteria
Endpoints
 All trials specify one effect caused by the
intervention and control – PRIMARY ENDPOINT
 Primary endpoint – what the investigators
measures to achieve the study objective
 Example: evaluating cholesterol-lowering effect
of a statin compared to placebo
Primary endpoint: change in average LDL-C
value
Follow-up Schedule/ Data Collection/ Compliance
 A study should be conducted for an appropriate
duration
 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
Sample Size
 Refers to the number of subjects randomized
into a study and of considerable importance to
the validity of study results
 Number of subjects to enrol – dependent upon
the expected magnitude of difference in the
endpoint effect between the intervention and
control
Results
 Contains primary and secondary endpoint
results and other useful information
 Patient demographics
 Dropout information
 Side effect incidence
Subject Demographics
 Describes the subjects actually enrolled and
randomized in the clinical trial
 Typical information
 Average age
 Male-to-female ratio
 Disease states
 Drug therapy among participants at
the time of enrolment
 Complicating factors
Subject Dropout/ Compliance
 Study dropout; lost to follow-up
 Not all subjects randomize in a clinical trial will
complete the entire duration
Reasons to discontinuing participation:
 Lack of desire to continue
 Subject relocation
 Subject violating study protocol
 Side effects
 Death
 A few subjects dropping out of the study may not
cause a substantial difference in the results
 Whereas a sizeable percentage may alter the study
results significantly
Intention-to-treat (ITT)
 Results will be analysed using data collected
from all randomized subjects, regardless of
whether they completed the entire study
duration
 Better mimics real-life application of an
intervention into practice
 Similar to real-life, all subjects in a clinical trial
may not complete the therapy as prescribed
Endpoints/ Safety
 Primary endpoint results - critical component
of the results section
 Safety assessments/ tolerability of all therapies
should be included in the results section
Discussion/ Conclusion  Clear statement of the objectives of the
 To evaluate and/or interpret the results of review
the clinical trial  Intervention or phenomena of interest
 Discussion section includes:  Relevant patient groups
1. Summary of the key findings  Types of evidence or studies
2. Potential explanation of study results  Appropriate outcomes
3. Interpretation of trial results of other Inclusion Criteria for Systematic Review Protocols
similarly designed studies Inclusion Details of criteria
identification and discussion of criteria This should be the highest level of
clinical trial limitations available evidence for the review aims
Conclusion section and objectives
 RCTs for effectiveness of
 Should provide an overall research
interventions
recommendation to the readers
 Prospective cohort studies for
 Should focus on primary endpoint results risk factors for disease onset
 Limited only to the information discussed in  Diagnostic accuracy studies for
previous sections of the trial diagnostic tests
______________________________________________  Qualitative studies for patient
SYSTEMATIC REVIEW OF LITERATURE experience
Type of study
 Provide an exhaustive summary of literature
relevant to a research question
Type of Define the participants in terms of
 Focuses on a research question and identifies, participants their:
appraises, selects and synthesizes all high  Diagnosis
quality research evidences relevant it  Age gender
COCHRANE COLLABORATION  If applicable, geographical
 Founded by Archie Cochrane in 1993 location, ethnic group
Type of Define the specific interventions of
 Independent, not-for-profit organization that
intervention interest and the comparison groups
produces systematic literature reviews of
you will consider (if applicable)
interventions in healthcare that are published in  Drug trials: formulation & dose
the Cochrane library of the drug
 It has over 10,000 reviewers internationally and  Surgery trials: specific surgical
is organized into review groups each with a techniques
specific area of interest.  Diagnostic tests
Systematic Review Process  Psychological therapies
Comparison Define the comparison groups of
1. Defining an appropriate healthcare question
interest (if applicable)
2. Searching the literature
 Intervention vs no intervention
3. Assessing the studies (eg. Waiting list control group)
4. Combining the results  Intervention vs placebo/sham
5. Placing the findings in context surgery
Examples:  Intervention vs another
Public Health in community pharmacy: a systematic intervention
review of pharmacist and consumer views Outcome Define the outcome measures of
measures interest. For example:
 Methods – “ five electronic databases were
searched for articles…”
 Results – “from the 5628 papers identified, 63 Searching the Literature
studies in 67papers were included”
 Careful search of the required studies
1. Defining appropriate healthcare question
  Covers all literature including non-English The PRISMA Statement
sources
 Hand-search of selected journals
 Search of references of full-text papers
 “Use of keywords”
 The search strategy needs to be sensitive rather
than specific
 Specific – identifies more relevant than
irrelevant papers but might miss some
important papers
 Sensitive – less likely to miss relevant studies
but might identify a reasonably large number of
irrelevant studies as well
 Example:
Search strategies for systematic reviews
relevant to surgery would need to include a
search of Medline, Embase, etc…
 Search using Medical Subject Headings
(MeSH) – standardized terms that are
used to index all papers and databases
 Text word searching
Assessing the studies
Section/Topic Checklist item
 Assess for eligibility against inclusion criteria
TITLE
(title and abstract)
title 1. Identify the report as a
 Retrieve full text papers that meet the inclusion systematic review, meta-analysis,
criteria or both
 Assessed for methodological quality ABSTRACT
 Poor quality studies: excluded but are usually Structured 2. Provide a structured summary
discussed in the review report summary including, as applicable
background objectives: data
 Create list f included studies
sources; study eligibility criteria,
 Assessment ideally conducted by two participants, and interventions;
independent reviewers study appraisal and synthesis
Preferred Reporting Items for Systematic Reviews and methods; results; limitations;
Meta-Analyses (PRIsmA) conclusions and implications of
 Ensures a transparent and complete reporting o key findings; systematic review
registration number.
systematic review/ meta-analysis
INTRODUCTION
 Not a quality assessment instrument but may Rationale 3. Describe the rationale for the
be useful for critical appraisal purposes review in the context of what is
already known
Objectives 4. Provide an explicit statement of
questions being addressed with
references to participants,
interventions, comparisons,
outcomes, and study design
(PICOS)
METHODS
Protocol and 5. Indicate if a review protocol
registration exists, if and where it can be
accessed (e.g. Web addressed,
and, if available, provide
registration information including
registration number
Eligibility 6. Specify study characteristics (e.g.
criteria PICOS, length of follow-up) and
report characteristics (e.g. years
considered, language, publication
status) used as criteria for
eligibility, giving rationale
www. Plosmedicine.org
Combining the Results
 Evidence synthesis: findings are aggregated to
produce a “bottom line” on the clinical
effectiveness, feasibility, etc..
 Inspects qualitative data: meta-synthesis is
conducted
 Quantitative data: met-analysis
To reduce selection bias, review authors choosing
articles should be blinded to:
 Names of study authors
 Institution of publication
 Results of the studies
 For the initial choice of study inclusion, only the
methods section should be reviewed
 2 or more authors should critique each study under
consideration
 All evaluators should concur on which studies will be
included in the systematic review
META-ANALYSIS
 Quantitative systematic review
 Provides quantitative and objective assessment
 Uses statistical methods to combine the results
of 2 or more studies
Meta-analysis assists in:
 Supporting or refuting lesser quality evidence
 Overcoming reduced statistical power of small
studies
 Assessing occurrence of rare events
 Providing guidance with limited/ conflicting
data
 Displaying sample sizes and treatment effects
graphically
 Assessing heterogenicity between studies and
publication bias
 Evaluating the natural history of disease
 Improving estimates of effect size
 Answering new questions not posed at the start
of individual trials

Feature Nonsystematic review Qualitative systematic Quantitative systematic

Clinical question
Literature search
Studies included
Includes unpublished
literature
Blinding of reviewers
Analysis of data
Results statistically
evaluated
Types of results
(narrative)
Often broadly defined
Methods of literature
search usually not explicitly
described
Methods determining which
studies to included not
usually described
Not usually
no
Variable and subjective
No
qualitative
review review (meta-analysis)
Clearly defined and focused Clearly defined and focused
Explicit description of Explicit description of
predefined and predefined and
comprehensive search comprehensive search
strategy strategy
Predefined inclusion and Predefined inclusion and
exclusion criteria exclusion criteria
possibly Possibly
yes yes
Rigorous and objective Rigorous and objective
No yes
qualitative Quantitative
EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES
 Systematically developed statements to assist Guideline Development Process
practitioner and patient decisions about health
care for specific circumstances
 Properly developed, valid practice guidelines
provide a concise summary of current best
evidence on what works and what does not
when considering specific health care
interventions
 Conscientious, explicit, and judicious use of
current best evidence in making decision about
the care of individual patients
 The practice of EBM refers to integrating
individual clinical expertise with the best
available external clinical evidence from
systematic research

Guidelines Development Methods

 Practitioners should have a thorough
understanding of practice guideline
methodology for involvement in appropriate
evaluation and implementation of these
guidelines
 The Agency for Healthcare Research and Quality
(AHRQ) developed methodology that has
influenced major guideline development
programs