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Patients were compared for baseline characteristics such as demographics, clinical and disease data,
and treatments and procedures. A third reviewer (TKM) resolved disagreements on study selection.
However, after randomisation, it is almost inevitable that some participants would not complete the
study for whatever reason. How real are patients in placebo-controlled studies of acute manic
episode. Philadelphia: American College of Physicians, 1997. This includes demographic
information (for example, age, gender, ethnic origin) and information on diagnosis, treatment,
response to treatment, and follow-up after treatment. (OCEBM Table of Evidence Glossary). The
technique prevents researchers from consciously or unconsciously influencing which participants are
assigned to a given intervention group. A very wide interval may indicate that more data should be
collected before anything definite can be said about the estimate. Implicit factors Implicit factors
that may have affected the external validity of RCTs were also identified in some of the studies
reviewed. Our website uses cookies to enhance your experience. The ranking has an evolutionary
order, moving from simple observational methods at the bottom, through to increasingly rigorous
methodologies. The investigator, on recruiting a patient, telephones a central randomisation service
which issues the treatment allocation. Such a study might be a waste of resources and potentially
unethical. Subjects over-represented in the clinical trial relative to the target real-world population
receive lower weights while those under-represented receive higher weights. It is usually called a
meta-analysis by the author or sponsoring body and should be differentiated from reviews of
literature. (PubMed). TKM is Director of, and SR is an employee of, Kennedy-Martin Health
Outcomes Ltd, and received financial support from Eli Lilly and Company for their contributions to
the conception and design of the study; the acquisition, analysis, and interpretation of the data; and
drafting of the manuscript. Detailed description of results and subjective author conclusions from
studies included in the review that employed Method A. (PDF 207 kb) Additional file 4: Key results
and main author conclusions from studies assessing rates of ineligibility for RCT participation in a
real-world patient population (Method B). Representation of women in randomized clinical trials of
cardiovascular disease prevention. Finally, simple descriptive analysis of real-world data can also be
employed in the trial planning stages to better understand the impact of specific design decisions (for
example, potential exclusion criteria) on the anticipated generalizability of the trial results and so
improve design. When people analysing data know which treatment group was which, there can be
the tendency to “overanalyse” the data for any minor differences that would support one treatment.
A range of different statistical methodologies were employed in the included studies, and it is
outside of the scope of this review to detail them all; the reader is referred to the individual studies
for more information. Additional files Additional file 1: Full Ovid MEDLINE search strategy for
literature searches. (PDF 280 kb) Additional file 2: Summary of real-world and RCT data sources
employed in included studies. Authors made a number of recommendations to improve external
validity. The use of propensity scores to assess the generalizability of results from randomized trials.
Additional analyses were conducted in some Method B studies as detailed in Table 1. Study
selection, data extraction, and reporting Search results were assessed for relevance by two
independent researchers by reviewing the title and abstract of all identified studies. A systematic
review is a critical assessment and evaluation of all research studies that address a particular clinical
issue. Furthermore, it was observed that large proportions of the general disease population were
often excluded from trial participation. The results from, say, the treatment A group are compared
with results from the treatment B group. CONSORT 2010 Statement: Updated guidelines for
reporting parallel group randomized trials.
Detailed description of data sources (real-world and RCT) used in studies included in review. (PDF
207 kb) Additional file 3: Key results and author conclusions from studies that compared baseline
characteristics between a real-world patient population and a patient sample enrolled in an RCT
(Method A). The main results should be analysed on the basis of intention to treat. The use of
propensity scores to assess the generalizability of results from randomized trials. Identifying
subgroups of patients who may respond better to certain treatments may help to improve clinical
outcomes in back pain. Review Methods The methodological framework of this literature review
was employed to examine the extent, range, and nature of research activity regarding the
representativeness of RCT patient samples and the implications of this to the external validity of the
findings. This situation could, however, mean that patients at highest baseline risk who might be
expected to receive the most benefit from a particular therapy are undertreated. Researchers should
ensure at the planning stage that there are enough participants to ensure that the study has a high
probability of detecting as statistically significant the smallest effect that would be regarded as
clinically important. 20. The highest number of studies was conducted in the USA (Table 1 ).
Exclusion criteria used in antidepressant efficacy trials: consistency across studies and
representativeness of samples included. Download citation Received: 09 March 2015 Accepted: 21
October 2015 Published: 03 November 2015 DOI: Share this article Anyone you share the following
link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently
available for this article. Patients with more co-morbidities or co-interventions may be more likely to
prematurely discontinue study participation, which could lead to high attrition rates and a negative
impact on trial validity and outcomes. Authors made a number of recommendations to improve
external validity. Potential factors influencing the external validity of RCTs In the majority of
included studies, the authors made some attempt to identify factors influencing the external validity
of RCTs. The PRECIS-2 tool: designing tools that are fit for purpose. BMJ. 2015;350:h2147.
Article. One way of trying to ensure that the groups are as identical as possible is to generate
separate block randomisation lists for different combinations of prognostic factors. Thus the main
rationale for random allocation is defeated, leading to potential bias. How representative of everyday
clinical populations are schizophrenia patients enrolled in clinical trials. The sources and settings
from which RCT samples and real-world patient populations were drawn are listed in Tables 2 and 3
(a more detailed summary of sources is provided in Additional file 2 ). A range of different statistical
methodologies were employed in the included studies, and it is outside of the scope of this review to
detail them all; the reader is referred to the individual studies for more information. Finally, simple
descriptive analysis of real-world data can also be employed in the trial planning stages to better
understand the impact of specific design decisions (for example, potential exclusion criteria) on the
anticipated generalizability of the trial results and so improve design. Of 4827 articles, 283 were
selected using a series technique. Any selection bias in an RCT invalidates the study design and
makes the results no more reliable than an observational study. Scoping studies: towards a
methodological framework. Conclusions In the majority of studies included in this literature review
it was concluded that patient samples in cardiology, mental health, and oncology RCTs are not
broadly representative of patients encountered in everyday practice. How real are patients in placebo-
controlled studies of acute manic episode. For more information, please refer to our Privacy Policy.
The ranking has an evolutionary order, moving from simple observational methods at the bottom,
through to increasingly rigorous methodologies. For more information, please refer to our Privacy
Policy. A third reviewer (TKM) resolved disagreements on study selection. In this article, I will
explain the hierarchy of evidence in assessing the effectiveness of interventions or treatments, and
discuss the randomised controlled trial, the gold standard for evaluating the effectiveness of
interventions.
Two things usually come into mind in making this decision—how big is the treatment effect, and
how likely is it that the result obtained is due to chance alone. Where necessary, additional analyses
restricted only to participants who fulfilled the intended protocol (per protocol analyses) may also be
reported. Methods of assignment that are prone to bias include alternating assignment or assignment
by date of birth or hospital admission number. 10. The technique prevents researchers from
consciously or unconsciously influencing which participants are assigned to a given intervention
group. The choice of a significance level is artificial but by convention, many researchers use a p
value of 0.05 as the cut off for significance. Assessment of differences in patient populations
selected for excluded from participation in clinical phase III acute myelogenous leukemia trials.
Method A involved a formal statistical comparison (for example, use of Wilcoxon rank sum test and
chi-square test for continuous and categorical variables, respectively) of baseline characteristics
between a real-world patient population and a patient sample enrolled in an RCT in the same specific
disease area. The 95% confidence interval (CI) of the estimate will be the range within which we are
95% certain that the true population treatment effect will lie. Issues to consider when reading an
RCT may be condensed into three important areas 8. Dose intensity and toxicities associated with
FE100C-D chemotherapy in a non-trial population of node positive breast cancer patients compared
with PACS-01 trial group. Additional files Additional file 1: Full Ovid MEDLINE search strategy
for literature searches. (PDF 280 kb) Additional file 2: Summary of real-world and RCT data sources
employed in included studies. When, rarely, study participants, data collectors, and data evaluators
such as statisticians are all blinded, the study is referred to as “triple blind”. 5. Hypertension patients
participating in trials differ in many aspects from patients treated in general practices. Effect of study
criteria on recruitment and generalizability of the results. While some pragmatic trials have good
internal validity and some observational studies may lack external validity, generally explanatory
RCTs tend to maximize internal validity at the expense of external validity, while studies conducted
in a setting more closely resembling real-world practice may do the opposite. For example, in a
randomised controlled trial where one is comparing enteral nutrition with corticosteroids in the
treatment of children with active Crohn’s disease, it may be impossible to blind participants and
health care professionals to assigned intervention, although it may still be possible to blind those
analysing the data, such as statisticians. For more information, please refer to our Privacy Policy.
Beyond the randomized clinical trial: the role of effectiveness studies in evaluating cardiovascular
therapies. Patients who are aware that they are receiving what they believe to be an expensive new
treatment may report being better than they really are. As Torgesson and Roberts have suggested, the
results of a supposed RCT which has had its randomisation compromised by, say, poor allocation
concealment may be more damaging than an explicitly unrandomised study, as bias in the latter is
acknowledged and the statistical analysis and subsequent interpretation might have taken this into
account. 14. Publications identified by this methodology indicated that RCT samples in cardiology,
mental health, and oncology studies that assessed pharmaceutical interventions in adult patients were
often not broadly representative of patients treated in everyday clinical practice and that caution
should be exercised when extrapolating data from trials to patients treated in usual care settings.
Thus the main rationale for random allocation is defeated, leading to potential bias. This goal could
be achieved by trial design modification to include a more representative patient sample and by
supplementing RCT evidence with data generated from observational studies. All exclusion criteria
were graded independently and in duplicate as either strongly justified, potentially justified, or
poorly justified according to previously developed and pilot-tested guidelines. Data Sources and
Study Selection The MEDLINE database was searched for RCTs published between 1994 and 2006
in certain general medical journals with a high impact factor. The outcomes of interest were any back
pain or pain-related measures. Patients with chronic heart failure encountered in daily clinical
practice are different from the “typical” patient enrolled in therapeutic trials. Hear from your peers
about the better TLIF by Medtronic For more information please click here. Taken together, RCT
and observational study data should provide a complementary body of evidence that optimizes both
internal and external validity. A cross-sectional analysis of clinical trial and observational study
samples. BMJ Open. 2012;2:e000833. Article.
Treatment effect in RCTs may be reported in various ways including absolute risk, relative risk, odds
ratio, and number needed to treat. Finally, the conclusions regarding external validity, as reported in
individual studies, were subjective, which limited our ability to more accurately synthesize and
summarize the findings. Results: This review included 18 studies involving 10 292 participants.
Conclusions In the majority of studies included in this literature review it was concluded that patient
samples in cardiology, mental health, and oncology RCTs are not broadly representative of patients
encountered in everyday practice. The populations studied using Method A were compared for
demographics, clinical characteristics, baseline treatments and procedures, and other variables (Table
1 ). Our website uses cookies to enhance your experience. Thought you might appreciate this item(s)
I saw in Journal of Neuroscience Nursing. The term blinding (sometimes called masking) refers to
the practice of preventing study participants, health care professionals, and those collecting and
analysing data from knowing who is in the experimental group and who is in the control group, in
order to avoid them being influenced by such knowledge. 16 It is important for authors of papers
describing RCTs to state clearly whether participants, researchers, or data evaluators were or were
not aware of assigned treatment. Can phase III trial results of antidepressant medications be
generalized to clinical practice. Patients were compared for baseline characteristics such as
demographics, clinical and disease data, and treatments and procedures. Eligibility criteria in
randomized phase II and III adjuvant and neoadjuvant breast cancer trials: not a significant barrier
to enrollment. The ranking has an evolutionary order, moving from simple observational methods at
the bottom, through to increasingly rigorous methodologies. Data were quality checked through
double-data extraction by a second researcher on 10 % of the records included to ensure the format
of data extraction tables was appropriate. The choice of a significance level is artificial but by
convention, many researchers use a p value of 0.05 as the cut off for significance. For example, there
could be the temptation for a doctor to give more care and attention during the study to patients
receiving what he perceives to be the less effective treatment in order to compensate for perceived
disadvantages. The authors thank Mick Arber for his assistance with the literature review. However,
bias could arise when there are flaws in the design and management of a trial. Eligibility criteria in
heart failure randomized controlled trials: a gap between evidence and clinical practice. A
comparison of depressed patients in randomized vs nonrandomized trials of antidepressant
medication and psychotherapy. The necessity for clinical reasoning in the era of evidence-based
medicine. The results from, say, the treatment A group are compared with results from the treatment
B group. Cardiology Studies included in the review generally demonstrated that, compared with
patients enrolled in major cardiology RCTs, patients encountered in everyday practice were more
likely to have higher risk characteristics as they were older, more likely to be female and to have
clinical impairment and co-morbid disease, were treated less frequently with guideline-recommended
therapy, and received fewer in-hospital procedures (Table 2 ). How many do I need? Basic principles
of sample size estimation. Are patients in clinical trials representative of the general population.
Dimensions of methodological quality associated with estimates of treatment effects in controlled
trials. Study recommendations for the improvement of external validity Many of the studies included
in the present review made recommendations to improve the external validity of RCTs. These
recommendations are outlined in Table 4 and include modifying RCT design to improve external
validity directly, and generating complementary evidence from alternative study types to address the
limited external validity of the RCT post hoc. Authors of articles could report both p values and CIs.
22 However, if only one is to be reported, then it should be the CI, as the p value is less important
and can be deduced from the CI; p values tell us little extra when CIs are known. 22, 23. Block
randomisation and stratification are strategies that may be used to help ensure balance between
groups in size and patient characteristics. 11. Relevance of exclusion criteria in antidepressant clinical
trials: a replication study.
The evidence for, and development of, the existing prediction rules is generally weak. A literature
review was conducted of published English language articles that reported the findings of studies
assessing external validity by a comparison of the patient sample included in RCTs reporting on
pharmaceutical interventions with patients from everyday clinical practice. A range of databases
were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology
Register). Statistically significant results were reported in 5 of the 18 (28%) studies. Conclusions The
RCTs published in major medical journals do not always clearly report exclusion criteria. Participants
are considered in blocks of, say, four at a time. Two things usually come into mind in making this
decision—how big is the treatment effect, and how likely is it that the result obtained is due to
chance alone. The results from, say, the treatment A group are compared with results from the
treatment B group. A second researcher checked the grouping of each study by category; in the
event of any disagreements, the findings of each paper were discussed until resolution was reached.
Increasing underrepresentation of elderly patients with advanced colorectal or non-small-cell lung
cancer in chemotherapy trials. The framework for categorizing the methods used in individual studies
and for interpreting individual study conclusions was consistent and clearly detailed, adding to the
methodological rigor of the review. Conclusions: Despite some isolated success, most MA
interventions in stroke survivors do not show statistically significant improvement. Effect of study
criteria on recruitment and generalizability of the results. Such exclusions may impair the
generalizability of RCT results. For example, there could be the temptation for a doctor to give more
care and attention during the study to patients receiving what he perceives to be the less effective
treatment in order to compensate for perceived disadvantages. Differences between clinical trial
participants and patients in a population-based registry: the German Rectal Cancer Study vs the
Rostock Cancer Registry. Of 4827 articles, 283 were selected using a series technique. All data
included in the final manuscript were quality checked. Assessment of differences in patient
populations selected for excluded from participation in clinical phase III acute myelogenous leukemia
trials. Thought you might appreciate this item(s) I saw in Journal of Neuroscience Nursing. An
additional six studies were identified through citation searching. Fig. 1 Study selection for a
literature review assessing the external validity of randomized controlled trials Full size image Study
design Of the 52 studies included, 18 (34.6 %) employed only Method A (comparison of baseline
characteristics) while 27 (51.9 %) employed only Method B (determination of percentage
ineligibility) (Table 1 ). Thirdly, the present review was limited to just three therapeutic areas
(cardiology, mental health, and oncology), and while a large proportion of the relevant literature was
focused in these areas, it is possible that findings may be different in other specialties. Randomized
controlled trials: do they have external validity for patients with multiple comorbidities. We note that
some differences in generalizability were observed between the different therapeutic areas studied in
the present review. Table 4 Recommendations for managing external validity issues made by
included studies Full size table Discussion The present analysis utilized a robust literature review
methodology to identify studies that compared the clinical characteristics of an RCT sample and
patients from a real-world source (Method A) or assessed the proportion of a real-world population
that would satisfy criteria for RCT inclusion (Method B). There is growing interest in different
analytical methods that utilize data from multiple studies to extend and complement the evidence
provided by a single clinical trial. Issues to consider when reading an RCT may be condensed into
three important areas 8. When such patients are excluded from the analysis, we can no longer be sure
that important baseline prognostic factors in the two groups are similar. In such a situation, we are
unable to demonstrate a difference between the groups and the result is usually referred to as not
statistically significant. The judgement of a doctor who expects a particular treatment to be more
effective than another may be clouded in favour of what he perceives to be the more effective
treatment.
Dose intensity and toxicities associated with FE100C-D chemotherapy in a non-trial population of
node positive breast cancer patients compared with PACS-01 trial group. Thirdly, the present review
was limited to just three therapeutic areas (cardiology, mental health, and oncology), and while a
large proportion of the relevant literature was focused in these areas, it is possible that findings may
be different in other specialties. There are various methods to randomize study participants to their
groups. (AHRQ Glossary of Terms). However, in “smaller” studies this may not be the case. For
more information, please refer to our Privacy Policy. Only those studies reporting on pharmaceutical
interventions studied as part of an RCT (placebo-controlled or active comparator) were included.
Findings from this review indicate that there is a need to improve the external validity of RCTs such
that physicians treating patients in real-world settings have the appropriate evidence on which to base
their clinical decisions. Clinical judgment and clinical practice guidelines. The revised CONSORT
statement for reporting randomised controlled trials: explanation and elaboration. Conclusions:
Despite some isolated success, most MA interventions in stroke survivors do not show statistically
significant improvement. An additional seven studies (13.5 %) used both Methods A and B. Case
reports, methodology papers, and conference abstracts were not considered, nor were studies that
undertook an analysis of patients who were recruited into an RCT compared with those that
declined participation, or studies that involved a pediatric (aged. CI may be used to assess statistical
significance, provide a range of plausible values for a population parameter, and gives an idea about
how precise the measured treatment effect is (see below). Data Extraction Trial characteristics and
the details regarding exclusions were extracted independently. The question should be focused on the
problem of interest, and should be framed in such a way that even somebody who is not a specialist
in the field would understand why the study was undertaken. This is particularly important when
subjective outcome measures are being used. Data were quality checked through double-data
extraction by a second researcher on 10 % of the records included to ensure the format of data
extraction tables was appropriate. Eligibility of patients with advanced non-small cell lung cancer for
phase III chemotherapy trials. BMC Cancer. 2009;9:130. Article. The highest number of studies was
conducted in the USA (Table 1 ). The review strategy was, however, relevant to the objective of the
present analysis, as it utilized a robust and transparent approach in order to identify key concepts and
the main sources of information available on the representativeness of RCT patient samples and the
external validity of RCT findings. The primary objective of the review was to assess the extent to
which RCT samples are representative of real-world populations (which may or may not affect the
external validity of the trial findings). Implicit factors Implicit factors that may have affected the
external validity of RCTs were also identified in some of the studies reviewed. TKM and SR
reviewed the search results and conducted the data extraction. The reference lists of relevant articles
were searched for further references. An analysis of eligibility criteria in randomized controlled trials.
Characteristics of advanced cancer patients with cancer-related fatigue enrolled in clinical trials and
patients referred to outpatient palliative care clinics. Hear from your peers about the better TLIF by
Medtronic For more information please click here. Patients were compared for baseline
characteristics such as demographics, clinical and disease data, and treatments and procedures. A
cross-sectional analysis of clinical trial and observational study samples. BMJ Open. 2012;2:e000833.
Article. However, after randomisation, it is almost inevitable that some participants would not
complete the study for whatever reason.