r ctice uidelines

n linic I rials
joseph M. Swanson, PharmD, BCPS

The volume of medically related research published

each year is staggering. Searching a medical citation
database will often produce in excess of 7 50,000 publications in one year's time. Unfortunately, the vast
amount of information produced presents a significant
dilemma for clinicians trying to stay up to date in their
practice. It is impractical-and likely impossible-for
any single clinician to review and process all of the
available literature pertaining to his or her practice.
Thus, a mechanism to inform clinicians about important information related to their clinical practice is
imperative.
Interestingly, despite the numerous publications
produced yearly, a significant number of unanswered
questions still exist for important clinical scenarios.
This dilemma may be even more difficult for the
practicing clinician, because he or she has nowhere
to turn to determine the appropriate action in such
cases. This situation is referred to as the art of
medicine. Unfortunately, patients are at risk of receiving less than optimal care in these situations.
Again, it is extremely important for clinicians to be
able to seek guidance for these troubling clinical
situations.
Even when the clinician is knowledgeable about
current literature supporting specific care, patients
often do not receive optimal care. Translating evidence produced in the medical literature into clinical
practice poses many problems, especially when new
data are generated that may alter the best approach to
a specific clinical condition. Additionally, conflicting
results often produce two or more schools of thought
as to the best practice despite adequate evidence of
any specific action.
Clinical practice guidelines incorporate the vast
evidence for a specific topic and present it in a con-

cise, organized, and easily understandable fashion.

Because clinical practice guidelines evaluate the available literature and provide clinicians with a system for
understanding the strength of this evidence, they are
often referred to as evidence-based guidelines.

271 Principles of Clinical

Practice Guidelines for
Various Diseases and
Their Interpretation in
the Clinical Setting
m

!:'%\~0~G::;:_::_';'Z;..;;::-;,,

literature Categories

When posed with a clinical dilemma, the clinician can

turn to colleagues for assistance, or he or she can
research the question using various types of literature. The literature available to the clinician ranges
widely. Any published literature may be incorporated into practice as long as the strengths and limitations of each are understood and addressed. Following
are various types of studies published in the medical
literature:
Randomized controlled trials, which are considered the most statistically rigorous
ra N onrandomized trials
c! Observational studies
o Cohort studies
o Case control studies
( Cross-sectional studies
The ability to apply individual studies directly to patient care can be impaired because of study limitations.

The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination

Therefore, scientists use other methods to investigate the results identified in individual studies:
~
!k'l

Meta-analysis
Review
Systematic review
Clinical practice guidelines

Clinical practice guidelines are generally broader than

the preceding types of literature, provide recommendations specifically to guide patient care, and are developed by leading clinicians in the field. A more detailed
description is provided later in this chapter.

Definition of

Evidence~Based

Medicine

To understand clinical practice guidelines, one must

discuss the foundation on which they are built. In
the 1950s, the first argument for a methodological
approach to medical decision making was presented.
It was suggested that incorporation of statistics and
probabilities could improve medical decision making.
The term decision analysis was introduced in the
1970s. In the 1980s, evidenced-based medicine (EBM)
and medical decision making (MDM) became more
prominent in the medical community. Both address
the concern for variations in clinical practice resulting in less than optimal care of patients. These variations are unrelated to a patient's severity of illness
but are often associated with other factors, such as
geography or socioeconomic status.
Although EBM and MDM have common foundations, the medical community has embraced EBM
more than MDM. Thus, EBM forms the basis for the
current approach to patient care. EBM approaches a
clinical dilemma as an answerable clinical question
represented by the mnemonic PICO.
The P refers to the patient's problem.
The I addresses the clinical intervention.
The C represents a comparison of the intervention with at least one alternative.
The 0 is for the desired clinical outcome that is
used to compare interventions.
Using the mnemonic provides a semiformal structure that can be applied to any clinical problem.
When using PICO, EBM highlights the quality of
literature used to support the intervention, and it
emphasizes different levels of significance based on
the research methods employed in the published
study. Additionally, it supports a systematic literature review or meta-analysis when conflicting evidence exists. Unfortunately, conducting a systematic

literature review is impractical for the individual clinician. Although a review can be done over a period of
time, it does not allow for immediate application of
information to a specific patient problem. Performing
a meta-analysis is extremely time consuming and
is likely not feasible for the practicing clinician.
Development of the Cochrane Collaboration was an
effort to provide regularly updated reviews of clinically important questions. The reviews are intended
for a broad readership that does not have time for an
individual, careful, and critical review of the literature.
More information on the Cochrane Collaboration is
available at www.cochrane.org.
The meta-analyses available through the Cochrane
Collaboration provide important information to
clinicians seeking answers to a very specific question. Clinical practice guidelines emulate the goals of
the Cochrane Collaboration, but on a broader scale.
Guidelines seek to provide evidence-based information
to the practicing clinician regarding various aspects
of a disease state or clinical condition.

Definition of Clinical Practice Guidelines

According to the Institute of Medicine, clinical practice
guidelines are "systematically developed statements to
assist practitioner and patient decisions about appropriate health care for specific clinical circumstances,"
and their purpose is "to make explicit recommendations with a definite intent to influence what clinicians
do" (Field and Lohr 1992). These statements incorporate key factors such as a systematic review of the literature, clinicians, patients, and specific clinical situations. Each is integral when applying evidence from
clinical trials to an individual patient with a specific
medical condition.
Essentially two types of clinical practice guidelines exist, the traditional form and the evidencebased form.
Experts in a specific field develop the traditional
clinical practice guidelines. The purpose is to provide recommendations for clinicians, generally in the
form of decision trees, flowcharts, tables, and best
practice guides. Although these guidelines usually
incorporate primary literature into the process, they
do not always include a comprehensive review and
often do not provide ratings for the strength of recommendations. Thus, varying portions of the guidelines are determined by expert opinion or perceived
best practices. Traditional clinical practice guidelines require the reader to trust that the expert
guideline developers have sufficiently evaluated the
available literature. Additionally, the reader must

Practice Guidelines and Clinical Trials

have faith that the guideline development was free

of bias, because that is not always evident in the
published document.
Evidence-based clinical practice guidelines take a
more systematic approach than do traditional guidelines. They are still developed by an expert panel.
However, a major difference is a comprehensive,
methodological review of the literature. This review
includes all literature on a specific topic, not only
randomized clinical trials but also less rigorous study
designs such as retrospective reviews, case studies,
and prospective nonrandomized studies. The use of
less-than-optimal literature leads to the next important
aspect of evidence-based guidelines, evaluation of
the strength of supporting literature. Evidence-based
guidelines identify the literature supporting specific
recommendations. They then apply a grade for the
recommendation that is based on the strength of available literature. These types of guidelines can include
expert opinions, and if so, this inclusion is clear in
the recommendation.
Both types of guidelines may provide insight into
important aspects of a clinical condition that the cur-

rently published literature does not adequately address.

That section is generally titled "Future Research" and
is used to stimulate researchers to attempt to answer
the important questions included there.

Anatomy of a Clinical Practice Guideline

The anatomy of a clinical practice guideline is fairly
simple. A guideline generally contains text introducing the guideline. A table usually provides the definitions for the grading of recommendations and supporting evidence. Following those sections, many
guidelines provide an abbreviated text of the recommendation, which is followed by a more detailed text
describing the supporting evidence for the recommendation. The detailed text focuses on the evidence
provided by important primary literature. Guidelines
often provide suggested clinical pathways for diagnosis and treatment of the clinical condition. The general
nature of these pathways is intended to provide a starting point for clinicians to incorporate regional or local
practice variations into guideline recommendations,
creating a customized pathway. Figure 27-1 provides

'at~l:l27~1. Generic Example of a Clinical Pathway

Clinical conditions that would qualify the

individual patient for entrance into the
treatment pathway
Yes

No

Patient is out of pathway or

requires periodic reevaluation

Actions to take (procedures,

medications, tests, etc.)

Patient response

Yes

Continue therapy and

monitor
Source: Author's representation.

No

Alternative therapy

The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination

a generic example. T abies are used to highlight important facts that all clinicians should remember. All
guidelines provide a references section that allows clinicians to find original studies supporting recommendations in the guidelines. The references also allow clinicians the opportunity to incorporate inclusion and
exclusion criteria of specific studies in local practice.
The general outline of a clinical practice guideline
should be included at the beginning of the document.
Box 27-1 provides a sample outline of a clinical practice guideline. Guidelines begin with a formal explanation of the intent, scope, and methodology used in the
development. Those sections provide the transparency
considered so important when evaluating the integrity
of a guideline. An introduction highlights the condition
and the reasons it is important to clinicians.
Following that section is a brief epidemiology of
the condition, if this information was not included in
the introduction. Most clinicians are relatively aware
of this information, but guidelines can provide the
most recent information. If pathogenesis is included
in a guideline, it should highlight recently identified
information. This information should have some relevance to the clinical condition and therapies that
address the newly identified pathogenesis.
Some conditions are preventable. A section describing the prevention of the condition may or may not be
relevant. In conditions where prevention is feasible,
separate guidelines may focus entirely on this aspect
of the condition.
Diagnosis and evaluation of the clinical condition
is one of the most important areas of a guideline and
likely contains the majority of recommendations.
Therapy for the condition is the only section that

1?,!J~~~ 271.

Outline of a Clinical Practice Guideline

Summary of the intent and scope of the clinical practice

guideline
Methodology used to develop and prepare the guideline
Grading system for ranking recommendations in the guideline
Introduction to the topic
Epidemiology of the clinical condition
Pathogenesis of the clinical condition
Prevention of the clinical condition (if possible)
Diagnosis and evaluation of the clinical condition
Therapy for the clinical condition
Evaluation of response to therapy
Identification of important clinical questions not addressed
in the literature
Suggestions for future research on the clinical condition

may contain as much information as the diagnosis

section. This section is one of the most important for
pharmacists, because it usually contains the relevant
literature for medications.
Some guidelines will contain sections that describe
how to monitor for response to therapy. These sections
can be important to pharmacists because they can
contain recommendations for determining medication
failure, changing the medication therapy, or identifying
medication-related adverse effects.
Some, but not all, guidelines include sections
identifying important clinical questions not yet answered and areas for future research. These sections
usually guide researchers toward areas of important
concern or possible breakthroughs in patient care.
Additionally, such sections alert clinicians to future
literature that may change practice.

levels of Evidence
As previously mentioned, clinical practice guidelines
provide clinicians guidance for recommendations.
The quality of evidence supporting recommendations
is described by grading systems. Grading systems are
presented in different variations of letters and numbers, depending on the expert panel developing the
guidelines. Although variations exist, most grading
tends to follow similar formats to that in Table 27-1.
The quality of evidence generally ranges from high to

1. Example of an Evidence Grading System

Quality of
supporting
evidence

Numbers

High

letters

Types of studies

Randomized controlled
trials without limitations

Moderate

Randomized controlled
trials with limitations or
nonrandomized controlled
trials (cohort, case-control
studies, etc.) without
limitations

Low

Nonrandomized controlled
trials with limitations or
noncontrolled studies
(observational studies,
case series, case reports,
etc.) without flaws

Very low

Noncontrolled studies with

flaws or expert opinions

Source: Author's compilation.

Source: Author's compilation.

Practice Guidelines and Clinical Trials

very low, as indicated by the corresponding letter or

number. The higher level of evidence usually correlates to a lower number or a letter appearing sooner
in the alphabet. Some guidelines will simplify the
grading level to high, moderate, and low. The belief
is that restricting the number of levels in a grading
system makes the system easier for the clinician to
understand. However, no direct evidence supports
this effect. Evidence-based guidelines provide an explanation of the grading system and study designs associated with each level.
Evidence-based guidelines not only grade the level
of supporting evidence, but also usually grade the
strength of the recommendation. Table 27-2 provides
an example of a grading system for guideline recommendations. The strength of a recommendation generally correlates with the strength of the supporting evidence. However, the strength of the recommendation
usually provides a risk-versus-benefit determination.
Recommendation strength can range from "recommend implementing the recommendation," usually
corresponding to a positive risk-versus-benefit ratio,
to "recommend not implementing the recommendation," usually with a negative risk-versus-benefit ratio.
These strengths are often represented by letters or
numbers, as with the grading of evidence. The symbols
used for the recommendation strength are usually different from those used for grading of evidence.
A combination of letters and symbols is often used
when providing strength for the recommendation

27=2. Example of a Recommendation

Grading System
Recommendation
strength

Numbers

Recommend
implementing

letters
A

Risk vs. benefit

Desirable effects
with benefit clearly
outweighing risk

Consider
implementing

Desirable effects
with benefit appearing to outweigh risk

Consider not
implementing

Possible undesirable effects with

risk appearing to
outweigh benefit

Recommend not
implementing

Undesirable effects
with risk clearly
outweighing
benefits

Source: Author's compilation.

and grading the supporting literature. The use of

two different scales provides an easily understandable
and concise form of grading. For example, a strong
recommendation with strong supporting evidence
would likely be graded as a 1A recommendation.
Interestingly, no research addresses the most effective method of grading either the recommendation or
the supporting evidence.
Although the combination of numbers and letters
can effectively communicate the strength of the recommendation, lack of uniformity may cause confusion. Current clinical guidelines have no standardized
method of grading the literature and recommendation. Many times the same number or letter has a different meaning depending on the organization or expert panel. This lack of standardization makes it
extremely important that the reader of the guideline
first determine what grading scale is used in a specific
clinical practice guideline. The GRADE (Grading of
Recommendations Assessment, Development, and
Evaluation) Working Group was formed with the
idea of reaching an agreement on a uniform, logical
approach to grading the quality of evidence and the
strength of recommendations. If this working group
is successful, all guidelines could provide the same
grading regardless of the expert panel developing the
guideline. This outcome would allow clinicians to
compare and contrast grading of recommendations
across the board. It is anticipated that standardized
grading could improve compliance by clinicians.
Until this occurs, clinicians are expected to review
each guideline carefully and determine how the recommendations and supporting eyidence are graded.
Finally, the clinician needs to sort out the differences
in grading levels and supporting evidence produced
in different guidelines.

Finding Applicable Guidelines

If a clinician wishes to apply EBM to one of his or her
patients, a complete review of the literature is impractical. One of the most efficient methods is to identify
a clinical practice guideline that addresses the patient's specific condition. As previously mentioned, a
guideline will have recommendations for clinically
important conditions. However, where does this clinician go to find the appropriate guidelines? Many
would immediately turn to a bibliographic database
such as the National Library of Medicine's MEDLINE.
A search of MEDLINE may produce the appropriate
guideline as long as it is published in an indexed journal. Unfortunately, not all practice guidelines appear
in indexed journals. Some are published online, and

The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination

others may appear in nonindexed journals. A search

of this database might miss important, clinically relevant guidelines. Additionally, MEDLINE does notalways provide access to the full text of cited guidelines.
Even if the clinician were to find the appropriate
guideline, he or she might not be able to access the
entire text and thus not be able to evaluate recommendations in the guideline. Fortunately, the clinician has
other options. In fact, the Internet offers several
choices to access a variety of guidelines. The Web sites
listed in Box 2 7-2 provide access to various guidelines.
The National Guideline Clearinghouse is an initiative
of the Agency for Healthcare Research and Quality
and U.S. Department of Health and Human Services.
It is a public resource for evidence-based clinical practice guidelines; it is frequently used to obtain fulltext clinical practice guidelines for multiple clinical
conditions. The site contains 3,060 guidelines from
289 organizations worldwide.
Examples of commonly referenced clinical practice guidelines are included in Table 27-3. As indicated in the table, more than one organization often
supports the guideline. Guidelines are generally pub-

Sources for Obtaining Clinical

Practice Guidelines
Agency for Healthcare Research and Quality, National
Guideline Clearinghouse, www.guideline.gov
Centers for Disease Control and Prevention, www.cdc.gov
Medical Matrix, www.medmatrix.org
National Library of Medicine, Health Servicesrrechnology
Assessment Text, www.ncbi.nlm.nih.gov/books/bv.fcgi?
rid=hstat
Source: Author's compilation.

lished in well-respected peer-reviewed journals, and

availability ranges from easily accessible online copies
to required journal subscription hard copies.

Evaluation of Clinical Practice Guidelines

The evaluation of clinical practice guidelines is important when determining whether to apply recommendations directly to patients, especially when more than
one set of guidelines exists for a specific clinical con-

'\"'1e 273. Some Commonly Used Clinical Practice Guidelines

Guideline

Supporting organization

Antithrombotic and Thrombolytic Therapy

American College of Chest Physicians

Reports of the Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure

National Heart, Lung, and Blood Institute

Guidelines tor the Diagnosis and Management of Asthma

U.S. Department of Health and Human Services; National Institutes of

Health; and National Heart, Lung, and Blood Institute

ACCF!AHA Guidelines for the Diagnosis and Management

of Heart Failure in Adults

American College of Cardiology Foundation and American Heart

Association

ADA Clinical Practice Recommendations

American Diabetes Association

Surviving Sepsis Campaign: International Guidelines for

Management of Severe Sepsis and Septic Shock

American Association of Critical-Care Nurses, American College

of Chest Physicians, American College of Emergency Physicians,
Canadian Critical Care Society, European Society of Clinical
Microbiology and Infectious Diseases, European Society of
Intensive Care Medicine, European Respiratory Society, International Sepsis Forum, Japanese Association for Acute Medicine,
Japanese Society of Intensive Care Medicine, Society of Critical
Care Medicine, Society of Hospital Medicine, Surgical Infection
Society, and World Federation of Societies of Intensive and Critical
Care Medicine

Therapeutic Monitoring of Vancomycin in Adult Patients:

A Consensus Review of the American Society of HealthSystem Pharmacists, the Infectious Diseases Society of
America, and the Society of Infectious Diseases Pharmacists

American Society of Health-System Pharmacists, Infectious Diseases

Society of America, and Society of Infectious Diseases Pharmacists

Source: Author's compilation.

Practice Guidelines and Clinical Trials

clition. A prime example is the CHEST (American

College of Chest Physicians) guidelines for the prevention of venous thromboembolism and the EAST
(Eastern Association for the Surgery of Trauma)
guidelines for management of venous thromboembolism. Both guidelines address prevention of deep
vein thrombosis in traumatically injured patients, but
the recommendations of each differ slightly. Therefore,
clinicians caring for trauma patients are responsible for
reviewing each set of guidelines and the literature supporting recommendations for each. Then the clinician
must determine which recommendations to incorporate in the care of his or her patients.
The Appraisal of Guidelines for Research and
Evaluation (AGREE) Instrument, which is available
at www .agreecollaboration.org/instrument, provides
a tool for guideline users to assess the methodological quality of clinical practice guidelines. The authors
of the AGREE Instrument state that it is intended for
use by the following groups:
Policy makers-to decide which guidelines can
be recommended for use in practice
m Guideline developers-to follow a structured
and rigorous development methodology and
to use a self-assessment tool to ensure that their
guidelines are sound
ulll Health care providers-to undertake their
own assessment before adopting the
recommendations
Educators or teachers-to help enhance critical
appraisal skills among health professionals
The AGREE Instrument consists of 23 items that
are organized in six different sections. Each section
addresses a different aspect of a guideline's quality.
!Ill

~~

illl

Scope and purpose. This section deals with the

major aspects of the guideline. It focuses on the
overall purpose of the guideline, the important
clinical questions addressed, and the target
patient population.
Stakeholder involvement. This section determines the degree to which the guideline represents the views of clinicians using the guideline
and the target patient population.
Rigor of development. This section investigates the
degree to which the development group researched
the available evidence. It addresses the processes
used to gather, synthesize, and evaluate the available literature. Additionally, it determines the
methods used to produce recommendations.
Clarity and presentation. This section focuses
on the language used in the guideline and how
the authors have formatted the document.

r'lll

rmJ

Applicability. This section addresses the key

factors in implementing the guideline, including
organizational, behavioral, and cost implications.
Editorial independence. This section deals
mostly with the developers of the guideline. It
evaluates the independence and possible conflicts
of interest of the development group.

The 23 items in the six sections are organized so that

the user of the instrument can rank his or her evaluation of the guideline. Each item may receive a minimum score of 1 (indicating the user strongly disagrees
with the item statement) and a maximum score of
4 (indicating the user strongly agrees with the item
statement). All items within a section are scored, and
the total score is tallied for each user review. The
total score for each user is added together to determine
the obtained score. The maximum score is the number
4 (strongly agree) times the number of items in a section, times the number of appraisers. The minimum
score is calculated in the same way as the maximum,
only the number 1 (strongly disagree) is used. The standardized score accounts for all users' input and the
maximum and minimum scores possible. Table 27-4
shows a sample score.

272. Integration of Scientific and

Systems.. Based Knowledge
into Treatment Protocols and
Clinical Practice Guidelines

"'"'"'~'"'"'""''''''"""''''"''!,,'JC-,-,,-

'

The two main reasons for directly applying to patients

the evidence-based recommendations from clinical
practice guidelines are as follows:
ft;\

Improving patient care. In 2000, the Institute

of Medicine published a report, To Err Is
Human, stating that up to 98,000 inpatients
die unnecessarily. These deaths can be attributed
to medical error. This rate is unacceptable
and has spurred attempts to improve patient
care. Additionally, other reports suggest that
Americans do not receive care based on the
best available scientific evidence. Incorporating
clinical practice guidelines into local practice
assists clinicians in identifying the best care.
In doing so, patient outcomes are improved.
For example, a study demonstrated that applying
the community-acquired pneumonia guidelines
to patients reduced their length of stay and
mortality in the hospital.

The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination

",,le 274. Example of AGREE Instrument Scoring

Total

Item 1

Item 2

Item 3

User 1

User 2

User 3

Total

2
8

Maximum score

(Strongly agree) x (number of users) x (number of items)

23
36

Example: 4 x 3 x 3
Minimum score

(Strongly disagree) x (number of users) x (number of items)

Example: 1 x 3 x 3
Standardized score

Obtained score- Minimum score

51.8%

Maximum score- Minimum score

Example:
23-9
36-9
Source: Based on AGREE Collaboration 2009.

Lowering cost. Applying clinical practice guidelines to patient care not only improves patient
outcomes but also can reduce costs. In the
community-acquired pneumonia example,
patient charges were reduced. If patients receive
better care, they will be more likely to address
health concerns sooner. If clinicians follow
guidelines, they will be less likely to miss important clinical issues. Identifying clinical issues
sooner permits reduction in medical costs or
avoidance of those costs altogether.
Common forms of incorporating clinical practice
guidelines into patient care include protocols, pathways, guidelines, and order sets. Although clinicians
view each of these methods differently, they can be
categorized by how much they restrict clinician decision making:

Protocols. A protocol is a plan for a course of

medical care of patients. It tends to be the most
restrictive form of dictating care. Depending on
the protocol, patient care may be completely determined by the protocol. Many clinicians are
concerned that protocols remove clinical decision making, thus removing the clinician from
the care of patients.
Pathways. In contrast, pathways provide a plan
for a course of action but generally allow the
clinician to make decisions. They are often considered less restrictive than protocols.

Guidelines. Although guidelines provide evidence,

they leave the decisions completely to the clinician.
They provide the most autonomy for clinicians.
tm Order sets. By providing options for clinicians,
order sets aim to clue the user into thinking
about specific aspects of care. They may be used
independently but are often combined with protocols, pathways, or guidelines.

tB

The general process of incorporating newly identified

clinical evidence or clinical practice guidelines into
direct patient care has several steps, as illustrated in
Figure 27-2. Pharmacists should be involved in each
step of this process.
The American Society of Health-System Pharmacists developed guidelines addressing the pharmacist's
role in this process:

''~1

Step 1: New evidence. Medical researchers generate new evidence and report the results of specific
studies in medical journals. Pharmacists are playing a bigger role in the generation of new evidence
now than ever before. However, the role for the
pharmacist in integration of new evidence into
direct patient care is most prominent in the later
steps in the process.
Step 2: Dissemination. All health care practitioners are responsible for disseminating newfound
knowledge, but pharmacists can be integral in this
step. Pharmacists can conduct journal club meetings to highlight important evidence that should

Practice Guidelines and Clinical Trials

27-2. Process by Which New Research Is Incorporated into Clinical Practice

Step 1: New evidence

Step 7: Assessment

Step 2: Dissemination

Step 6: Implementation

Step 3: Acceptance

Step 5: Development
Step 4: Consensus

Source: Author's representation.

!i!ll

l1lli

be applied directly to patients. Pharmacists should

monitor important guidelines that apply to their
practice area. They should help inform other
health care practitioners when updates or new
guidelines are published.
Step 3: Acceptance. Whether new evidence is
accepted depends highly on the quality of the evidence. If new evidence clearly provides a great
benefit with very little risk, it is usually welcomed
by all. More controversy usually arises when the
risk-to-benefit ratio is not as dear. The pharmacist's role in acceptance is to highlight the risks and
benefits and discuss them with other pertinent
health care professionals. Placing the risks and
benefits into perspective will facilitate an understanding of new evidence.
Step 4: Consensus. To achieve consensus, one
must bring local practice leaders together to
determine the best method of applying the new
evidence to patient care. Pharmacists may be the
practice leader or they may assist other leaders
in this process.
Step 5: Development. This step involves the
incorporation of the new evidence into a new or
currently existing clinical protocol, pathway, or
order set. In the hospital setting, development is
usually performed by a multidisciplinary team
that likely includes a pharmacist.
Step 6: Implementation. This step occurs immediately following development. Implementation
includes education of all health care practitioners involved in applying the new evidence to

the patient. Following the initial education,

members of the development team are usually
available to help with troubleshooting any problems with the new evidence.
~ Step 7: Assessment. This final step involves measuring the effect of implementing the new evidence
by auditing patient outcomes after implementation. An important part of the assessment phase
is providing feedback to the development team.
Feedback is used to augment or revise the implementation. Additionally, it can identify ways to
improve the implementation prbcess, such as providing enhanced education or awareness raising.
The entire process is circular, in that new evidence is
constantly generated. Although not all evidence will
be incorporated, continual monitoring of newly published evidence is essential to ensure that patients receive the most effective care.

27 ..3., Evaluation of Clinical Trials

That Validate Treatment
Usefulness
Research enhancing patient outcomes can greatly
improve clinical practice. Although new research is
exciting and often quickly adapted to clinical practice,
results should be confirmed in independent study to
ensure that the initial results were true. Thus, validation of research is extremely important. Validation

The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination

generally occurs on a single-study basis, meaning that

one study shows improved patient outcomes and is
validated by a different single study; however, with the
increased use of clinical guidelines, studies are being
published that validate the entire guideline:
li!J

Validation of a single study. An example is a

study investigating early goal-directed therapy

for hemodynamic support of patients with sepsis presenting to the emergency department.
The study documented a decrease in mortality
of 16%. Following this study, a different group
of researchers investigated the use of the goaldirected therapy from the original study. These
researchers were able to achieve a 9% reduction in mortality. This study validated theresults from the original research and allowed
clinicians to apply the results to patients with
confidence.
~ Validation of clinical practice guidelines. In
2003, the Canadian clinical practice guidelines
for nutrition support in critically ill patients receiving mechanical ventilation were published.
These guidelines systematically review the pertinent literature regarding the topic and provided
clinicians a set of recommendations. In 2004, a
validation of these guidelines was published. It
is impossible to conduct a randomized controlled trial evaluating the numerous recommendations provided in the practice guidelines.
Therefore, the validation study was a multicentered, prospective observational study of
59 intensive care units (ICUs). The researchers
investigated the association between five recommendations in the clinical practice guidelines
and adequacy of enteral nutrition. The study
concluded that ICUs more consistent with
guidelines demonstrated more success with
enterally feeding patients.
Unfortunately, two factors often prevent clinicians
from confidently implementing promising results:
fiffi

Lack of validation studies. Ensuring that the

results found in one study are correct can be
difficult. Researchers and clinicians rely on
sound study design and statistical evaluation
to provide confidence in the results obtained.
However, a possibility always exists that the
promising results occurred by chance or that some
unknown factor contributed to the improved
outcomes. If a separate study confirms the initial
study's promising results, clinicians have more
confidence that the improved outcome is indeed

a real effect. Some well-conducted single studies

have such a great influence on the medical
community that it is difficult or impossible to
perform a validation study. Following are the
two main reasons for this difficulty:
o If one study shows a significant benefit, and
the medical community supports the results, a
validation study may be considered unethical.
Clinicians may believe so strongly in the benefit that a controlled trial may be considered as
placing study subjects at unnecessary risk. For
this scenario to occur, the original study would
have to be extremely well conducted, well designed, and controlled and would need to have
a sufficient study population. Alternatively, a
multitude of well-conducted smaller studies
can demonstrate similar results.
One major barrier to the successful completion of a validation study is physician preference. If a physician believes the original study
results are convincing enough, he or she may
prefer to withhold patients from enrollment in
a validation study, especially if the validation
uses a placebo-controlled arm. The physician
may want to ensure his or her patients receive
the therapy from the original study, hoping
that they will receive the benefit originally
found.

Conflicting results in validation studies.

Numerous examples show significant research
results being confounded by subsequent studies
unable to validate the original results. A prime
example is a study investigating the use of lowdose steroids in patients with septic shock.
The original study found improved mortality
in certain patients receiving low-dose steroids.
Unfortunately, a large multicentered study was
unable to confirm the mortality benefit identified
in the initial study. The results from the second
study have produced a dilemma for clinicians
wanting to use low-dose steroids in their patients.
Whether this treatment will benefit patients is
now uncertain.
Despite the difficulties with validating original research, these studies are essential to clinicians who
want to ensure their patients receive the best evidencebased care available. When new research has not
been validated, the clinician needs to evaluate the
risk-to-benefit ratio of the new findings. If the new
research is implemented, clinicians have to monitor
patients closely for the desired outcome and any potential adverse effects.

Practice Guidelines and Clinical Trials

27 .. 4. Key Points
$""
.;:::;rr;:;:I:2::.2:;'!'7ITL~~"';'

!ilil

Eill

ll;J

t:iJ

&J

!!tl

~!;]

!ilil

!ill

~~3

u:i1

1'1
!l1l

2.

:'J',::<~' ~-,"

A staggering volume of medical literature is

published yearly.
Clinical studies fall into two major categories:
treatment and observational.
The most statistically rigorous clinical trial design
is the blinded, randomized, controlled trial.
Evidence-based medicine approaches a clinical
dilemma as an answerable clinical question.
The Cochrane Collaboration was developed to
provide regularly updated reviews of clinically
important questions.
Evidence-based guidelines provide the strength
of a recommendation based on the quality of the
supporting literature.
A clinical practice guideline generally consists of
abbreviated text containing a recommendation
for quick reference by the clinician.
A clinical practice guideline contains text describing the literature that supports the provided
recommendations.
The lack of a standardized grading scale in
clinical practice guidelines makes it extremely
important that the reader first determine how
recommendations were developed.
The National Guideline Clearinghouse Web site
(www.guideline.gov) contains 3,060 guidelines
from 289 organizations worldwide.
The AGREE Instrument consist of 23 items
organized into six different sections and is used to
evaluate the quality of clinical practice guidelines.
Seven steps are taken to apply clinical practice
guidelines to patient care: new evidence, dissemination, acceptance, consensus, development, implementation, and assessment.
Validation studies are essential for confirming
original research findings.
Validation studies have begun to demonstrate
the usefulness of applying clinical practice
guidelines to patient care.

A.
B.
C.
D.
3.

4.

Use of blinding in a clinical trial is expected to

Which of the following best describes a

meta -analysis?
A. A qualitative method of combining the results of multiple independent studies and
synthesizing the results to arrive at a conclusion about the specific question studied
B. A single-center independent study
C. A quantitative method of combining the
results of multiple independent studies and
synthesizing the results to arrive at a conclusion about the specific question studied
D. A nonquantitative review of the literature

5. What is the difference between a clinical

practice guideline and a review?
A. There is no difference between a review
and clinical practice guideline.
B. Reviews have a broader scope than clinical
practice guidelines.
C. Reviews provide recommendations that
are specifically designed to guide patient
care.
D. Clinical practice guidelines provide recommendations that are specifically designed
to guide patient care.
6.

Which organization is best known for developing meta-analyses for important clinical
conditions?
A.
B.
C.
D.

1. Medically related literature published each

year consists of approximately
1,000 publications.
5,000,000 publications.
50,000 publications.
750,000 publications.

Cohort
Case control
Randomized
Cross-sectional

A. decrease bias in the study.

B. increase bias in the study.
C. have no effect on bias.
D. increase and decrease bias in the study.

27 .. 5m Questions

A.
B.
C.
D.

Which study design is considered the most

statistically rigorous?

7.

Cochrane Collaboration
National Meta-Analyses Group
International Society for Meta-Analysis
National Library of Medicine

Which methodological approach to patient

care looks at clinical dilemmas as answerable
clinical questions?

~I~~I'

The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination

A.
B.
C.
D.

Medical decision making

Decision analysis
Evidence-based medicine
Standard medical analysis

C. Consider implementing the recommendation.

D. Consider not implementing the
recommendation.

13. Which of the following Web sites contains

8.

3,060 guidelines from 289 organizations

worldwide?

How do evidence-based clinical practice

guidelines differ from traditional clinical
practice guidelines?
A. A methodological review of the literature
is performed for evidence-based guidelines.
B. Traditional clinical practice guidelines
provide recommendations that are more
specific.
C. Nationally renowned experts develop
evidence-based clinical practice guidelines.
D. Traditional clinical practice guidelines are
published only online.

9. Which of the following sections of clinical

practice guidelines are most important to
pharmacists?
A.
B.
C.
D.

Introduction
Diagnosis
Future research
Therapy

10. What is the general purpose of sample clinical

pathways used in practice guidelines?
A. To dictate exact care provided in the
pathway
B. To provide a foundation for customized
pathways
C. To reduce thinking by clinicians
D. To change policies of medical insurers
11. If a clinical practice guideline provided a recommendation supported by a well-conducted
randomized controlled trial, what number
would it likely be graded?
A. 4
B. 5
c. 3
D.1
12. If a clinical practice guideline provided a D
recommendation, what are the experts likely
recommending?
A. Recommend not implementing the
recommendation.
B. Recommend implementing the
recommendation.

A.
B.
C.
D.
14.

www.medmatrix.org
www.cdc.gov
www.myguidelines.org
www.guideline.gov

Which of the following groups should use the

AGREE Instrument?
A.
B.
C.
D.

Patients
Hospital policy makers
Patients' families
No one

15. If three users evaluate five items in an AGREE

Instrument section, what is the maximum
possible score for that section?
A. 10
B. 45
c. 60
D.100
16. If the maximum possible score for an AGREE
Instrument section is 64, the minimum possible score is 16, and the obtained score is 56,
what is the standardized score?
A. 83%
B. 17%
c. 50%
D.25%

17. Which of the following is a rationale for

incorporating clinical practice guidelines into
patient care?
A.
B.
C.
D.

To
To
To
To

reduce physician independence

increase medical errors
increase physician independence
reduce medical errors

18. Which of the following is the last step in

incorporating clinical practice guidelines into
direct patient care?
A.
B.
C.
D.

Acceptance
Consensus
Assessment
Implementation

Practice Guidelines and Clinical Trials

19. Which of the following best describes a

validation study?
A. Original research not previously reported
B. Confirmation of original research by an
independent group
C. Laboratory research supporting a clinical
trial
D. Recommendation by a clinical expert
20.

Which of the following prevents clinicians

from implementing new evidence in patient
care?
A.
B.
C.
D.

Lack of interest
Lack of validation studies
Confirmatory validation studies
Incorporation into clinical practice
guidelines

27 .. 6e Answers
1.
2.

3.

4.

5.

6.

7.

8.

D. Searching MEDLINE by 1-year increments

produces approximately 750,000 publications.
C. Use of a randomized design decreases the
likelihood for other factors to influence the
outcome of a clinical trial.
A. Blinding reduces bias in the study by preventing those conducting the study to influence
the outcomes of the study.
C. The definition of a meta-analysis is a quantitative method of combining the results of multiple independent studies and synthesizing theresults to arrive at a conclusion about the specific
question studied.
D. A review compiles and synthesizes information about a topic, but a practice guideline
provides weighted recommendations that are
designed to guide each aspect of care related
to that topic.
A. The Cochrane Collaboration was established specifically to conduct meta-analyses.
The National Library of Medicine is the world's
largest medical library and the other organizations are fictitious.
C. Evidence-based medicine is based on the
"answerable clinical question" and is represented by the mnemonic PICO (Patient's problem, clinical Intervention, Comparison with at
least one alternative, and clinical Outcome)
A. Clinical practice guidelines that are not
evidence based often represent opinion. Only
evidence-based guidelines can ensure that a

9.

10.

11.
12.

13.

14.

15.

16.

17.

18.

19.

20.

methodological review of the literature was

performed.
D. Pharmacists are medication experts. Medication therapy is the focus of all pharmacists.
Although the sections addressing other issues are
very important, they may not pertain to pharmacists as much as the section covering therapy.
B. Many local pathways will differ from those
provided in guidelines. This is acceptable and
sometimes preferred. Adapting guideline pathways to local care is very important to address
the most effective approach to patient care.
D. Guidelines generally use a lower number to
represent a strong grading.
A. Similar to grading, recommendations are usually less strong as they move through the alphabet.
Thus a recommendation of choice A is usually
better than a recommendation of choice D.
D. The Web site of the National Guideline
Clearinghouse, www.guideline.gov, states that
it contains such guidelines.
B. Neither patients nor their family members
would use the AGREE document to evaluate
practice guidelines. However, hospital policy
makers should be able to grade the strength of
a guideline.
C. If there are five items, there are 20 possible
points per reviewer because each item has a
maximum score of 4. Thus, 5 x 4 = 20. If all
three reviewers provide the maximum score
on each item, there is a total of 60 points. Thus,
3 X 20 = 60.
A. The standardized score=f .(obtained scoreminimum score)/(maximum score- minimum
score). If this score is reported as a percentage,
it is multiplied by 100. Thus, (56 -16)/(64 -16)
= 40/48 = 0.83 X 100 = 83%.
D. The only beneficial answer is to reduce medical errors. Guidelines do not attempt to reduce
or increase physician independence.
C. The seven steps are new evidence, dissemination, acceptance, consensus, development, implementation, and assessment. Hence, assessment in
the final step.
B. Validation studies duplicate (to some degree)
an original study that shows benefit to determine
if the benefit can be reproduced, thereby suggesting a true beneficial effect.
B. Validation studies are important to help
determine if the beneficial effect is true or just
occurred by chance. Clinicians prefer to wait
until a study has been validated before automatically implementing the studied intervention
into clinical practice.

The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination

27 ..7. References
AGREE Collaboration. Appraisal of Guidelines for
Research & Evaluation (AGREE) Instrument.
AGREE Collaboration, London; 2009. Available
at: www .agreecollaboration.org.
American Society of Health-System Pharmacists. ASHP
guidelines on the pharmacist's role in the development, implementation, and assessment of critical
pathways. Am J Health-Syst Pharm. 2004;61(9):
939-45.
Annane D, Sebille V, Charpentier C, et al. Effect of
treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71.
Elstein AS. On the origins and development of
evidence-based medicine and medical decision
making. Inflamm Res. 2004;53(suppl2):S184-89.
Field MJ, Lohr KN. A provisional instrument for
assessing clinical practice guidelines. In: Field MJ,
Lohr KN, eds. Guidelines for Clinical Practice:
From Development to Use. Washington, D.C.:
National Academies Press; 1992:346-410.
Geerts WH, Bergqvist D, Pineo GF, et al. Prevention
of venous thromboembolism: American College
of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133
(Suppl6):381S-453S.
Hargrove P, Griffer M, Lund B. Procedures for using
clinical practice guidelines. Lang Speech Hear Serv
Sch. 2008;39(3 ):289-302.
Hauck LD, Adler LM, Mulla ZD. Clinical pathway
care improves outcomes among patients hospitalized for community-acquired pneumonia. Ann
Epidemiol. 2004;14(9):669-75.
Hayward RS, Wilson MC, Tunis SR, et al. Users'
guides to the medical literature: VIII. How to use
clinical practice guidelines-A. Are the recommendations valid? The Evidence-Based Medicine Working Group. ]AMA. 1995;274(7):570-74.
Heyland DK, Dhaliwal R, Day A, et al. Validation
of the Canadian clinical practice guidelines for
nutrition support in mechanically ventilated, crit-

ically ill adult patients: Results of a prospective

observational study. Crit Care Med. 2004;32(11):
2260-66.
Heyland DK, Dhaliwal R, Drover JW, et al. Canadian
clinical practice guidelines for nutrition support in
mechanically ventilated, critically ill adult patients.
J Parenter Enteral Nutr. 2003;27(5):355-73.
Institute of Medicine. To Err Is Human: Building a
Safer Health System. Washington, D.C.: National
Academies Press; 2000.
Jones AE, Focht A, Horton JM, Kline JA. Prospective
external validation of the clinical effectiveness of an
emergency department-based early goal-directed
therapy protocol for severe sepsis and septic shock.
Chest. 2007;132(2):425-32.
O'Connor GT, Quinton HB, Traven ND, et al.
Geographic variation in the treatment of acute
myocardial infarction: The Cooperative Cardiovascular Project. ]AMA. 1999;281(7):627-33.
Peterson ED, Shaw LK, DeLong ER, et al. Racial variation in the use of coronary-revascularization procedures: Are the differences real? Do they matter?
N Eng! J Med. 1997;336(7):480-86.
Rivers E, Nguyen B, Havstad S, et al. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Eng! J Med. 2001;345(19):
1368-77.
Rogers FB, Cipolle MD, Velmahos G, et al. Practice
management guidelines for the prevention of
venous thromboembolism in trauma patients: The
EAST practice management guidelines work group.
J Trauma. 2002;53(1):142-64.
Sammer CE, Lykens K, Singh I\-P. Physician characteristics and the reported effect of evidence-based
practice guidelines. Health Serv Res. 2008;43(2):
569-81.
Schiinemann HJ, Best D, Vist G, Oxman AD. Letters,
numbers, symbols and words: How to communicate grades of evidence and recommendations.
CMAJ. 2003;169(7):677-80.
Sprung CL, Annane D, Keh D, et al. Hydrocortisone
therapy for patients with septic shock. N Eng! J
Med. 2008;358(2):111-24.