Using Evidence to Guide Drug

Therapy Decisions
Dean Haxby, Pharm.D.
Associate Professor of Pharmacy
Oregon State University, College of
Pharmacy

To receive 1.5 AMA PRA Category 1 Credits,
you must review this progam and pass the CME
quiz at the end.

Release Date: January 2009 Expiration Date: January 2012


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that supplement the presentation.
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Program Funding
This work was made possible by a grant from the
state Attorney General Consumer and Prescriber
Education Program which is funded by the multi-state
settlement of consumer fraud claims regarding the
marketing of the prescription drug Neurontin.
Continuing Education Sponsors
Continuing Medical Education for the following
activity titled Using Evidence to Guide Drug
Therapy Decisions, is jointly sponsored by The
University of Texas Southwestern Medical Center


and the Federation of State Medical Boards
Research and Education Foundation.










Program Speaker/Author: Dean Haxby, PharmD,

Course Director: Barbara S. Schneidman, MD, MPH
Federation of State Medical Boards Research and Education Foundation, Secretary
Federation of State Medical Boards , Interim President and Chief Executive Officer
Program Directors: David Pass, MD
Director, Health Resources Commission, Oregon Office for Health Policy and Research
Dean Haxby, PharmD
Associate Professor of Pharmacy Practice, Oregon State University College of Pharmacy
Daniel Hartung, PharmD, MPH
Assistant Professor of Pharmacy Practice, Oregon State University College of Pharmacy

Target Audience: This educational activity is intended for health professionals who are involved with medication
prescribing, and those that are involved with committees involved with medication use policies.

Educational Objectives: Upon completion of this activity, participants should be able to: Describe the advantages
and limitations of evidence-based medicine (EBM), and its role in improving prescribing decisions; Describe the
steps in the EBM process; Identify strategies to search for evidence-based medical literature, including useful web
sites; Review key factors that should be appraised with systematic reviews, clinical practice guidelines, and
individual RCTs; Describe the influence different methods of presenting study results can have on decisions; Given
the results of a study calculate ARR and NNT; Discuss how EBM principles can be applied to evaluating new
drugs.





CME Information
CME Policies
Accreditation: This activity has been planned and implemented in accordance with the
Essential Areas & Policies of the Accreditation Council for Continuing Medical
Education through the joint sponsorship of The University of Texas Southwestern
Medical Center and the Federation of State Medical Boards Research and Education
Foundation. The University of Texas Southwestern Medical Center is accredited by the
ACCME to provide continuing medical education for physicians.

Credit Designation: The University of Texas Southwestern Medical Center designates
this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits.
Physicians should only claim credit commensurate with the extent of their participation
in the activity.

Conflict of Interest: It is the policy of UT Southwestern Medical Center that
participants in CME activities should be made aware of any affiliation or financial
interest that may affect the authors presentation. Each author has completed and signed a
conflict of interest statement. The faculty members relationships will be disclosed in
the course material.

Discussion of Off-Label Use: Because this course is meant to educate physicians with
what is currently in use and what may be available in the future, off-label use may be
discussed. Authors have been requested to inform the audience when off-label use is
discussed.

DISCLOSURE TO PARTICIPANTS
It is the policy of the CME Office at The University of Texas Southwestern Medical Center to ensure balance,
independence, objectivity, and scientific rigor in all directly or jointly sponsored educational activities.

Program directors and authors have completed and signed a conflict of interest statement disclosing a financial or
other relationship with a commercial interest related directly or indirectly to the program.

Information and opinion offered by the authors represent their viewpoints. Conclusions drawn by the audience
should be derived from careful consideration of all available scientific information. Products may be discussed in
treatment outside current approved labeling.


FINANCIAL RELATIONSHIP DISCLOSURE

Faculty Type of Relationship/Name of Commercial Interest(s)

David Pass, M.D. None
Dean Haxby, Pharm.D Employment/CareOregon
Daniel Hartung, Pharm.D., MPH None
Barbara S. Schneidman, MD, MPH None


Learning Objectives
Describe the advantages and limitations of
evidence-based medicine (EBM), and its role in
improving prescribing decisions
Describe the steps in the EBM process
Identify strategies to search for evidence-based
medical literature, including useful web sites
Review key factors that should be appraised with
systematic reviews, clinical practice guidelines,
and individual RCTs

Learning Objectives
Describe the influence different methods of
presenting study results can have on decisions

Given the results of a study, calculate ARR and
NNT

Discuss how EBM principles can be applied to
evaluating new drugs.
Problems With Drug Therapy
Over the past 15 years, drug costs have
escalated at a higher rate than any other area
of health care
The US has 5% of the worlds population,
but has 50% of drug consumption
The US ranks very low in measures of
health care quality
Overuse, underuse and inappropriate use of
medications are an important quality issue
Many of these problems are preventable





Limitations of the FDA Drug
Approval Process
FDA review determines if a drug is effective and
has acceptable safety.
It does not determine place in therapy.
Value not assessed.
Often there are many unanswered questions at the
time a drug is approved.
Limited numbers and types of patients
Limited duration of studies
May not know outcomes of greatest interest
Much of the FDA funding comes from industry

What is Evidence-based
Medicine?
A process to identify and use the best available
scientific evidence to guide decision making
Patient care
Policy
The scientific evidence is integrated with clinical
judgment and the patients unique circumstances to
provide the best clinical decisions

The result is predictable improvement in patient
outcomes
David Eddy. Formulary 2002;37:525-
30

EBM Drug Therapy Decisions
When there is evidence of benefit and
value, do it.
When there is evidence of no benefit, harm
or poor value, dont do it.
When there is insufficient evidence to know
for sure, be conservative.
Decision Making in Clinical
Practice
Unfortunately, many decisions are made based on
unreliable evidence
Personal observation or anecdotal experience
Tends to overestimate efficacy
Reasoning based on pharmacology, pharmacokinetics or
theory instead of patient oriented evidence that matters
Use of observational studies or case series to draw cause
and effect conclusions
Expert opinion plays a heavy role in medical decision
making
Opinions vary
Unbiased expert opinion using EBM is very useful
The consensus approach based on uncontrolled clinical experience
risks widespread application of useless or even harmful treatment
Advantages of Using an EBM
Approach
Guides prescribing decisions to get predictable
improvements in patient outcomes.
Helps sort through the marketing, opinions, and
theory to get an accurate assessment of the
benefits and risks of various treatments.
Can help identify and target opportunities to
improve drug therapy.
Assists with decisions about use of limited
resources.
Provides incentive to conduct useful research.

Limitations of EBM
Studies may not answer the question you are
trying to answer
Evidence may be lacking or of low quality
Surrogate endpoints
The body of evidence continues to change
It can take a lot of resources to conduct clinical
trials or create original high quality evidence
reviews
It does not make clinical decisions or value
judgments about cost versus benefit
But it can assist you in doing so

Steps in the EBM Process
Formulate the question(s) to be answered
Gather Evidence
Decide on type of literature
Conduct search
Critical appraisal to identify the best evidence
Evidence summary
Evaluating the strength of the evidence
Magnitude benefits and risks (ARR,NNT, NNH)
Form recommendations/conclusions and apply the
evidence
Step 1: Formulate Clinical
Question(s)
An important and sometimes difficult step

Well constructed questions guide the
process

Helps define what you really want to know

Clinical Questions
Ask for information about managing
patients
Contain several important components
(PICOS)
1. Population and/or clinical problem/disorder
2. Intervention
3. Comparison intervention (placebo, gold standard)
4. Outcomes
helps define what is most important
5. Setting
Clinical Question Example
For cigarette smokers, does varenicline
differ in efficacy for promoting long term
smoking cessation than bupropion SR or
NRT in the primary care setting?
Population: cigarette smokers
Intervention: varenicline
Comparator: bupropion, NRT, placebo
Outcome: smoking cessation at one year
Setting: Primary Care

Step 2: Gathering Evidence
When evaluating drug therapy, several
types of literature are typically most useful
Randomized controlled trials
Systematic reviews of RCTs
Evidence-based CPGs
The goal is to locate the best available
evidence to answer your questions

Evidence Hierarchy
Lab studies and Animal Research
Case Reports
Case Control Studies
Systematic
Reviews
RCTs
Cohort Studies
Case Series
Editorials and Opinions
Strengths of Randomized
Controlled Trials (RCT)

The foundation for evidence-based evaluation of
drug therapy
If high quality, can establish benefits and harms of
drug therapy
Effective randomization minimizes risk of
unexpected factors influencing results
(confounding)
Fortunately, RCTs are required for FDA approval

Limitations of RCTs
Experimental design and inclusion-
exclusion criteria may not reflect general
practice and make it difficult to apply or
generalize results (external validity)
Outcomes trials in chronic diseases may
take years
Expensive
It takes time and effort to review individual
studies once they are published
Systematic Reviews (SRs)
Usually a good starting place when gathering evidence
about drug therapy
A SR is an evidenced-based review of the medical
literature up to a certain time point
Predefined, detailed methods are used to search, screen,
critically evaluate, and summarize the medical research to
answer specific questions
SRs can be qualitative or quantitative (meta-analyses)
Meta-analyses combine results of individual studies, but
not all meta-analyses are SRs
High quality SRs save time and can provide a clearer
picture of the body of evidence than individual studies
Traditional Reviews
Typically lack the rigor of a systematic
review
Can be more of an opinion piece rather than
a careful unbiased review of the literature.
Selective use of literature can be used to
support the authors point of view.
The medical literature is full of non-
systematic reviews.

Clinical Practice Guidelines
Usually broader in scope than SR; goal - influence practice
Are especially useful if they are well developed and free
from bias
Political, financial or other factors can introduce bias
Over 2500 guidelines are available
Vary in quality (evidence vs. consensus opinion) and
recommendations can vary, so need to carefully evaluate
High quality guidelines have two major components
A systematic review of the evidence
Specific recommendations with explicit links to the
evidence and graded for strength of evidence
Searching for Evidence
This program will focus on a few basic
search strategies or useful sources to locate
the following:
RCTs
Systematic reviews
Clinical practice guidelines
Additional sources of information useful for
evaluating new drugs
Search Criteria
Decide on the type of literature best suited
to answer your question
The clinical question components can help
guide the search (PICOS)
Select search terms
Screening to make sure the literature is
addressing your question
Searching for Evidence: PubMed
A very user friendly approach to Medline
Can access online through various medical libraries
Can also go to pubmed.gov
Enter your search terms based on your clinical question
Example: varenicline smoking cessation
Click on limits tab and scroll down to type of article
limit to types of literature you want (RCT, Meta-
analysis and/or guidelines)
other limits can also help target your search
Can adjust search based on results
PubMed: Searching for
Systematic Reviews
On the PubMed side bar on the left of the
screen, click on Clinical Queries
Scroll down to Find Systematic Reviews
Enter your search terms based on your
clinical question
This search retrieves systematic reviews, meta-
analyses and other EBM literature
High Quality Systematic Reviews
Drug Effectiveness Review Project (DERP)
Contains systematic reviews of various drug classes
Developed by the OHSU Evidence-based Practice
Center
http://www.ohsu.edu/ohsuedu/research/policycenter/DE
RP/about/final-products.cfm
http://www.oregonrx.gov
Canadian Agency for Drugs & Technologies in
Health
www.cadth.ca/
Therapeutics Initiative
www.ti.ubc.ca




High Quality Systematic
Reviews
Agency for Health Care Research and Quality Effective
Healthcare Program
http://effectivehealthcare.ahrq.gov
Cochrane Collaboration (subscription)
Can include unpublished data
http://www.cochrane.org
Center for Reviews and Dissemination (CRD)
http://www.crd.york.ac.uk/crdweb
Database of abstracts of reviews of effects (DARE)


Clinical Practice Guidelines
National Guidelines Clearinghouse
www.guideline.gov
New Zealand Guidelines Group
www.nzgg.org.nz/
National Institute for Health and Clinical
Excellence (NICE)
www.nice.org.uk/
Veterans Health Administration
www.oqp.med.va.gov/cpg/cpg.htm
www.pbm.va.gov (monographs, drug use criteria)

FDA Website: fda.gov
An important place to look for data regarding new
drugs, but can be a difficult site to navigate
The advisory panel transcripts can contain a
wealth of information including information on
studies not published, and analyses by fda staff
Information about unresolved issues and post
marketing requirements may be available
Drug approval letter and product labeling

Information from Manufacturers
Package Insert
A great starting point for a new drug review
Will indicate how many studies were used in
the review and approval of the drug
AMCP Dossier Format
Can be a source of information on unpublished
studies
Contains an economic analysis
http://clinicalstudyresults.org


Step 3: Critical Appraisal
Once you have identified literature that meets your criteria,
it needs to be critically appraised to decide if it is worth
using.
Critical appraisal is an important step in the EBM process.
This step helps identify the best evidence to answer our
question.
Much of the medical literature is not useful or reliable, and
in some cases may even be misleading.
With critical appraisal, we determine confidence in the
results (internal validity) and if the results are applicable to
our practice (external validity).

Additional Programs on Critical
Appraisal
In this program, a very brief introduction to
critical appraisal will be provided.
For a more in-depth review, please see the
following programs that are available from the
same website you accessed this program:
Critical Appraisal: Randomized Controlled Trials for
Drug Therapy
Critical Appraisal: Systematic Reviews and Clinical
Practice Guidelines for Drug Therapy
Evaluating Individual RCTs
Internal validity reflects the confidence that
the results are due to the intervention
Focus on the methods and results sections
Good studies provide a valid estimate of the
efficacy of an intervention and are usually
easier to review
Form your own conclusions based on the
above


Items to Evaluate for Internal
Validity of RCTs
Adequate sample size
with statistical power
Randomization
methods appropriate
Comparable groups at
baseline
Equal co-treatment
Compliance
Low dropout rate
Adequate length of
follow-up
Blind assessment
Equal assessment
Intention-to-treat
analysis
Post-hoc analysis


Applicability (External Validity)
of RCTs
How relevant is the study?
Were clinically meaningful endpoints studied?
What is the magnitude of the treatment effect and is it
clinically significant?
How generalizable are the results?
How comparable were the patients studied to your
practice?
Does the study reflect real world practice?
If internal validity unacceptable, the applicability
is irrelevant


Pharmaceutical Industry
Sponsored Studies
Generally have acceptable internal validity
Applicability is more often the issue
Active controls may not be gold standard
Surrogate outcomes often involved
Dosing regimens not comparable
Population may not reflect population of most
interest
Publication bias
Items to Assess with Systematic
Reviews
Evaluate for bias, methods and generalizability
Is there a clear, clinically relevant question that addresses
what you are looking for, that was defined before hand?
Were study eligibility criteria defined and appropriate?
Was the search detailed and exhaustive?
Were the studies critically appraised by more than one
person?
Were methods for data synthesis described?
Were conclusions clear and reflect evidence?
Was funding disclosed and potential conflict of interest
minimized?
DARE
Database of Abstracts of Reviews of Effects
A useful resource for readers of SRs
Provides concise summaries of published
SRs of healthcare interventions
Assesses strengths and weaknesses
http://www.crd.york.ac.uk/crdweb and
click on DARE tab
Critically Evaluate Clinical
Practice Guidelines (CPG)
Studies of guidelines have found that
methodological problems, or potential conflicts of
interest, are common
Objectives, key questions and applicable
population clearly defined
Stakeholders involvement (relevant disciplines,
patient views, target user pilot)
Editorial independence from funding, methods to
manage conflict of interest, bias

CPG Rigor of Methods
Systematic methods used to search for evidence
Criteria for selecting evidence described
Appropriate and clearly defined methods for
formulating recommendations
Benefits, risks and costs considered
Explicit link between supporting evidence and
recommendations (grades of recommendations)
Guideline externally reviewed by unbiased experts
Step 4: Evidence Summary
Rate Confidence in Strength of Evidence
High : Large, well-designed randomized
controlled trials, rigorous systematic
reviews
Small, or not-so-well designed controlled
clinical trials
Non-randomized prospective cohort
studies
Non-randomized case-control studies
Low : Case series

Evidence Summary: Quantify
Results
RR: % treatment group
% control group
RRR: 1-RR X 100%
ARR: % difference between control and treatment

NNT: 100%
ARR

RR= Relative Risk RRR = Relative Risk Reduction
ARR = Absolute Risk Reduction/absolute response rate NNT = Number Needed to Treat


Limitations of Relative Risk
Example 1: risk of death is 1% Tx and 2% P
RRR is a 50% reduction
ARR is 1%
NNT= 100
Example 2: risk of death: 25% Tx vs 50%P
RRR is a 50% decrease
ARR is 25%
NNT= 4
Same RRR, but different clinical implications

Calculating ARR and NNT
Useful if a statistically significant difference exists
the confidence interval helps determine precision
Important to link to the treatment duration
Can only do this if specific responders are reported
Cant do calculations if results are presented as mean
changes for the population.
Examples:
Mean change in BP vs. % reaching target BP
Mean change in HgA1c vs. % below HgA1c of 7


Example Calculation
95% of patients with AOM are improved
after 10days with gorillacillin vs. 85% on
placebo (p<.05)
What is the:
ARR = ?
NNT = ?

Example: Amitiza for IBS-C
patients receiving Amitiza were nearly twice as
likely to acheive a statistically significant overall
response compared to those given placebo (from
the monthly prescribing reference)
Study 1: 13.8% respond to Amitiza vs 7.8% P
Study 2: 12.1% Amitiza vs. 5.7% P
Response = responded 2 out of 3 months
ARR = about 6% will respond 2 out of 3 months
NNT= For every 16 patients treated for 12 weeks,
one will respond two out of three months

Eddy DM.Formulary 2002;37:525-30
Step 5: Form Conclusions and
Apply the Evidence
When there is evidence of benefit and
value, do it.
When there is evidence of no benefit, harm
or poor value, dont do it.
When there is insufficient evidence to know
for sure, be conservative.
Do it Examples
Thiazides for hypertension
Aspirin to prevent CVD events
ACEI in CHF
Statins in secondary prevention
Warfarin in atrial fibrillation
Beta-blockers post-MI
Dont do it Examples
Estrogen/progestin to prevent CVD in late
postmenopausal women
Alpha-blockers in hypertension
Calcium blockers with systolic ventricular
dysfunction
Zelnorm, Vioxx
Antibiotics for acute URI
Eddy DM. Formulary 2002;37:525-
30
What be conservative means
With new drugs, burden of proof is on the
manufacturer
If we use a new treatment without adequate
evidence, there is little incentive to do the
research
For old drugs, we should not actively
promote without good evidence.
Summary: EBM Process
Formulate the questions to be answered
Gather Evidence
Decide on type of literature
Conduct search
Critical appraisal to identify the best evidence
Evidence summary
Evaluating confidence in the strength of the evidence
Quantitative benefits and risks (ARR,NNT, NNH)
Form conclusions and apply the evidence
Conclusions
Using an evidence-based process results in prescribing
decisions that lead to predictable improvements in patient
care.
There are numerous sources for high quality systematic
reviews and clinical practice guidelines that provide a
sound framework for drug therapy decisions.
Prescribing agents that have the best evidence for benefits
vs. harms, and that provide good value can help address
some of the problems associated with prescription drug
use.


Thank you
This work was made possible by a grant from the
state Attorney General Consumer and Prescriber
Education Program which is funded by the multi-state
settlement of consumer fraud claims regarding the
marketing of the prescription drug Neurontin.
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