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Disseminating Findings of Drug
Effectiveness Reports to Prescribers:
The Case of Neurontin
Tim Carey MD MPH
Cathy Melvin PhD, MPH
May, 2007
Funding source: Neurontin Special Committee
Policy Issues
• When is a study of sufficiently high quality that
it can influence health policy?
– Are all randomized trials of high quality?
– When to incorporate observational studies?
– How does one distinguish among conflicting
studies or identify consensus among them?
• When is the accumulation of scientific
evidence sufficient to consider “case closed?”
• How to effectively translate research evidence
to clinicians and policymakers?
Disseminating the Evidence-Based Drug Review:
Anti-Epileptic Drugs (AED’s) for Mood Disorders
Objectives:
• Create derivative products based on the final
drug class review of AED’s sponsored by the
Drug Effectiveness Review Project (DERP)
report and the results of formative market
research with relevant audiences
• Develop and implement a national
dissemination strategy for the derivative
products
• Cooperate and assist in evaluating
dissemination of the derivative products.
External Advisors
• Science Panel to advise us on clinical
issues related to product development and
dissemination
• Dissemination Panel to advise us on
evidence-based dissemination strategy
development and implementation for
select audiences
Four Key Inputs
1. Current data on prescribing patterns for AEDs,
especially for bipolar disorder
2. The 2006 drug effectiveness report and
subsequent updates of relevant literature
Update of report performed in late 2006
Early recognition that ‘just say no to neurontin’
was not a good option
3. Audience research with prescribers
4. A review of evidence-based dissemination
strategies
Drug Class Reviews:
Subset of Systematic Review
• Within a class of drugs, is there a difference in efficacy,
effectiveness or adverse events among agents?
• Optimally requires head-to-head trials between agents at
equivalent doses
• Comparing placebo-controlled trials of different agents
possible, but should be viewed with caution
• Many reviews done or underway through DERP and
AHRQ:
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Second generation antidepressants
AED’s
Disease modifying drug for arthritis
Targeted immune modulators
Inhaled steroids for COPD
Alzheimer’s drugs
Strength of Evidence
• When is sufficient evidence present to say “case
closed.”
• GRADE (Grading of Recommendations, Assessment,
Development, and Evaluation) system seems to be center of
emerging consensus
– Transparent, plain English
– Takes multiple factors into account:
• Study design, study limitations, consistency, size of relative and
absolute effect, importance
– Global qualitative assessment
– What is the likelihood that an additional study would lead to a
different conclusion?
• Relationship between strength of evidence assessment
and ‘guideline’
– Guidelines take into account additional information including
cost, convenience, acceptability, cultural and policy issues
GRADE Rating
Grade
Definition
• High
Further research is very unlikely to change our
confidence in the estimate of effect
• Moderate
Further research is likely to have an important
Impact on our confidence in the estimate of
effect and may change the estimate
• Low
Further research is very likely to have an
important impact on our confidence in the
estimate of effect and is likely to change the
estimate
• Very low
Any estimate of effect is very uncertain
Guyatt G, ACP J Club 2006
The Weight of the Evidence
Deriving Key Concepts from a
Systematic Review
• Read it, read it again, include source materials
• Multi-disciplinary “Science Panel”
– EPC faculty, psychiatry, PharmD, primary author of
evidence report
– Clinical context important:
• Chronic disease, high treatment failure rates
• 8 versions of 10 key concepts
– Iterative process
– Start general, become successively more specific,
then back off to more general (‘granularity’)
– Lots of discussion on language
Key Concept 4
(Version 8.2)
There is limited evidence showing that gabapentin
is no more, and perhaps less, efficacious than
placebo in the treatment of bipolar I disorder with
recent mania and rapid cycling bipolar disorder.
No acceptable evidence was found to support the
use of gabapentin in achieving remission or
preventing relapse in bipolar disorder. Evidence
regarding efficacy of topiramate for any of the
above conditions (bipolar I disorder with recent
mania, hypomania, or mixed episodes and bipolar
II disorder) is sparse. Current evidence regarding
use of topiramate for acute mania shows no
evidence of efficacy.
Key Concept 1
(Version 8.2)
Current evidence supports the conclusion that three AEDs
(carbamazepine, valproic acid/valproate and lamotrigine)
are efficacious in achieving and maintaining remission for
outpatient adults with primary diagnoses of bipolar I
disorder with recent mania or mixed episodes.
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The overall magnitude of benefit obtained with AEDs in bipolar I disorder
with recent mania or mixed episodes was an absolute improvement of the
probability of attaining remission ranging from 7-28%; the relative rate of
attaining remission was between 1.17-2.87, compared to placebo. The
strength of evidence for this indication is low (GRADE criteria).
Carbamazepine is the only AED that has been shown in fair-quality
published trials to be significantly better than placebo in reducing mania
scores in acute therapy of outpatient adults.
There was no acceptable evidence to support choice of one agent over
another based on speed of onset in attaining remission.
Key Concept 1 Details
– The overall magnitude of benefit obtained with AEDs
in bipolar I disorder with recent mania or mixed
episodes was an absolute improvement of the
probability of attaining remission ranging from 7-28%;
the relative rate of attaining remission was between
1.17-2.87, compared to placebo. The strength of
evidence for this indication is low (GRADE criteria).
– Carbamazepine is the only AED that has been shown
in fair-quality published trials to be significantly better
than placebo in reducing mania scores in acute
therapy of outpatient adults.
– There was no acceptable evidence to support choice
of one agent over another based on speed of onset in
attaining remission.
Key Concepts to Key Messages
• The derived concepts:
– have excellent fidelity to the underlying evidence
report
– represent template against which to compare
messages and dissemination products
• By themselves too nuanced to be useful in
dissemination
• Iterative process seemed essential
– 5+ revisions of key messages, currently in field testing
• Need for periodic update
AED Key Messages (V 5.2)
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There remains no acceptable clinical trial evidence which
supports use for either gabapentin (Neurontin®) or
topiramate (Topamax®) in bipolar mood disorder.
Current evidence supports the use of three antiepileptic
drugs—(1) carbamazepine (Tegretol®), (2) valproic
acid/valproate (Depakote®, Depakene®) and (3) lamotrigine
(Lamictal®) in achieving and maintaining remission for
outpatient adults with primary diagnoses of bipolar I and
bipolar II disorders.
Antiepileptic drugs have been shown to be no better than
lithium, which is an established and efficacious treatment for
bipolar mood disorders. Lithium (Lithobid®, Eskalith® and
various generic products) should continue to be used as
outlined in best practice and treatment guidelines.
Although the types of adverse events vary across different
AEDs and lithium, there is insufficient evidence to determine
if the overall risk of adverse events differs between AEDs
and lithium.
Lessons Learned
• Plan significant lead time to digest,
interpret and distill many systematic
reviews
• Utilize multi-disciplinary panels early in the
process
• Key concepts are not the same as
transmissible messages
• Simplify, simplify, simplify…..but adjust
Key challenges
• Nature of bipolar disorder and other severe
chronic illness
• Absence of evidence….
• “Tailoring” of therapy
– Difficult to predict success or failure of an agent within
a drug class for an individual patient
– Now good evidence that antidepressants have similar
efficacy (~60%) but no ability to predict response to a
given agent. 30% response with second agent
– Choose based on:
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Patient or provider preference?
Harms, if data available?
Dread of adverse reaction?
Genetic profile in the future?