1. 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

2. 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?

3. 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.

5. 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

6. 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

7. 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: –Second generation antidepressants –AED’s –Disease modifying drug for arthritis –Targeted immune modulators –Inhaled steroids for COPD –Alzheimer’s drugs

8. 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

9. GRADE Rating GradeDefinition HighFurther research is very unlikely to change our confidence in the estimate of effect ModerateFurther research is likely to have an important Impact on our confidence in the estimate of effect and may change the estimate LowFurther 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 lowAny estimate of effect is very uncertain Guyatt G, ACP J Club 2006

10. The Weight of the Evidence

11. 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

12. 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.

13. 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. –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.

14. 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.

15. 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

16. AED Key Messages (V 5.2) 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.

17. 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

18. 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: Patient or provider preference? Harms, if data available? Dread of adverse reaction? Genetic profile in the future?