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					American Epilepsy Society
2004 Annual Meeting



      Daniel H. Lowenstein, M.D.
        President
        American Epilepsy Society

        University of California, San Francisco
        San Francisco, CA
               AES Service Award Winner


Robert Fisher, M.D., Ph.D.

   Stanford University
   Stanford, CA

“Recognizing outstanding service by
an AES member in the field of epilepsy
including non-educational and non
scientific) with emphasis on exemplary
contributions to the welfare of the
American Epilepsy Society and its
members.”
        William G. Lennox Award



 Given annually to a senior
member who has a record of
  lifetime contributions and
accomplishments related to
                    epilepsy.
                 Lennox Award Winner



Yukio Fukuyama, M.D., Ph.D.

  Tokyo Women’s Medical University
  Tokyo, Japan


 “Significant Contributions to the Field of
                  Epilepsy”
   AES AET Symposium



Evidence-Based Guidelines in
    Anti-epileptic Therapy


Blaise F.D. Bourgeois, M.D., Co-chair

James C. Cloyd, Pharm. D., Co-chair
 Thank You To Our Supporters



        Abbott Laboratories
             Eisai Inc.
          GlaxoSmithKline
Novartis Pharmaceuticals Corporation
Thank You To Our Supporters



Ortho-McNeil Pharmaceutical, Inc.
            Pfizer Inc
          Shire US Inc.
       UCB Pharma, Inc.
Welcome and Introduction

   Blaise F. D. Bourgeois, MD
         Program Co-chair
      Harvard Medical School
     Boston Children’s Hospital
            Boston, MA
Hot Air Douche Treatment




                       Stanley Burns Archives /
                           Neurology Reviews.
        Evidence-Based Guidelines
         in Antiepileptic Therapy

•   Evidence-based guidelines represent a
    critical review of available evidence
•   Today’s symposium will consist of a critical
    review of evidence-based guidelines
       Evidence-Based Guidelines
        in Antiepileptic Therapy
Why are evidence-based guidelines necessary?

How are evidence-based guidelines generated?

Who generates evidence-based guidelines?

What is the evidence for AE therapy?

Where is the lack of evidence?

How should guidelines be used?
      Evidence-Based Guidelines
       in Antiepileptic Therapy



Who should talk about evidence-based
    guidelines in antiepileptic therapy?
      Guidelines: Terminology
         and Methodology
              Tracy A. Glauser, MD
   Associate Professor of Pediatrics and Neurology
      Director, Comprehensive Epilepsy Program
Director of Drug Trials Program for Neurologic Disease
     Cincinnati Children’s Hospital Medical Center
                     Cincinnati, OH
Guidelines: Come In All Shapes and Sizes
Biological       Legal       Philosophical
                  Medical Guidelines
•   Earliest guidelines were empirical
•   1622–first proposed clinical trial
     Van Helmont–medicinal chemist
     ―Let us take out of the hospitals, out of the Camps,
      or from elsewhere, 200, or 500 poor People, that
      have Fevers, Pleurisies, etc. Let us divide them into
      half, let us cast lots, that one half of them may fall to
      my share, and the other to yours. We shall see how
      many funerals both of us shall have. But let the
      reward of the contention or wager, be 300 florens,
      deposited on both sides.‖
                         Medical Guidelines
•   1754–first controlled clinical trial
                                 Scurvy, N = 12


Quart of             Ether   Vinegar Seawater                     Paste*            Oranges,
Cider/day                                                         Mixture           Lemons
  n=2                n=2      n=2          n=2                     n=2                n=2
                                    6 days
                                     later
    Still            Still    Still        Still                     Still               Well
    Sick             Sick     Sick         Sick                      Sick
*Garlic, radish,
peru balsam, myrrh            Lind J. A Treatise of the Scurvy in Three Parts. A. Millar. London; 1758.
                    Medical Guidelines

•   1977–NIH Consensus Development Program
•   1989–Move to evidence-based approach
     3 US Federal Acts created AHCPR
          • Office to create practice guidelines
•   1989 - Omnibus Budget Reconciliation Act
     Practice guidelines proposed to help
      contain costs
     Established National Advisory Council to
      advise AHCPR on development of guidelines
     Awarded contract to IOM to develop priorities
      and form definitions
                             Terminology
•   Practice guideline: systematically developed statements to
    assist practitioner and patient decisions about appropriate
    health care for specific clinical circumstances (IOM)1
•   Practice parameter: ―strategies for patient management,
    developed to assist physicians in clinical decision-
    making…including standards, guidelines, and other patient
    management strategies‖ (AMA)2
     Should be comprehensive, integrate evidence and clinical
      experience, current, widely disseminated


          1. Institute of Medicine. Clinical Practice Guidelines: Directions for a New Program.
                      Field MJ, Lohr KN, eds. National Academy Press. 1990. Washington, DC
                  2. Available at: http://search.ama-assn.org/. Accessed November 19, 2004.
           US Interest in Guidelines

  ACR             108                  ACCP                42
  CDC              94                  AAN                 37
  AAP              79                  AGA                 30
  ICSI             55                  IDSA                25
  USPSTS           45                  CCHMC               23

Professional organizations          Government agencies

                   Non profit organizations

                                              National Guideline Clearinghouse.   .
     Worldwide Interest in Guidelines
• North America          • Europe
   Canada (CCOPGI)         Denmark (DSAM)
• Asia                      England (CHSR, RCP London)
   Singapore (NMRC)        Finland (Duodecim)
• Australia/Oceania         France (ANAES, FNCLCC)
   Australia (NHMRC)       Germany (AWMF)
   New Zealand (NZGG)      Italy (ARHS)
                            Netherlands (CBO)
                            Scotland (SIGN)
                            Sweden (SBU)
              Guideline Development:
               Overview of Activities
                       Build a           Form a
 Pick topic                              clinical
                       team              question


Disseminate


                                     Evidence
                   Develop
                                        a. Find
                   Recommendations
 Validate                               b. Abstract
                   and
                                        c. Analyze
                   Algorithm
                                        d. Grade/Rate
              Guideline Development: 1
•   Identify and evaluate the topic
     Is there a gap between current practice and the evidence?
     Is there disagreement/controversy?
     Is there sufficient medical evidence?
     Is it feasible and reasonable to try to bridge the gap?
•   Assemble a multidisciplinary team
     Physicians, nurses, PharmDs, clinical pharmacologists
     Statisticians, epidemiologists, health economists
     Consumers, patient representatives
                Guideline Development: 2
•   Form the clinical question
     Use 5 part PECOT structural approach
       • Patients/participants/population
       • Exposure/interventions
       • Comparison
       • Outcomes
       • Time
     Example: for adult with partial onset seizures (P), which
      AED (E) compared to an adequate comparator (C)
      provides the highest efficacy (O) over the first year of
      exposure (T)?
             Guideline Development: 3
•   Find the evidence
     Define inclusion/exclusion criteria
     Search clinical question and inclusion/exclusion criteria
     Potential sources to search
        • electronic databases (MEDLINE, Current Contents)
        • Cochrane Library
        • published literature/references
        • unpublished data
        • English/non English studies
     Perform multiple searches
             Guideline Development: 4a
•   Abstract, analyze, and grade/rate the evidence
     Specific relevant variables as measure of quality
     ―Major‖ variables
       • Randomization
       • Control group
       • Masked outcome assessment
       • Adequate comparator (assay sensitivity)
       • Adequate enrollment to detect difference
       • Detectable non-inferiority boundary
               Guideline Development: 4b
•   Abstract, analyze and grade/rate the evidence
     ―Minor‖ variables
       •   Primary outcome clearly defined
       •   Inclusion/exclusion criteria clearly defined
       •   Equivalent treatment groups at baseline
       •   Adequate duration of assessment
       • Drop out rate and how it is handled statistically
     Summarize abstraction/analysis into tabular form
       • Evidence tables
             Guideline Development: 4c
•   Abstract, analyze, and grade/rate the evidence
     Grading/rating scale based on relevant variables
     Usually 4 categories
       • Top group–RCTs with best evidence, meet all criteria
       • Next group–RCTs missing some ―minor‖ criteria
       • Third group–trial missing some ―major‖ criteria
       • Last group–low quality trials missing most or all ―major‖
         criteria OR only expert opinion
     Significant variability in grading/rating scales across
      guidelines
             Guideline Development: 5
•   Translate evidence and develop recommendations
     Usually 4 or 5 levels of recommendations
     Levels defined using output of grading/rating scale
     At least one recommendation per question
•   Develop algorithm (if possible)
•   Validate guideline
     Internal/external peer review
•   Implement and disseminate guideline
           Epilepsy Guidelines
• Topic
   Role of 7 new AEDs in the management of new
    onset and refractory epilepsy
• Team
   Twenty-four members (neurologists, PharmDs)
   One country




                                French JA, et al. Epilepsia. 2004.
                Epilepsy Guidelines
•   Clinical Questions (n=9)
     Q1: How do the efficacy and tolerability of the new
      AEDs compare with those of older AEDs in patients
      with newly diagnosed epilepsy?
     Q2: What is the evidence that the new AEDs are
      effective in adults or children with primary or
      secondary generalized epilepsy?
     Q3-9: What is the evidence that the new AEDs are
      effective in refractory [type of epilepsy] as [mono or
      adjunctive therapy]?


                                          French JA, et al. Epilepsia. 2004.
                Epilepsy Guidelines
•   Evidence–key rating variables
     Clearly defined primary outcome(s)
     Clearly defined exclusion/inclusion criteria
     Adequate accounting for dropouts and crossovers
     Baseline variables for treatment groups




                                          French JA, et al. Epilepsia. 2004.
                 Epilepsy Guidelines
•   Rating–4 Classes
     Class I: a masked RCT, meeting all key variable criteria
     Class II: a masked prospective matched-group cohort study
      in a representative population that meets all key variable
      criteria OR an RCT in a representative population that lacks
      one of the key variable criteria
     Class III: all other controlled trials in a representative
      population, where outcome assessment is independent of
      patient treatment
     Class IV: evidence from uncontrolled studies, case series,
      case reports, or expert opinion



                                            French JA, et al. Epilepsia. 2004.
                Epilepsy Guidelines

•   Recommendations–4 Levels
     Level A: 1 Class I RCTs OR 2 Class II RCTs
       • Established as effective, ineffective, or harmful
     Level B: 1 Class II RCTs OR 3 Class III RCTs
       • Probably effective, ineffective, or harmful
     Level C: 2 Class III RCTs
       • Possibly effective, ineffective, or harmful
     Level U: Data inadequate or conflicting



                                           French JA, et al. Epilepsia. 2004.
                      Conclusions
•   Guidelines use a common methodology backbone
•   Hard to compare guidelines for the same topic
     Different PECOT questions asked
     Variability in rating/grading evidence scales
     Variability in recommendation criteria
•   Both the ILAE and AAN/AES guidelines use
    appropriate methodology to provide evidence
    based recommendations to specific clinically
    relevant questions
    Add-On and Monotherapy
Antiepileptic Therapy for Patients
    With Refractory Epilepsy:
  Evidence-Based Guidelines
         Jacqueline A. French, MD
            Department of Neurology
    Hospital of the University of Pennsylvania
                 Philadelphia, PA
     Guidelines on Refractory Epilepsy

•   AAN
     Efficacy and Tolerability of the New Antiepileptic
      Drugs II: Treatment of Refractory Epilepsy
     No guidelines on the use of ―standard‖ AEDs


•   ILAE
     Only initial monotherapy discussed—no
      guidelines on refractory
               AAN Clinical Questions
What is the evidence that new AEDs are safe,
well tolerated, and effective in:
 •   Adults:
      Refractory Partial epilepsy
        • Adjunctive therapy and monotherapy
      Refractory Idiopathic generalized epilepsy
 •   Children:
      Refractory Partial
        • Adjunctive and monotherapy
      Refractory Idiopathic generalized epilepsy

 •   Children and/or adults:
      Lennox-Gastaut syndrome
         How to Use Guideline: Example


•   24-year-old with refractory GTCC,
    currently receiving valproate with
    no response
•   EEG shows generalized spike-
    wave activity
•   Patient is planning a family—
    monotherapy would be ideal
•   QUESTION: do the guidelines
    help in selecting next AED?
               Practice Guideline

    Many
                                      Cochrane
   Specialty              ILAE   AAN Collaboration
   Societies



Consensus-Based                     Evidence-Based
Double-Blind Placebo-Controlled Trial

                         Dose 2 + AEDs

                         Dose 1 + AEDs

1-2 AEDs                Placebo + AEDs


                                         Taper
Baseline    Titration     Treatment      + Follow-up
           (2-6 wks)      (3 months)     (or blinded
                                         conversion to
                                         open label)
   Not Your Average Patient: Typical
Inclusion/Exclusion Criteria for Add-On
        Trials in Refractory Patients
 • Ages 16-65
 • Failed >2 AEDs
 • Currently receiving 1-3 AEDs
 • Seizure frequency:
     Partial: >3-4 seizures/month
     Generalized: >1 seizure/month
•   No status epilepticus within 6-12 months
•   No serious psychiatric illnesses
•   No serious medical illnesses
  Effect of Last Observation Carried
               Forward:
      Seizure Freedom Example




             33%   67%

Dropouts
Completers
 Effect of Last Observation Carried
              Forward:
     Seizure Freedom Example

 Seizure free                       % Seizure free
                            30             27%
    (22%)
                            25   22%
                13%
                            20
             9%             15

                            10
                                                     9%
                      54%
              24%            5

Dropouts                     0
                                   Intent Completers ITT
                                 -to-treat         completers
Completers
Level A Evidence: Adjunctive Therapy for
       Refractory Partial Seizures
                  Adult     Pediatric

  Gabapentin      YES         YES

  Lamotrigine     YES         YES

  Topiramate      YES         YES

  Tiagabine       YES          ?
  Oxcarbazepine   YES         YES

  Levetiracetam   YES          ?
  Zonisamide      YES          ?
 Level A Evidence: Adjunctive Therapy for
     Refractory Generalized Seizures
                                 Symptomatic
                   Idiopathic      (Lennox-
                                   Gastaut)
Gabapentin        NO (1200 mg)       ?
Lamotrigine            ?             YES
Topiramate         YES (GTCC)        YES
Tiagabine              ?             ?
Oxcarbazepine          ?             ?
Levetiracetam          ?             ?
Zonisamide             ?             ?
Do the New Drugs Work as Monotherapy?

  •   Trials are performed as withdrawal to
      monotherapy

  1-2 AEDs
                                       Treatment


                                      Pseudoplacebo


 Baseline    Titration   Withdrawal    Maintenance
               ESCAPE CRITERIA

•   Doubling of average monthly seizure rate
•   Doubling of highest consecutive 2-day seizure
    rate
•   Emergence of new, more severe seizure type
•   Clinically significant prolongation of
    generalized tonic-clonic seizures
         Lamotrigine Monotherapy Results

                  220 PTS SCREENED
                  156 PTS RANDOMIZED
             N=76                  N=80
TITRA   LAMOTRIGINE                       DEPAKOTE
TION       250 BID                          500 BID
          20 WITHDRAWN                   9 WITHDRAWN
AED
          13 ESCAPE                         27 ESCAPE
TAPER
             N=43                             N=44
        2 PROTOCOL VIOLATION        3 PROTOCOL VIOLATION
MONO         6 WITHDRAWN                 7 WITHDRAWN
THERAPY         7 ESCAPE                   21 ESCAPE
             N=28                             N=13
                    *Gilliam et al Neurology 1998
Efficacy in Conversion to Monotherapy in
            Refractory Patients

                   Partial     Generalized and
 AED             Monotherapy      Pediatric
                   (Adults)     Monotherapy

 Gabapentin          NO              ?
 Lamotrigine      Level B            ?
 Topiramate       Level A            ?
 Tiagabine            ?              ?
 Oxcarbazepine    Level A            ?
 Levetiracetam        ?              ?
 Zonisamide           ?              ?
    Adverse Effects of AEDs

•   Dose-related
•   Idiosyncratic
•   Teratogenic
Dose-Related Adverse Events-Level A
 AED             Dose-Related AE

 Gabapentin      Somnolence, dizziness, fatigue
 Lamotrigine     Ataxia, dizziness, diplopia, somnolence,
                 headache
 Levetiracetam   Dizziness, somnolence, asthenia,
                 headache, infection

 Oxcarbazepine   Somnolence, dizziness, headache,
                 ataxia, nausea, vomiting
 Tiagabine       Dizziness, tremor, abnormal thinking,
                 nervousness, abdominal pain
 Topiramate      Somnolence, fatigue, nausea, anorexia,
                 weight loss, paresthesia, psychomotor
                 slowing, confusion

 Zonisamide      Fatigue, dizziness, somnolence,
                 anorexia, abnormal thinking
           Non–Dose-Related Adverse Events
                    (Consensus)
 AED                  Serious Adverse Events        Nonserious Adverse Events
 Gabapentin           None                          Weight gain, peripheral edema,
                                                    behavioral changes*
 Lamotrigine          Rash, including Stevens-      Tics* and insomnia
                      Johnson and TEN,
                      hypersensitivity reactions

 Levetiracetam        None                          Irritability/behavior change

 Oxcarbazepine        Hyponatremia, rash            None

 Tiagabine            Stupor or spike-wave stupor   Weakness

 Topiramate           Renal calculi, open-angle     Metabolic acidosis, weight loss,
                      glaucoma, hypohidrosis*       language dysfunction

 Zonisamide           Rash, renal calculi,          Irritability, photosensitivity,
                      hypohidrosis*                 weight loss
* Children only or predominantly children
Major Issues Not Addressed by Practice
              Parameters



•   How do the new AEDs compare with old
    AEDs?
•   How do the new AEDs compare with each
    other?
How Do New AEDs Compare With Old AEDs?
    How Do the New AEDs Compare With
               Each Other?

•   No controlled head-to-head trials in refractory
    patients
•   Only data in refractory partial epilepsy via
    meta-analysis
     Can this inform us with regard to relative
      benefits?
          Problem With Meta-Analysis
•   Different doses used
     All doses combined for many analyses
     Some AEDs were overdosed or underdosed during
      trials
•   Differing patient populations
•   Non-ideal titration schedules
     Titration period may or may not be included in
      analysis
                          EFFICACY OF NEW AEDS IN
                           REFRACTORY PATIENTS
                                50% Sz Reduction (minus placebo)
                 40%                                       OXC
                                                TPM
                                                                   LEV
                 30%
 % of Patients




                                     TGB
                                                                          ZNS
                 20%
                        GBP   LTG

                 10%


                 0%
                                               200
                                               400
                                               600
                                              1000
                        600
                        900
                       1200
                       1800

                              300
                              500

                                    16
                                    32
                                    56




                                                            600
                                                           2400

                                                                   1000
                                                                   3000

                                                                          100
                                                                          200
                                                                          400
                                         Dose
*after Cramer et al, 1999
                                      Odds Ratio of Response
                                        Versus Withdrawal
                            4.5

                             4
                                           •
Odds ratio's for response




                            3.5

                             3                     •                                    GBP
                                                                                        LTG
                            2.5

                             2
                                               •                                        TGB
                                                                                        TPM
                                                                                        VGB
                            1.5                                                         ZNS
                                                                                        LEV
                             1

                            0.5                                                     • OXC
                             0
                                  0    1          2            3         4
                                           Odds ratio's for withdrawal       Marson et al., 2001,1997
        How to Use Guideline: Example

• 24-year-old with refractory
  GTCC, currently receiving
  valproate with no response.
  Generalized spike wave on
  EEG

• Patient is planning a family—
  monotherapy would be ideal
      How to Use Guideline: Example



AED             Generalized Add-On   Generalized
                                     Monotherapy
Gabapentin             NO                ?
Lamotrigine             ?                ?
Topiramate        YES (GTCC)             ?
Tiagabine               ?                ?
Oxcarbazepine           ?                ?
Levetiracetam           ?                ?
Zonisamide              ?                ?
      How to Use Guideline: Example



AED             Generalized Add-On   Generalized
                                     Monotherapy
Gabapentin             NO                ?
Lamotrigine             ?                ?
Topiramate            YES                ?
Tiagabine               ?                ?
Oxcarbazepine           ?                ?
Levetiracetam           ?                ?
Zonisamide              ?                ?
          STATE OF THE EVIDENCE

•   Answer to question:
     There is evidence that
      treatment is effective
     There is evidence that
      treatment is ineffective/harmful
     There is no evidence (study not
      done)
                  Clinical Decision



Several class I studies:
 Treatment is effective
          or
                           Evidence
  ineffective/harmful
                           Clinical Decision

                              Risk-Benefit

Controlled study has not
       been done
           or                  Experience
  only class III studies



                               Evidence
     Evidence to the “Height” of Absurdity

•   Parachute use to prevent death and major
    trauma related to gravitational challenge:
    systematic review of randomised controlled
    trials1
     No randomised controlled trials of parachute
      use have been undertaken
     The basis for parachute use is purely
      observational, and its apparent efficacy could
      potentially be explained by a ―healthy cohort‖
      effect
     Individuals who insist that all interventions need
      to be validated by a randomised controlled trial
      need to come down to earth with a bump

                                                     1. Smith GC, et al. BMJ. 2003.
    The Impact of the New AED
   Assessment in and Beyond the
        Clinician’s Practice
               Andres M. Kanner, MD
Professor of Neurological Sciences, Rush Medical College
 Director, Laboratory of EEG and Video-EEG-Telemetry
               Rush Epilepsy Center and
       Rush University Medical Center, Chicago, IL
The Problem: So Many Choices…
The Clinician’s Expectations. . .




                            Finally!... This
                      assessment will tell me
                       which AED is the best
                      for the different types of
                              epilepsy…
The Reality. . .
                I thought it
               was going to
               be so much
                  easier…
      Before Evidence-Based Medicine

                 The Old Paradigm
•   Unsystematic observations from clinical
    experience are a valid way of building and
    maintaining knowledge in medicine
•   A combination of traditional medical training
    and common sense is sufficient to evaluate
    new tests and treatments
•   Expertise and clinical experience are sufficient
    to generate valid guidelines
          Evidence-Based Medicine

                 The New Paradigm
•   Assumption: Physicians whose practice is
    based on understanding of underlying
    evidence will provide superior patient care
•   Systematic attempts to record observations in
    an unbiased way can markedly increase
    confidence in treatment procedures
•   Puts lower value on authority
                  Potential Impact of
                  AED Assessments
•   Increase clinician’s prescribing options of AEDs:

     Provide the necessary efficacy and safety data for the
      use of (new) AEDs in seizure disorders and age
      groups for which there is no FDA indication available
     Endorsement of new prescribing options by
      professional societies has important medical-legal
      implications to the clinician
                Potential Impact of AED
                 Assessments (con’t.)

•   Clinician’s education on:
     Efficacy and safety data of multiple AEDs in a single document
     Methodology of AED development
     Limitations of data derived from FDA regulatory studies
•   Funding agencies:
     Identify the areas in need of investigation
•   Federal Regulatory Agencies:
     Suggest alternative criteria for regulatory studies
Do the recommendations of the AAN
assessment for the use of new AEDs
  differ from the FDA indications?
Change in Clinician’s Prescribing Options for
    Patients With Refractory Epilepsy:
    New AEDs With Evidence of Efficacy According to AAN
         Assessment But Without FDA Indications

                Partial                                        Partial
                           Partial     Primary     Symptomatic
    AED         adjunctive                                     adjunct
                           monotherapy generalized generalized
                adult                                          pediatric
Oxcarbazepine     Yes             Yes                No       No    Yes

  Tiagabine       Yes             No                 No       No    No

  Topiramate      Yes            Yes*                Yes      Yes   Yes

 Zonisamide       Yes             No                 No       No    No

                     * Not FDA approved for this indication
Change in Clinician’s Prescribing Options:
   New AEDs With Evidence of Efficacy
According to AAN Assessment But Without
  FDA Indications in New-Onset Epilepsy

                   Newly diagnosed
                    monotherapy                     Newly diagnosed
     AED
                                                       absence
                      Partial/mixed

  Gabapentin                Yes*                          No

  Lamotrigine               Yes*                         Yes*

  Topiramate                Yes*                          No

   Tiagabine                 No                           No

                *Not FDA approved for this indication
  Can the data from the studies reviewed in
these assessments help me decide on how to
   use these AEDs in my clinical practice?




                         Well…
                         Sort of!
         Problems associated with
    the methodology of AED development
Treatment of Refractory Epilepsy: Monotherapy


•   Dosages used in the trials are often higher than
    those that might be used in practice, because
    the goal is to retain as many patients as possible
    and achieve a significant result
•   Most importantly, the goal of these studies is not
    to determine whether patients improve after they
    are converted to monotherapy. Rather, the goal
    is to determine whether they deteriorate less
    than the comparison group
Problems with the methodology of AED development
  Treatment of Refractory Epilepsy: Monotherapy

 •   The studies performed to demonstrate
     effectiveness of new AEDs in monotherapy in
     refractory partial-seizure patients are driven by
     FDA requirements to show superiority over
     placebo or ―pseudoplacebo‖ rather than by
     clinical questions


 •   The assessment does not provide clinicians with
     the necessary information to safely convert
     patients with refractory epilepsy to monotherapy
     regimens
Problems with the methodology of AED development
  Treatment of New-Onset Epilepsy: Monotherapy

  Attempts to infer superiority or inferiority with respect to
  efficacy from data included in assessment may lead to false
  conclusions for the following reasons:
  • Primary outcome variables differ and include endpoints
   such as time to exit, time to first seizure, and percentage
   of patients rendered seizure free
  • All of these factors can influence response to monotherapy
   and complicate comparison between studies
Potential errors in interpretation of data presented in
                      assessments
          Treatment of Refractory Epilepsy


 •   Attempts to infer superiority or inferiority with
     respect to efficacy from data included in
     assessment may lead to false conclusions
      EXAMPLE: Dropout rates may appear higher for
       drugs that were studied at high doses (eg,
       topiramate and oxcarbazepine);
       efficacy may appear lower for drugs studied at low
       doses (eg., gabapentin)
            Lesson for the clinician
    AAN New AED Assessment of Treatment
     of New-Onset Epilepsy: Monotherapy

•   Some studies reviewed demonstrated better
    tolerance with equivalent efficacy than the
    standard AED.


•   It is not necessary to aim for high serum
    concentrations when starting an AED in
    patients with new-onset epilepsy
         Questions left unanswered
       AAN New AED Assessment of
      Treatment of Refractory Epilepsy

•   No comparative data on efficacy or safety
    among the 7 AEDs reviewed




Recommendation to funding agencies
•   Need for studies that compare the new drugs in a
    head- to-head fashion
           Questions left unanswered
         AAN New AED Assessment of
       Treatment of Refractory Epilepsy:
        Idiopathic Generalized Epilepsy

•   There are little data on the management of refractory
    idiopathic generalized epilepsy
•   All the studies performed in patients with juvenile
    myoclonic epilepsy have been uncontrolled case series




Recommendations
•   Controlled studies are needed for this patient population
      Question left unanswered
AAN New AED Assessment of Treatment
 of New-Onset Epilepsy: Monotherapy

The data reviewed cannot speak to the importance
of differences between old and new AEDs, such
as:
• Simpler pharmacokinetics
• Absence of apparent disturbance of the hormonal
milieu
• Less need for laboratory monitoring
• Cost benefits related to these issues
    Implications for Advocacy Agencies

Facilitate lobbying process in:
•   The incorporation of new AEDs that do not have
    FDA indications into hospital/HMO drug
    formularies
•   Averting the need to prove failure of seizure
    control with standard AEDs before approving use
    of new AEDs
Additional recommendations based on the review of
   the data analyzed in the AED assessments…

   •   Regulatory studies must be supplemented with
       controlled trials that investigate optimal clinical
       use.
   •   Comparison studies should be performed,
       titrated to optimal doses, and followed them for
       years.
   •   Both old and new AEDs should be compared.
       In addition, extended release formulations
       should be used when available.
   •   New scales should be developed that are
       better at assessing improvement beyond
       seizure reduction.
Additional recommendations based on the review of
   the data analyzed in the AED assessments…


      Standardization of trial design and inclusion criteria in active
       control comparison trials in newly diagnosed patients. This would
       ―even the playing field‖ for all drugs.
      Comparable trial durations and outcome variables among studies
       would minimize the impact of dropouts due to side effects, or bias
       the outcome in other ways
      Selection of a more stable population that could increase the
       likelihood of a ―no difference‖ outcome, even where a difference
       actually exists.
      Studies should be powered to demonstrate true non-inferiority.
      While new AEDs may have some desirable characteristics, they
       are much more expensive than standard drugs. Future research
       using economic decision analysis would help to determine
       whether the potential benefits are worth the additional cost.
             Guideline Limitations

•   Too many guidelines can be confusing to the
    user, especially if they differ from each other
•   Guidelines depend on who is making them and
    their access to information
•   Recommendation levels may be arbitrary
•   Not proven that they actually improve
    patient care
•   Clinical experience must have weight
    What Do Guidelines and Experience
          Mean for Patient Care?
•   Regardless of overall recommendations,
    patient individuality is most important
•   Expense, availability, ease of use, severity of
    condition, and other factors may vary
    considerably for different patients
•   Combine guidelines with the skill, knowledge,
    and experience of the individual physician
                           The Place of Guidelines in
                            Clinical Decision Making

                                                                      PATIENT/PHYSICIAN
                               EVIDENCE
                                                                           FACTORS
                        1. Patient data                                  1. Cultural beliefs
                        2. Basic, clinical, and                            2. Personal values
                           epidemiologic                  Knowledge
                                                                           3. Experiences
                           research
                                                                           4. Education
                        3. Randomized trials
                        4. Systematic reviews              CLINICAL
                                                          DECISIONS
                                              Guidelines                 Ethics



                                                         CONSTRAINTS
                                                      1. Formal policies, laws
                                                      2. Community standards
                                                      3. Time
                                                      4. Reimbursement

Figure. Factors that enter into clinical decisions.                               Mulrow CD, et al. Ann Intern Med. 1997.
Questions and Answers
Summary and Closing Remarks

       James C. Cloyd, PharmD
              Program Co-chair
University of Minnesota College of Pharmacy
               Minneapolis, MN

				
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