Comparing treatments in the new health care environment What works and who benefits?

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Comparing treatments in the new health care
environmentWhat works and who benefits?

• Tim Carey MD MPH
• Jan 2009

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Support

• NIAMS- National Institute of Arthritis and
  Musculoskeletal Disease
• NIH CTSA award to UNC
• NCMHD-National Center for Minority Health and
  Health Disparities
• AHRQ-Agency for Healthcare Research and Quality
• Health Resources and Services Administration
• GSK Foundation
• RWJ Foundation
• DERP- Drug Effectiveness Review Project
• Dissemination grant supported by the Neurontin
  Special Committee

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Nothing new

• Clinicians have always compared one treatment
  with another
• Most conditions have therapeutic options
• Meds vs PCI vs CABG for CAD
• Surgery vs radiation for prostate CA
• Decompression vs fusion vs exercise for spine
  disease
• Lovastatin vs simvastatin for hyperlipidemia
• Fluoxetine vs. paroxetine for depression
• Increase in efficacious treatments, and
  especially expensive efficacious rx
• Rise in healthcare costs has led to renewed
  emphasis on comparative effectiveness and
  cost-effectiveness
• Increased emphasis on comparing treatments
• Medications with each other
• Procedures with each other
• Procedures compared with medications or physical
  treatments (exercise, PT, etc)

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Efficacy and effectiveness

• Efficacy Does the treatment work in an ideal
  situation?
• Generally addressed in relatively small RCTs,
  often sited at tertiary care settings
• Effectiveness Does the treatment work for the
  average patient in the average practice?
• Populations in primary care (or setting where
  most pts treated)
• Less stringent eligibility criteria
• Health outcomes assessed
• Long study duration clinically relevant
  treatment modalities
• Assessment of adverse events
• Adequate sample size to assess a minimally
  important difference from a patient perspective
• Intention to treat analysis

Gartlehner et al J Clin Epid 2006
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Applicability

• Does the evidence from the clinical literature
  apply to most patients, or groups of patients,
  with the condition of interest?
• Does the evidence from the clinical literature
  apply to the next patient I am going to see in my
  practice?
• PICOTS approach
• Population Intervention Comparator Outcome
  Timeframe Setting

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What is being compared?

• Similar treatments?
• Appropriate outcomes
• Are harms being searched for?
• Is the comparison treatment the current state of
  the art treatment?
• Patient preferences taken into account?

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Coke vs Pepsi

• Risk of losing perspective- how well does
  treatment work at all for the condition?
• Is it an interesting question to compare two
  similar medications (or procedures)?
• Two statins
• Patent vs generic (Kesselheim JAMA Dec 3, 2008)
• Harm profiles
• Drug vs procedure invasive vs non-invasive
• Potential audiences for comparative effectiveness
• Payers and regulators
• Practice community, hospital PT committees
• Patients
• Research investment
• Secondary analysis vs primary data collection
• Large, simple trials (ALLHAT, CATIE)

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Strength of Evidence

• When is sufficient evidence present to say case
  closed.
• Relationship between strength of evidence
  assessment and guideline
• Guidelines take into account additional
  information including cost, convenience,
  acceptability, cultural and policy issues
• Strength systems take into account number of
  studies, size of studies, quality of research,
  reproducibility (coherence), etc
• GRADE system seems to be center of emerging
  consensus
• Transparent, plain English
• Global qualitative assessment
• What is the likelihood that an additional study
  would lead to a different conclusion?

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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, ACP J Club 2006
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Comparative effectiveness reviews Subset of
Systematic Review

• Within a class of treatments (often meds), is
  there a difference in efficacy, effectiveness or
  adverse events among agents?
• Optimally requires head-to-head trials between
  agents at equivalent doses
• CATIE (antipsychotics), ALLHAT (antihypertensives)
  , STAR-D (antidepressants)
• Comparing placebo-controlled trials of different
  agents possible, but should be viewed with
  caution
• Reviews underway through DERP and AHRQ at UNC
• Non-drug treatment s for refractory depression
• Antiepileptic drugs for bipolar disorder
• Disease modifying drug for arthritis
• Controller drugs for asthma

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Methods

• Prior systematic review methods often highly
  variable
• Cochrane methods manual provides consistency, but
  questions often very narrow
• In the past, little funding for methods work
• Europeans (British, Dutch) often leaders
• Role of NICE
• EPC methods manual substantial advance, now in
  2nd revision
• New chapters on dx test methods, use of prior
  systematic reviews
• Risk of consistent methods leading to lack of
  innovation
• Peer reviewed, chapters published in J Clin Epid,
  Annals of Internal Medicine

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COMPARATIVE EFFECTIVENESS OF SECOND-GENERATION
ANTIDEPRESSANTS IN THE PHARMACOLOGIC TREATMENT OF
ADULT DEPRESSIONFinal ReportDecember 2006

• Prepared for Agency for Healthcare Research and
  QualityU.S. Department of Health and Human
  ServicesPrepared byRTI International-Universit
  y of North CarolinaResearch Triangle Park, North
  Carolina

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Key Question 1

• Do antidepressants differ in efficacy and
  effectiveness for the treatment of major
  depressive disorder, dysthymia, and subsyndromal
  depression?

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Included Medications
Other Bupropion Duloxetine Mirtazapine
Nefazodone Venlafaxine Trazodone

• SSRIs
• Citalopram
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline

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Results Excluded Studies

• 62 studies excluded because of
• poor internal validity
• High loss to followup
• Single blinding
• No intention-to-treat analysis
• No systematic literature search for systematic
  reviews

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Major Depressive DisorderBody of Evidence

• 72 head-to-head trials (including 3 effectiveness
  trials) on 16,780 patients
• 18 studies assessed quality of life
• We conducted 4 meta-analyses and 62 adjusted
  indirect comparisons
• Outcome of interest response to treatment

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Major Depressive DisorderEvidence of
Comparative Efficacy

• Overall, no substantial differences in efficacy
• Statistically significant results from
  meta-analyses modest and likely not clinically
  important
• No differences in quality of life
• Strength of evidence moderate

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Major Depressive Disorder Evidence of
Comparative Efficacy

• Although efficacy is similar, second-generation
  antidepressants are not identical
• Mirtazapine has a significantly faster onset of
  action than SSRIs
• Bupropion has less effect on sexual functioning
  than SSRIs
• Strength of evidence moderate

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Major Depressive Disorder Evidence of
Comparative Effectiveness

• 3 effectiveness trials studies conducted under
  real world conditions
• No differences in effectiveness among examined
  drugs
• No differences in quality of life
• Strength of evidence moderate

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Summary of Results of Direct and Indirect
Comparisons

• Results are summarized in 3 forest plots
• One comparing SSRIs and SSRIs
• One comparing
• SSRIs and SSNRI (duloxetine)
• SSRIs and SNRIs (mirtazapine venlafaxine)
• SSNRI/SNRI and SNRI
• One comparing
• SSRIs, SSNRI, and SNRIs vs. other
  second-generation antidepressants
• other second-generation antidepressants with each
  other

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Indirect comparisons

• Attractive option when no or limited head to head
  RCT data
• Statistics opaque
• Loss of much of the benefit of randomization
• Limited statistical power
• Need 4x the subjects to achieve same power as
  head to head trial
• Overlapping confidence intervals does not mean
  that treatments are the same

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Unadjusted Indirect Comparison
A P A P A P A
P A D A D A
E A F
B P B P B P B
C B C B D B
E B F
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Adjusted Indirect Comparison
A P A P A P A
P A D A D A
E A F
B P B P B P B
C B C B D B
E B F
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Favors first SSRI
Favors second SSRI
Based on meta-analysis of head-to-head trials
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Favors SSRI
Favors SSNRI
Favors SSRI
Favors SNRI
Favors SSNRI SNRI
Favors SNRI
Based on meta-analysis of head-to-head trials
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How certain can we be that the treatments are the
same?

• Overlapping confidence intervals is not the same
  as therapeutic equivalence
• Indirect comparisons of limited power to detect
  differences
• Non-inferiority trials lead to plethora of small,
  underpowered studies.

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What about harms?

• Limited data from RCTs
• Better data collection than in observational
  studies, but patient population young, fewer
  co-morbidities
• Inconsistent definitions of harms from study to
  study
• Secondary data and cohort studies may complement
  RCT information
• Need for better data- EMRs, pt reports?
• Assessment of benefits and harms may require
  qualitative, patient-centered judgments
• Function vs longevity short vs long-term
  effects etc.

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Remaining Issues for Clinicians and Patients in
treatment of depression

• Multiple treatment options may be necessary for
  many patients
• 40 of patients do not achieve clinical response
  with initial treatment
• 10 - 15 discontinue treatment because of
  adverse events
• Antidepressants differ significantly in dosing
  regimens
• Need for rx of med-refractory patients

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Quality of studies

• Good studies should get more attention than bad
• Quality ratings to date lack transparency,
• ? Susceptible to gaming?
• Many good studies should have more impact
• gt40 scales for rating quality of randomized
  trials
• Some commonalities across scales
• Randomization
• Similarity of groups at baseline
• Allocation concealment
• Blinded assessors
• Intention to treat analysis
• Adequate and non-differential drop-out rate

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Whats left out of systematic reviews?

• Case series, other types of observational studies
• Can be helpful for emerging treatments, harms
  identification, ?procedures
• Role of case series influencing clinical
  practice.
• Neurontin case series in the late 90s
• Small size
• Modest duration
• Often unclear setting
• High dropout
• Stereotyped conclusions

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Number of case series studies on neurontin in
bipolar disorder
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Publication bias

• We know it occurs..
• Statistical tests
• Funnel plots
• Fill and trim
• Low statistical power
• FDA site
• Efficacy and harms issues
• Trial registries

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The Weight of the Evidence
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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
• 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

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Key Concept 1

• 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

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Key Concept 2

• The rates of achieving and maintaining remission
  during treatment with the three AEDs mentioned
  above are similar to those obtained with lithium
  treatment for bipolar I disorder. For
  outpatient adults with acute mania, carbamazepine
  and valproate were similar, relative to lithium,
  in terms of response rates.
• a. The incidence of recurrence in the
  studies examined ranged between 16 and 70 with
  placebo, and between 6 and 65 with medication
  treatment. The broad range of these estimates is
  due to the variable definitions of recurrence
  used and variable duration of follow-up.
  Recurrence is a significant problem for these
  patients even with treatment with AEDs.

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Key Messages v6.1

• There remains no scientifically acceptable
  clinical trial evidence which supports use of
  either gabapentin or topiramate in bipolar mood
  disorder, either as monotherapy or as an adjunct
  to other therapies.
• Research supports the use of three antiepileptic
  drugs(1) carbamazepine, (2) valproic
  acid/valproate and (3) lamotrigine in achieving
  and maintaining remission for outpatient adults
  with primary diagnoses of bipolar I disorder.
  Evidence of efficacy is less clear for these
  treatments for type II bipolar disorder.
• 3. Carbamazepine, valproic acid/valproate, and
  lamotrigine work as well as lithium in achieving
  and maintaining remission in bipolar I disorder.
   
• 4. The types of adverse events vary among
  anti-epileptic drugs and lithium. There is
  insufficient evidence to determine if the overall
  risk of adverse events differs among AEDs. Unlike
  the AEDs, lithium poses significant risk when
  taken in an overdose.

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Current comparative effectiveness activities

• Head to head trials
• Comparative effectiveness reports
• Meta-analyses
• Secondary data analyses
• Administrative claims data
• Re-analyses of existing RCT data
• Use of data derived from electronic medical
  records
• Large effectiveness trials

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Why not more large effectiveness trials?

• CATIE, ALLHAT, Womens Health Initiative,
  Endarterectomy trials all substantially changed
  practice
• But did they change practice enough?
• Expense
• Difficulty determining the appropriate comparison
  treatment
• Risk (SPORT trials for back pain)
• Problems with non-inferiority trials
• Marketing issues

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Funding sources

• FDA
• Regulatory role, not research
• ?regulatory capture in PADUFA
• NIH
• Historically not involved with comparative
  effectiveness
• ALLHAT, CATIE, STARD, SPORT. More to come?
• CTSA and Type II (bench to bedside)
  translational research
• AHRQ
• Effective Health Care Program
• EPCs and DEcIDE
• Discussion of increase in funding by several
  hundred million dollars
• Rapid response secondary data analyses
• EMR analyses
• Selected head-to-head trials
• Industry
• Limited incentive
• Do you feel lucky- some potential to game
  comparisons

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Current UNC activities

• Evidence-based Practice Center
• Multiple comparative effectiveness reviews
• DEcIDE Center
• Secondary database analyses
• Depression treatment strategies
• Effectiveness of cancer treatments
• Moderate RCT activities
• CATIE study
• Substantial expertise in trial coordination
• Only modest activity comparing procedures with
  treatments or in assessing devices
• Methods work on propensity score analysis (EPID),
  more efficient methods of conducting literature
  searches using text recognition (SILS)

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Public good, public guardian

• Widespread recognition that current system is
  dysfunctional
• FDA role likely to change
• Avandia, Vioxx, stents, etc
• Concern regarding FDA funding stream
• CMS taking increasing role
• State Medicaid programs form consortium

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Schematic for Bedside to Clinic Translational
Research
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Current proposals

• Substantial budgetary allocations of 100m to 1B
• Secondary data analyses
• Systematic reviews and meta-analyses
• Head to head real world effectiveness trials
• FDA
• Established, decades of experience, diminished
  credibility
• AHRQ
• Established, good methods, hx of political
  vulnerability
• Institute of Medicine (IOM)
• Universal respect, not a research entity, often
  slow
• Public-private Partnership
• Potentially nimble, risk of regulatory capture
• Federal Reserve model
• National health board favored by Sen Daschle
• Political independence

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Stimulus package

• 1.1 billion over 2 yr for comparative
  effectiveness research (currently 50
  million/year)
• Probable administration by AHRQ and NIH, mixture
  of RCTs, secondary data analyses, reviews.
• How shovel ready is CER work?
• Career development awards http//grants.nih.gov/gr
  ants/guide/pa-files/PAR-09-085.html

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Resources

• Agency for Healthcare Research and Quality
  www.ahrq.gov
• Cochrane collaboration
• Drug Effectiveness Review Project DERP
• http//www.ohsu.edu/drugeffectiveness/

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Comparative effectiveness research

• (Sort of) new wine
• Interest is predominantly driven by technology
  availability, payer interest, rising chronic
  disease burden
• New bottle
• Definitely, federal and payer interest likely to
  be great in the next few years
• Critical will be to maintain equipoise
• Some research will find that more expensive
  treatments may be a dominant strategy