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

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


1
Comparing treatments in the new health care
environmentWhat works and who benefits?
  • Tim Carey MD MPH
  • Jan 2009

2
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

3
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)

4
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
5
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

6
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?

7
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)

8
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?

9
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
10
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

11
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

12
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

13
Key Question 1
  • Do antidepressants differ in efficacy and
    effectiveness for the treatment of major
    depressive disorder, dysthymia, and subsyndromal
    depression?

14
Included Medications
Other Bupropion Duloxetine Mirtazapine
Nefazodone Venlafaxine Trazodone
  • SSRIs
  • Citalopram
  • Escitalopram
  • Fluoxetine
  • Fluvoxamine
  • Paroxetine
  • Sertraline

15
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

16
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

17
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

18
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

19
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

20
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

21
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

22
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
23
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
24
Favors first SSRI
Favors second SSRI
Based on meta-analysis of head-to-head trials
25
Favors SSRI
Favors SSNRI
Favors SSRI
Favors SNRI
Favors SSNRI SNRI
Favors SNRI
Based on meta-analysis of head-to-head trials
26
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.

27
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.

28
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

29
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

30
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

31
Number of case series studies on neurontin in
bipolar disorder
32
Publication bias
  • We know it occurs..
  • Statistical tests
  • Funnel plots
  • Fill and trim
  • Low statistical power
  • FDA site
  • Efficacy and harms issues
  • Trial registries

33
The Weight of the Evidence
34
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

35
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

36
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.

37
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

43
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

44
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

45
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)

46
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

47
Schematic for Bedside to Clinic Translational
Research
48
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

49
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

50
Resources
  • Agency for Healthcare Research and Quality
    www.ahrq.gov
  • Cochrane collaboration
  • Drug Effectiveness Review Project DERP
  • http//www.ohsu.edu/drugeffectiveness/

51
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
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