ACLA 14th Annual Meeting

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ACLA 14th Annual Meeting Comparative
Effectiveness Research Upside, Downside, and
Implications for Clinical Labs
Washington, DC May 7, 2009 Clifford Goodman,
PhD Senior Vice President The Lewin
Group clifford.goodman_at_lewin.com
2
Getting to CER Inception Timeline
1 RCT of streptomycin for pulmonary tuberculosis,
sponsored by Medical Research Council (UK)
1948 2 Origin of TA (not focused on health) in
1965 US Congressman Daddario first
experimental HTA by National Academy of
Engineering in 1969 (multiphasic screening)
Office of Technology Assessment published first
HTA in 1974 3 Patient Outcomes Assessment
Research Program (later, PORTs) initiated by
NCHSR (later renamed AHCPR now AHRQ) in 1986
(promote research with respect to patient
outcomes of selected medical treatments and
surgical procedures for the purpose of assessing
their appropriateness, necessity and
effectiveness ) 4 HCFA (later renamed CMS)
Effectiveness Initiative 1988 5 Early published
appearance of pharmacoeconomics Bootman et al.
1989 6 Evidence-based Eddy 1990
Evidence-based medicine Guyatt et al. 1992 7
Medicare Prescription Drug, Improvement, and
Modernization Act of 2003 (MMA) specifies AHRQ
role in comparative clinical effectiveness
American Recovery and Reinvestment Act of 2009
(ARRA) authorizes major national investment in
CER 8 CMS draft guidance in 2005 formalized in
2006. Medicare and other payers began linking
coverage to clinical research in
1990s Source The Lewin Group
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What Decision-Makers Want to Know About
Alternative Health Care Interventions

• Are patient outcomes improved?
• What are the harms?
• Do benefits outweigh harms?
• What is the added value of intervention?
• Is the real-world net benefit the same as in
  clinical trials?
• What are the costs?
• Given the net benefits and costs, is the
  intervention worth it?

4
CER Attributes (1)

• No standard definition of CER. Generally common
  attributes
• Direct comparisons of alternative interventions
  (as opposed to comparison with placebo or
  indirect comparisons)
• May apply to all types of interventions
• pharma, biotech, devices/equipt, medical and
  surgical procedures, lab services organization,
  delivery, management, financing
• Effectiveness (in realistic health care settings)
  rather than efficacy (in ideal circumstances)
• Health care outcomes (e.g., morbidity, mortality,
  QoL, adverse events, and symptoms) rather than
  surrogates or other intermediate endpoints

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CER Attributes (2)

• Primary and secondary data collection
• Preferred head-to-head RCTs/PCTs that meet
  reqts for effectiveness research, where feasible
• Observational studies, including registries,
  claims data, epidemiological use of EHRs
• Systematic reviews (may include meta-analyses) of
  head-to-head comparisons (direct preferred over
  indirect comparative effectiveness reviews)
• No consensus regarding incorporation of
  cost-effectiveness analysis or other economic
  analysis (Back to this later )

6
CER in ARRA

• Provides 1.1 billion, available through Sept.
  30, 2010
• AHRQ 300 million
• NIH 400 million
• DHHS Secretary 400 million
• Provide annual report to Congress on CER
• Provide Operating Plan to Congress for FY 2009
  expenditures by July 30, 2009 and Plan for FY
  2010 by Nov. 1, 2009
• Report on actual expenditures every six months
• Establishes Federal Coordinating Council for CER
  allocates funding for IOM
• both will advise DHHS Secretary on CER priorities
• Source American Recovery and Reinvestment Act
  of 2009

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CER as Described in ARRA

• Provided, That the funding appropriated in this
  paragraph shall be used to accelerate the
  development and dissemination of research
  assessing the comparative effectiveness of health
  care treatments and strategies, through efforts
  that
• (1) conduct, support, or synthesize research
  that compares the clinical outcomes,
  effectiveness, and appropriateness of items,
  services, and procedures that are used to
  prevent, diagnose, or treat diseases, disorders,
  and other health conditions and
• (2) encourage the development and use of
  clinical registries, clinical data networks, and
  other forms of electronic health data that can be
  used to generate or obtain outcomes data
• Source American Recovery and Reinvestment Act
  of 2009

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Provisions Distancing CER from Payment

• AHRQ MMA 2003, Section 1013
• AHRQ shall not mandate national standards of
  clinical practice or quality health care
  standards.
• CMS may not use data obtained through this
  provision to withhold coverage of a prescription
  drug
• Federal Coordinating Council for CER ARRA 2009
• Nothing in this section shall be construed to
  permit the Council to mandate coverage,
  reimbursement, or other policies for any public
  or private payer.
• None of the reports submitted under this section
  or recommendations made by the Council shall be
  construed as mandates or clinical guidelines for
  payment, coverage, or treatment.

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Senate Finance Committee April 29, 2009CER
Policy Options (1)

• ARRA funds are temporary and must be obligated by
  end of 2010.
• Consider options to establish long-term or
  permanent framework to set national priorities
  and provide for conducting CER
• Fund existing HHS entities through annual
  appropriations (as in ARRA)
• Establish private, non-profit Institute for CER
• Balanced, multistakeholder board
• Contract with AHRQ, NIH, other federal and
  private entities to conduct CER
• Subject to regular GAO reviews

Source Description of Policy Options.
Transforming the Health Care Delivery System
Proposals to Improve Patient Care and Reduce
Health Care Costs. Senate Financing Committee.
April 29, 2009.
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Senate Finance Committee April 29, 2009CER
Policy Options (2)

• Other provisions
• Expert committee on methodological standards
• Transparency and public input (e.g., via expert
  advisory panels, public comment)
• Findings understandable to patients and providers
• Account for patient subgroups
• No direct or fast-track link to payment
• Funding
• Annually by appropriations or by mix of public
  and private sector funds, e.g.
• general revenues, contributions from Medicare
  trust funds, assessment on private insurance (in
  proportion to share of total national health
  expenditures)

Source Description of Policy Options.
Transforming the Health Care Delivery System
Proposals to Improve Patient Care and Reduce
Health Care Costs. Senate Financing Committee.
April 29, 2009.
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Senate Finance Committee April 29, 2009CER
Policy Options (3)

• No direct or fast-track link to payment
• Institute or other entity conducting research
• should be prohibited from issuing medical
  practice recommendations or from making
  reimbursement or coverage decisions or
  recommendations.
• Medicare could use findings only in way that
• is transparent
• in context of all available evidence
• considers effects on beneficiary subpopulations
• allows public comment on draft proposals that use
  this information
• This would prohibit HHS agencies from creating a
  fast-track process for automatically linking
  research findings to coverage or reimbursement
  decisions in public programs.

Source Description of Policy Options.
Transforming the Health Care Delivery System
Proposals to Improve Patient Care and Reduce
Health Care Costs. Senate Financing Committee.
April 29, 2009.
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CER One Element of Proposed Health Reform

• Section I Payment Reform Options to Improve
  the Quality and Integrity of Medicare Payment
  Systems
• Section II Long-Term Payment Reforms Options
  to Foster Care Coordination and Provider
  Collaborations
• Section III Health Care Infrastructure
  Investments Tools to Support Delivery System
  Reform
• Health IT
• Comparative Effectiveness Research
• Transparency
• Workforce
• Section IV Medicare Advantage Options to
  Promote Quality, Efficiency and Care Management
• Section V Public Program Integrity

Source Description of Policy Options.
Transforming the Health Care Delivery System
Proposals to Improve Patient Care and Reduce
Health Care Costs. Senate Financing Committee.
April 29, 2009.
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Implications of CER for Clinical Laboratories (1)

• Regulatory and payment requirements are being
  joined by further CER evidence requirements
• Evidence standards are not getting any lower
• its difficult to demonstrate causal connection
  between test and health outcomes (clinical
  utility)
• Anticipate evidence requirements of
  decision-makers throughout technology lifecycle
  Who will want what evidence when?
• Monitor and participate in developments
  pertaining to building national CER capacity
• Monitor CER processes, stakeholder involvement,
  transparency, accountability

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Implications of CER for Clinical Laboratories (2)

• Emphasize need to build PM needs into CER
  priorities, research, reporting, and translation
• Track CER priority setting Where and how will
  it involve lab testing?
• Find opportunities CER may steer innovation
  toward higher value, accompanied by some
  shake-out
• Consider risk Do CER? Wait for CER to happen to
  you?
• Keep sight of big picture CER is just one
  element of proposed national health reform

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Priority Conditions AHRQ Effective Health Care
Program (MMA Sec. 1013)

• Diabetes mellitus
• Functional limitations and disability
• Infectious diseases including HIV/AIDS
• Obesity
• Peptic ulcer disease and dyspepsia
• Pregnancy including pre-term birth
• Pulmonary disease/asthma
• Substance abuse

• Arthritis and non-traumatic joint disorders
• Cancer
• Cardiovascular disease, including stroke and
  hypertension
• Dementia, including Alzheimers disease
• Depression and other mental health disorders
• Developmental delays, ADHD and autism

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IOM Committee on CER Priorities, 2009

• Priority-setting criteria
• Disease burden
• Increasing prevalence
• Morbidity and mortality
• Variability in care
• Cost
• Information gap (e.g., little known about topic)
• Funding gap (e.g., minimal research being done)
• Public interest
• Controversy
• Disproportionate impact by subpopulation
• Potential to act on the information once
  generated
• Utility of the answer for decision-making

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AHRQ Effective Health Care Program Reports

• Testing for Cytochrome P450 Polymorphisms in
  Adults With Non-Psychotic Depression Treated With
  Selective Serotonin Reuptake Inhibitors (SSRIs)
• Comparative Effectiveness of Core Needle Breast
  Biopsy and Surgical Excision Biopsy for
  Diagnosing Breast Lesions (Draft)
• Infrastructure to Monitor Utilization and
  Outcomes of Gene-Based Applications An
  Assessment
• Impact of Gene Expression Profiling Tests on
  Breast Cancer Outcomes (2008)
• HER2 Testing to Manage Patients with Breast or
  Other Solid Tumors (2008)
• Computer-based Clinical Decision Support (CDS)
  Tools for Gene-based Tests Used in Breast Cancer
  BRCA Tool, Gene Expression Profiling Tool (in
  progress)
• A Case Control Study to Assess Association of
  Variations in OCT Genes with Effectiveness of
  Metformin in Diabetic Patients (in progress)
• MRSA Reservoirs in Hospitals and Nursing Homes
  (in progress)

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• Evidence Report/Technology Assessment
• Number 146
• Testing for Cytochrome P450 Polymorphisms in
• Adults With Non-Psychotic Depression Treated With
• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Prepared for
• Agency for Healthcare Research and Quality
• U.S. Department of Health and Human Services
• 540 Gaither Road
• Rockville, MD 20850
• www.ahrq.gov
• Contract No. 290-02-0025
• Prepared by
• Duke Evidence-based Practice Center, Durham, NC
• AHRQ Publication No. 07-E002
• January 2007

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• Evidence Report/Technology Assessment
• Number 146
• Results A review of 1,200 abstracts led to the
  final inclusion of 37 articles. The evidence
• indicates the existence of tests with high
  sensitivity and specificity for detecting only a
  few of the
• more common known polymorphisms of 2D6, 2C19,
  2C8, 2C9, and 1A1. There is mixed
• evidence regarding the association between CYP450
  genotypes and SSRI metabolism, efficacy,
• and tolerability in the treatment of depression,
  mainly from a series of heterogeneous studies in
• small samples. There are no data regarding (a)
  if testing for CYP450 polymorphisms in adults
• entering SSRI treatment for non-psychotic
  depression leads to improvement in outcomes
  versus
• not testing, or if testing results are useful in
  medical, personal, or public health
  decisionmaking
• (b) if CYP450 testing influences depression
  management decisions by patients and providers in
• ways that could improve or worsen outcomes or
  (c) if there are direct or indirect harms
• associated with testing for CYP450 polymorphisms
  or with subsequent management options.
• Conclusions There is a paucity of good-quality
  data addressing the questions of whether testing
• for CYP450 polymorphisms in adults entering SSRI
  treatment for non-psychotic depression
• leads to improvement in outcomes, or whether
  testing results are useful in medical, personal,
  or
• public health decisionmaking.

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Analytic Framework Diagnostic Test and
Alternative Treatments

7
6
IntermediateOutcomes
AlternativeTreatments A B

• Mortality
• Morbidity
• Quality of Life

Detection of Target Condition
Symptomatic Population
Dx Test
1
3
5
2
4
Adverse Effects of A or B
Adverse Effects

• Is diagnostic test accurate for target condition?
• Does diagnostic test result in adverse effects?
• Do treatments change intermediate outcomes?
• Do treatments result in adverse effects?
• Are changes in intermediate outcomes associated
  with changes in health outcomes?
• Does treatment improve health outcomes?
• Is there direct evidence that diagnostic test
  improves health outcomes?
• Adapted from Harris, Helfand, Woolf,
  et al. 2001

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Analytical Framework for Genetic Testing
The numbers correspond to the following key
questions 1. Overarching question Does testing
for cytochrome P450 (CYP450) polymorphisms in
adults entering selective serotonin reuptake
inhibitor (SSRI) treatment for nonpsychotic
depression lead to improvement in outcomes, or
are testing results useful in medical, personal,
or public health decision-making? 2. What is the
analytic validity of tests that identify key
CYP450 polymorphisms? 3. Clinical validity A,
How well do particular CYP450 genotypes predict
metabolism of particular SSRIs? B, How well does
CYP450 testing predict drug efficacy? C, Do
factors such as race/ethnicity, diet, or other
medications, affect these associations? 4.
Clinical utility A, Does CYP450 testing
influence depression management decisions by
patients and providers in ways that could improve
or worsen outcomes? B, Does the identification of
the CYP450 genotypes in adults entering SSRI
treatment for nonpsychotic depression lead to
improved clinical outcomes compared to not
testing? C, Are the testing results useful in
medical, personal, or public health
decision-making? 5. What are the harms associated
with testing for CYP450 polymorphisms and
subsequent management options?
Source Teutsch SM et al. EGAPP Working Group.
Genet Med 200911(1)3-14.
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Analytical Framework Wheres Emphasis?
Source Teutsch SM et al. EGAPP Working Group.
Genet Med 200911(1)3-14.
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Hierarchies for Evaluating Genetic Tests and
Other Genomic Applications - EGAPP
Source Teutsch SM et al. EGAPP Working Group.
Genet Med 200911(1)3-14.
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Hierarchies for Evaluating Genetic Tests and
Other Genomic Applications - EGAPP
Source Teutsch SM et al. EGAPP Working Group.
Genet Med 200911(1)3-14.
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Hierarchies for Evaluating Genetic Tests and
Other Genomic Applications - EGAPP
Source Teutsch SM et al. EGAPP Working Group.
Genet Med 200911(1)3-14.
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Hierarchies for Evaluating Genetic Tests and
Other Genomic Applications - EGAPP
Source Teutsch SM et al. EGAPP Working Group.
Genet Med 200911(1)3-14.
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(No Transcript)
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Infrastructure to Monitor Utilization and
Outcomes of Gene-Based Tests (2)

• Objectives
• Conduct an assessment of existing databases in
  the US health care system for monitoring the
  utilization and outcomes of gene-based
  applications (including tests and related
  interventions) in the health care system
• Provide recommendations to establish appropriate
  and practical systems to assess use and outcomes
  of gene-based clinical applications.

Source AHRQ. Infrastructure to Monitor
Utilization and Outcomes of Gene-Based
Applications An Assessment. AHRQ Pub. No.
08-EHC012. May 2008.
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Infrastructure to Monitor Utilization and
Outcomes of Gene-Based Tests (3)

• Findings
• Only limited, sporadic information is available
  on the utilization of gene-based tests over time.
• Some research and surveys suggest that knowledge
  on the part of some providers about the
  availability and utility of tests may be
  reasonably widespread and accurate.
• Little or nothing is known about the extent to
  which patients and their families are aware of
  tests and knowledgeable about their benefits and
  harms.
• There are few longitudinal data to indicate the
  benefits and risks of using genetic tests to
  guide interventions and medical decisions, such
  as in the selection of therapies, and their
  short- or long-term outcomes.

Source AHRQ. Infrastructure to Monitor
Utilization and Outcomes of Gene-Based
Applications An Assessment. AHRQ Pub. No.
08-EHC012. May 2008.
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Infrastructure to Monitor Utilization and
Outcomes of Gene-Based Tests (4)

• Recommendations
• Improve the coding of gene-based tests in many of
  the relevant databases so that the test types,
  reason for test, and test results can be readily
  determined.
• Develop or adopt standards for the proper
  collection and storage of data from genetic
  testing laboratories for archiving the tests
  performed and facilitating interoperability
  between databases.
• Explore the possibility of adding questions to
  ongoing surveys or developing new surveys to
  monitor the availability of genetic testing
  centers, adequate counseling, and barriers to
  accessing counseling services.
• Consider establishing survey of genetic testing
  laboratories similar to National Ambulatory
  Medical Care Survey for medical clinics and the
  National Hospital Discharge Survey for hospitals
• Develop pilot studies for a small set of diseases
  and tests.

Source AHRQ. Infrastructure to Monitor
Utilization and Outcomes of Gene-Based
Applications An Assessment. AHRQ Pub. No.
08-EHC012. May 2008.
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CER and Personalized Medicine Contradictory or
Complementary?

• Population-based evidence must be complemented by
  personalized evidence based on discrete genomic
  and other personal traits of specific patients
• CER should respond to and support PM
• PM interventions must be supported with evidence
  of clinical validity and utility from diverse
  populations and routine health care settings
• Need population-based research with sufficient
  power for subgroup analyses (esp. prospective) to
  identify and quantify relationships among genomic
  traits, biomarkers, therapies and health outcomes
• Integrate research priorities, study design and
  conduct, reporting, and translation into practice
  

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Symposium on CER Research Methods

• June 1- 2, 2009, symposium will examine new and
  emerging methods for conducting CER
• Two main emphases
• Enhance inclusion of clinically heterogeneous
  populations in comparative and clinical
  effectiveness studies
• Implement longitudinal investigations that
  capture longer term health outcomes, including
  patient-reported outcomes
• 22 author presentations, with the proceedings
  published in peer-reviewed, open-access, journal
  supplement
• Presentations will be concurrently broadcast on
  Internet using webinar format

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CER Open Questions

• Continued transparency of CER priority-setting,
  funding, other processes?
• Continued ability for non-government stakeholder
  input into priority-setting, other processes?
• Use of cost-effectiveness analysis, other
  economic analyses under CER?
• Use of CER findings for coverage and payment
  decisions by Medicare and other payers?
• Establishment of a separate (e.g., private,
  non-profit) CER institute?
• Role of CER in broader US health reform?

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ACLA 14th Annual Meeting Comparative
Effectiveness Research Upside, Downside, and
Implications for Clinical Labs
Washington, DC May 7, 2009 Clifford Goodman,
PhD Senior Vice President The Lewin
Group clifford.goodman_at_lewin.com