Clinical, Regulatory, Economic,

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Clinical, Regulatory, Economic, Policy
Challenges In Translating Genomics Into Clinical
Practice Health Policy

• Kathryn A. Phillips, PhD
• Visiting Scholar, HPCGG New England Healthcare
  Institute
• Dept. Clinical Pharmacy/School of Pharmacy
• Institute for Health Policy Studies
• UCSF Comprehensive Cancer Center
• UCSF
• PhillipsK_at_pharmacy.ucsf.edu

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Why Am I on Sabbatical in Boston? OrHow I
Learned to Stop Worrying and Love Awful Weather
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Objective

• Discuss a research agenda on
• Clinical application
• Economic
• Regulatory
• Policy challenges
• in translation of personalized medicine
  genetically-enabled health care

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The Trend Towards Personalized Medicine

• Increased understanding of genomics raises hopes
  that health care can become more personalized
• Personalized medicine (PM) focuses on genetic
  information (also individual, clinical,
  environmental factors)
• Genomics includes inherited somatic genetic
  mutations
• Pharmacogenomics - targeting of drugs based on
  genetic characteristics of individual or disease
• Targeted therapies - based on mechanisms that
  target critical molecular pathways
• Genetically-enabled health care use of genomics
  to personalized medicine improve therapies

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Will our new knowledge of genomics
revolutionize health care?
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Or is there a train wreck coming?
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Revolution or Train Wreck?

• In 20 years we will have predictive,
  personalized, preemptive health care
• NIH Director Zerhouni
• Overall, inevitable trend towards greater
  stratification targeting
• Knowledge of human genomics
• Emphasis on safety
• High drug costs
• Regardless of whether hype or not
• Inevitable that will change landscape
• of health care

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Questions

• Do you see the emergence of personalized medicine
  as changing how you do your research?
• What do you see as the key issues for your
  research areas how they will intersect, e.g.,
  with prevention? drug policy?

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The Train Has Left The Station

• Many genetic tests available or coming
• 1700 clinics/labs using genetic tests for gt 1300
  diseases
• W/in cancer, 62 tests clinically available 104
  in development
• Most activity in oncology but more coming in CHD,
  asthma, diabetes, mental health
• Industry using PGx data for drug development
• FDA pursuing initiatives to promote PGx
• Payors looking for approaches to better target
  interventions and PM offers hope
• Government looking to PM to provide better care
  at lower cost
• CMS developing initiatives

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The Train Has Left The Station

• PM is being or could be used in clinical practice
  increasingly for common, chronic diseases
• HER2 testing for trastuzumab (Herceptin)
• Gene expression profiling for breast cancer
  (Oncotype Mammaprint)
• Lynch Syndrome (HNPCC) screening
• EGFR screening for lung cancer drugs
• CYP2D6 testing for tamoxifen
• UGT1A1 testing for irinotecan
• Bcr/abl, C-kit testing for Gleevec
• TMPT testing for leukemia etc.
• CYP2C9 VKOR testing for coumadin (Warfarin)
• CYP2D6 C19 testing for SSRIs
• CYP2D6 testing for codeine

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What is a Health Economist doing Working on
Genomics?

• Ive got a feeling were not in Kansas anymore
• Dorothy
• Interest grew out of
• Research on who gets care how we pay for it
• Screening diagnostics
• Focus on using quantitative tools to examine
  policy-relevant issues
• Desire to venture outside of Ivory Tower
• Few health services researchers/economists
  working in field
• Example NCI recently held workshop to develop
  research agenda
• Great need for research but not enough being
  done

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Wearing Three Hats

• Academic (primary role)
• UCSF for 15 years
• Sabbatical Research Policy
• Harvard Partners Center for Genetics Genomics
• Established 2001
• Focus on translation of basic science
• New England Healthcare Institute
• Non-profit technology assessment group
• Brings together all sectors to address health
  care issues with practical solutions.
• Board/members Deans of medical schools, CEOs of
  biotech/pharma/insurers, venture capitalists

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Wearing Three Hats

• Government
• Advisor to the FDA on PM
• Member of CDC-sponsored national group on
  application of genetic testing (EGAPP)
• Co-Chair, NCI Research Agenda Setting Workshop
• Nominated, HHS Secretarys Advisory Group on
  Genetics, Health, Society
• Previously worked for federal government
• Industry
• Board member/consultant to start-up companies
  VCs on how to measure value
• Speaker at industry conferences

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What Have I Learned So Far in Boston

• If you dont like the weather, wait a day. You
  probably still wont like it, but at least it
  will be different.
• Being at Harvard is like being a kid in a candy
  store
• There are endless goodies
• But its hard to find the best stuff its easy
  to gorge

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Four Key, Interrelated Topics On
Challenges/Opportunities for Personalized Medicine

• Industry paradigms.
• Value/economics
• Reimbursement

• Innovation
• Technology assessment
• Regulation
• Legislation

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Personalized Medicine How Its Hitting the
Policy Radar Screen

• Two Examples

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The I should have had a V8 study

• Phillips et al, Potential Role of
  Pharmacogenomics in Reducing Adverse Drug
  Reactions A Systematic Review, JAMA, 2001
• Linkage of 2 distinct perspectives
• Quality of care/HSR folks need to reduce high
  rate of ADRs due to drugs
• But how?
• PGx/basic sci folks increased knowledge of role
  of genetics in drug metabolism could reduce ADRs
• But how?

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PGx Reducing ADRs

• First study to systematically combine data on
• which specific drugs are linked to ADRs
• genetic variability in drug metabolizing enzymes
  relevant to those drugs

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PGx Reducing ADRs

• Found that drugs linked to ADRs much more likely
  to be associated with genetic variation
• 59 of the drugs cited in studies on ADRs are
  metabolized by at least 1 enzyme with a variant
  allele known to cause poor metabolism
• Vs. 22 of drugs in US
• Vs. 7 of top selling US drugs
• Suggests that genetic variability could be a
  significant cause of ADRs
• Widely cited
• But also demonstrates challenges in
  interdisciplinary research moving agenda forward

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HER2/neu trastuzamab (Herceptin) How Even a
Successful Product Generates Questions

• Best known example of PGx success
• 30 of pts w/ breast cancer over-express
  HER2/neu can benefit so routinely recommended
• Enormous financial success for Genentech
• 3rd best-selling drug
• But questions remain
• Little known about who gets tested treated
• If underserved population?
• Which of two tests?
• How many getting drug do not have positive test?
• Ambiguity on most cost-effective approach
• Herceptin 50K/year
• Cost-effectiveness analyses are inconclusive
• Tip of iceberg for issues coming down the pike

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Findings from Our Pilot Study on HER2/neu
Herceptin

• NO secondary dataset available to examine
  utilization (!!??) so conducted chart review
• Found that chart review can identify who is
  tested gets tx how tested but complex
  expensive
• Wide variation in type of testing performed
• Majority get one test (IHC), which is less
  accurate may be less cost-effective
• Variation seen in trastuzumab use by HER2/neu
  status
• Only 56 of patients had documentation of a
  clearly positive test
• Consistent w/ proprietary insurer study
  anecdotal information
• 10-40 taking trastuzumab do not have clearly
  positive test
• 20 of tests are inaccurate

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Key Policy Challenges

• Aligning Incentives
• Balancing Regulation Innovation
• Demonstrating Value
• Designing Appropriate Reimbursement

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Challenge 1 Aligning Incentives

• Many factors determine whether PM intervention
  will be successful
• Often contradictory convoluted
• Experience to date suggests industry-driven
  markets may not produce socially optimal outcomes
• Pharma is reluctant to segment market
• Unclear who is in drivers seat Industry?
  Payors? FDA? Professional organizations?
• Phillips, Health Affairs, 2006

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P450 Testing (AmpliChip) Slow Adoption Despite
Potential Wide Impact

• Tests for CYP2D6 2C19 mutations
• Involved in metabolism of many drugs
• E.g., CYP2D6 testing COULD have large impact
• Relevant to 189M scrips 12.8B
  expenditures/annually in US
• Particularly mental health and heart disease
  drugs
• Used for drug development research purposes but
  not clinical practice
• Insufficient data to assess impact of testing
• Limited data on clinical outcomes of testing
• Anecdotal reports small observational studies
• An example of where everyone benefits so no one
  wants to pay
• Phillips et al, Nature Reviews Drug
  Discovery, 2005

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Challenge 2 Balancing Regulation Innovation

• FDA taking proactive evolving stand on PGx
• Issued multiple guidance documents
• McClellan was champion
• Where is the FDA headed?
• Must balance
• Competing concerns about innovation vs. safety
• Historically more extensive regulation for drugs
  vs. diagnostics
• Push for value with no mandate to consider
  value
• Difficult political climate
• Proposed legislation to ensure quality of genetic
  testing
• Concerns about cost of Medicare scrip coverage
• Phillips et al, Medical Care Research and
  Review 2006

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The Balancing Act Continued

• Unclear whether FDA will use carrot or stick
  approach to promote PGx
• Will regulatory efforts facilitate or impede
  innovation adoption?
• Push for greater regulation has industry
  concerned

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Challenge 3 Demonstrating Value

• Value must be demonstrated for adoption
  reimbursement
• Is there a big enough pie?
• Magnitude of the problem
• Is a piece of the pie worth the cost?
• Cost-effectiveness of product
• Few economic analyses of PM
• Phillips et al, Pharmacogenomics 2004
• Many (most?) products are not evaluated early
  enough!!!

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Challenge Value of Personalized Medicine Can be
Difficult to Measure

• Lack of data linking PM to outcomes
• Up-front PM testing cost perceived as higher than
  downstream savings
• PM often has benefit of PREVENTING what has not
  occurred but value of prevention hard to
  measure
• Requires creative approaches to measure value of
  complex interventions

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Challenges

• Diagnostic industry has historically been
  secondary to pharma industry but now playing
  increasingly important role
• Gene expression profiling test - Oncotype
  (Genomic Health) now darling of industry
• Requires integration of historically divided
  industries and regulatory mechanisms
• Requires early consideration of diagnostics in
  drug development process
• Difficulties in developing validating
  biomarkers that lead to diagnostics (IOM)
• Less health service research on diagnostics
• Phillips et al, Nature Reviews Drug Discovery,
  2006

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Challenge 4 Appropriate Reimbursement

• Example of critical issue
• Are PM tests considered screening vs.
  diagnosis?
• Medicare only covers diagnosis unless mandated
• Complexity of reimbursement systems!!!
• System for diagnostics vs. for drug therapy
• Black box
• Phillips et al, Pharmacogenomics, 2004

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Challenges for Diagnostics

• Diagnostics must overcome reimbursement barriers
• Traditionally not value-based reimbursement
• Lack of data on utilization
• Coding complexities inability to identify in
  claims data

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Our Research Agenda Clinical, Regulatory,
Economic, Policy Challenges In Translating
Genomics Into Clinical Practice Health Policy

• Four Areas
• Utilization/Access
• Preferences
• Value
• Evidence Base
• Funding
• Current NCI R01, Blue Shield Foundation CA
• Proposed
• NCI Program Project Grant (P01) (4 years, 6M, 6
  projects/cores, 7 universities, 30 collaborators)
• NIH Roadmap Methods Grant (4 years, 1M)
• Blue Shield Foundation CA Grant (2.5 years, 900K)

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Conceptual Framework
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Utilization

• Why?
• - Understanding access utilization are
  critical to developing appropriate policies
• - Glaring gap in available data on diagnostics
  has implications for growing use for ability to
  determine value
• Examining access to and use of
• HER2/neu testing, test results, Herceptin
• Gene expression profiling for breast cancer
  (Oncotype Mammaprint)
• SEER-Medicare data
• Chart review data from large national managed
  care organization

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Preferences

• Why?
• New technologies are more likely to be be adopted
  if valued by patients providers
• Preferences have implications for predicting
  utilization determining value
• Examining patient preferences for genetic risk
  information
• Qualitative quantitative methods
• Stated preferences (discrete choice/conjoint
  analysis)
• Compare patient preferences v. physician estimate
  of patient preferences
• Example of Lynch syndrome screening
• Impact on behavior family members is critical

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Economics

• Why?
• Existing approaches may need to be adapted to
  appropriately measure value of personalized
  medicine
• Particularly impact on family members, relevance
  to multiple drugs conditions, dx/drug
  combinations
• Cost-effectiveness analyses
• Colorectal cancer risk stratification
  subsequent screening and surveillance
• Tumor testing treatment strategies for women
  with breast cancer

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Evidence Base

• Why?
• Evidence base is needed to assess adoption,
  impact, and value
• Data required to address to clinical, economics,
  policy, regulatory issues are lacking or widely
  dispersed
• Identify, describe, assess available data
  sources for evidence base on personalized
  medicine interventions for colorectal breast
  cancer
• Conduct case studies

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Illustrative Articles

• What are the broader policy issues?
• Using genetics to target drugs Implications for
  biotechnology and health policy. Health Affairs
  2006.
• Genetic testing and pharmacogenomics Issues for
  determining the impact to health care delivery
  and costs. Am J of Managed Care 2004.
• How can the FDA move PM forward while balancing
  regulation vs. innovation?
• Priming the pipeline A review of the clinical
  research and policy agenda for diagnostics and
  biomarker development, Nature Reviews Drug
  Discovery 2006.
• Regulatory perspectives on pharmacogenomics A
  review of the literature on key issues faced by
  the US Food and Drug Administration. Medical Care
  Research and Review 2006

Phillips et al
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Illustrative Articles

• What data are needed and where can we get that
  data?
• Building an evidence base for personalized
  medicines translation to clinical practice and
  health policy. Personalized Medicine 2006.
• Measuring value and cost-effectiveness analysis
• Measuring the value of pharmacogenomics using a
  resource allocation framework. Nature Reviews
  Drug Discovery. 2005.
• A systematic review of cost effectiveness
  analyses of pharmacogenomic interventions.
  Pharmacogenomics 2004.
• An Introduction to cost-effectiveness analysis
  and cost-benefit analysis of pharmacogenomics.
  Pharmacogenomics, 2003.
• Cost-effectiveness analysis of genetic testing
  for familial long QT syndrome in symptomatic
  index cases, Heart Rhythm. 2005

Phillips et al
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In Conclusion

• Theres a wonderful rule of thumb for American
  health care Shift happens
• Uwe Reinhardt
• Give me data or give me death
• Joe Newhouse