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					Meeting the Translational Challenge
                        Francis S. Collins, M.D., Ph.D.
                 Director, National Institutes of Health
                             National Health Council’s
  24th Annual Voluntary Health Leadership Conference
                                     February 10, 2011
NIH: Steward of Medical and Behavioral
Research for the Nation
               ―Science in pursuit of fundamental
               knowledge about the nature and
               behavior of living systems ...
               and the application of that
               knowledge to extend healthy life
               and reduce the burdens of illness
               and disability.‖
Age-Adjusted Death Rates for Coronary Heart
Disease, U.S., 1950–2004
Deaths/100,000 Population
600     Risk Factors defined                                   Risk Factors
               1961                       Primary and Secondary Prevention
500                                      CASS          Physical Intervention
                                             1983
                                                TIMI
 400                                            1985
                         NHBPEP
                          1972
 300
                                      HDFP
                                      1979
 200
                               BHAT
                               1981                     NCEP
 100                                                    1985
                                             CPPT              ALLHAT
                                             1984               2002

  0
  1950      1960       1970            1980            1990    2000        2010
                                       Year
The Benefits of Biomedical and Public Health
Advances: U.S. Life Expectancy
              80
              78
              76
              74
              72
              70
              68
              66




                    NIH Accomplishments
Reduction in deaths from:                    Increased survival rates for:
 Heart disease                                   Breast cancer
 Stroke                                          Cervical cancer
 HIV/AIDS                                        Colon cancer

              Source: CDC National Vital Statistics Reports, Vol 57, No 14, April 17, 2009
The Benefits …
Chronic Elderly Disability

                     27
        % Disabled
                     23

                     19

                     15
                          1982 1984 1989 1994 1999           2005

 NIH Accomplishments
                     Innovative treatments for:
                      Cardiovascular disease
                      Age-related macular degeneration
                      Musculoskeletal conditions
                                   Source: KG Manton et al., PNAS (2006) 103: 18374
Fundamental   Application of
Knowledge     Fundamental
              Knowledge
The Cancer Genome Atlas (TCGA)

 A comprehensive, collaborative effort led by NIH
   – To map genomic changes in major types, subtypes of
     cancer …
   – To help chart a new course in cancer research
 Pilot project initiated in 2006
   – Established scientific infrastructure; demonstrated ―proof
     of concept‖
   – Focused on 3 types of cancer: glioblastoma multiforme;
     ovarian; lung
   – Success of pilot  expansion: Phase II
TCGA: Phase II
 FY2010 – FY 2011 budget: $275M
   – One of seven NIH-ARRA ―signature projects,‖ to receive
     special emphasis; $175M in ARRA funds
   – Supplemented by $50M each from NCI and NHGRI
 Expansion: to identify recurrent genomic and
  epigenomic drivers for at least 20 cancers over
  next 5 years
   – 6 decided: lung, breast, kidney, endometrial, colon, and
     acute myeloid leukemia
   – Others to be added based on prevalence
 Data are made available rapidly to worldwide
  research community
All the Mutations: Acute Myeloid Leukemia
 Acute myeloid leukemia (AML)
   – Cancer of blood-forming cells in the bone marrow
   – ~13,000 cases diagnosed in U.S. annually
   – 5-year survival rate: 21%
 Landmark study of AML genome
   – Completed DNA sequences of skin (normal) cells and tumor
     cells in patient; compared sequences
   – Found all mutations unique to tumor: 10
 Research has continued; to date:
   – Whole genome analysis of normal; tumor – 50 patients
   – All data, plus 150 additional AML specimens, to TCGA
A New Possibility for Cure: iPS Cells?
                 Despite greater investments in R&D by pharma,
                 FDA approvals of new medical entities appear to
                 be declining
                 60                                                                              $60


                 50                                                                              $50
Number of NMEs




                 40                                                                              $40




                                                                                                       $ Billions
                 30                                                                              $30


                 20                                                                              $20


                 10                                                                              $10


                  0                                                                              $0



                                             FDA Approvals           PhARMA Investment in R&D

        Glaxo tries biotech model to spur drug innovations. Wall Street Journal, July 1, 2010.
        Sources: Pharmaceutical Research and Manufacturers of America; FDA
Approximately 95% of Candidate
Compounds Prove Ineffective




                - Pharmaceutical Research and Manufacturers of America; FDA
                                    Probe                                                      FDA
          Target   Assay                      Pre-      FDA
Disease                     HTS       to                        Ph. I      Ph. II   Ph. III    Re-    CER
            ID      Dev.                     Clinical   IND
                                    Lead                                                       view




                                              TRND                                                    HMORN
NIH Supported      NIH Molecular Libraries                              NIH Clinical Center,
Basic Research           Initiative           RAID
                                                                             CTSAs                    PCORI



                                                  New NIH-FDA Partnerships

                                                 Cures Acceleration Network
The Problem of Rare and Neglected
Diseases
 ~7,000 diseases affect humankind – but only a small fraction
  support commercial development of therapeutic agents
 Two types of neglected diseases:
   – Low prevalence, i.e., ―rare‖ (<200,000 diagnosed in U.S.)
       • There are >6000 rare (orphan) diseases
       • Cumulative prevalence in U.S. ~ 25 – 30 million
       • Most are single gene diseases
       • <200 have any pharmacotherapy available
   – High prevalence but ―neglected‖
       • Occur chiefly among impoverished and marginalized
         populations in developing nations (treatment costs
         prohibitive)
       • Most are infectious
NIH Therapeutics for Rare and Neglected
Diseases (TRND) Program
Creating a Drug Development Pipeline at NIH
 Congressionally-mandated effort to speed development of
  new drugs for rare and neglected diseases
 Collaboration between NIH-intramural and extramural labs
  with appropriate expertise
 Projects will:
   – Enter TRND at a variety of stages of development
   – Be taken to phase needed for external organization to adopt
     for clinical development
   – Not duplicate PhRMA projects
 TRND will encourage creative partnerships; novel
  approaches to intellectual property
TRND Pilot Projects

                                                               Compound
     Disease          Type      Pathology      Collaborators                     Stage
                                                                 type

 Schistosomiasis,               Infectious                                     Early (lead
                    Neglected                   Extramural        NME
   Hookworm                      parasite                                     optimization)

                                               Disease Fnd,    Repurposed
                                    CNS,
       NPC            Rare                      Extramural,     approved       Mid-stage
                                liver/spleen
                                                Intramural        drug

                                                 Biotech,      Intermediate
      HIBM            Rare        Muscle                                        Pre-IND
                                                Intramural     replacement

                                                 Nonprofit,
    Sickle Cell
                      Rare        Blood         Intramural,       NME          Mid-stage
     Disease
                                                Extramural
     Chronic                                   Disease Fnd,    Repurposed
   Lymphocytic        Rare        Cancer                        approved        Pre-IND
    Leukemia                                    Extramural        drug
Therapeutics for Rare and Neglected
Diseases (TRND): Pilot Project on SCD
 Compound originally identified at VCU
 Structure: 5-hydroxymethyl-2-furfural
  (Aes-103)
   – Binds to sickle hemoglobin and increases its
     oxygen affinity
 Stage of project: late preclinical




                 Aes-103 0mM       Aes-103 5mM
          HOLD




NIH and AesRx partnership: next stage
 Will take Aes-103 beyond pre-clinical development and into
  initial clinical trials
 Trials (2) to be conducted in NIH Clinical Center (CC)
 Supported by NIH through TRND; CC; National Heart, Lung,
  and Blood Institute
                                    Probe                                                      FDA
          Target   Assay                      Pre-      FDA
Disease                     HTS       to                        Ph. I      Ph. II   Ph. III    Re-    CER
            ID      Dev.                     Clinical   IND
                                    Lead                                                       view




                                              TRND                                                    HMORN
NIH Supported      NIH Molecular Libraries                              NIH Clinical Center,
Basic Research           Initiative           RAID
                                                                             CTSAs                    PCORI



                                                  New NIH-FDA Partnerships

                                                 Cures Acceleration Network
Clinical and Translational Science Awards
55 CTSA sites in 28 states; 60 sites when fully implemented
                                    Probe                                                      FDA
          Target   Assay                      Pre-      FDA
Disease                     HTS       to                        Ph. I      Ph. II   Ph. III    Re-    CER
            ID      Dev.                     Clinical   IND
                                    Lead                                                       view




                                              TRND                                                    HMORN
NIH Supported      NIH Molecular Libraries                              NIH Clinical Center,
Basic Research           Initiative           RAID
                                                                             CTSAs                    PCORI



                                                  New NIH-FDA Partnerships

                                                 Cures Acceleration Network
New NIH-FDA Partnership
 NIH-FDA Joint Leadership Council
   – Established 2010
 NIH and FDA will:
   – Invest in advancing translational and regulatory science
   – Better define regulatory pathways for coordinated
     approval of co-developed diagnostics and therapeutics
   – Develop risk-based approaches for appropriate and
     accurate review of diagnostics
   – Make accurate information about
     tests readily available
                                    Probe                                                      FDA
          Target   Assay                      Pre-      FDA
Disease                     HTS       to                        Ph. I      Ph. II   Ph. III    Re-    CER
            ID      Dev.                     Clinical   IND
                                    Lead                                                       view




                                              TRND                                                    HMORN
NIH Supported      NIH Molecular Libraries                              NIH Clinical Center,
Basic Research           Initiative           RAID
                                                                             CTSAs                    PCORI



                                                  New NIH-FDA Partnerships

                                                 Cures Acceleration Network
A Bold New Paradigm:
Cures Acceleration Network (CAN)
 Established by the Affordable Care Act
 CAN will
   – Advance the development of ―high need cures‖
   – Reduce barriers between research discovery and clinical trials in
     areas that the private sector is unlikely to pursue in an adequate
     or timely way
 Review Board advises NIH Director
   – 24 members, including representatives from academia,
     private industry, and patient advocacy groups
Cures Acceleration Network:
Funding Mechanisms
 Grant Awards:
   – Up to $15 million per award per fiscal year
 Partnership Awards:
   – $1 match for every $3 from NIH
   – Up to $15 million per award per fiscal
 Flexible Research Awards:
   – DARPA-like authority
   – Not to exceed 20% of total appropriated funds in any fiscal year
                   National Center for Advancing Translational Sciences




                                     Probe                                                      FDA
          Target    Assay                      Pre-      FDA
Disease                      HTS       to                        Ph. I      Ph. II   Ph. III    Re-    CER
            ID       Dev.                     Clinical   IND
                                     Lead                                                       view




                                               TRND                                                    HMORN
NIH Supported       NIH Molecular Libraries                              NIH Clinical Center,
Basic Research            Initiative           RAID
                                                                              CTSAs                    PCORI



                                                   New NIH-FDA Partnerships

                                                  Cures Acceleration Network
Molecular Libraries
Program


Therapeutics for Rare
and Neglected Diseases
                           National          Clinical &
                                                               National
                                             Translational
                          Center for         Science Awards     Center
Rapid Access to Inter-    Advancing                              for
ventional Development    Translational                        Research
                                             Other NCATS
                           Sciences          Programs?
                                                              Resources
Cures Acceleration
Network                    (NCATS)

FDA NIH Regulatory
Science


                                 Relevant
                                Institutes
                                & Centers
      National
     Center for
     Advancing
    Translational
      Sciences
      (NCATS)




  NIH       Relevant
Clinical   Institutes
Center     & Centers
                                   Academic
 FDA
                                  Researchers
                National
               Center for
               Advancing            Patient
Pharma
              Translational        Advocates
                Sciences
                (NCATS)
                                   Non-Profit
Biotech
                                  Organizations




            NIH       Relevant
          Clinical   Institutes
          Center     & Centers
Draft Mission Statement for
National Center for Advancing
Translational Sciences (NCATS)

To advance the discipline of translational science
and catalyze the development of novel diagnostics
and therapeutics across a wide range of human
diseases and conditions
Fundamental   Application of
Knowledge     Fundamental
              Knowledge
Comparative Effectiveness Research
at NIH

   Prevention
   Diagnosis
   Treatment
   Behavior change
   Health systems
   Special populations




    NIH 2009: research in 88/100 IOM CER priority areas
    NIH 2011: research in ~100/100 priority areas
Delivery: Diabetes Prevention
Program (DPP) Trial
 57 million Americans at high risk for developing type 2
  diabetes (pre-diabetes)
 DPP trial: NIH-funded study of 3,000+ high-risk adults
   – Metformin reduces risk by 31%
   – Modest lifestyle changes reduce risk by 58%
      • 5-7% lower body weight; exercise 30 minutes/5x per week
      • Recent follow-up: protective effects persist for at least a
        decade
DPP Trial: Taking Research Results to
The Public

 ―Small Steps, Big Rewards‖ – NIH campaign (with CDC;
  200+ private partners)

 ―DEPLOY‖ (Diabetes Education and Prevention with a
  Lifestyle Intervention Offered at the YMCA): NIDDK/NIH
Patient-Centered Outcomes Research
Institute (PCORI)
 Non-profit corporation to organize, fund CER
   – Board of Directors announced on September 23, 2010
   – Includes Directors of NIH, AHRQ
   – Standing methodology committee includes NIH, AHRQ
 Charged to identify
   – National research priorities
   – New clinical evidence; evidentiary gaps
   – Relevance; standards; economic correlates
Patient-Centered Outcomes Research
Institute (PCORI)
 Non-profit corporation to organize, fund CER
   – Board of Directors announced on September 23, 2010
   – Includes Directors of NIH, AHRQ
   – Standing methodology committee includes NIH, AHRQ
 Charged to identify
   – National research priorities
   – New clinical evidence; evidentiary gaps
   – Relevance; standards; economic correlates
                     600

                     500

                     400
                                                                               Estimated Funding
        $ Millions




                     300

                     200
                                                                                 Annual per-capita charges
                     100                                                         Appropriated funds
                       0
                            FY   FY   FY   FY   FY   FY   FY   FY   FY   FY
                           2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
HMO Research Network Collaboratory
      A New Opportunity to Advance the Science of
             Health Care Decision-making


A consortium of 16
 integrated health
 systems covering
more than 13 million
      people

 Increase accessibility of existing HMO research resources
 Scale up scientific, data, and operational infrastructure
 Accelerate large epidemiology studies, clinical trials, and health care
  services research
 Focus on risk factors, rare diseases, CER, patient accrual, and
  reimbursement models
                                               http://www.hmoresearchnetwork.org/about.htm
                  NIH Total Annual Budget in Current Dollars
                  vs. Value in 1998 Dollars
                  (FY 1998–FY 2011 Revised President's Budget Request/Alternative Levels)
                $40

                $35

                $30

                $25
(in billions)




                $20

                $15

                $10

                 $5

                 $0
                      1998


                             1999


                                    2000


                                            2001


                                                   2002


                                                          2003


                                                                  2004


                                                                          2005


                                                                                 2006


                                                                                         2007


                                                                                                  2008


                                                                                                         2009


                                                                                                                2010

                                                                                                                       2011 Full




                                                                                                                                   2008 Level
                                                                                                                       Year CR
                                                                                                                        (2010)

                                                                                                                                    2011 at
                              ARRA         ARRA in 1998 Dollars          Program Level          Value in 1998 Dollars
Opening a New Door for Unfunded
Research Projects
 Problem: <25% of NIH research grant applications
  funded in FY 2010
 Creative Solution: New database to match researchers
  with private funders; created by NHC with input from NIH
 Researchers can post abstracts of unfunded proposals
 Patient advocacy groups can upload their requests for
  applications
 Plans to expand to other funding sources, including
  private investors and corporations



                   www.healthresearchfunding.org
Cutting the deficit by gutting our investments in
innovation and education is like lightening an
overloaded airplane by removing its engine.
It may make you feel like you're flying high at
first, but it won't take long before you feel the
impact.
     — President Barack Obama, 2011 State of the Union
One Voice …
Tell us what you think…
www.nih.gov
      Turning discovery
NIH   into health

				
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