NCA TS Advisory Council and CAN Review Board CHRISTOPHER P . - - PowerPoint PPT Presentation

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Director’s Report

NCA TS Advisory Council and CAN Review Board

CHRISTOPHER P . AUSTIN, M.D. DIRECTOR, NCATS JUNE 13, 2016

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Selected Translational Innovation Highlights

• Early-st age t ranslat ion: chemical probe/ lead

development for target validation and therapeutic hypothesis testing

• Mid-st age t ranslat ion: preclinical

development to first-in-human studies

• Lat e-st age t ranslat ion: large-scale studies in

humans

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Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant Depression

Hamilton Depression Rating Scale (HAM-D)

5 10 15 20 25 30 Placebo Ketamine

• 60

80 230 110 40 Day 1 Day 3 Day 2 Day 7

* ** ** *** *** ***

Drop in Depression Rating following a Single Ketamine Infusion (N=18)

• Rapid Effect in Major

Depressive Disorder

• Rapid Decreases in

Suicidal Ideation

• Rapid Effect in

Treatment Resistant Bipolar (BP) Depression

Zarate et al. Arch Gen Psychiatry 2006

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DPI

Ketamine Metabolites for Depression

• Collaborators
• University of Maryland S

chool of Medicine

• National Institute of Mental Health and National Institute on Aging
• Background
• S

evere depression affects ~16%

• f the world population
• Current therapies require prolonged administration for clinical

improvement and some patients are non-responsive

• Proj ect
• Non-competitive, glutamatergic NMDAR antagonist (R,S

)-ketamine exerts quick and prolonged antidepressant effects after a single dose, but also has side effects.

• S

howed that ketamine metabolite ((2R,6R)-HNK) reversed depression-like behaviors in mice without triggering anesthetic, dissociative, or addictive side effects

• Data illustrate novel mechanism and have potential for the

development of next-generation antidepressants

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5

Extensive metabolism of ketamine

(R,S)

• norketamine

O H2N Cl O H2N Cl OH O H2N Cl O H2N Cl OH OH O H2N ClOH O H2N ClOH O H2N Cl O MeHN Cl O MeHN Cl OH O MeHN Cl OH O H2N Cl OH

(R,S)

• ketamine

(R,S)

• DHNK

(2R,6S)

• HNK

(2R,6S)

• HK

(2R,6R)

• HK

(2R,6R)

• HNK

(2R,5R)

• HNK

(2R,5S)

• HNK

(2R,4S)

• HNK

(2R,4R)

• HNK

O MeHN Cl

(R)

• ketamine

(S)

• ketamine

O H2N Cl

(R)

• norketamine

(S)

• norketamine

O H2N Cl

(R)

• DHNK

(S)

• DHNK

O H2N Cl OH O H2N Cl O H2N Cl OH OH O H2N ClOH O H2N ClOH O MeHN Cl OH O MeHN Cl OH O H2N Cl OH

(2S,6R)

• HNK

(2S,6R)

• HK

(2S,6S)

• HK

(2S,6S)

• HNK

(2S,5S)

• HNK

(2S,5R)

• HNK

(2S,4R)

• HNK

(2S,4S)

• HNK

R)

• ketamine derived HNKs and HKs

S)

• ketamine derived HNKs and HKs

( (

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Selected Translational Innovation Highlights

• Early-st age t ranslat ion: chemical probe/ lead

development for target validation and therapeutic hypothesis testing

• Mid-st age t ranslat ion: preclinical

development to first-in-human studies

• Lat e-st age t ranslat ion: large-scale studies in

humans

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North America Mitochondrial Diseases Consortium Consortium of Eosinophilic Gastrointestinal Disease Researchers Rare Lung Diseases Consortium NIH ORDR/NCATS, NCI, NHLBI, NIAID, NIAMS, NICHD, NIDCR, NIDDK, NIMH, NINDS, ODS The Data Management and Coordinating Center Dystonia Coalition Brain Vascular Malformation Consortium Nephrotic Syndrome Study Network Porphyria Rare Disease Clinical Research Consortium The Frontotemporal Lobar Degeneration Clinical Research Consortium Primary Immune Deficiency Treatment Consortium Lysosomal Disease Network Autonomic Disorders Consortium Inherited Neuropathies Consortium Rare Kidney Stone Consortium Urea Cycle Disorders Consortium Vasculitis Clinical Research Consortium Chronic Graft Versus Host Disease Rett, MECP2 Duplications and Rett-Related Disorders Consortium Clinical Research in ALS & Related Disorders for Therapeutic Development Sterol and Isoprenoid Diseases Consortium Developmental Synaptopathies Associated with TSC, PTEN And SHANK3 Mutations Brittle Bone Disorders Consortium Genetic Disorders of Mucociliary Clearance

• Collaborative Clinical

Research

• Centralized Data

Coordination and Technology Development

• Public Resources and

Education

• Training

PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG PAG

Coalition of Patient Advocacy Groups (CPAG for RDCRN)

PAG PAG PAG PAG PAG PAG

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Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that primarily affects women of childbearing age that is often fatal

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RDCRN-Rare Lung Diseases Consortium (RLDC)

Development of sirolimus for LAM

• S

irolimus (aka rapamycin, Rapamune) is an mTOR inhibitor

• riginally approved for prevention of transplant rej ection
• LAM is associated with inappropriate activation of mTOR

signaling, which regulates cellular growth and lymphangiogenesis

• RLDC conducted Multicenter International LAM Efficacy and

S afety of S irolimus (MILES ) trial

• PI: Frank McCormack, University of Cincinnati
• Collaborative effort among RDCRN-RLDC, Pfizer, LAM Foundation
• FDA approved sirolimus for LAM in March 2015
• First drug approved by FDA for the treatment of this rare disease

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New Therapeutic Uses Program

• First round of proj ects

Disease Academic Partner Pharma Partner Alzheimer’s Disease Yale AstraZeneca Alcoholism U Rhode Island/NIAAA Pfizer Calcific Aortic Stenosis Mayo Clinic Sanofi Duchenne Muscular Dystrophy Kennedy Krieger/UWash Sanofi Lymphangioleiomyomatosis Baylor AstraZeneca Peripheral Artery Disease U Virginia AstraZeneca Smoking Cessation VCU/Pittsburgh Janssen Schizophrenia (2) Indiana U Lilly Yale Pfizer

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• Translational Innovation S

uccess Measures

• Does use of template agreements speed negotiation time?
• Does crowdsourcing of indications generate new ideas?
• Do studies result in new indications/ approvals?

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NTU project: AZD0530 (saracatinib) for LAM

• S

rc family kinase inhibitor originally developed for cancer

• Also being t est ed in NTU for Alzheimer’s Disease
• S

rc is activated in LAM cells

• Cont ribut es t o oncogenic propert ies of LAM cells
• NTU LAM Phase 2a trial ongoing
• PI: Tony Eissa (Baylor)
• Frank McCormack (Universit y of Cincinnat i)
• S

t ephen Rouss (S t anford Universit y)

• Daniel Dilling (Loyola Universit y, Chicago)
• Elizabet h Henske & S
• uheil El-Chemaly (Brigham and

Women’s Hospit al)

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Selected Translational Innovation Highlights

• Early-st age t ranslat ion: chemical probe/ lead

development for target validation and therapeutic hypothesis testing

• Mid-st age t ranslat ion: preclinical

development to first-in-human studies

• Lat e-st age t ranslat ion: large-scale studies in

humans

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The NCATS Clinical and Translational Science Awards Program CTSA Hubs

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Clinical Trials

Opportunity for Operational Innovation

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Califf RM et al. JAMA 2012; Hirsch BR et al. JAMA Intern Med 2013; Goswami ND et al. PLOS One 2013; Alexander KP et al. JAHA 2013;Todd JL et al. Annals ATS 2013; Inrig JK et al. Am J Kidney Dis 2014

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Clinical Trials

Opportunity for Operational Innovation

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Califf RM et al. JAMA 2012; Hirsch BR et al. JAMA Intern Med 2013; Goswami ND et al. PLOS One 2013; Alexander KP et al. JAHA 2013;Todd JL et al. Annals ATS 2013; Inrig JK et al. Am J Kidney Dis 2014

Current Work Models

Small, frequently single-center studies Inconsistent power, rigor Poor enrollment Suboptimal scientific impact

Operational Challenges

Research:Clinical parallel universes Fragmented, duplicative infrastructure Lack of collaborative efforts Misaligned incentives

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Clinical Trials

Opportunity for Operational Innovation

Current Work Models

Small, frequently single-center studies Inconsistent power, rigor Poor enrollment Suboptimal scientific impact

Operational Challenges

Research:Clinical parallel universes Fragmented, duplicative infrastructure Lack of collaborative efforts Misaligned incentives

Opportunity for Operational Innovation

Invent and deploy new approaches to clinical studies

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Califf RM et al. JAMA 2012; Hirsch BR et al. JAMA Intern Med 2013; Goswami ND et al. PLOS One 2013; Alexander KP et al. JAHA 2013;Todd JL et al. Annals ATS 2013; Inrig JK et al. Am J Kidney Dis 2014

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NIH Clinical Trials

Opportunity for Operational Excellence

NIH Budget – FY 2015 $3.2 B $27.1 B

Clinical Trials ~10%

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NIH Budget Office; Mullard A. Nature Reviews Drug Disc 2016; GAO Report, 2016; Innovation for Healthier Americans, 2015

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NIH Clinical Trials

Opportunity for Operational Excellence

NIH Budget – FY 2015 $3.2 B $27.1 B

Clinical Trials ~10%

Results of Current Work Models

Trials not finishing on time or within budget Frequently large unobligated balances Suboptimal return on research investments Decreased public trust

Operational Challenge

Enhance stewardship and accountability of NIH clinical trials

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NIH Budget Office; Mullard A. Nature Reviews Drug Disc 2016; GAO Report, 2016; Innovation for Healthier Americans, 2015

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NIH Clinical Trials

Opportunity for Operational Excellence

NIH Budget – FY 2015 $3.2 B $27.1 B

Clinical Trials ~10%

Results of Current Work Models

Trials not finishing on time or within budget Frequently large unobligated balances Suboptimal return on research investments Decreased public trust

Operational Challenge

Enhance stewardship and accountability of NIH clinical trials

Opportunity for Operational Excellence

Execute trials better, faster, & more cost-effectively

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NIH Budget Office; Mullard A. Nature Reviews Drug Disc 2016; GAO Report, 2016; Innovation for Healthier Americans, 2015

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Imagine … A Clinical Trials Superhighway

A Network that Accelerates the Translation of Novel Interventions to Evidence Based Treatments

• Single IRB Reliance Model
• Master Contracts
• Harmonized Data

Collection

• Streamlined Protocols
• Poised Research Teams
• Patient Engagement

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NCATS Trial Innovation Network

Mission

• Leverage the unmatched talent, expertise, and

resources of the CTS A Program to transform clinical trials

• Collaborat ive nat ional net work
• Accelerat e planning & implement at ion of high qualit y

mult i-cent er t rials & st udies

• Provide more t reat ment s t o more pat ient s
• Improve public healt h
• Create a national laboratory to study, understand,

and improve multi-center clinical trials

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NCATS Trial Innovation Network

What Is It?

CTSA Hubs

Network Center

Trial Innovation Centers (TICs) Recruitment Innovation Centers (RICs)

Collaborative Strategic Management

NCATS & Network Exec.

• Comm. & CTSA

Partners

NIH ICs Federal Non-federal

Partners Patients

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NCATS Trial Innovation Network

How Will It Work?

Partnership

CTSA Hubs NCATS TICS RICS

Trial Innovation Network

Early Protocols Robust Clinical Trials

Scientific Questions

• NIH Institutes
• Industry
• Other Partners

Operational Excellence

• Doing Trials Better,

Faster, & More Cost- Efficiently

Results

• New Science
• Studies that Finish on

Time & within Budget

• Generate Evidence to

Change Clinical Practice

Operational Questions

• NCATS

Operational Innovation

• Testing New Approaches to

Clinical Trials

• Recruitment, Contracts, IRB, Other

Results

• New Operational

Approaches

• Generate Evidence to

Change Research Practice

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NCATS Trial Innovation Network

Built on Operational Innovations from the CTSA Program

Master Contracts SMART IRB Reliance Platform Standards for Competencies & Training in Clinical Trials EHR Based Recruitment

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NCATS Trial Innovation Network

Value Proposition

• For Investigators
• One-st op shopping t o implement clinical t rials
• TICS

& RICS – expert ise in operat ional innovat ion &

• perat ional excellence
• CTS

A Hubs – broad expert ise; large, diverse pat ient populat ions

• More compet it ive clinical t rials applicat ions t o NIH ICs,

indust ry

• For NIH Institutes and Industry Partners
• Trials complet ed on t ime and wit hin budget
• S

hared NIH mission t o innovat e & t ransform clinical t rials & opt imize st ewardship

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NCATS Trial Innovation Network:

Implementation Timeline

Collaborative Strategic Planning & Management

May NCATS Council June Awards Released First 6 Months Develop Network Strategic Plan Launch Demonstration studies Year 1 Demonstrate & disseminate key elements of “superhighway” Year 2 Launch large scale clinical trials

Operationalize SMART IRB Model, Master Contracts, Workflows, Other Strategic Priorities in Demonstration Studies

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CAN Update

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FY2016 Budget

• November 2, 2015: President signed Bipart isan Budget Act of

2015 (P .L. 114-74)

• Raises S

equester caps for FY16 and FY17

• Cont inuing Resolut ions: t hru Dec. 11, Dec. 16, and Dec. 22
• December 18, 2015: President signed Consolidat ed

Appropriat ions Act , 2016 (P .L. 114-113)

• NIH: $32 B ($2 B increase over FY 15)
• NCATS

: $685.4 M ($52.7 M increase over FY 15)

• CTS

A: $500 M

• Includes $22.7M increase to implement IOM recommendations,

such as building network capacity (i.e. TICs, RICs, CCIAs)

• CAN: $25.8 M ($16M increase over FY 15)

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New CAN Program:

Biomedical Data Translator Program

• New signature initiative, utilizing OTA
• Informatics platform enabling interrogation of

relationships across full spectrum of data types:

• Disease names
• Clinical signs & symptoms
• Organ and cell pathology
• Genomics
• Drug effects
• …

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• First stage: Team-based proposals to address architecture

needs to build Translator and assess technical feasibility

• Timeline
• Call for proj ects posted: April 29
• Proposals received: June 1
• In person presentations: June 29-30
• Negotiations begin: July
• Awards announced: S

eptember

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Policy and Legislative Updates

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FY 2017 Budget

• February 9, 2016: President releases FY 2017 budget
• NCATS

’ request is $685.417 million (same as FY16)

• Congressional Hearings
• House: March 16, 2016
• Witnesses: Drs. Collins, Fauci (NIAID), Hodes (NIA), Lowy (NCI),

Volkow (NIDA)

• S

enat e: April 7, 2016

• Witnesses: Drs. Collins, Austin, Hodes (NIA), Koroshetz (NINDS

), Lowy (NCI), and Volkow (NIDA)

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Congressional Visit to NIH

• April 12, 2016 – Five Representatives visited NIH to

learn more about NIH’s mission and programs

• David Valadao (R-CA)
• S

usan Brooks (R-IN)

• Robert Dold (R-IL)
• Kat herine Clark (D-MA)
• Joseph Kennedy (D-MA)
• Met with Drs. Collins, Austin, Gibbons (NHLBI), and

Volkow (NIDA)

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• Organized by NCATS

and CC

• Featured speakers included
• Rare Disease Congressional Caucus – 4 co-chairs
• S

enator Orrin Hatch (R-UT) – via video

• S

enator Amy Klobuchar (D-MN)

• Rep. Leonard Lance (R-NJ)
• Rep. Joseph Crowley (D-NY)
• S

haron Terry, President & CEO, Genetic Alliance

• Mike Porath, Founder & CEO, The Mighty
• Martha Rinker, Vice President of Public Policy, National Organization of Rare

Disorders (NORD)

• Reached >900 people
• View the videocast at http:/ / 1.usa.gov/ 1Q8Exi9

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NCATS Strategic Plan

Updated Timeline

https:/ / ncats.nih.gov/ strategicplan

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NCATS Office of Policy, Communications and Strategic Alliances

Proposed Changes

• Remove the Office of S

trategic Alliances from the Policy and Communications Office

• Bet t er reflect ion of NCATS

alignment and priorit ies

• Establish an Education Office
• Ensure NCATS

remains a leader in public educat ion and communit y involvement relat ed t o t ranslat ional science

• Both changes are budget neutral and will utilize

existing resources within the Center

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Existing OPCSA Structure

Office of the Director Executive Office Office of Grants Management and Scientific Review Division of Pre- Clinical Innovation Division of Clinical Innovation Office of Rare Disease Research Office of Policy, Communications, and Strategic Alliances Office of Science Policy Office of Communications Office of Strategic Alliances

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Proposed New Structure

Office of the Director Executive Office Office of Grants Management and Scientific Review Division of Pre- Clinical Innovation Division of Clinical Innovation Office of Rare Disease Research Office of Policy, Communications, and Strategic Alliances Science Policy Branch Communications Branch Education Branch Office of Strategic Alliances

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Questions or Comments

• Please email NCATS

ReOrgComments@ mail.nih.gov by Thursday, June 30

• Include your name, and when applicable, your

professional affiliat ion

• NCATS

will respond to your email by Friday, July 15

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Discussion

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