Charting Our Future Together: Building a Clinical Trials Enterprise for the 21st Century

Gary H. Gibbons, M.D. Director

National Heart, Lung, and Blood Institute

Cardiovascular Clinical Trialists Forum December 5, 2014

A Dialogue with the NHLBI Circle of Partners: A Diverse Community Creating a Common-Wealth of Opportunity

Researchers

Professional Societies/

Foundations

Academic Health Centers

International Organizations Private

Sector

Policymakers & Gov’t

Agencies

Primary Care

Community Organizations

Patients Citizen-Science

A Diverse, Connected Community Collectively Creating the Clinical

Trials Enterprise for the 21st Century

NHLBI Mission - Discovery Science That Enhances Human Health: Enduring Principles for Sustained Success

Enduring Principles

§ Value investigator-initiated fundamental discovery science.

§ Maintain a balanced, cross-disciplinary portfolio (basic, translational, clinical, population science).

§ Train a diverse new generation of leaders in science.

§ Support implementation science that empowers patients and enables partners to improve the health of the nation.

§ Innovate an evidence-based elimination of health inequities in the US and around the world.

Today’s Investments Toward NHLBI-2025 Science Bringing Unprecedented Opportunities to Bear on Clinical Trials

§ Systems biology/medicine § Reparative biology/medicine § Health inequities (local & global) § Predictive health; Precision Medicine § Pre-emption of Chronic Disease

§ New tools and platforms § ‘Omics’ § Imaging § Informatics / computational biology / Big Data § Stem cells § Nanotechnology/bioengineering § Collaborative knowledge-exchange networks

T3 T2

Biomedical Model Biomedical and Socioecological

Model

Bench Research • Discovery Science

− Omics − Stem Cells

• Preclinical

Bedside • 1st Human Studies • Controlled

Observations • Phase I/II Trials

Patients • Phase III Trials • Guideline

Development

Practices • Phase IV Trials • Comparative

Effectiveness Research

Real World • Implementation

and Dissemination Science

T1 Discovery Science

Translation to Humans

Translation to Patients

Translation to Clinical Practices

Translation to Real World

Settings T4

The Discovery Pipeline to Next-Gen Clinical Trials: Leveraging Innovation for Public Health Impact

Mensah. Global Heart September 2013;8(3): 283-284. Based on and informed by the models of Khoury et al. Genet Med 2007;9:665-74, and the Harvard Catalyst; The Harvard Clinical and Translational Science Center, available at: http://catalyst.harvard.edu/pathfinder/. Accessed August 28, 2013.

iPSCs

Genomics

Inheriting a Legacy of Excellence & Stewardship: The Public Health Impact of NHLBI Investments

Adapted from: New York Times, January 4, 2014 Data: Centers for Disease Control and Prevention; National Vital Statistics System

Heart disease death rate for 1958: 56 per 10,000 people 2010 death rate: 18 per 10,000

Compared with 1958, this is a reduction of 38 deaths per 10,000

1958 ‘60 1970 1980 1990 2000 2010

2010 cancer death rate: 17 per 10,000

Compared with 1958, a reduction of 2

10 deaths per 10,000 people

20

30

40

50

2010 stroke death rate: 4 per 10,000

Compared with 1958, a reduction of 14

Heart Disease down 68%

Stroke down 79%

Cancer down 10%

(down 20% since 1990 peak)

18

19

Public Health Implementation

Science

Collaboration/Role of Industry

Clinical Research

Basic Research

Observational Studies

Building Upon a Legacy of Excellence: NHLBI Success Story – A Balanced Approach

Framingham Risk Factors

Intramural Research Program: Frederickson, Stadtmans

Clinical Research: Tangier’s Disease (HDL Cholesterol)

Brown and Goldstein: Nobel Prize (LDL Cholesterol) NHLBI Trial: Lowering Cholesterol Cuts CHD Risk

Roy Vagelos: Statins

Value of Lifestyle Interventions

The Iterative Challenge for Clinical Trials: Filling the Gaps in Evidence-based Patient Care

Lifestyle; Cholesterol; Overweight & Obesity; Risk Assessment

NHLBI Announcements on New Collaborative Model: June 19 & August 8, 2013

Joint AHA/ACC Guidelines Published in Circulation: Nov 12, 2013

Hypertension Systematic Evidence Review Published on NHLBI Website: August 2014

A Systems Science Approach to Clinical Efficacy Trials: Targeting the Molecular Mediators of HLBS Disorders

Barbabasi A. NEJM 2007;357:404-7

Infection

Exposome

Circulating Biomarkers

Imaging Pathophysiology

Tissue ‘Omic’ Analysis

Progenitor/Stem Cell ‘Omics’

Epigenomics

Genomics

From Bench-to-Bedside in Regenerative Medicine: Is the Time Ripe?

Patients with STEMI and primary PCI had no significant recovery in LV function following infusion of intracoronary bone marrow mononuclear cells.

JAMA. 2012;308(22):2380-2389

Defining Functional/Causal Genetic Variants: Predictive Biology and HLBS Precision Medicine

Disease Gene Clinical Application

Disease Mediator Gene Function

Disease Loci Discovery

Time à

Res

ourc

es à

2015 2020 2025

Courtesy of Chris O’Donnell and Cashell Jaquish

Raal F et al. Circulation 2012;126:2408-2417

Extending the Legacy in Genetics and Heart Disease: From Bench-to-Bedside-to-Patient Care Marketplace

From Population Science Discovery-to-Clinical Trial Testing: Mediator Role of Ezetimibe Target on LDL and CVD?

Carriers of inactive mutation of NPC1L1 had lower levels of LDL cholesterol and 53% reduced risk of coronary disease.

Today’s Discoveries for Tomorrow’s Breakthrough: Putting APOC3 to the Test

Carriers of APOC3 gene mutation had 40% lower risk of CHD, suggesting inhibition of APOC3 as a new potential strategy for therapeutic development.

N Engl J Med 2014; 371:22-31 and 371:2200-6

APOC3 levels reduced to 90% and TG levels to 86%. APOC3 potential key regulator of LPL-independent pathways of TG metabolism.

Cohort Datasets

Genomics

Proteomics/Metabolomics iPSCs

Big Data- Ontologies Computational Models

Cardiovascular Phen-Omics Atlas Systems Medicine

Data Commons

Biorepositories Imaging

Astute Clinicians Phenotyping

Cardiovascular ‘Phenomics’: Refining Patient Subsets & Clinical Risk for Targeted Interventions

NHLBI Precision Medicine Data Commons

• Clinical Phenotype • Genomics • Transcriptome • Proteome • Microbiome

Toward an NHLBI Precision Medicine Data Commons: Large-Scale Resources for Investigator-Initiated Clinical Science

Ext

ram

ural

Com

mun

ity/C

ounc

il/B

EE

/NIH

W

orki

ng G

roup

Investigator-Initiated R

01s

HLBS Predictive Biology and Computational Medicine

Sequencing Existing HLBS

Cohorts

Proteomic/ Sequencing

Centers

Data Coordinating

Centers

BD2K/ Bioinformatics

‘Bending the Curves’ of Racial Inequities in Health: What If? – Precisely, Predicted and Pre-empted CKD?

CDC, 1996

Genomic Admixture Analysis: African American

African ancestry

Shared African and European ancestry

European ancestry

Genomics

Rising Medicare Costs For CKD

Bustamonte PNAS 2009

Incident Chronic Kidney Failure By Race

Molecular Mediators of CVD Health Disparities: From Population Science Discovery-to-Clinical Trials?

Among African Americans in the NHLBI-funded cohorts, SCT was associated with increased risk of CKD, decline in eGFR, and albuminuria. SCT may be

associated with higher risk of CKD in African Americans.

JAMA. 2014;312(20):2115-2125

§ > 5-fold increased risk of ESKD § Hypertension, HIVAN, SCD § 12% of AA have 2 risk alleles (G1/G2)

APOL1 Risk Variant for Kidney Failure in African-Americans: Increased Risk of Chronic Kidney Disease and Hypertension

Association of Trypanolytic ApoL1 Variants with Kidney

Disease in African-Americans

G Genovese, DJ Friedman…JB Kopp, E Pays, MR Pollack

13 August 2010 Volume 329, Issue 5993

A T T A T C C T T T A A A A T A A A C T A G A A T 360 370 380

A

Start anti-hypertensive treatment at lower goal of 130/80 in at-risk APOL1/SCT carriers

Angiotensin Blockers in African-Americans with high-risk APOL1/SCT genotype

New drugs targeting mediators downstream of APOL1 /SCT to prevent kidney failure

Pharmacogenomics New therapies Risk prediction

The Promise of ‘Big Data’ for Clinical Trials: Innovation and Data-2-Knowledge in the Digital Age

‘Big Data’ to Networked Knowledge Exchanges: Catalyzing Clinical Trials with High Patient Care Impact

Diverse Cohort & Patient-powered Networks

Community Health Knowledge Networks

Systems Biology and Computer Modeling

Patient & Community Organization Networks

Health System Clinical Networks (AHCs; FQHCs; HMOs)

Biomedical Informatics

Cross-disciplinary Investigators

Nationwide Clinical & Community

Research Network

Enabling Citizen Science: What If – We Engaged/Empowered the Public in Knowledge Generation/Clinical Trials?

Ivacaftor associated with improvements in lung function, pulmonary exacerbations, and patient-reported symptoms.

Discovered in a collaboration between Vertex and Cystic Fibrosis Foundation which provided scientific, clinical & financial support.

Emerging Collaborative Models of Precision Medicine Clinical Trials: Lessons from NCI’s “Lung Map”

GA 98 Fetal

Monkey

20X

E14.5 Fetal

Mouse 20X

4232

Gen

es

(com

pend

ium

of

clus

ters

C1 Myo-fibroblast

C7 Growth / Housekeeping

C6 Cell Cycle

C5 Myeloid

C4 Epithelial

C3 Endothelial

C2 Matrix Fibroblast

Single Cell RNAseq E16.5 Mouse Lung

“Omic”-Driven Phenotypes and Drug Targets

What If? “Omics’ and Imaging Tools Provided Better Refinement of Patient Subsets for Targeted HLBS Interventions?

Right Drug

Right Dose

Right Time

Right Person

Promise of Precision Medicine

NHLBI -- An Adaptive, Nimble, Learning Organization: Strategic, Data-Guided Portfolio Management

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Dol

lars

(in

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ions

)

Fiscal Year

Appropriation in Current $ Appropriation in Constant 2012 $

§ IOM diagnostics

§ Long delays from research idea-to-protocol activation

§ Sub-optimal participant accrual and retention § Regulatory and Risk management challenges

§ NCI ‘bends the curve’ § Improve speed and efficiency of

development and conduct of trials § Incorporate innovative science and

trial design § Improve trial prioritization, selection,

support, and completion § Ensure participation of patients and

physicians in system

Enhancing Clinical Trials for the 21st Century: Adaptive Change Opportunities

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yea

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NHLBI Accountable Stewardship: Maximizing ROI in the Clinical Trial Portfolio

Clinical Trial Investment Portfolio – Operational Excellence: Squeezing More Clinical Science/$$ with Better Outcomes

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Months Since Start of Recruitment Target 75% of Target Red Zone Actual

§ How can we further maximize the scientific/clinical impact of our trials by increasing the efficiency-effectiveness-economy of NHLBI clinical trial management processes/systems?

Clinical Science Investment Portfolio: Achieving the Appropriate Balance and Maximizing Patient Benefit

What is the right balance? o R01s (Single Trials) vs. Clinical Trial Networks? o Large-scale Phase III vs. Small Phase II Trials? o Surrogate Endpoints vs. Clinical Events? o Pragmatic vs. Mechanistic trials? Are we maximizing the ROI? o Targeting the Most Compelling Science? o CTSA-Network HLBS Phenotype Registries? o Health System/AHC Embedded Cohorts ? o Direct-to-Patient Networks? o Promoting Cost-effective Trial Execution?

Creating a Clinical Trials Enterprise for the 21st Century: Some Key Building Blocks for Success

NIH Clinical Trials

Enterprise

Mission-relevant and Compelling

Science Feasible Timely

Appropriate Design &

Power

Efficient; Well Trained Workforce

Carefully Monitored; Effectively Managed

Independent Data & Safety

Oversight

Stakeholders

Council

Think Tanks

BEE Staff Working Groups

Think Tanks/WGs Crowdsourcing

Strategic Visioning Priority Setting & Portfolio

Gap Analysis

Investigators

Strategic Priority Setting

Data-guided Resource Allocation

Systematic Program Review

Funding Optimal Clinical Trials: Identifying the Most Compelling Questions:

Multi-Stakeholder Dialogue

Patients Industry

Goal 1

Aligning the NHLBI Mission and Strategic Visioning: The Framework – Mission-Based Strategic Goals

To expand knowledge g the normal function of HLBS systems.

To extend knowledge of the pathobiology of HLBS disorders and enable clinical investigations that advance disease prevention and treatment.

Basic Science

Goal 2

Clinical Science

To facilitate innovation and accelerate research translation, knowledge dissemination and implementation science that enhances public health.

Goal 3

Research Translation

To train and enable a diverse biomedical workforce with the skills and tools to pursue emerging scientific opportunities.

Goal 4

Research Training

CHARGE: Develop the guiding ‘Compelling Questions’ and ‘Critical Challenges’ that map and align with the NHLBI Strategic Goals.

Identifying Strategic Scientific Priorities and Compelling Questions for Clinical Trials

Accountable Stewardship: Inclusive Approach to Collectively Creating Our Future Together

Other NIH ICs

HHS Agencies (e.g., CDC, CMS)

Policymakers & Gov’t

Agencies

International Organizations Private

Sector

Investigators

Academic Health Centers

Professional Societies/

Foundations

Patients

Future State