Charting Our Future Together: Building a Clinical Trials Enterprise for the 21 st Century Gary H. Gibbons, M.D. Director National Heart, Lung, and Blood Institute Cardiovascular Clinical Trialists Forum December 5, 2014
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
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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
020406080
100120140160180200
0 1 2 3 4 5 6 7 8 9 10 11Cita
tions
per
tria
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yea
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Years Since Completion
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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50
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Patie
nts
Ran
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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