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The Failing Clinical Trial Enterprise in the US: Efforts of CTTI to Improve our National and Global Evidence Generating Capability
Robert M Califf MDVice Chancellor for Clinical Research, Duke University
3
US Clinical trials in crisis
Trial start-up times lengtheningEnrollment slowingCosts increasingMany investigators pulling out of clinical research
5
Clinical Trial Cost Estimates
$0
$50
$100
$150
$200
$250
$300
$350
$400
$450
T o tal
Co o rd in atin g Cen ter
S ite Paym en ts
Oth er
Full Cost Industry
Streamlined Industry
More Streamlined
$ In US 2007 Millions
6
The Globalization of Clinical Investigators
80% 77%70%
62%57%
9% 10%
11%
13%14%
5%12% 13%
19%25% 29%
86%
9%
0%
25%
50%
75%
100%
1997 1999 2001 2003 2005 2007P
US-Based Western Europe Rest of WorldPercent of Total1572s Filed
Sources: Tufts CSDD
7
Which Treatment is Best for Whom?High-Quality Evidence is Scarce
7 Tricoci P et al. JAMA 2009;301:831-41Tricoci P et al. JAMA 2009;301:831-41
ACC/AHA Grading SchemaACC/AHA Grading SchemaClassification of Recommendations and Level of EvidenceClassification of Recommendations and Level of Evidence
Class of Recommendation: Class of Recommendation: value judgment by guidelines authorsvalue judgment by guidelines authors
Level of Evidence: Level of Evidence: objective description of existence/types of supporting studiesobjective description of existence/types of supporting studies
Level of Evidence ALevel of Evidence ACurrent Guidelines*Current Guidelines*
*Guidelines expressing *Guidelines expressing Level of EvidenceLevel of Evidence
*Guidelines expressing *Guidelines expressing Level of EvidenceLevel of Evidence
11.7%11.7%
26.4%26.4%
15.3%15.3%
13.5%13.5%
12.0%12.0%
22.9%22.9%
6.4%6.4%
6.1%6.1%
23.6%23.6%
0.3%0.3%
9.7%9.7%
11.0%11.0%
19.0%19.0%
4.9%4.9%
4.8%4.8%
0%0% 10%10% 20%20% 30%30%
AFAF
Heart failureHeart failure
PADPAD
STEMISTEMI
PerioperativePerioperative
Secondary preventionSecondary prevention
Stable anginaStable angina
SV arrhythmiasSV arrhythmias
UA/NSTEMIUA/NSTEMI
Valvular diseaseValvular disease
VA/SCDVA/SCD
PCIPCI
CABGCABG
PacemakerPacemaker
Radionuclide imagingRadionuclide imaging
Level of Evidence CLevel of Evidence CCurrent Guidelines*Current Guidelines*
*Guidelines expressing *Guidelines expressing Level of EvidenceLevel of Evidence
*Guidelines expressing *Guidelines expressing Level of EvidenceLevel of Evidence
58.6%58.6%
54.3%54.3%
25.1%25.1%
47.2%47.2%
32.0%32.0%
8.3%8.3%
54.5%54.5%
56.5%56.5%
29.6%29.6%
70.6%70.6%
58.5%58.5%
47.8%47.8%
20.0%20.0%
58.2%58.2%
26.3%26.3%
0%0% 20%20% 40%40% 60%60% 80%80%
AFAF
Heart failureHeart failure
PADPAD
STEMISTEMI
PerioperativePerioperative
Secondary preventionSecondary prevention
Stable anginaStable angina
SV arrhythmiasSV arrhythmias
UA/NSTEMIUA/NSTEMI
Valvular diseaseValvular disease
VA/SCDVA/SCD
PCIPCI
CABGCABG
PacemakerPacemaker
Radionuclide imagingRadionuclide imaging
11
It’s a “Systems Problem”
All members of the clinical research enterprise have played a part in this problem
Fixing it will require a collaborative effortFDA/global regulatorsIndustryAcademia/NIHInvestigators in clinical practiceConsumers
12
A collaborative effort to find solutions
U.S. FDA’s Office of Critical Path Programs established a public-private partnership:
The Clinical Trials Transformation Initiative (CTTI)
All stakeholders involved
Through a memorandum of understanding with FDA, Duke University serves as the host of CTTI
13
Executive Committee
Co-Chairs: Rob Califf(Duke) and Rachel Behrman(FDA)
Academia: David DeMets
At-large representative: Ken Getz
FDA: Bob Temple, CDER and Bram Zuckerman, CDRH
Industry: Glenn Gormley, Jay Siegel, Susan Alpert, Alberto Grignolo
Patient representative: Nancy Roach
NIH liaison: Amy Patterson
Non-US regulatory liaison: Hans-Georg Eichler, EMEA
Ex-Officio Members: James Ferguson and Briggs Morrison, Steering Committee Co-chairs; Judith Kramer, Executive Director
14
Steering Committee Representation
Category # organizations
Academic institutions 9
Pharmaceutical companies 8
Clinical research organizations 7
Professional societies 6
Government 6 (FDA [OC,CDER, CBER, CDRH] AHRQ, CMS, NIH, OHRP, VA)
Device companies 5
Biotechnology companies 3
Clinical investigator groups 3
Trade organizations 3
Patient representatives/at-large 3
Private equity firm 1
Regulatory law firm 1
*Began recruiting members May 2008
15
Mission
To identify practices that through broad adoption will increase the quality and efficiency of clinical trials
16
Scope
CTTI will generate evidence about how to improve the design and execution of clinical trials
CTTI will foster widespread change based on evidence
CTTI was created to address a crisis for US clinical research, however…
Trials and issues are globalCTTI seeks to identify practice improvements that can be applied internationallyCTTI is engaging international collaborators
17
Strategy to Accomplish our Mission
Aggressively pursue development of evidenceConduct “research on research”Pursue collaborative activities with other organizations sharing similar goals
Parallel activities:Systematically analyze the clinical trials process and potential impact of our activitiesMaintain awareness of other effortsPromote adoption of CTTI recommendations
18
Initial Priority Areas* for Research on Research
Design principles
Data quality and quantity (including monitoring)
Study start-up
Adverse event reporting
*Defined by CTTI’s Executive Committee
19
Status of CTTI Projects
2 Ongoing Projects (with 7 workstreams)
Effective and efficient monitoring as a component of quality assurance in the conduct of clinical trials
Improving the system of reporting and interpreting unexpected serious adverse events (SAEs) to investigators conducting research under an IND
2 Project plans in development
Executive and Steering Committees held a brainstorming session in September
3 Collaborations established
20
Effective and Efficient Monitoring Project
Goal Identify best practices and provide sensible criteria
to help sponsors select the most appropriate monitoring methods for a trial, thereby improving quality while optimizing resources
Specific objectives1. Describe the range of current monitoring practices
and examine factors that drive their adoption
2. Define key quality objectives for clinical trials
3. Illustrate strengths and weaknesses of the various monitoring practices in meeting quality objectives for a range of clinical trial settings
21
Effective and Efficient Monitoring Project Organization
Effective andEfficient Monitoring…
Rachel Behrman, MD, MPH
FDACo-Team Leaderand WS 2 Leader
Martin Landray, PhD, MRCP
University of OxfordCo-Team Leaderand WS 3 Leader
Briggs Morrison, MD Pfizer Inc.
Co-Team Leader and WS 1 Leader
David NickersonProject Manager
Pfizer Inc.
Melissa RobbSenior Program Mgr.
FDA
Workstream 1 Team
Workstream 3 Team
Workstream 2 Team
Project Mgmt
22
Improving SAE Reporting to IND Investigators
Goal: To generate empirical evidence about the current
US system for reporting SAEs to investigators under an IND
Consider potential modifications of the current system to more efficiently and effectively inform investigators of these events
23
Improving SAE Reporting to IND Investigators
Subprojects1.Document current range of sponsor practices for:
a. Reporting unexpected SAEs to investigators; b. Oversight of product safety (eg DSMBs, safety
committees)2. a. Quantify investigators’ time spent receiving,
interpreting, and communicating individual expedited reports
b. Assess perceived value to investigators of individual expedited reports in updating product’s risk profile
3. Compare current practice of submitting individual SAEs with an alternative approach based on European Commission’s guidance
4. Convene an expert group to integrate results and recommend ways to optimize reporting of SAEs to investigators and assure subject protection
24
Collaborations
Use of clinical trials in evaluation of comparative effectiveness
Collaboration between the Center for Medical Technology Policy (CMTP), Pragmatic Approaches to Comparative Effectiveness (PACE), and CTTIExpert meeting held May 6, 2009—directed to policy-makers
— New approaches to clinical trials will make them more attractive for comparative effectiveness research
— Manuscript proposing increased operational efficiency, analytical efficiency, and generalizability of clinical trials published in Aug. 4th issue Annals of Internal Medicine
25
Collaborations (continued)
FDA-initiated training course directed to clinical investigators
Collaborative effort to standardize definitions and data collection methods/case report forms for cardiovascular trials
FDA-initiated effort involving academics, industry, CDISC, and HL7
26
How do we effect widespread change?
Problems with clinical trials widely recognized
Need to go beyond elucidation of problems to effect change
Current behavior often driven by incentives and fears not consistent with the goal of increased efficiency Decision makers at different levels have variable understanding of the “big picture”
— Organizations engage in activities that may not add value
— Trade off of cost vs. value not explicitWide spread perception that clinical trials just take that long and cost that much!
27
How do we effect widespread change?
CTTI’s Approach
Involve all sectors in selection, conduct, and interpretation of projects
Explore the business case for change from different perspectives
Keep dialogue open across sectors
Provide evidence that can influence regulatory guidance
Attempt to create a “level playing field” when recommending change (i.e. don’t place a single organization or sector at risk)
28
For more information….
CTTI Website-Homewww.trialstransformation.org
Projectswww.trialstransformation.org/projects
Member organizationswww.trialstransformation.org/members/member-organizations/
How to joinwww.trialstransformation.org/join
Clinical Trials 2008; 5: 38-39 Sensible Guidelines Conference January 25-26, 2007
Sensible guidelines for the conduct of large randomized trials
Large trials are importantLarge trials are important
Complexity and cost Complexity and cost increasingincreasing
GCP ≠ good, or clinically GCP ≠ good, or clinically relevant, or even relevant, or even practicalpractical
Excess data, number of Excess data, number of visits, onsite monitoringvisits, onsite monitoring
Layers of ethics Layers of ethics approvalsapprovals
“For a scientific method that is at the heart of evidence-based medicine, no good evidence that the layers of complexity, approvals, processes, and laws to protect subjects have actually achieved their purpose.
What is clear is that such processes are extremely expensive and delay studies.
Goal: stimulate reform and simplification of clinical trials procedures, while enhancing patient safety and autonomy, improving the scientific validity and integrity of trials and making them more affordable.”
Clinical and Translational Science Award (CTSA)
At peak a $500 million investment by the NIH in translating scientific
discoveries to better human health
Disruptive innovation is needed to create a very Disruptive innovation is needed to create a very different system based on electronic data different system based on electronic data collection in practice with quality built in through collection in practice with quality built in through a systematic approach.a systematic approach.
The Cycle of Quality: Generating Evidence to The Cycle of Quality: Generating Evidence to Inform PolicyInform Policy
Califf RM et al, Califf RM et al, Health Affairs, 2007Health Affairs, 2007
Measurement Measurement andand
EducationEducation
Measurement Measurement andand
EducationEducation
Early Translational
Steps
Early Translational
Steps
ClinicalTrials
ClinicalTrials
ClinicalPractice
Guidelines
ClinicalPractice
Guidelines
PerformanceMeasures
PerformanceMeasures
OutcomesOutcomes
Discovery ScienceDiscovery Science
DataDataStandardsStandards
DataDataStandardsStandards
NetworkNetworkInformationInformation
NetworkNetworkInformationInformation
EmpiricalEmpiricalEthicsEthics
EmpiricalEmpiricalEthicsEthics
PrioritiesPrioritiesand Processesand Processes
PrioritiesPrioritiesand Processesand Processes
InclusivenessInclusivenessInclusivenessInclusiveness
Use forUse forFeedbackFeedback
on Prioritieson Priorities
Use forUse forFeedbackFeedback
on Prioritieson Priorities
Conflict-of-interestConflict-of-interestManagementManagement
Conflict-of-interestConflict-of-interestManagementManagement
Evaluation of SpeedEvaluation of Speedand Fluencyand Fluency
Evaluation of SpeedEvaluation of Speedand Fluencyand Fluency
Pay forPay forPerformancePerformance
Pay forPay forPerformancePerformance
TransparencyTransparencyto Consumersto ConsumersTransparencyTransparencyto Consumersto Consumers
FDAFDACritical PathCritical Path
FDAFDACritical PathCritical Path
NIH RoadmapNIH RoadmapNIH RoadmapNIH Roadmap12 3
4
5
6
7
8
910
11
12
The Learning Health SystemThe Learning Health System
Articulated goal of the Institute of MedicineArticulated goal of the Institute of Medicine
By implementing electronic health records, By implementing electronic health records, data warehouses and disease registries, every data warehouses and disease registries, every patient’s data will be used to further knowledgepatient’s data will be used to further knowledge
This means that all places of practice will This means that all places of practice will become research sitesbecome research sites
Research must become a normal part of clinical Research must become a normal part of clinical practice, not something done separately from practice, not something done separately from clinical practice (except for very special early clinical practice (except for very special early phase and highly controlled types of studies)phase and highly controlled types of studies)
% of Randomized Discontinued in A
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
Disc. May 06Disc. September 06
Protocol Adherence and Adverse EventsProtocol Adherence and Adverse Events
Non-Non-AdherenceAdherence
Withdrawal:Withdrawal:AE’sAE’s
Withdrawal: Withdrawal: Subject Subject preferencepreference
Withdrew Withdrew ConsentConsent
UKUK 39.7%39.7% 12%12% 17%17% 5555
USUS 35.5%35.5% 7%7% 16%16% 166166
Poland Poland 14.8%14.8% 2%2% 9%9% 22
ChinaChina 6.1%6.1% 5%5% 5%5% 11
ArgentinaArgentina 13.6%13.6% 2%2% 8%8% 11
The Demise of EmpiresThe Demise of Empires
Dominance at a point in timeDominance at a point in time
Arrogance about superiorityArrogance about superiority
Failure to pay attention to quality of workFailure to pay attention to quality of work
Leaders content to “ride the wave”Leaders content to “ride the wave”
Entrenched interests can buy stability through Entrenched interests can buy stability through controlling laws and regulationscontrolling laws and regulations
Inability to create or respond to innovationInability to create or respond to innovation
Cost of transactions exceeds cost of Cost of transactions exceeds cost of actually doing the work!actually doing the work!
Disruptive Innovation in Clinical TrialsDisruptive Innovation in Clinical Trials Electronic health recordsElectronic health records
Data warehouses in integrated health systemsData warehouses in integrated health systems
Learning health systemsLearning health systems
Use same information for clinical care and Use same information for clinical care and research research
Electronic permissions systems for Electronic permissions systems for participation in researchparticipation in research
Evaluation of RESEARCH SITES on a periodic Evaluation of RESEARCH SITES on a periodic basis with constant electronic surveillance and basis with constant electronic surveillance and periodic audits for causeperiodic audits for cause