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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 MD Vice Chancellor for Clinical Research, Duke University. The Official Talk. US Clinical trials in crisis. Trial start-up times lengthening

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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 MD

Vice Chancellor for Clinical Research, Duke University


The official talk
The Official Talk CTTI to Improve our National and Global Evidence Generating Capability


Us clinical trials in crisis
US Clinical trials in crisis CTTI to Improve our National and Global Evidence Generating Capability

Trial start-up times lengthening

Enrollment slowing

Costs increasing

Many investigators pulling out of clinical research


Clinical trial cost estimates
Clinical Trial Cost Estimates CTTI to Improve our National and Global Evidence Generating Capability

$ In US 2007 Millions

Full Cost Industry

Streamlined Industry

More Streamlined


The globalization of clinical investigators
The Globalization of Clinical Investigators CTTI to Improve our National and Global Evidence Generating Capability

Percent of Total

1572s Filed

Sources: Tufts CSDD


Which treatment is best for whom high quality evidence is scarce
Which Treatment is Best for Whom? CTTI to Improve our National and Global Evidence Generating CapabilityHigh-Quality Evidence is Scarce

Tricoci P et al. JAMA 2009;301:831-41

7


Acc aha grading schema classification of recommendations and level of evidence
ACC/AHA Grading Schema CTTI to Improve our National and Global Evidence Generating CapabilityClassification of Recommendations and Level of Evidence

  • Class of Recommendation: value judgment by guidelines authors

  • Level of Evidence: objective description of existence/types of supporting studies


Level of evidence a current guidelines

AF CTTI to Improve our National and Global Evidence Generating Capability

Heart failure

PAD

STEMI

Perioperative

Secondary prevention

Stable angina

SV arrhythmias

UA/NSTEMI

Valvular disease

VA/SCD

PCI

CABG

Pacemaker

Radionuclide imaging

*Guidelines expressing Level of Evidence

Level of Evidence ACurrent Guidelines*

11.7%

26.4%

15.3%

13.5%

12.0%

22.9%

6.4%

6.1%

23.6%

0.3%

9.7%

11.0%

19.0%

4.9%

4.8%

0%

10%

20%

30%


Level of evidence c current guidelines

AF CTTI to Improve our National and Global Evidence Generating Capability

Heart failure

PAD

STEMI

Perioperative

Secondary prevention

Stable angina

SV arrhythmias

UA/NSTEMI

Valvular disease

VA/SCD

PCI

CABG

Pacemaker

Radionuclide imaging

*Guidelines expressing Level of Evidence

Level of Evidence CCurrent Guidelines*

58.6%

54.3%

25.1%

47.2%

32.0%

8.3%

54.5%

56.5%

29.6%

70.6%

58.5%

47.8%

20.0%

58.2%

26.3%

0%

20%

40%

60%

80%


It s a systems problem
It’s a “Systems Problem” CTTI to Improve our National and Global Evidence Generating Capability

All members of the clinical research enterprise have played a part in this problem

Fixing it will require a collaborative effort

FDA/global regulators

Industry

Academia/NIH

Investigators in clinical practice

Consumers


A collaborative effort to find solutions
A collaborative effort to find solutions CTTI to Improve our National and Global Evidence Generating Capability

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


Executive committee
Executive Committee CTTI to Improve our National and Global Evidence Generating Capability

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


Steering committee representation
Steering Committee Representation CTTI to Improve our National and Global Evidence Generating Capability

*Began recruiting members May 2008


Mission
Mission CTTI to Improve our National and Global Evidence Generating Capability

To identify practices that through broad adoption will increase the quality and efficiency of clinical trials


Scope
Scope CTTI to Improve our National and Global Evidence Generating Capability

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 global

CTTI seeks to identify practice improvements that can be applied internationally

CTTI is engaging international collaborators


Strategy to accomplish our mission
Strategy to Accomplish our Mission CTTI to Improve our National and Global Evidence Generating Capability

Aggressively pursue development of evidence

Conduct “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 activities

Maintain awareness of other efforts

Promote adoption of CTTI recommendations


Initial priority areas for research on research
Initial Priority Areas* for Research on Research CTTI to Improve our National and Global Evidence Generating Capability

Design principles

Data quality and quantity (including monitoring)

Study start-up

Adverse event reporting

*Defined by CTTI’s Executive Committee


Status of ctti projects
Status of CTTI Projects CTTI to Improve our National and Global Evidence Generating Capability

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


Effective and efficient monitoring project
Effective and Efficient Monitoring Project CTTI to Improve our National and Global Evidence Generating Capability

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 objectives

Describe the range of current monitoring practices and examine factors that drive their adoption

Define key quality objectives for clinical trials

Illustrate strengths and weaknesses of the various monitoring practices in meeting quality objectives for a range of clinical trial settings


Effective and CTTI to Improve our National and Global Evidence Generating CapabilityEfficient Monitoring…

Project Mgmt

Rachel Behrman,

MD, MPHFDA

Co-Team Leaderand WS 2 Leader

Martin Landray,

PhD, MRCP University of Oxford

Co-Team Leaderand WS 3 Leader

David NickersonProject ManagerPfizer Inc.

Briggs Morrison, MD Pfizer Inc.

Co-Team Leader

and WS 1 Leader

Melissa RobbSenior Program Mgr.FDA

Workstream 1

Team

Workstream 2

Team

Workstream 3

Team

Effective and Efficient Monitoring Project Organization


Improving sae reporting to ind investigators
Improving SAE Reporting to IND Investigators CTTI to Improve our National and Global Evidence Generating Capability

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


Improving sae reporting to ind investigators1
Improving SAE Reporting to IND Investigators CTTI to Improve our National and Global Evidence Generating Capability

Subprojects

1.Document current range of sponsor practices for:

a. Reporting unexpected SAEs to investigators;

b. Oversight of product safety (eg DSMBs, safety committees)

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

Compare current practice of submitting individual SAEs with an alternative approach based on European Commission’s guidance

Convene an expert group to integrate results and recommend ways to optimize reporting of SAEs to investigators and assure subject protection


Collaborations
Collaborations CTTI to Improve our National and Global Evidence Generating Capability

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 CTTI

Expert 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


Collaborations continued
Collaborations CTTI to Improve our National and Global Evidence Generating Capability(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


How do we effect widespread change
How do we effect widespread change? CTTI to Improve our National and Global Evidence Generating Capability

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 explicit

Wide spread perception that clinical trials just take that long and cost that much!


How do we effect widespread change1
How do we effect widespread change? CTTI to Improve our National and Global Evidence Generating Capability

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)


For more information
For more information…. CTTI to Improve our National and Global Evidence Generating Capability

CTTI Website-Home

www.trialstransformation.org

Projects

www.trialstransformation.org/projects

Member organizations

www.trialstransformation.org/members/member-organizations/

How to join

www.trialstransformation.org/join


Large trials are important CTTI to Improve our National and Global Evidence Generating Capability

Complexity and cost increasing

GCP ≠ good, or clinically relevant, or even practical

Excess data, number of visits, onsite monitoring

Layers of ethics approvals

“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 Trials 2008; 5: 38-39 Sensible Guidelines Conference January 25-26, 2007Sensible guidelines for the conduct of large randomized trials


Clinical and translational science award ctsa

Clinical and Translational CTTI to Improve our National and Global Evidence Generating Capability Science Award (CTSA)

At peak a $500 million investment by the NIH in translating scientific discoveries to better human health


My opinion this does not represent ctti
My Opinion—This does not represent CTTI CTTI to Improve our National and Global Evidence Generating Capability


Disruptive innovation is needed to create a very different system based on electronic data collection in practice with quality built in through a systematic approach.


The cycle of quality generating evidence to inform policy

3 system based on electronic data collection in practice with quality built in through a systematic approach.

2

4

1

DataStandards

NIH Roadmap

NetworkInformation

FDACritical Path

Early TranslationalSteps

5

EmpiricalEthics

Discovery Science

6

Prioritiesand Processes

Measurement andEducation

ClinicalTrials

Outcomes

12

7

Transparencyto Consumers

Inclusiveness

11

8

ClinicalPracticeGuidelines

Pay forPerformance

PerformanceMeasures

Use forFeedbackon Priorities

9

10

Conflict-of-interestManagement

Evaluation of Speedand Fluency

The Cycle of Quality: Generating Evidence to Inform Policy

Califf RM et al, Health Affairs, 2007


The learning health system
The Learning Health System system based on electronic data collection in practice with quality built in through a systematic approach.

  • Articulated goal of the Institute of Medicine

  • By implementing electronic health records, data warehouses and disease registries, every patient’s data will be used to further knowledge

  • This means that all places of practice will become research sites

  • Research must become a normal part of clinical practice, not something done separately from clinical practice (except for very special early phase and highly controlled types of studies)


Of randomized discontinued in a
% of Randomized Discontinued in A system based on electronic data collection in practice with quality built in through a systematic approach.


Protocol adherence and adverse events
Protocol Adherence and Adverse Events system based on electronic data collection in practice with quality built in through a systematic approach.


Image Source: http://www.pandora.ca/pictures21/900666.jpg system based on electronic data collection in practice with quality built in through a systematic approach.


The demise of empires
The Demise of Empires system based on electronic data collection in practice with quality built in through a systematic approach.

  • Dominance at a point in time

  • Arrogance about superiority

  • Failure to pay attention to quality of work

  • Leaders content to “ride the wave”

  • Entrenched interests can buy stability through controlling laws and regulations

  • Inability to create or respond to innovation

  • Cost of transactions exceeds cost of actually doing the work!


Disruptive innovation in clinical trials
Disruptive Innovation in Clinical Trials system based on electronic data collection in practice with quality built in through a systematic approach.

  • Electronic health records

  • Data warehouses in integrated health systems

  • Learning health systems

  • Use same information for clinical care and research

  • Electronic permissions systems for participation in research

  • Evaluation of RESEARCH SITES on a periodic basis with constant electronic surveillance and periodic audits for cause


Thank you system based on electronic data collection in practice with quality built in through a systematic approach.


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