1. Clinical Research: Contract Research and Academic Research Organizations
Laura Mauri, MD, MSc
Brigham and Women’s Hospital
Harvard Medical School
Harvard Clinical Research Institute

2. Laura Mauri, MD Consulting Fees: Cordis Corporation Abbott Medtronic
Research support to Harvard Clinical Research Institute from:
Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Inc., Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals Partnership, Eli Lilly and Company and Daiichi Sankyo Company Limited

3. CROs and AROs
Contract research organization (CRO) and what services they provide
What is the difference between CRO and ARO (Academic research organization)
What are the relative strengths or limitations of CROs and AROs
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

4. CROs and AROs
Both CROs and AROs provide some component of research execution as a service
Not all clinical trial CROs or AROs provide all the services required for a clinical trial
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

5. Clinical Trial Management
Organizational Structure
Steering Committee
Industry Sponsor
Regulatory Agencies
Independent
Data Monitoring
Committee (DSMB)
This is a typical clinical trial organizational structure.
Each responsibility is actually designated to the clinical trial sponsor, but in many cases one or more of these is designated by contract to an external group or contract research organization (CRO).
Statistical Analysis
Center
Site and Data
Management Center
Central Units
Core Labs etc
CEC
Clinical
Investigators
Adapted from M. Fisher, E. Roecker, D. Demets.
Drug Inf J. 2001;35:115

6. CROs and AROs
Both CROs and AROs provide some component of research execution as a service
Trial Design
Project Management
Site Management
Data Management
Safety, Regulatory oversight
Management of Clinical Events Committee,
DSMB
Statistical Analysis and Reporting
Publications
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

7. CROs and AROs Tasks required of data management
Build validated database, compliant with standards
Secure and verifiable data entry
Procedures for treatment assignment/randomization
Timely data collection from external sources, quality checking, monitoring
Data cleaning, export for event adjudication, safety reporting, and analysis
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

8. CROs and AROs CROs and AROs differ in their stakeholders
Academic research organizations stakeholders include:
Clinical investigators
University
Academic medical centers
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

9. CROs and AROs CROs and AROs differ in their mission
Beyond providing the service of clinical trial services, academic research organizations generally intend to:
provide clinical context and strategy
provide scientific objectivity
advance medical knowledge and innovation
disseminate results
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

10. CROs and AROs Research functions generally unique to AROs include
Trial strategy (clinical and statistical)
Principal investigator leadership
Clinical coordinating center role
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism

11. Academic Research Organization Capabilities and Services
Unique ARO “Value-Added” Services
Scientific leadership input into trial design and data management plan
Ongoing scientific and clinical management
Establish and manage Clinical Event Committees
Establish and manage independent Data and Safety Monitoring Boards

12. Academic Research Organization Capabilities and Services
Unique ARO “Value-Added” Services
Clinical trial strategy consulting from clinical and statistical experts
Scientific publications (interpretation and early dissemination of results)
Ability to design investigation that spans the results of one individual study or sponsor
extend results beyond those of an individual product evaluation

13. Academic Research Organization Advantages
Integrated involvement of clinical research operations and scientific leadership
Independence of experts available for trial design, medical management and analysis of results

14. Academic Research Organization Disadvantages
Sponsor may relinquish some control
Autonomy of academic authors for interpretation and publication
Access of academic authors to dataset
To conclude it is fair to mention the disadvantages

15. Academic Research Organization: example
Harvard Clinical Research Institute
Academic Research Organization: example
May 18, 2011
Department
Project Management
Trial Design (including physicians)
Biostatistics
Clinical Safety
Clinical Events
Site Management
Data Management
ECG Core Laboratory
Quality of Life Core Laboratory
QA/Regulatory
Supporting Departments
(IT, Finance, Business Development, Administrative Services)
Academic Research Organization (ARO) with full CRO capabilities
Not-for-Profit 501(c)(3) Corporation
~200 FTE
Clinical trials ranging from 20-26,000 subjects
Active studies span industry, NIH, and investigator-initiated trials
Site Management: 18 (as of August 23)
QA Update (8/30)
DM Update (9/6)

16. March 2008 Statement of FDA Principles following DCRI\FDA Critical Path Think Tank Meeting on need for DAPT Trial:
A need for a large, pragmatic public health trial exploring the benefit of extending thienopyridine treatment beyond one year in patients treated with DES needs to be done expeditiously
FDA expects that the results of the study will change clinical practice and provide valuable new information in product labeling for DES.
Bram Zuckerman TCT 2008

17. A multistakeholder opportunity
The FDA request resulted in a unique public-private collaboration among 4 manufacturers of DES and current manufacturers of thienopyridine/antiplatelet medications
AdvaMed facilitated a proposal process from academic CROs along the parameters of a basic trial specifications from FDA and industry
2008 Harvard Clinical Research Institute IDE approved by FDA
2011 Enrollment +26,000 subjects worldwide completed
2012 (Feb) ~9000 randomized
Results expected 2014
HCRI and the principal investigators are responsible for the independent analysis of trial data, and dissemination of results 18 18

18. Total Subject Enrollment
Don Cutlip, Harold Dauerman
Daniel Simon, David Kandzari
DES n = 23,212
David Lee, Kirk Garratt
James Hermiller, Mitch Krucoff
Laura Mauri, Dean Kereiakes
BMS n = 2,986
Laura Mauri, Dean Kereiakes 19

19. A multistakeholder opportunity
Largest randomized trial regarding coronary stents
First randomized trial in cardiology supported by multiple different companies
The DAPT Study has brought together diverse stakeholders
FDA
Academia
Industry (4 stent and 4 drug companies)
Without the context of ARO coordination and leadership, such a multistakeholder effort would not be possible

20. CROs and AROs
CROs and AROs each may provide sponsors or investigators clinical trial services
While independent statistical analysis may be performed by either type of organization
AROs differ in the central mission of coordinating clinical leadership throughout trial execution, providing scientific objectivity, interpretation, and dissemination of results
Information is now available in all treated patients. Driven by payors and government. Can these data improve medical care? Some skepticism