1. Investigator Initiated Studies and Challenge of Sponsor Responsibility
Sadaf Aslam, MD,MS
Assistant Professor
Department of Internal Medicine and
Director of Research Education and Training
Office of Research, USF Health, MCOM
USF Health

2. Learning Objectives
Main focus for Investigator Initiated Studies (IIS)
Investigator’s responsibilities & role of study coordinators
Review the steps in initiating IIS
Essential documentation
Minimizing risks associated with IIS

3. Investigator Initiated Studies or ??
Investigator Initiated Trials (IITs)
Investigator Initiated Studies (IISs)
Investigator Sponsored Trials (ISTs)
Investigator Initiated Research (IIR)
Non Registration trials (NRTs)
Non Sponsored Trials

4. Main Issues of IISs Categories and Design of IISs
Regulatory and Legal Issues
Management of IIS
Education, Training and Authorship
Funding

5. Key Stakeholders
Group 1: Academic Institutions/Universities, Healthcare Providers/Hospitals
Group 2: Regulators
Group 3: Patients, General Public
Group 4: Industry

7. Rationale for Conducting IISs
A report including combined data from approx studies shows that industry-sponsored clinical trials are significantly more likely to reach conclusions in favor of the industry vs non-industry studies- possibly publication bias or selection of an inappropriate comparator to the drug being evaluated
(J. E. Bekelman, Y. Li and C. P. Gross J. Am. Med. Assoc. 289, 454–465; 2003).

8. Why Do We Need Investigator Initiated Studies?
Innovation, exchange of information, gaps in knowledge, benefits patients
Demand for efficiency in healthcare
Cost effective way to advance research as compared with industry
Research that would otherwise not happen

9. Etiology, pathophysiology, discovery of t/m, diagnostics, technology and biologics
Testing new discoveries
NIH National Center for Advancing Translational Sciences

10. Investigator
An individual who conducts research (under whose immediate directions the drug is administered and dispensed)
In an event an investigation is conducted by a team, the investigator is the responsible leader of the team
(21 CFR 212.3)

11. Sponsor and Sponsor Investigator
Sponsor is an entity who takes the responsibility of initiating a clinical investigation. This can be an individual, academic institution, pharmaceutical company, government agency, private or non profit organizations.
The sponsor does not actually conduct the investigation unless the sponsor is sponsor –investigator
Sponsor Investigator plans, designs, conducts, monitors, manages the data, prepares reports, owns data and publication and oversees all regulatory and ethical matters
(21 CFR 312.3)

12. Qualifications of the PI
An appropriately qualified person in the relevant field of health care with research interest
Trained and experienced in clinical research
Familiar with the study background and requirements

13. Types of IISs Therapeutic Prevention Early detection/diagnostic
Disease Management
Correlative
Population-based studies:
Epidemiological
Observational
Quality-of-life

14. Investigator-Initiated Studies Categories
With or without company drugs
With IND/IDE
With or without FDA approval or prior to marketing authorization
Non drug studies
Post first marketing authorization

16. “Performing an IIT according to the new requirements is nearly impossible for clinicians and academic researchers without cooperating with expensive specialized experts such as project managers, statisticians, pharmacists and monitors”
Welzing et al (2007)

17. Industry Sponsored vs. Investigator-Initiated
Well organized and Structured
SOPs and Processes in place
Experienced team
Budget
Investigator Initiated
Somewhat Structured
SOPs not available
Less Experienced
Low Budget

18. Industry Sponsored vs. Investigator-Initiated Challenges
Time line from preclinical to Phase IV
Regulatory hurdles
Recruitment
Investigator-initiated
Protocol development
Data management / analysis
Funding
Resources

19. Steps in Initiating IIS and PIs Responsibilities
Formulating a research question
Literature review
Developing research protocol
Include all essential elements (ICF, CRFs, Data Collection tools)
Determine if an IND/IDE is required
If IND is required initiate FDA paperwork

20. Responsibilities of the PI
Create Study Policy and Procedures
Scientific, Departmental and Feasibility Review
Obtain IRB approval of the protocol and informed consent prior to the initiation of the study
Study Initiation ( staff training, regulatory)
Atory)

21. Responsibilities of the PI
Be familiar with any regulations that may impact the study design or participation
Drug approval and accountability
Information about intervention/drugs (where, how, costs)
Drug/device accountability as applicable
Human tissues, biological samples (storage, use, transfer to another institution)
Funding policies or rules

22. Responsibilities of the PI
Notify IRB and/or Sponsor of any issues that pose a threat to the safety and well-being of the patients in the study
Submit any changes (amendments) made to the protocol to the IRB for approval
Provide information about protocol progress to the IRB on an annual basis (annual continuing reviews)
Data Safety Monitoring Board as applicable
Publication

23. Things to Consider as an Investigator
Protocol and oversight plans in place
Knowing the responsibility and answering these questions
Will you be effective as a leader?
Do you have enough resources
Are you prepared to conduct the protocol?
What if you or your institution is unable to carry out some protocol related procedures or tests?
Should you agree to participate?
Does your institution have a formalized policy for the oversight of IIS

24. Investigator Initiated Studies at USF
Simultaneous submission of IRB application and USF Division of Sponsored Research (DSR) Internal Form
Research Proposal, Protocol, Abstract
Budget to include: Grant Proposal, budget justification page
Financial Management Plan from eCOI Module in ARC, if applicable
Reporting Outside Activities Database (ROAD)
Nepotism Memo, if there are any relatives or related persons participating in the research

25. Steps for initiating IIS with Industry/NIH
Investigator submits a Letter of Intent (LOI) to Industrial sponsor/ NIH
Idea/RQ
Project proposal
Available resources
Address Federal regulatory requirements
OCR/ Office of Sponsored Research
Possible Funding Budget
Plan for data ownership, publication
Go /no go decision for funding
Agreement

26. Study Coordinators Role
Coordinates the study, not responsible for the conduct of the study
Should use the Delegation of Responsibilities Log
Ask the PI about the details of the study
Is protocol understandable?
What type of data will be collected?
How to select participants, target population, recruitment methods, enrollment plan
If data collection supports the study objectives

27. Coordinators Role Maintains, ethical conduct and data Integrity
Follows GCP Guidelines
Knowledge about Drug/Device/Biologics
Provides Clinical Care
Deals with Clinical Trial Budgets & Financial Management
Regulations and Guidelines applicable to Clinical Research
Data Management

28. Coordinators Role Role in the 3 stages of a study Pre-study Phase
Study Conduct Phase
Study Closeout

29. Coordinators Role (Pre study)
Human subject protection adequately described
ICF written according to the guidelines
IRB approval is obtained before the PI can start enrollment
???

30. Coordinators Role (Study Conduct)
Ensuring that the protocol and ICF have current approval
Most current ICF is used
Protocol compliance
Subject safety
Serious adverse events are identified and reported

31. Coordinator’s Role Data Integrity
Application and continuing review submitted
Subjects visits are scheduled in time
Data collection tools are complete
Abstracting data into Database or Case Report Forms

32. Coordinators Role- Study Conduct
Regulatory Binder
CRFs
Source Documents
Subject Binder
Test Article Binder
Financial Record

33. Most Common Violations
Failure to follow protocol
Discrepancies between source documents and CRFs
Inadequate drug/device accountability
Enrolling ineligible patients
Failure to report SAEs
Failure to list all investigators on form 1572
Inadequate ICF
Failure to monitor study

34. Most significant violation
Enrolling ineligible participants
Enrollment exceeding IRB approved
No safety assessments
Violated clinical hold
Use of drug before IND/IDE submission

35. How to Minimize Risks Associated with IIS
Requires Scientific Review and Pre-Implementation Planning
Institutional responsibility
Adequate Monitoring
Implementation of Mechanisms to ensure adverse event reporting

36. Accountability to Federal regulations GCP and ICH guidelines
State laws
Institutional Policies and SOPs
Protocol compliance
Contractual agreements

37. Regulatory and Legal Considerations
Food, Drug and Cosmetic Act
International Conference on Harmonization and Good Clinical Practice Guidelines
US Department of Health and Human Services
Federal Code of Regulations
Office of Inspector General (Compliance Guidance)
Sunshine Act
Federal Anti Kickback Statute

38. “The right to search for truth implies also a duty -one must not conceal any part of what one has recognized to be true”
-Albert Einstein