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
Learning Objectives
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Main focus for Investigator Initiated Studies (IIS)
Investigator’s responsibilities & role of study coordinators
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Review the steps in initiating IIS
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Essential documentation
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Minimizing risks associated with IIS
Investigator Initiated Studies or ??
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Investigator Initiated Trials (IITs)
Investigator Initiated Studies (IISs)
Investigator Sponsored Trials (ISTs)
Investigator Initiated Research (IIR)
Non Registration trials (NRTs)
Non Sponsored Trials
Main Issues of IISs
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Categories and Design of IISs
Regulatory and Legal Issues
Management of IIS
Education, Training and Authorship
Funding
Key Stakeholders
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Group 1: Academic Institutions/Universities,
Healthcare Providers/Hospitals
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Group 2: Regulators
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Group 3: Patients, General Public
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Group 4: Industry
Rationale for Conducting IISs
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A report including combined data from approx. 1140 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).
Why Do We Need Investigator Initiated Studies?
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Innovation, exchange of information, gaps in
knowledge, benefits patients
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Demand for efficiency in healthcare
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Cost effective way to advance research as
compared with industry
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Research that would otherwise not happen
Etiology, pathophysiology, discovery
of t/m, diagnostics, technology and
biologics
NIH National Center for Advancing Translational Sciences
Testing new discoveries
Investigator
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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)
Sponsor and Sponsor Investigator
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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.
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The sponsor does not actually conduct the investigation
unless the sponsor is sponsor –investigator
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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)
Qualifications of the PI
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An appropriately qualified person in the relevant field of
health care with research interest
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Trained and experienced in clinical research
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Familiar with the study background and requirements
Types of IISs
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Therapeutic
Prevention
Early detection/diagnostic
Disease Management
Correlative
Population-based studies:
• Epidemiological
• Observational
• Quality-of-life
Investigator-Initiated Studies Categories
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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
“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)
Industry Sponsored vs. Investigator-Initiated
Industry Sponsored
 Well organized and Structured
 SOPs and Processes in place
 Experienced team
 Budget
Investigator Initiated
 Somewhat Structured
 SOPs not available
 Less Experienced
 Low Budget
Industry Sponsored vs. Investigator-Initiated Challenges
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Industry Sponsored
 Time line from preclinical to Phase IV
 Regulatory hurdles
 Recruitment
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Investigator-initiated
 Protocol development
 Data management / analysis
 Funding
 Resources
Steps in Initiating IIS and PIs Responsibilities
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Formulating a research question
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Literature review
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Developing research protocol
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Include all essential elements (ICF, CRFs, Data Collection
tools)
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Determine if an IND/IDE is required
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If IND is required initiate FDA paperwork
Responsibilities of the PI
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Create Study Policy and Procedures
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Scientific, Departmental and Feasibility Review
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Obtain IRB approval of the protocol and informed consent
prior to the initiation of the study
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Study Initiation ( staff training, regulatory)
Responsibilities of the PI
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Be familiar with any regulations that may impact the study
design or participation
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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
Responsibilities of the PI
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Notify IRB and/or Sponsor of any issues that pose a threat to
the safety and well-being of the patients in the study
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Submit any changes (amendments) made to the protocol to
the IRB for approval
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Provide information about protocol progress to the IRB on an
annual basis (annual continuing reviews)
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Data Safety Monitoring Board as applicable
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Publication
Things to Consider as an Investigator
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Protocol and oversight plans in place
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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?
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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
Investigator Initiated Studies at USF
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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
Steps for initiating IIS with Industry/NIH
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Investigator submits a Letter of Intent (LOI) to
Industrial sponsor/ NIH
1.
Idea/RQ
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Project proposal
3.
Available resources
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Address Federal regulatory requirements
 OCR/ Office of Sponsored Research
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Possible Funding Budget
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Plan for data ownership, publication
 Go /no go decision for funding
 Agreement
25
Study Coordinators Role
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Coordinates the study, not responsible for the conduct of the
study
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Should use the Delegation of Responsibilities Log
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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
Coordinators Role
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Maintains, ethical conduct and data Integrity
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Follows GCP Guidelines
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Knowledge about Drug/Device/Biologics
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Provides Clinical Care
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Deals with Clinical Trial Budgets & Financial Management
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Regulations and Guidelines applicable to Clinical Research
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Data Management
Coordinators Role
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Role in the 3 stages of a study
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Pre-study Phase
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Study Conduct Phase
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Study Closeout
Coordinators Role (Pre study)
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Human subject protection adequately described
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ICF written according to the guidelines
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IRB approval is obtained before the PI can start
enrollment
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???
Coordinators Role (Study Conduct)
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Ensuring that the protocol and ICF have current approval
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Most current ICF is used
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Protocol compliance
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Subject safety
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Serious adverse events are identified and reported
Coordinator’s Role
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Data Integrity
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Application and continuing review submitted
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Subjects visits are scheduled in time
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Data collection tools are complete
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Abstracting data into Database or Case Report Forms
Coordinators Role- Study Conduct
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Study Conduct
Regulatory Binder
CRFs
Source Documents
Subject Binder
Test Article Binder
Financial Record
Most Common Violations
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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
Most significant violation
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Enrolling ineligible participants
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Enrollment exceeding IRB approved
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No safety assessments
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Violated clinical hold
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Use of drug before IND/IDE submission
How to Minimize Risks Associated with IIS
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Requires Scientific Review and Pre-Implementation
Planning
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Institutional responsibility
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Adequate Monitoring
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Implementation of Mechanisms to ensure adverse event
reporting
Accountability to
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Federal regulations
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GCP and ICH guidelines
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State laws
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Institutional Policies and SOPs
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Protocol compliance
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Contractual agreements
Regulatory and Legal Considerations
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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
“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