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

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

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

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

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

Rationale for Conducting IISs 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? 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

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

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)

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)

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

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

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

“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 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 Time line from preclinical to Phase IV Regulatory hurdles Recruitment Investigator-initiated Protocol development Data management / analysis Funding Resources

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

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)

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

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

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

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

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

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

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

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

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 ???

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

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

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

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

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

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

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

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

“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