Investigator Initiated Studies and Challenge of Sponsor Responsibility

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 • Areport 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).

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 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

18. Industry Sponsored vs. Investigator-Initiated Challenges • Industry Sponsored • 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)

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 • 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