Investigator Initiated Studies and Challenge of Sponsor Responsibility

Sadaf Aslam, MD,MSAssistant 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

NIH National Center for Advancing Translational Sciences

Etiology, pathophysiology, discovery of t/m, diagnostics, technology and biologics

Testing new discoveries

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

Industry SponsoredWell organized and StructuredSOPs and Processes in placeExperienced teamBudget

Investigator Initiated Somewhat StructuredSOPs not availableLess ExperiencedLow Budget

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

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)

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

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Steps for initiating IIS with Industry/NIH

Investigator submits a Letter of Intent (LOI) to Industrial sponsor/ NIH

1. Idea/RQ2. Project proposal 3. Available resources4. Address Federal regulatory requirements

OCR/ Office of Sponsored Research 5. Possible Funding Budget6. Plan for data ownership, publication7. Go /no go decision for funding8. 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

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