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"Getting Your Protocol Through the IRB"

Human Participant Research at

University of Maryland, Baltimore

Jon Mark Hirshon, MD, MPH, PhD

Senior IRB Vice-Chair

http://www.umaryland.edu/

Nuremberg Code (1947)

First Codification of Research Guidelines

• Prior animal data

• Scientific value; Anticipated results justify the risks

• Favorable risk/benefit ratio

• Suffering by subjects should be avoided

• No expectation of death/disability

“The voluntary

consent of the human

subject is absolutely

essential.”

• No coercion in informed consent

• Subjects must be free to stop at any time.

• Medical Practice

– Ethics: guided by Hippocratic Oath

– Patient is silent; dutifully obedient to the beneficent physician

– Doctor’s primary obligation is the patient

– Doctor acts in the patients’ best interest

• Research

– Lies outside of the context of the physician-patient relationship

– Primary goal is to test a hypothesis

– Secondary obligation is to subject

– Conflict of roles?

Lessons Learned from Nuremberg Trials

Tuskegee Syphilis Study (1932 - 1972) • In 1932, medical authorities firmly believed in the

efficacy of arsenic therapy for treating syphilis

• Tuskegee, Alabama

– High prevalence of syphilis

– Although treatment existed, blacks in the rural southern town were not receiving treatment

– Lack of funds/Lack of doctors

– “Promiscuous” blacks would not seek treatment

• Study natural course of syphilis – Enrolled 400 black males infected with syphilis to

study the natural course of syphilis

– Not an experiment but rather a “study in nature”

Tuskegee Syphilis Study (1932 - 1972)

Ethical Issues

• Inadequate disclosure of

information

• Subjects believed they were

getting free treatment

• Told that spinal taps were

therapy

• US Gov’t actively prevented

men from receiving penicillin

• 1972 press reports caused the

U.S. Gov’t to stop the study

Balancing Two Goals

Advancement

of Science Protection of

Subject’s Rights

& Welfare

Introduction to the Human Research Protections Office

(HRPO)

Research Review: Nomenclature

• HRPP: Human Research Protection Program

• HRPO: Human Research Protection Office

• OHRP: Office of Human Research Protection

• AAHRPP: Association for the Accreditation of Human Research Protection Programs

Research Review: Nomenclature

• A Research Submission to the IRB is NOT……..

•An IRB

DEFINITIONS

• “Medical Practice” (IRB is not involved)

– Interventions designed solely to enhance the well-being of the patient.

– Provides diagnosis, prevention or therapy with the expectation of a successful outcome.

• "Experimental"

– Defined as new, untested or different.

– An experimental procedure is not automatically categorized as research.

– A new "experimental" procedure should be formally researched (investigated) to determine if is safe and effective.

DEFINITIONS

• “Research” (IRB is involved) – Activities designed to contribute to generalizable

knowledge.

– Tests a hypothesis and draws conclusions.

– Research is described in a formal protocol and a set of procedures designed to reach an objective.

– The line between practice and research is often blurred.

– Research and practice can occur simultaneously

What is a Human Subject?

– A “human subject” (participant, volunteer) is a living individual about whom an investigator conducting research obtains:

• data through intervention or interaction with the individual

or

• identifiable private information

From: 45 Code of Federal Regulations (CFR) 46.102

Responsibilities of the IRB and Human Research Protections Program

• Protect the rights and welfare of human research subjects

• Determine if Benefit of the research (to the individual or society) exceeds the Risk to the participant (subject, volunteer, patient)

Human Research Protection Program

Human Research Protection Office

Institutional Review Board

Human Research Protection:

UMB Model

Human Research Protection Office (HRPO)

• The HRPO is the coordinating office for the Human Research Protections Program (HRPP) – The HRPP is a comprehensive system designed to ensure

the protection of the rights and welfare of subjects in Human Research.

• HRPO provides support for the Institutional Review Board – Oversight of > 2,000 clinical research protocols.

HRPO’s Mission

• The mission of our Human Research protection program plan is to protect the rights and welfare of subjects involved in Human Research that is overseen by this organization.

– Foster a high caliber research culture through the support of investigators

Functions of the Human Research Protections Office

• Review Protocol Transactions

– New, Amendments, Renewals, Reportable New Information

• Organize IRB meetings

• Monitor and Audit investigators to ensure compliance with regulations

• Educate the research community

What is an Institutional Review Board (IRB)?

• The group or committee that is given the responsibility by an institution to review research projects involving human subjects.

• Its primary purposes are – to assure the protection of the safety, rights and welfare of

the human subjects. – determine if Benefit of the research (to the individual or

society) exceeds the Risk to the participant (healthy volunteer or patient)

• By federal law, the group contains both scientific and non-scientific (community) members

IRB Leadership

Robert Rosenthal,

Chair

Jon Mark Hirshon,

Senior Vice Chair James Campbell, Vice

Chair, CRTMP Director

Seth Himelhoch,

Vice Chair

Steve Seliger,

Vice Chair

Carla Alexander,

Vice Chair Tim Meiller,

Vice Chair

Chris DeFilippi,

Vice Chair

IRB Meetings

• Small Committees

• Frequent (3x/week meetings)

• Affiliated Scientists

• Non-Scientists

• Unaffiliated Community Members

• Representative Advocates for Vulnerable Populations

• VA Representatives as Appropriate

IRB Function: Levels of Review

• Full Board review of greater than minimal risk protocols – New protocols – Continuing reviews ( at least annually) – Modifications

• Expedited review of exempt and many minimal risk

protocols

Transactions Reviewed by the IRB

• New Protocols

• Renewals

• Amendments

• Reportable new information

– Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events

– Includes serious and continuous noncompliance

Levels of Research Risk

• Minimal

• Greater than Minimal Risk

Minimal Risk Research

• The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.*

*[From: 45 CFR 46.102 i.]

Examples of Minimal Risk Research

• Chart review

• Survey

• Physical exam

• Drawing blood

• Review of previously collected specimens

• Collection of stool or sputum specimens

Exempt Research

• Certain minimal risk research activities are “exempt” (45 CFR 46.101b)

• The IRB, not the investigator, determines if the research is “exempt”

• Six exempt categories – Category #4

• Example: Retrospective chart/database review

• The most common exempt category at UMB

Expedited Review

• Minimal risk studies

• Expedited review and approval normally 2-3 weeks faster than full board review

• Does not have to be reviewed at fully convened meeting – But full board needs to approve of expedited review

Full Board Review

• Greater Than Minimal Risk Transactions

• Review conducted at a convened meeting

• A full quorum is assembled – Non-scientists/unaffiliated members

• Decision is rendered by a majority of the assembled quorum

• No member with a conflict of interest participates in the decision

What Aspects Are Important for an IRB Review?

• Subjects adequately protected

• Potential Benefits > Risk

• Study design/scientific integrity of research

• Equitable Subject Selection (No Coercion)

• Appropriate Informed Consent

• Privacy & Confidentiality Protection

• Data & Safety Monitoring

IRB must determine that the following requirements have been satisfied:

• 1. Risk(s) to participants are minimized • 2. Risk(s) to participants are reasonable in relation to

anticipated benefits and to the importance of the expected knowledge.

• 3. Selection of participants is equitable • 4. Informed consent will be sought and the consent

form includes all elements and in language understandable to participants

IRB Review Requirements (cont.)

• 5. Provisions for obtaining and documenting informed consent are appropriate

• 6. Privacy and confidentiality are adequately protected

• 7. Research plan makes provisions for data safety monitoring (if applicable)

• 8. Additional safeguards are included to protect the rights and welfare of vulnerable participants (if applicable)

Vulnerable Population Examples

• Pregnant Women, Human Fetuses and Neonates (45 CFR 46, Subpart B)

• Prisoners (45 CFR 46, Subpart C)

– (requires prison advocate review)

• Children (45 CFR 46, Subpart D)

• Cognitively Impaired/ Impaired Decision Making Capacity

• Students/employees

• Wards of the State

Responsibilities & Authority of the IRB

• Approve, Disapprove, or Modify Research Protocols;

•Suspend or Terminate Research Protocols

• Conduct Continuing Review of Research Protocols

• Critique and Monitor Informed Consent Process

• Monitor Ongoing Research Studies

• Perform audits on study conduct; Investigate RNI

• Evaluate Financial Interests of investigators and Research

Staff

PI Responsibilities: • Investigators must have appropriate expertise • Assures that the conduct of the study

complies with all ethical, scientific, and financial principles espoused by UMB and the federal government

• Assures that there are adequate resources (space, staff, funding) to accomplish the research

• Assures that staff are adequately trained

Collaborative Institutional Comprehensive Evaluation

of Research Online (CICERO)

CICERO

• Electronic System – Creating, submitting, reviewing,

documenting, communicating, storing – Web-enabled database – Benefits:

• Reduces administrative burden • Improves consistency • Improves efficiency • Improves accountability

– Modifiable

Introduction to CICERO*

*https://cicero.umaryland.edu

https://cicero.umaryland.edu/

University of Maryland, Baltimore- Research Review

Cicero Submission/Review

• All PI’s must be 51% employed by U of MD

• Mandatory Cicero and HIPAA Research Training

• Cicero Submission Created by PI/Submitted

• Scientific Review by Departmental Reviewer

• Protocol Arrives at HRPO

• Human Subject Research?

• Level of Risk Determination

Cicero Submission/Review

• Minimal Risk: Review by Designated Reviewer

– Reviewed by EC Member

– Reviewed by IRB Member Designated Reviewer

• Greater than Minimal Risk

– Assigned to Full Board Review

– 2-3 Independent Reviews

– Approve, Modifications Required to Secure Approval, Deferred, Disapproved

UMB Human Research Protections Program*

* http://www.hrpo.umaryland.edu/

http://www.hrpo.umaryland.edu/

Speed Bumps to Approval • Know your scientific reviewer and understand

the process of departmental review

• Fill out the Cicero application completely and accurately.

• Pay particular attention to vulnerable populations and data safety monitoring plan.

• If you have questions, ask before submission.

• Procedural questions may be addressed to any of the office administrative staff.

• Substantive questions should be addressed to the directors or EC members.

The PI needs to:

• Assure appropriate oversight of research

• Respond to participant concerns

• Have adequate Data & Safety Monitoring

• Give appropriate care to the participants

The principal investigator is the critical component in the conduct of high quality research and in the assurance of human

research subjects’ safety

Additional Review Processes

• Specialty Reviews: Pediatrics, Cancer Center, Shock Trauma Center

• Environmental Health and Safety: http://www.ehs.umaryland.edu

• Investigational Drug Service

• Radiation Safety: See EHS Web page

• Conflict of Interest: http://www.umaryland.edu/offices/accountability/

Research Resources On Campus

• Human Research Protections Office

– http://hrpo.umaryland.edu/index.html

• Environmental Health and Safety

– http://www.ehs.umaryland.edu

• Center for Clinical Trials

– http://www.umaryland.edu/cct

• General Clinical Research Center

– http://medschool.umaryland.edu/gcrc

Environmental Health and Safety

• Biosafety – Shipping & DNA policy

• Environmental Management – Chemical Waste & Disposal Guidelines

• Radiation Safety – Approve research using radiation

• Training – Bloodborne pathogens & shipping certification

Center for Clinical Trials

• Assists by facilitating contracts with University investigators to conduct studies

–Phase I through Phase IV

–Single-site and multiple-site studies

General Clinical Research Center

• GCRCs are designed to provide researchers with the

resources they need to conduct high quality clinical

research in patients and normal subjects

• The GCRC is available to all University of Maryland

clinical investigators who have

– a need for GCRC resources

– will conduct clinical research of scientific merit

• NIH funded research has top priority, but studies

funded by foundations, industry, and other sources are

also welcome.

GCRC Resources:

• Nursing support for inpatient and outpatient data collection and patient care

• DEXA scans

• Bioinformatics and Biostatistics assistance

• Funds to pay for ancillary services

• A Genomics Core

Questions?

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