Human Subject Research

Institutional Review Board (IRB) and Human Subject ResearchResearch Administration Training Series : 

Institutional Review Board (IRB) and Human Subject ResearchResearch Administration Training Series September 23, 2008

Course Objectives : 

Course Objectives At the conclusion of this course, students will 1. List and summarize the background and regulations for the protection of human research subjects. 2. Something about adverse outcomes Non-compliance 3. Apply principles of the Human Research Protection Program to case studies and their individual research projects. Informed consent process Vulnerable populations Serious Adverse Event (SAE) reporting Inclusion and exclusion criteria HIPAA authorization Protocol application 4. Use the Electronic Research Integrity Compliance Administration (ERICA) program. (Login to ERICA) 5. List and summarize Institutional Review Board (IRB) documentation standards 6. Create bibliography of documents and resources for this subject

History : 

History Claude Bernard, 1865 “The principle of medical and surgical morality consists in never performing on man an experiment which might be harmful to him to any extent, even though the result might be highly advantageous to science, i.e., the health of others.”

History : 

History Henry K Beecher, MD: “Ethics and Clinical Research” NEJM, 1966. 22 examples of published studies in which investigators “endangered the health or the life of their subjects” without permission. Example 3: Chloramphenicol for typhoid fever: 23 additional subjects died in placebo control group Beecher’s article was a “milestone” because a respected member of the research community sought to create significant focus on ethical conduct of research

Which Event Initially Led to International Focus on the Ethical Conduct of Research? : 

Which Event Initially Led to International Focus on the Ethical Conduct of Research? Tuskegee Study Birth Defects from Thalidomide Death of Jesse Gelsinger Nuremberg Trial Vioxx Recall

Nazi Experiments : 

Nazi Experiments Freezing Sea Water High Altitude Chamber Infectious Diseases Traumatic Injuries Killing / Genocide Surgery Sterilization

Brief Background : 

Brief Background What is an IRB? How did IRBs come to be? United States Regulations Federal Wide Assurance Office for Human Research Protection (OHRP) Food and Drug Administration (FDA) Health and Human Services (HHS) Inspections and Noncompliance

OHRP Regulations : 

OHRP Regulations 45 Code of Federal Regulations (CFR) 46 Subparts A through D A - Basic HHS Policy for Protection of Human Subjects B - Additional Protections for Pregnant Women, Fetuses, and Neonates C - Additional Protections for Prisoners D - Additional Protections for Children

FDA Regulations : 

FDA Regulations 21 CFR 56 Subpart A General Provisions Subpart B Organization and Personnel Subpart C IRB Functions and Operations Subpart D Records and Reports Subpart E Administrative Actions of Noncompliance

FDA Regulations : 

FDA Regulations CFR Title 21 Part 11 CFR Title 21 Part 50 CFR Title 21 Part 54 CFR Title 21 Part 56 CFR Title 45 Part 46 CFR Title 45 Part 164 Subpart E

HHS Regulations : 

HHS Regulations Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule and Research Protected Health Information (PHI) Privacy Board Authorization for Use/Disclosure of PHI Waiver of Authorization Limited Data Set

Effects of Noncompliance : 

Effects of Noncompliance Immediate loss of funding for all federally funded human subject research Damage to a institution’s reputation Future ability to secure research funding Damage to investigator’s reputation Adverse effects on graduate research student

The Regulatory Definition of Research : 

The Regulatory Definition of Research “A systematic investigationdesigned to develop or contribute to generalizable knowledge.”

The Three Pillars : 

The Three Pillars

What is the Focus of IRB Review? : 

What is the Focus of IRB Review? Ethical principals set forth in the Belmont Report: Respect for Persons Beneficence Justice Risk/Benefit Ratio Informed Consent Inclusion/Exclusion Criteria

Which of the Following is NOT Considered a Vulnerable Population? : 

Which of the Following is NOT Considered a Vulnerable Population? Pregnant women and fetuses Adult cancer patients People with diminished capacities Children Prisoners

Vulnerable Human Subjects : 

Vulnerable Human Subjects Pregnant Women and Fetuses Prisoners Children Mentally Incompetent The Mentally Disabled Placebo-only Arm evaluating the effect of Antidepressants Educationally and Economically Disadvantaged Temporarily Incapacitated or Emergency Subjects

Pregnant Women and Fetuses 45 CFR 46. Subpart B : 

Pregnant Women and Fetuses 45 CFR 46. Subpart B How will pregnancy be determined? Describe how participants will be monitored. Birth control methods must be described. Participants must be educated on the requirement not to become pregnant. How will pregnancy be determined? Describe how participants will be monitored.

Prisoners 45 CFR 46.301-306 : 

Prisoners 45 CFR 46.301-306 Risks involved are not greater that would be for non-prisoner volunteers. Follow up. Adequate provisions are made for care after their participation has ended. Human subject becomes a prisoner after the research has commenced? Why a vulnerable population? At least 1 member be a prisoner rep at board meeting.

Children45 CFR46- Subpart D : 

Children45 CFR46- Subpart D Inclusion must be explicitly justified 46.404: Minimal risk 46.405: Prospects of direct benefit 46.406: Greater than minimal risk and no prospects of benefit Of vital interest to understanding the condition. Must be only a minor increase over minimal risk Commensurate with actual or expected experiences of the child 46.407: Federal review

Children45 CFR46- Subpart D (continued) : 

Children45 CFR46- Subpart D (continued) Normally written assent 7 or older. Parental Permission Minimal Risk/ Direct Benefit – Oneparent 406/407 – Both Parents Wards require special protections

Case Study : 

Case Study An investigator proposes to conduct a pharmacokinetic study of a new drug for ADHD. The study calls for giving a one-time dose of the drug to children with ADHD with dose escalation between groups of children and serial blood draws (5 samples at 30 min, 1 hour, 2 hours, 4 hours, 12 hours). Children ages 3 - 6 will be recruited.

What is Your Opinion? : 

What is Your Opinion? Would you vote to approved this study as a member of the IRB? Strongly Agree Agree Disagree Strongly Disagree

Mentally Impaired : 

Mentally Impaired No reasonable Alternative All individuals who have been determined to lack capacity to consent to participate in a research study must have legally authorized representative (LAR) to enroll that person in the study. Should the person object to participating, the objection will be heeded.

Placebo Controls : 

Placebo Controls Explicit justification Scientific/methodologic justification No established treatments Patient refractory to available treatments Minor health problems Strategies Careful monitoring Immediate intervention Quarterly reports

Case Study : 

Case Study Children ages 10 - 14 with depression who have not responded to first-line agents will be randomized to an investigational drug or placebo for 6 weeks. Serial evaluations and close monitoring is planned. As an add-on, investigators will recruit a subset of children for PET scanning.

Temporarily Incapacitated or Emergency Subjects : 

Temporarily Incapacitated or Emergency Subjects Temporarily incapacitated or emergency subjects are in especially vulnerable positions and research on them should be avoided if possible. Special care should be taken to explain the nature of the research either to the patient or, in cases in which this is not possible, to the patient's LAR.

Case Study - Deception : 

Case Study - Deception Measured the willingness of participants (S) to obey an authority figure (E) Participants told they would be shocking someone in the next room Confederate (A) would scream as though they were being shocked Staged Experiments on Obedience to Authority, Stanley Milgram, Yale University, 1960’s. “I observed a mature and initially poised businessman enter the lab smiling and confident. Within 20 minutes, he was reduced to a twitching, stuttering wreck… rapidly approaching a point nervous collapse. He pulled on his earlobe, twisted his hands, and at one point pushed his fist into his forehead and muttered, ‘Oh God, let’s stop it.’ And yet, he continued to respond to every word of the experimenter, and obeyed to the end.”

What is Your Opinion? : 

What is Your Opinion? Do you feel it is ethical to conduct research that involves an element of deception? Strongly Agree Agree Disagree Strongly Disagree

Translating Ethics into Regulations : 

Translating Ethics into Regulations Informed Consent = Informed Trust Consent as a process

Risks : 

Risks Description of any reasonably foreseeable risks or discomforts to the participants. All expected and occasional side effects no matter how rare. State if there are no risks? Unforeseeable Risk Statement

Benefits : 

Benefits Which may be reasonably be expected from participating in the research. There may be no direct benefit from participating. Extra attention – Coercive Do not include compensation.

Inclusion / Exclusion : 

Inclusion / Exclusion Protocol Summary – Detailed as necessary to define the patient population. Precise Criteria. Specific Inclusion / Exclusion Use this information for evaluating consent status.

HIPAA Authorization : 

HIPAA Authorization IRB is the U of U Privacy Board Waiver of Consent and Authorization It is okay to use general language Future unspecified research De-identified Data Limited Data Sets

Tips to Save Time and Effort When Working With the IRB : 

Tips to Save Time and Effort When Working With the IRB Read Instructions Provide complete information or ask Be as thorough as possible Consents should be simple and use lay language Respond quickly Do not be afraid to ask questions

Sometimes the IRB Process Can Be a Challenge… : 

Sometimes the IRB Process Can Be a Challenge… -By Brett Shirley, IRB Staff

How Do I Submit an IRB Application? : 

How Do I Submit an IRB Application? ERICA Web-based Username and Password Types of IRB Applications New Studies, Amendments, Renewals, and AE’s, and other reportable events

Research Administration Portal : 

Research Administration Portal Integrate Committee Review and Workflow: Clinical Cancer Investigation Committee (CCIC) Resource for Genetic and Epidemiologic Research (RGE) General Clinical Research Centers (GCRC)/CTSA Radioactive Drug Research Committee (RDRC) Conflict of Interest (CoI)

True or False… : 

True or False… True False IRB determinations can be overturned by University administration.

Answer… : 

Answer… False. Determinations made by the Board can only be altered by the Board itself.

True or False… : 

True or False… True False If your study involves cancer patients, it must receive CCIC approval before it can be given IRB approval.

Answer… : 

Answer… True. The Clinical Cancer Investigations Committee (CCIC) is responsible for reviewing cancer-related protocols for scientific merit, scientific progress, and participant accrual.

Yes or No… : 

Yes or No… A study receiving an “Expedited” review will gain approval more quickly than a study receiving a Convened Board review. Yes No

Answer… : 

Answer… No. The term “Expedited” does not mean cursory; documentation of substantive review is essential. An Expedited study may receive fewer reviews before approval, but the process is very similar to Full Reviews. The IRB Staff always makes the effort to get Expedited Reviews completed and approved as quickly as possible.

True or False… : 

True or False… True False “My study does not involve any invasive procedures, so it must be minimal risk.”

Answer… : 

Answer… False. Think of risk of criminal or civil liability, financial risk, employment risk, insurability, stigmatization, or embarrassment in addition to physical risk when deciding if risk is truly minimal.

ERICAhttps://erica.research.utah.edu : 

ERICAhttps://erica.research.utah.edu IRB Web Site www.research.utah.edu/irb

Resources : 

Resources OHRP - http://www.hhs.gov/ohrp/ Regulations and Policy Guidance FDA - http://www.fda.gov/ Information Sheet Guidances Compliance Program Guidance Manual HHS HIPAA Privacy Rule Guidance for HIPAA and Research

Resources : 

Resources IRB Website: Submissions Page IRB Forms and Templates Guidelines A to Z Index Publications IRB Management and Function (Bankert and Amdur) Regulations and Guidance on the Protection of Human Subjects: Investigator, IRB, and Sponsor Responsibilities IRB Member Handbook (Robert Amdur)

Institutional Review Board (IRB) : 

Institutional Review Board (IRB) John Stillman IRB Director (801) 587-9136john.stillman@hsc.utah.edu IRB Main Office (801) 581-3655 IRB Fax (801) 587-9138 Email: irb@hsc.utah.edu Web site: www.research.utah.edu/irb

Office of the Associate Vice-President for Research Integrity : 

Office of the Associate Vice-President for Research Integrity John Stillman Director Institutional Review Board E-Mail: john.stillman@hsc.utah.edu Phone: 587-9136 Office Contact: Front Desk 581-3655

Research Administration Training Series : 

Research Administration Training Series Tony Onofrietti, M.S., CRSS Director of Research Education Research Administration Building (RAB) 75 South 2000 East, #205Salt Lake City, UT 84112-8930 (801) 585-3492tony.onofrietti@hsc.utah.edu www.education.research.utah.edu

IRB Bloopers… Did You Remember to Proofread? : 

IRB Bloopers… Did You Remember to Proofread? “You will receive the benefit of the investigators company.” “If a patient is capable of hearing children, this patient will be required to take a pregnancy test.” “You will not be eligible for this Registry if any of these items apply: You are currentlypsychotic.”

What is Your Position? : 

What is Your Position? Faculty / PI Research Administrator Study Coordinator Nurse Other

What is Your Departmental Affiliation? : 

What is Your Departmental Affiliation? Main Campus Health Sciences Huntsman Cancer Institute PCMC Off-Campus Other

How Long Have You Workedin Your Current Position? : 

How Long Have You Workedin Your Current Position? 0 - 2 years 3 - 5 years 6 - 10 years 10+ years

Course Objectives : 

Course Objectives Background and Regulations Human Research Protection Program Protection of Research Participants Informed Consent Protecting Vulnerable Human Subjects ERICA

Reminder ….. : 

Reminder ….. Please leave yourcompleted evaluation formand the ResponseCard®Thank You! Research Administration Training Series

Slide 61: 

“My challenge to leaders of academic medical centers, university presidents, and everyone else involved in the oversight of… research is to take the responsibility, and the necessary actions to strengthen the conduct of research at their institutions… Above all, [this] means providing IRBs…with the stature, authority and resources they need to do their jobs.” -Donna Shalala, former Secretary, DHHS New England Journal of Medicine, September 2000