GEARING UP FOR AAHRPP

A Presentation for IRB Members – March 2011

Beverley Esparza, CIPAssistant Director, Human Research Protections

2

Learning Objectives – March 2011

Principles, regulations, and statutes

What is Human subject research

Level of risk to subjects determines review process

IRB requirements, composition and authority

Coming in April: Considerations during the IRB review process

3

Principles, Regulations, & Statutes Response to

Research Abuses Nazi atrocities in World War II drew attention to the lack of

international standards on research with human participants and led to the formulation of the Nuremburg Code (1947).

The thalidomide disaster led to the adoption of the "Kefauver Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed consent from potential subjects before administering investigational medications.

The Declaration of Helsinki drafted by the world Medical Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used today.

4

Research Tragedies in the U.S.A.Tuskegee Syphilis Study(1932-72)

5

Tuskegee Syphilis Study The U.S. Public Health Service (now the Center for Disease

Control) conducted a study in Alabama to record natural history of syphilis to justify treatment programs for blacks.

The study involved 600 black men--399 with syphilis and control group.

Researchers told the men they were being treated for "bad blood," a local term used to describe several ailments, including syphilis, anemia, and fatigue.

Compensation: free medical exams, free meals, and burial

insurance

Study projected to last 6 months, actually went on for 40 years.

6

Tuskegee Syphilis Study & The National Research Act of 1974

What went wrong?

No informed consent - Although the men had freely agreed to be examined and treated there is no evidence that researchers had informed them of the study or its real purpose.

Withheld treatment - The men were never given adequate treatment for their disease. Even when penicillin became the drug of choice for syphilis in 1947, researchers did not offer it to the participants.

Participants were never given the choice of quitting the study - even when penicillin became widely used.

In 1973, a class-action lawsuit ended in a settlement that gave more than $9 million to the study participants. As part of the settlement, thegovernment promised to give free medical and burial services to all livingparticipants, including wives, widows, and children who had beeninfected because of the study.

The National Research Act (1974) passed primarily in response to the syphilis study, codified the requirement that human participants in research must be protected and set the stage for the issuance of the Belmont Report.

7

Belmont Principles (1979) Respect for Persons (Be Respectful)

Individuals should be treated as autonomous agents

Individuals with limited autonomy are entitled to protection

Beneficence (Be Nice) Do no harm Minimize risk/maximize benefits

Justice (Be Fair) Fair distribution of risks and benefits of

research

8

Regulations & Statutes Protecting Human Subjects

in ResearchFederal 45 CFR Part 46 – OHRP 21 CFR Parts 50 and 56 – FDA Health Insurance Portability and Accountability Act – HIPAA Family Educational Rights and Privacy Act – FERPA Protection of Pupil Rights Amendment – PPRA

State Health and Safety Code: Protection of Human Subjects in Medical

Experimentation Act Health and Safety Code: Consent for Minors Health and Safety Code: Use of Death Data Records

9

Subpart A: “The Common Rule”The Common Rule is a federal policy regarding Human Subjects Protection that applies to 17 Federal agencies and

offices.

10

DHHS Federal Policy for the Protection of Human

Subjects

Subpart A: Basic HHS Policy “Common Rule”

Subpart B: Pregnant Women, Fetuses and Neonates

Subpart C: Prisoners

Subpart D: Minors (shared by FDA)

45 CFR Part 46 (enforced by the Office of Human Research Protections)

11

What is Human Subject

Research?

When accessing if an activity is human subject research, BOTH DHHS and FDA

regulations must be considered.

First, lets look at DHHS…

12

Human Subject Research - DHHS

IS THE ACTIVITY RESEARCH? DHHS regulations define research at 45 CFR

46.102(d) as follows: Research means a systematic investigation, including research

development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.

ARE HUMAN SUBJECTS INVOLVED? DHHS regulations define a human subject as follows:

A Human Subject is a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual; or (2) identifiable private information. (DHHS)

13

Human Subject Research - DHHS

Definitions…

Intervention includes both physical procedures by which data are gathered (e.g., venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

Interaction includes communication or interpersonal contact between investigator and subject.

Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

14

Human Subject Research - FDAIS THE ACTIVITY RESEARCH? The FDA defines a clinical investigation at 21 CFR 50.3

as follows: Any experiment that involves a test article and one or more

human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit…

ARE HUMAN SUBJECTS INVOLVED? The FDA defines a human subject as follows:

Human subject means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient.

WHEN TESTING THE EFFICACY OF IN-VITRO DEVICES: FDA definition of a human subject includes an individual on whose specimen a device is to be used. This includes those specimens that are anonymous.

15

Human Subject Research

Refer to this checklist: Determining Whether a Proposed Activity is Human Research According to DHHS or FDA Regulatory Definitions

Remember: publication does not equal research

16

Level of Risk Generally Determines Level of Review

Exempt*Chair Confirmation

Expedited*Subcommittee

Convened IRB Meeting-Full Committee

Minimal Risk

RISK*defined by lists in regulations

Virtually No Risk

> Minimal Risk

17

UCI’s Definition of Minimal Risk

• Risk: The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant.

18

IRB Process

19

Composition of the IRBPer federal regulations each IRB is required to have:

• Five members, with varying backgrounds to promote complete and adequate review of research activities.

• One member whose primary concerns are in nonscientific areas.

• One member not otherwise affiliated with the institution and not part of the immediate family of a person who is affiliated with the institution.

• No IRB member may participate in initial or continuing review of any research if the member has a conflicting interest. (See Purple Laminated Sheet)

20

IRB Members Must Disclose Conflict of Interest

Subcommittee and Full Committee: Have on hand IRB Member Conflict of Interest Disclosure laminated sheets (Purple Sheet)

Disclosure requirements

All members disclose annually

HRP Staff create spreadsheet to track conflicts for reviewer assignment purposes

Reviewer Checklist has IRB Member address COI

IRB members leave the room for discussion and vote if they have a conflict (IRB members recuse themselves)

21

UCI’s IRB UCI has three IRB Committees:

IRBs “A” and “B” review biomedical research

IRB “C” reviews social/behavioral research

UCI IRB Members and Alternates are appointed to a three-year renewable term

UCI IRB Chairs & Vice Chairs are appointed to a two-year renewable term (with term limits)

22

IRB “C” – Social / Behavioral In general, a protocol’s hypothesis or

research question determines whether a protocol is reviewed by a biomedical Committee or the social/behavioral Committee.

Social/behavioral research may include prospective collection of biological specimens and/or collection of data via non-invasive measures that customarily may be considered clinical in nature, and involve no greater than minimal risk.

23

IRB “A” & IRB “B” – Biomedical

Research that does not qualify for review by the social/behavioral IRB requires review by one of the biomedical IRB committees.

Research that involves testing the safety and effectiveness of an investigational drug, biologic or medical device always requires review by a biomedical IRB.

24

IRB Authority Protocol Review of all human subjects research

covered by the regulations. IRB must notify the institution and the investigator in writing of its decision Approved as is (A). Require minor changes to secure approval (M).

Revisions can be reviewed and approved by the Chair outside of the Full Committee.

Require substantial revisions and tabled for re-review by Committee (T). Resubmit revised documents to Full Committee/Subcommittee.

Disapproved (D). Rarely occurs only after multiple attempts by IRB to resolve issues. Can only occur at a convened IRB meeting.

25

IRB Authority Conduct Continuing Review Research (annually)

Review progress report of study and subject accruals to reassess actual risks/discomforts to subjects

Research Oversight May observe or have a third party observe the

consent process and/or the research May embargo of publications/presentations or

disqualification of thesis/dissertation May suspend or terminate approval of research

not conducted in accordance with the regulations associated with unexpected serious harm to

subjects

26

IRB Authority – Informed Consent

Verify that consent process will be conducted in accordance with the regulations

Ensure all elements of consent are included in consent document

Review and approve consent document or verify that request for waiver or alteration (use of information sheet, short form) is in accordance with the regulations

When involving children, if 45 CFR 46.404 or 45 CRF 46.405, indicate if 1 signature is acceptable

27

Learning Objectives – Scheduled for April 2011

Considerations During IRB Review

Conflict of interest

Devices

Drugs

Quality improvement

28