Institutional Review Board / Institutional Ethics Committee (IRB/IEC) Roles and Responsibilities (7% - 11%)

Institutional review board (IRB) definition:

Committee that review, approve, and monitor clinical trial.

Primary goal of IRB:

Protect the right and safety of human subjects who participate in clinical trial.

Ethics review committee (ERC) definition:

Term used for IRB for countries outside the United States.

FDA 21 CFR 56.102(g) defines IRB as:

The Institutional Review Board (IRB) means any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects. The term has the same meaning as the phrase institutional review committee as used in section 520(g) of the act.

Other notes regarding IRBs:

1. IRB can be a part of an institution or centralized.

2. IRBs that are affiliated to an institution often serve only that institution.

3. Centralized IRBs (also known as independent IRBs) do not have affiliation to any institution.

4. Centralized IRBs can review, approve, and monitor any clinical trials that are within the geographical area under their regulatory allowance.

5. One of the largest centralized IRBs in the United States is Western Institutional Review Board (WIRB) (Puyallup, WA, USA).

Responsibilities of an IRB/IEC:

1. Review, approve, or disapprove all research activities under its jurisdiction based on benefits and risks evaluation and conduct continuing review of research activities at least once per year

2. Oversee informed consent process and all documents to be used to present to subjects

3. Determine when and at what level of informed consent is required or waived

4. Evaluate amount and method of payment to avoid coercion.

5. Monitor any protocol deviations and / or any safety hazards to subjects

6. Terminate any research that is not being conducted following regulations or research that caused unexpected serious harm to subjects

7. Report any significant issues to appropriate agencies as required by local, state, and federal reporting requirements.

8. Maintain IRB compliance in term of its policies and standard of practice with the requirements of all relevant regulatory agencies

21 CFR 56.111 (a) requires the following criteria that an IRB committee must find when approving a study:

1. Risks are minimized

2. Risks are reasonable for the anticipated benefits

3. Selection of subjects is equitable

4. Informed consent will be sought following 45 CFR 46.116 or 21 CFR 50.25 and documented following 45 CFR 46.117 or 21 CFR 50.27

5. The research plan must make adequate provisions for monitoring the data collected to ensure the safety of subjects (e.g. whether data and safety monitoring is required)

6. Privacy of subjects and confidentiality of data is protected

7. Additional safeguards are in placed to protect vulnerable populations such as children pregnant women, and prisoners.

Additional considerations for an IRB committee:

1. Research has valid scientific rationale

2. Principal investigator and co-investigator(s) have qualifications, experience, training, and time to conduct and oversee the research study

3. There are qualified staff, facilities, support services, and other resources needed to conduct the study

4. There are study population available to allow for sufficient recruitment

21 CFR 56.108 (a) requires IRBs to follow written procedures:

This requirement includes the preparation, maintenance, and implementation of written procedures for:

1. Conducting initial and continuing review of research

2. Reporting its findings and actions to the investigator and the institution

3. Determining which projects require review more often than annually and which projects need verification from sources other than the investigator that no material changes have occurred since previous review

4. Ensuring prompt reporting to the IRB of changes in research activity

5. Ensuring that changes in approved research are not initiated without prior IRB review and approval, except to eliminate immediate hazards to the human subjects

6. Ensuring prompt reporting to the IRB, Sponsor, and the Food and Drug Administration, and applicable regulatory authorities, of any unanticipated problems involving risks to human subjects or others, any instances of serious or continuing noncompliance with regulations or requirements any suspension or termination of IRB approval for the research

21 CFR 56.107 summarizes the criteria for IRB membership:

1. Have five or more members with different backgrounds, experience, and expertise, diversity (race, gender, cultural backgrounds, and community attitudes).

2. The members must include persons knowledgeable in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice.

(For example, if the IRB reviews clinical trial that involves a vulnerable population (e.g children, prisoners, pregnant women, etc.), the IRB should have members who have working knowledge about the subject group.)

Also- at least one member who has scientific expertise to evaluate the clinical trial. At least one member who is non-scientific. At least one member who is not affiliated with the institution and is not part of the immediate family of a person affiliated with the institution.

21 CFR 56.109 describes an approach for IRB review of research as follows:

1. An IRB shall review, approve, require modifications, or disapprove all research activities

2. An IRB shall require that information given to subjects as part of informed consent is in accordance with 21 CFR 50.25

3. An IRB shall require documentation of informed consent except:
- Study that meet informed consent waiver requirement where the research presents no more than minimal risk of harm to subjects and involves no procedures where written consent is normally required in clinical setting. Note: IRB may require a written statement about the research to be provided to subjects
-Emergency research that meet requirements under 21 CFR 50.24

4. An IRB shall notify investigators and the institution in writing of its decision (approval, disapproval, modifications required, etc.)

5. An IRB shall conduct continuing review of research at intervals appropriate to the degree of risk, but not less than once per year. IRB shall have authority to observe or have a third party observe the consent process and the research.

6. An IRB shall provide in writing to the sponsor of research involving an exception to informed consent under a copy of information that has been publicly disclosed to communities

7. For study involving children, an IRB must determine that the research study is in compliance with 21 CFR 50 subpart D

IRB Scheduling of Meetings:

The IRB should meet at regular intervals to ensure timely review of research studies. A schedule of regular IRB meetings should be established by each IRB and made available to public to help investigators in estimating time required for research review.

Review of an IRB Application:

The IRB should review the items submitted in the IRB application from investigator(s)

The IRB application should contain all the information necessary to evaluate the study, including:

1. Purpose of the research

2. Scientific rationale behind the study

3. Research setting where the study will take place

4. Whether prospective participants will be vulnerable to coercion or undue influence

5. Inclusion and exclusion criteria

6. Recruitment and enrollment procedures

7. Method of advertising and the content of the advertising

8. Time required for participation

9. Study procedures to be performed

10. Payment amount and payment schedule and the risks and potential benefits of the research.

IRB approval period

1 year

Expedited IRB Review

Certain research may be reviewed and approved by the IRB under expedited review process if it is considered Minimal risk research

Minimal risk definition

Minimal risk means that 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.

An IRB may use the expedited review process if either or both of the following is met:

1. Some or all of the research involve no more than minimal risk

2. Minor changes in previously approved research during the approval period (of 1 year or less)

Expedited review procedure allows:

Review by the IRB chairperson or by one or more experienced reviewers designated by the IRB chairperson. The reviewers may exercise all of the authorities of the IRB. However, the reviewers may not disapprove the research. Disapproval of a research can only be done with the non-expedited review procedure

Continuing IRB Review:

Continuing review and re-approval of a research study is needed-
IRB should notify investigator(s) in advance of the approaching annual continuing renewal prior to the approval expiration date. Regardless of any availability of the notification from the IRB, it is the investigator's responsibility to keep a record of the IRB approval expiration date and submit required information for a renewal application.

Three types of medical device studies are listed under the Investigational Device Exemptions (IDE) regulation (21 CFR 812):

1. Significant risk (SR)

2. Non-significant risk (NSR)

3. Exempt studies

Significant Risk (SR) defined by FDA:

1. Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject

2. Is purported or represented to be for use supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject

3. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject

4. Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

Non-significant Risk (NSR) defined by FDA:

A non-significant risk device is an investigational device that does not meet the Significant Risk requirement (not the same as minimal risk)

Minimal risk studies:

do not increase the likelihood of injury (expedited review can be used)

Exempt Studies:

1. A device in commercial distribution on or before May 28, 1976.

2. A device that FDA deemed substantially equivalent to a device in criteria 1 above

3. A diagnostic device where the testing is non-invasive, does not require an invasive sampling procedure that presents significant risk, does not by design or intention introduce energy into a subject, and is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.

4. A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk.

5. A device intended solely for veterinary use.

6. A device shipped solely for research on or with laboratory animals

Clinical study pathway for significant risk (SR):

1. IRB approval prior to conducting clinical trials and continuing review by the IRB is required. Informed consent must also be obtained following 21 CFR 50

2. Sponsors are responsible for making the initial determination whether the device under study is SR or NSR and present it to the Institutional Review Board (IRB)

3. FDA may also be available to help the sponsor, clinical investigator, IRB in determining the risk of the device.

4. SR studies must meet the full IDE requirements under 21 CFR 812. SR studies are first submitted to the FDA for review and approval of the IDE application, and then to the IRB.

5. If the IRB determines that the device is SR, then the IRB will request that the sponsor submit an IDE application to the FDA. Written approval obtained from the FDA will be needed before the research can start.

Clinical study pathway for Non-significant risk (NSR):

1. IRB approval prior to conducting clinical trials and continuing review by the IRB is required. Informed consent must also be obtained following 21 CFR 50

2. Sponsors are responsible for making the initial determination whether the device under study is SR or NSR and present it to the Institutional Review Board (IRB)

3. FDA may also be available to help the sponsor, clinical investigator, IRB in determining the risk of the device.

4. NSR studies need to meet the abbreviated IDE requirements under 21 CFR 812.2 (b). NSR studies do not required an IDE during initial IRB application submission. IRB will determine whether it considers the device to be SR or NSR.

5. If the IRB determines that the device is NSR, the study may proceed after IRB approval following the abbreviated IDE regulations without the need for further FDA review and approval.

IRB must prepare and maintain the following documentation of IRB activities: research proposals

Copies of all research proposals reviewed and their attachments:

1. Scientific evaluations

2. Approved sample consent documents

3. Progress reports submitted by investigators

4. Reports of injuries to subjects

IRB must prepare and maintain the following documentation of IRB activities: meeting minutes

Minutes of IRB meetings which show:

1. Attendance at the meetings

2. Actions taken by the IRB

3. The vote on these actions including the number of members voting for, against, and abstaining

4. The basis for requiring changes in or disapproving research

5. A written summary of the discussion of controverted issues and their resolution

IRB must prepare and maintain the following documentation of IRB activities: Continuing review

Records of continuing review activities

IRB must prepare and maintain the following documentation of IRB activities: correspondence

Copies of all correspondence between the IRB and the investigators

IRB must prepare and maintain the following documentation of IRB activities: IRB Members

A list of IRB members identified by:

1. Name

2. Degrees

3. Representative capacity

4. Indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to IRB deliberations

5. Any employment or other relationship between each member and the institution

IRB must prepare and maintain the following documentation of IRB activities: procedures

Written procedures for the IRB as required by 21 CFR 56.108 (a and b)

IRB must prepare and maintain the following documentation of IRB activities: findings

Statements of significant new findings provided to subjects 21 CFR 50.25

Considerations for an IRB when developing a document tracking system:

1. All IRB records should be kept secure in locked filing cabinets or locked storage rooms.

2. Electronic records should be kept secure in access protected drive.

3. Access to IRB records should be limited to staff with appropriate clearance.

4. Paper back up copy and electronic back up of documents should be stored in a way that is safe from hazard (e.g. fireproof cabinet) and can be readily accessible.

5. Written procedures for documentation and maintenance of IRB documents should be developed and implemented.

6. Commercially available electronic document system should meet the above considerations.

Record Retention requirements (IRB / IEC):

1. IRB records be retained for at least three years after completion of the research.

2. The records should be accessible for inspection and copying by authorized representatives of the Food and Drug Administration (FDA) at reasonable times and in a reasonable manner.

3. FDA may refuse to consider a clinical investigation in support of an application for a research or marketing permit if the institution or the IRB that reviewed the investigation refuses to allow an inspection above (21 CFR 56.115 (c))