45 CFR Part 46

Question 1

Which part of 45 CRF Part 46 is called “The Common Rule”?

Answer 1

Subpart A

Question 2

What is Subpart A of 45 CFR Part 46 called?

Answer 2

The Common Rule

Question 3

What is Subpart B of 45 CFR Part 46 about?

Answer 3

Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research

Question 4

What is Subpart C of 45 CFR Part 46 about?

Answer 4

Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects

Question 5

What is Subpart D of 45 CFR Part 46 about?

Answer 5

Additional Protections for Children Involved as Subjects in Research

Question 6

What is Subpart E of 45 CFR Part 46 about?

Answer 6

Registration of Institutional Review Boards

Question 7

What portion of 45 CFR 46 deals with protection of pregnant women, fetuses, and neonates?

Answer 7

Subpart B

Question 8

What portion of 45 CFR 46 deals with protection of prisoners?

Answer 8

Subpart C

Question 9

What portion of 45 CFR 46 deals with protection of children?

Answer 9

Subpart D

Question 10

What portion of 45 CFR 46 deals with registration of IRBs?

Answer 10

Subpart E

Question 11

Which part of 45 CFR 46 matches another CFR? And which CFR does it match?

Answer 11

45 CFR 46.111 matches 21 CFR 56.111

Question 12

What are the 8 categories of research eligible for IRB exempt status?

Answer 12

1. Research in educational settings w/normal educational practices that won’t adversely affect the students’ learning opportunity or assessment of the educators.
2. Research w/educational tests, surveys, interviews, or observation of public behavior if 1 of 3 is met: information recorded is not easily identifiable, disclosure wouldn’t put subject at increased risk of liability or personal damage, or info is recorded in a way so that the human subject’s identity can be ascertained and the IRB can conduct a limited review. (This only applies to children if the investigator does not participate in the observed activities).
3. Benign behavioral interventions in adults (verbal, written or audiovisual) and subject prospectively agrees. (And at least 1 of the 3 criteria listed in #2 above). Deceit is not allowed unless the subject agrees to ahead of time to being mislead about the nature or purpose of the research.
4. Secondary research for which consent is not required. Uses identifiable private info or biospecimens if the info or biospecimens are publicly available or the information is recorded so the subject cannot be readily identified, the investigator doesn’t contact them, and they do not re-identify them.
5. Research & projects conducted or supported by federal departments/ agencies for public benefit or service projects.
6. Taste & food quality evaluation and consumer acceptance studies (wholesome food w/out additives or ingredients /contaminants at or below safe levels per FDA / EPA / Food Safety & Inspection Service.
7. Storage or maintenance for secondary research or which broad consent is required.
8. Secondary Research for which broad consent is required. (Broad consent was obtained, documentation of consent or waiver of documentation obtained, IRB conducts limited review and determined research meets scope of the broad consent, investigator does not return results to subjects).

Question 13

What is the “point” of 45 CFR 46?

Answer 13

Protection of human subjects

Question 14

What are 45 CFR 46.111 and 21 CFR 56.111 about?

Answer 14

Criteria for IRB approval of research

Question 15

What are the three types of IRB review?

Answer 15

Exempt, Expedited, and Convened (Full Committee). “Limited review” is a subset of Exempt review.

Question 16

Which types of Exempt research sometimes or always need Limited Review?

Answer 16

SOMETIMES need Limited Review:
Category 2 (Educational tests/surveys/interviews/observing public behavior)

Category 3 (Benign behavioral interventions in adults, collecting verbal/written/audiovisual responses)

ONLY IF the recorded information could readily be used to identify the subjects. Limited review must determine whether requirements of 46.111.7 (adequate privacy/confidentiality provisions) are met.

ALWAYS need Limited Review:
Category 7 (Storage of identifiable private info/biospecimens for secondary research for which broad consent IS required). Limited review must determine that broad consent is obtained/documented, and that any change in storage/maintenance protects privacy/confidentiality.

Category 8 (Secondary research with identifiable private info/biospecimens for which broad consent IS required). Limited review must determine whether requirements of 46.111.7 (adequate privacy/confidentiality provisions) are met.

Question 17

Which types of Exempt research do NOT need Limited Review?

Answer 17

Category 1: Research in educational setting with normal educational practices that aren’t likely to adversely impact students’ ability to learn or assessment of educators
Category 4: Secondary research for which consent isn’t required.
Category 5: Research by a Federal department to examine public services.
Category 6: Taste/food quality evaluation and consumer acceptance studies

Question 18

What are the types of secondary research for which consent isn’t required?

Answer 18

Category 4:
1) identifiable info is publicly available
2) info isn’t readily identifiable and won’t be re-identified
3) info for health care operations/public health activities/purposes
4) research done by/for a Federal department using government created/collected info that was obtained for non-research purposes.

Question 19

What are the potential outcomes of an IRB vote?

Answer 19

1) Approve
2) Require modifications (modifications may require review by one IRB member for approval or require another review by the convened IRB)
3) Disapproved
4) Table or Defer - Used for example if they run out of time or lose a quorum. This is not a required option per the CFR but included by many IRBs

Question 20

Groups susceptible to coercion or undue influence

Answer 20

Children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantages persons

Question 21

Nine elements of informed consent (per 45 CFR 46)

Answer 21

1) Statement that the study involves research
2) Description of foreseeable risks or discomforts
3) Description of expected benefits
4) Disclosure of appropriate alternatives that may be advantageous
5) Description of the extent confidentiality will be maintained
6) If more than minimal risk - Explanation of any compensation and access to medical treatments for injuries
7) Whom to contact with questions about the research, subject rights, and in the event of injury
8) Statement that research is voluntary, no loss of benefits for not participating, & can end at any time
9) Statement about how biospecimens will be identified and if they will be distributed or used for future research

Question 22

Additional elements of consent to include if relevant

Answer 22

1) Statement that there may be unforeseeable risks
2) Circumstances under which participation may be terminated
3) Approximate # of subjects in the study
4) Statement that biospecimens may be used for commercial profit and the subject will or will not share in the profit
5) Consequences for withdrawal
6) Any additional costs for participating
7) Statement that significant new findings that may relate to willingness to participate will be provided
8) Statement regarding whether clinically relevant research results will be disclosed to the subject (and when)
9) If there are biospecimens, whether the research will or might include whole genome sequencing

Question 23

When can broad consent be used?

Answer 23

For the storage, maintenance, and secondary research use of identifiable private information and identifiable biospecimens

Question 24

Elements of broad consent

Answer 24

• Risks
• Benefits
• Confidentiality
• Voluntary participation
• Commercial profit
• Whole genome sequencing
• Broad description of the types of research that may be conducted
• Description of information or biospecimens to be used
• Length of maintenance/storage/use
• Details provided re: subsequent research?
• Clinically relevant results disclosed?
• Contact information

Question 25

What is the topic of 45 CFR 46.116?

Answer 25

Broad consent

Question 26

HHS regulations for allowing waiver or alteration of informed consent

Answer 26

• Government Projects (evaluate/study projects for public benefit or service programs, procedures for obtaining benefits/services under those programs, changes or alternatives, changes in methods or payments for benefits/services, cannot be carried out without waiver)
• General waivers and alterations (No more than minimal risk, cannot be done without a waiver, any identifiable private info or samples need to be identifiable to practicably do the research, no adverse affects to rights/welfare of subjects, when appropriate provide pertinent info after)
• Screening, recruiting, or determining eligibility

Question 27

When does the HHS allow waiver of signed consent / use of oral consent?

Answer 27

• Consent would be the only link between research and the subject and principle risk to the subjects would be breach of confidentiality
• Minimal risk of harm and no procedures requiring consent outside context of the study
• Subjects (or LAR) are members of a distinct cultural group or community in which signing forms is not the norm, no more than minimal risk, and appropriate alternative mechanism for documenting consent was obtained.

IRB may require a written summary be provided.

The FDA only cares about research being minimal risk and research involving no procedures requiring consent outside context of the study.

Question 28

What do HHS regulations require regarding electronic consents

Answer 28

Electronic consents are permitted. A written copy must be given to the person signing the consent (either paper or electronic format is okay)

Question 29

How do the HHS requirements for consent differ from the FDA requirements for consent?

Answer 29

HHS requires that the information in consents be understandable to the subject and presented in a way that facilitates comprehension.

Question 30

What does 45 CFR 46 require regarding public availability of trial information?

Answer 30

45 CFR 46 requires one consent form per clinical trial be posted to a federal website for clinical trials conducted or supported by a federal department or agency. This is not required by the FDA or ICH E6

Question 31

What is 45 CFR 46 Subpart D section 46.404 about?

Answer 31

Research with children not involving greater than minimal risk.

“HHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in § 46.408.”

Requires at least one parent’s consent (IRB can allow just one parent).

Question 32

What is 45 CFR 46 Subpart D section 46.405 about?

Answer 32

Research with children involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.

1) Risk must be justified by potential benefit to subjects.
2) Relation of risks to benefits is as favorable as alternatives.
3) Provision to request child’s assent and parents’ permission.

Requires at least one parent’s consent (IRB can allow just one parent)

Question 33

What is 45 CFR 46 Subpart D section 46.406 about?

Answer 33

Research with children involving greater than minimal risk and no prospect of direct benefit to the individual subjects.

1) No more than minor increase over minimal risk (not defined, but, no serious risk to health/safety).
2) Risk commensurate with inherent risks of actual medical situation.
3) Likely to yield vital knowledge about the disease/condition.

Requires both parents’ consent (unless other parent not applicable/available).

Question 34

What is 45 CFR 46 Subpart D section 46.407 about?

Answer 34

Research with children otherwise not approvable.

Must be reviewed by a panel of experts appointed by secretary of DHHS

Requires both parents’ consent (unless other parent not applicable/available).

Question 35

How does the FDA guidance about children in research differ from the DHHS guidance?

Answer 35

FDA regulation does not allow waiver of parental permission except in emergency research.

DHHS allows waiver, but only for studies approvable as minimal risk (45 CFR 46.4064).

Question 36

What types of studies does OHRP have jurisdiction over?

Answer 36

OHRP has jurisdiction over clinical trials that use HHS (US Department of Health and Human Services) funds. Organizations receiving HHS funds must file an FWA assuring OHRP it will follow regulations for human subjects protection (45 CFR 46)

Question 37

How is OHRP’s oversight managed?

Answer 37

OHRP oversight is mostly conducted and resolved through correspondence with organizations, targeted to the IRB, but they also do approximately 10 site visits per year.

Question 38

What happens after OHRP reviews compliance of a site?

Answer 38

A Determination Letter is issued. The determination letter is posted on OHRP’s website. Results can include:
- Organization is in compliance
- Improvements suggested
- Assurance is restricted, suspended, or withdrawn
- Temporary or permanent suspension of an investigator recommended
- Debarment recommended (A government wide sanction against an institution or investigator)
- OHRP refers the matter to another federal department or agency for further review or action.

Question 39

What is the “Final Rule”?

Answer 39

Updates to 45 CFR 46 subpart A (the common rule) that added a requirement for key information to be presented in a clear and concise manner at the beginning of consents.

Key info:
- The consent is for research and participation is voluntary
- The purpose of the study, the duration of participation, and procedures
- Reasonable foreseeable risks and discomforts
- Benefits to the subject or to others that may reasonably be expected
- Appropriate alternative procedures or courses of treatment, if any, which may be advantageous