Levels of IRB Review

It is important to note that “exempt” does not always mean exempt from all of the Common Rule requirements (HHS 2017). For example, under the 2018 requirements, the new exempt Category 7 includes specific regulatory requirements of broad consent and limited Institutional Review Board (IRB) review as a condition of being exempt from other regulatory requirements.

Below are the eight categories from the 2018 requirements.

Category 1: Research in Established or Commonly Accepted Educational Settings

This category has been amended from the pre-2018 rule, formerly 46.101(b)(1), to include a condition that the research is not likely to have adverse impacts on students’ opportunity to learn required educational content or the assessment of educators who provide instruction (HHS 2017). The exemption may only be used for studies about normal educational practices.

Category 2: Educational Tests, Surveys, Interviews, Observations of Public Behavior

The Final Rule (HHS 2017) allows for exemption as long as one of three criteria is met:

1. Information Obtained is not identifiable
2. Disclosure outside of the research would not put subjects at risk of harm
3. Information obtained can be identifiable, but the IRB has a limited IRB review in keeping with 46.111(a)(7), which related to there being adequate provisions for protecting privacy and maintain confidentiality.

Category 3: Benign Behavioral Interventions in Conjunction with the Collection of Information From Adult Subjects

The Final Rule defines benign behavioral interventions as “brief in duration, harmless, painless, not physically invasive, not likely to have a significant adverse lasting impact on the subjects, and the investigator has no reason to think the subjects will find the interventions offensive or embarrassing” (HHS 2017).

Category 4: Secondary Research for Which Consent is Not Required

This category covers secondary research uses of identifiable private information or identifiable biospecimens. Category 4 does not require informed consent if at least one of the criteria listed below is met (HHS 2017).

1. Use of publicly available identifiable private information or identifiable biospecimens;
2. Information recorded by the investigator in such a way that the identity of the subjects cannot be readily ascertained, and the investigator will neither contact the subjects nor re-identify subjects;
3. Reseat use of identifiable health information when that use is regulated by HIPAA as healthcare operations, research or public health activities and purposes as those terms are defined by HIPAA; and,
4. Analysis of data on behalf of a federal agency or department-as opposed to an investigator-initiated analysis of federally supplied data-if the requirements or certain federal laws are met.

Category 5: Research and Demonstration Projects that Are Conducted or Supported by a Federal Department or Agency

This category:

1. Allows research supported by a federal agency (not just conducted) to qualify for this exemption
2. Provides examples of the types of public benefit and service programs covered by the exemption
3. Clarifies the federal components for which the exempt research is subject to approval (for example, delegated subordinate agencies)

Category 6: Taste and Food Quality Evaluation and Consumer Acceptance Studies

Taste and food quality evaluation and consumer acceptance studies,

1. if wholesome foods without additives are consumed or
2. if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

Category 7: Storage or Maintenance for Secondary Use for Which Broad Consent is Required

This category is for the storage of identifiable biospecimens and identifiable private information, prior to secondary analysis. The storage and maintenance may be exempt if the “IRB conduct a limited IRB review to ensure that adequate provisions are in place to protect the privacy of subjects and maintain the confidentiality of data,” and if broad consent is obtained (HHS 2017).

Category 8: Secondary Research for Which Broad Consent is Required

This category allows the secondary analysis of existing private identifiable data and identifiable biospecimens provided broad consent was secured and the documentation of consent was either secured or waived. The IRB must also conduct a limited IRB review to determine that “there are adequate provisions to protect the privacy of subjects and maintain the confidentiality of data as noted in 46.111(a)(7),” and that the use is within the scope of the broad consent (HHS 2017). Category 8 also stipulates that the investigator does not return individual research results to subjects; however, the exemption does not prevent investigators from returning results if required by law.

Similar to Category 7, this category may be more widely used by biomedical researchers. However, social and Behavioral researchers may also use identifiable private information for secondary analysis.

Under four of the new exempt categories created by the U.S. Department of Health and Human Services’ (HHS) Final Rule (HHS 2017), research activity may be required to undergo limited Institutional Review Board (IRB) review as a condition of exemption.

Limited IRB Review is Required by Exempt Category 2(iii)

3. Research that only includes interactions involving educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior (including visual or auditory recording) if at least one of the following criteria is met:
   1. The information obtained is recorded by the investigator in such a manner that the identity of the human subjects cannot readily be ascertained, directly or through identifiers linked to the subjects;
   2. Any disclosure of the human subjects’ responses outside the research would not reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, educational advancement, or reputation; or
   3. The information obtained is recorded by the investigator in such a manner that the identity of the human subjects can readily be ascertained, directly or through identifiers linked to the subjects, and an IRB conducts a limited IRB review to make the determination required by § __.111(a)(7) (HHS 2017).

Limited IRB Review is Required by Exempt Category 3(i)(C)

3. Research involving benign behavioral interventions in conjunction with the collection of information from an adult subject through verbal or written responses (including data entry) or audiovisual recording if the subject prospectively agrees to the intervention and information collection and at least one of the following criteria is met:
   1. The information obtained is recorded by the investigator in such a manner that the identity of the human subjects cannot readily be ascertained, directly or through identifiers linked to the subjects;
   2. Any disclosure of the human subjects’ responses outside the research would not reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, educational advancement, or reputation; or
   3. The information obtained is recorded by the investigator in such a manner that the identity of the human subjects can readily be ascertained, directly or through identifiers linked to the subjects, and an IRB conducts a limited IRB review to make the determination required by § __.111(a)(7) (HHS 2017).

Limited IRB Review is Required by Exempt Category 7

7. Storage or maintenance for secondary research for which broad consent is required: Storage or maintenance of identifiable private information or identifiable biospecimens for potential secondary research use if an IRB conducts a limited IRB review and makes the determinations required by § __.111(a)(8) (HHS 2017).

Limited IRB Review is Required by Exempt Category 8

1. Secondary research for which broad consent is required: Research involving the use of identifiable private information or identifiable biospecimens for secondary research use, if the following criteria are met:
   1. Broad consent for the storage, maintenance, and secondary research use of the identifiable private information or identifiable biospecimens was obtained in accordance with § __.116(a)(1) through (4), (a)(6), and (d);
   2. Documentation of informed consent or waiver of documentation of consent was obtained in accordance with § __.117;
   3. An IRB conducts a limited IRB review and makes the determination required by § __.111(a)(7) and makes the determination that the research to be conducted is within the scope of the broad consent referenced in paragraph (d)(8)(i) of this section; and
   4. The investigator does not include returning individual research results to subjects as part of the study plan. This provision does not prevent an investigator from abiding by any legal requirements to return individual research results (HHS 2017).

The Limited IRB review process is intended to “ensure that there are adequate privacy safeguards for identifiable private information and identifiable biospecimens” (HHS 2017).

In addition to other criteria, limited IRB review is also needed to ensure respect for subject’s autonomy and that the research conducted is within the scope of broad consent (HHS 2017) for both:

• Category 7 (the category that requires broad consent for storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens)
• Category 8 (the category that requires broad consent for secondary research use of identifiable private information or identifiable biospecimens)

Limited IRB review involves making and documenting these determinations. It is a conditional review for exemption.

Research activities that involve no more than minimal risk, minor changes in previously approved research during the period (of one year or less) for which approval is authorized, and research that has been approved by the IRB of another institution may be considered for expedited review.

Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure (63 FR 60364-60367, November 9, 1998).

Applicability:

1. Research activities that (1) present no more than minimal risk to human subjects, and (2) involve only procedures listed in one or more of the following Research Categories (see below), may be reviewed by the IRB through the expedited review procedures authorized by 45 CFR §46.110 and 21 CFR §56.110. The activities listed should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedure when the specific circumstances of the proposed research involve no more than minimal risk to human subjects.
2. The categories in this list apply regardless of the age of subjects, except as noted.
3. The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.
4. The expedited review procedure may not be used for classified research involving human subjects.

The standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review.

Research Categories

1. Clinical studies of drugs and medical devices only when condition (a) or (b) is met.
   1. Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.)
   2. Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.
2. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:
   1. from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8-week period and collection may not occur more frequently than 2 times per week; or
   2. from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8-week period and collection may not occur more frequently than 2 times per week.
3. Prospective collection of biological specimens* for research purposes by noninvasive means.
4. Collection of data through noninvasive procedures** (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)
5. Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis). (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR §46.101(b)(4). This listing refers only to research that is not exempt.)
6. Collection of data from voice, video, digital, or image recordings made for research purposes.
7. Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR §46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.)
8. Continuing review of research previously approved by the convened IRB as follows:
   • where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or
   • where no subjects have been enrolled and no additional risks have been identified; or
   • where the remaining research activities are limited to data analysis.
9. Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.

*Examples: (a) hair and nail clippings in a nondisfiguring manner; (b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; (c) permanent teeth if routine patient care indicates a need for extraction; (d) excreta and external secretions (including sweat); (e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) supra- and sub-gingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques; (i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after saline mist nebulization.

**Examples: (a) physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subjects’ privacy; (b) weighing or testing sensory acuity; (c) magnetic resonance imaging; (d) electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.