Chapter 6: Types of IRB Submissions

The initial determination of whether a study is or is not human subjects research is made by referring to the federal (45 CFR 46) definitions of human subjects and research. Any activity that meets OHRP definitions of both “research” and “human subjects” or the FDA definitions of both “clinical investigation” and “human subjects” is considered human subjects research. FDA and DOD have different definitions.

What is Human Subjects Research (HSR)

• • Human Subjects Definitions

    The following are definitions used by OHRP, FDA, and DOD:

    • • OHRP(46.102(e)1-4)
        A human subject is a living individual about whom an investigator (whether professional or student) conducting research
        1. Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or
        2. Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.”

    “Identifiable biospecimens” and “identifiable private information”– is a biospecimen or private information for which the identity of the subject is or may be readily be ascertained.

    Intervention includes both physical procedures by which Information or biospecimens are gathered (for example, 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, information that has been provided for specific purposes by an individual and that the individual reasonably expects the information will not be made public e.g., a medical record).

  • FDA(21 part 50.3)
    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 an investigational device is used on a specimen, the specimen may be considered a “human subject” under FDA definitions.

  • Department of Defense (DOD)[32 CFR 219.102(f) reference (c)]
    “Research Involving a Human Being as an Experimental Subject” is: “An activity, for research purposes, where there is an intervention or interaction with a human being for the primary purpose of obtaining data regarding the effect of the intervention or interaction. Examples of interventions or interactions include, but are not limited to, a physical procedure, a drug, a manipulation of the subject or subject’s environment, the withholding of an intervention that would have been undertaken if not for the research purpose.” (DODD 3216.02, E2.1.3)

Defining Research

• • • OHRP 46.102(l)
      Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes.
    • 82 Fed. Reg. at 7175
      The following IS considered research per the Common Rule 2018: ‘‘studies using methods such as participant observation and ethnographic studies, in which investigators gather information from individuals in order to understand their beliefs, customs, and practices, and the findings apply to the studied community or group, and not just the individuals from whom the information was obtained’’

Clinical Trial / Clinical Investigation Defined

• • OHRP 46.102(b)
    Clinical trial means a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes.
  • FDA (21 part 50.3)
    A “clinical investigation” is “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 FDA under section 505(i)* or 520(g)** of the act, or is not subject to requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of part 58 of this chapter, regarding non-clinical laboratory studies.”

    *505(i) any use of a drug other than the use of an approved drug in the course of medical practice

    **520(g) any use of a medical device other than the use of an approved medical device in the course of medical practice.
    and

NIH definition of “clinical trial”
A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. (45 CFR 46.102(d)(f))

The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial.

An “intervention” is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. Examples include: drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies.

“Health-related biomedical or behavioral outcome” is defined as the pre- specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life. Examples include: positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression); positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers; reading comprehension and /or information retention); positive or negative changes to disease processes; positive or negative changes to health-related behaviors; and, positive or negative changes to quality of life.

What is Not Human Subjects Research

Some activities do not meet the federal definition of research and/or the federal definition of human subjects according to OHRP and FDA regulations. Examples of research that are considered “Not Human Subjects Research” are classroom research, institutional research, oral history, research with autopsy specimens, program evaluations, quality improvement projects and literature searches.

Federal regulation (46.102 (l) deems the following activities NOT to be research: Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research, and historical scholarship), public health surveillance activities, collection and analysis of information for criminal justice agencies or authorized operational activities of national security agencies.

If a study does not meet the definition of human subjects and/or research, and a researcher requires a determination from the IRB, submit an application via iStar (iStar item 1.1). In response to the application, the IRB can issue a letter stating that the study does not qualify as human subjects research and therefore does not need to be approved by the IRB. A non-human subjects, or human subjects research, determination cannot be made retroactively. Refer to Section 6.5 – Not Human Subjects Research Submissions. To discuss whether the study requires review by the IRB, contact the IRB office.

Research involving autopsy materials or cadavers is not considered human subjects research and does not require review by the IRB. The activity may still be subject to the Health Insurance Portability and Accountability Act (HIPAA) regulations. Contact the IRB office for questions.

The intent to publish in professional journals and/or present at national or regional meetings does not automatically make a project human subjects research requiring IRB review and approval. If you have questions regarding publishing or presenting, please contact the IRB office for further guidance.

The OHRP Human Subjects Regulations Decision Charts “are intended to aid those who need to decide if an activity is research involving human subjects that must be reviewed by an institutional review board (IRB) and whether informed consent or the documentation of informed consent can be waived under the 2018 Requirements found for the U.S. Department of Health and Human Services (HHS) at 45 CFR part 46, Subpart A.” Chart link: https://www.hhs.gov/ohrp/regulations-and-policy/decision- charts-2018/index.html

Primary Investigator and Self-experimentation

Application of submission for USC IRB review is required for human subjects studies entailing self-experimentation.

USC policy does not distinguish between self-experimentation and research on subjects who are recruited for a specific project. As part of its commitment to the protection of the rights and welfare of individuals participating in research, USC’s Research Protection Program requires investigators who wish to act as participants in their own studies to submit for IRB review and approval – following standard procedures as outlined in the IRB policy. All human subject research must be reviewed to assure safety of those involved and the integrity of the research at the university. While researchers may be aware of the risks of self-experimentation, they may also be more willing to accept risks that are ill-advised. Application for review with the IRB office allows a neutral third party to raise concerns and/or propose measures to promote the welfare of researchers.

Distinctions Between Biomedical and Social Behavioral Research

Biomedical Research

Biomedical research refers to the study of specific diseases and conditions (mental or physical), including,

• the detection
• the cause
• the prophylaxis
• the treatment and rehabilitation of persons
• the design of methods
• the drugs and devices used to diagnose, support, and maintain the individual during and after treatment for specific diseases or conditions and/or the scientific investigation required to understand the underlying life processes which affect disease and human well-being, including such areas as cellular and molecular bases of diseases, genetics, immunology.

This research is typically quantitative and not qualitative.*  Biomedical research is often patient-oriented, and the research involves:

• Studies of mechanisms of human disease
• Studies of therapies or interventions for disease
• Clinical trials involving drugs and devices that are FDA regulated (see definitions of clinical trial)
• Studies to develop new technology related to disease and human well-being

Social Behavioral Research

Social-behavioral research refers broadly to research that deals with human attitudes, beliefs, and behaviors and is often characterized by data collection methods such as questionnaires, interviews, focus groups, direct or participant observation, and non-invasive physical measurements. The research may be qualitative or quantitative. Social-behavioral research also includes epidemiological or outcomes research and health services research:

• Epidemiological and behavioral studies: These types of studies examine the distribution of disease, the factors that affect health, and how people make health-related decisions.
• Outcomes and health services research: These studies seek to identify the most effective and most efficient interventions, treatments, and services.

Important Notes:

• Social-behavioral studies that involve the use of drugs or devices that are FDA regulated, radiation and radiolabeled tracers, and other invasive procedures require review by the Biomedical IRB.
• Retrospective and prospective medical chart reviews are assigned to the either the Social Behavioral IRB or the Biomedical IRB
• Prospective collection of biological specimens (e.g., blood, saliva) and/or collection of data via non-invasive measures (e.g. magnetic resonance imaging without the use of radiotracers, tests of sensory acuity, electrocardiography) that are usually considered clinical in nature may be reviewed by the Social Behavioral IRB if:
  • The purpose of the research is primarily social-behavioral in nature;
  • The physiological interventions are sufficiently benign as to involve no more than minimal risk to subjects.

Types of studies that might cause confusion

1. Studies that involve lifting weight or objects (carrying weight, lifting weight to test or gauge ideal weight range). The focus is not on understanding a disease.
2. Mindfulness studies that are intended to reduce substance use.
   1. Low dose drug being used that is being used as intended and not FDA regulated.

* McLeod, S. A. (2019, July 30). Qualitative vs. quantitative research. Simply Psychology. https://www.simplypsychology.org/qualitative-quantitative.html

Research activities in which the only involvement of human subjects will be in one or more of the categories listed below are exempt from federal regulations listed under 45 CFR 46.104, unless otherwise required by department or agency heads Exempt review studies must be submitted to the IRB. The IRB determines whether a study qualifies as an exempt study; investigators do not have the authority to make exempt determination themselves. (See also 7.4 Review of Exempt Research)

1. 1. Research in educational settings

      Research, conducted in established or commonly accepted educational settings, that specifically involves normal educational practices that are not likely to adversely impact students’ opportunity to learn required educational content or the assessment of educators who provide instruction (46.104(d)(1)). This includes most research on regular and special education instructional strategies, and research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods such as:

      1. Research on regular and special education instructional strategies, or
      2. Research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.

   2. Surveys, interviews & observation

      Research that only includes interactions involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior (including visual or auditory recording) is exempt if at least one of the following criteria is met (46.104(d)(2)):

      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 of the research would not reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, 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 (addressing privacy and confidentiality safeguards) to make the determination required by §46.111(a)(7).

   3. Benign behavioral interventions

      Benign behavioral interventions (46.104(d)(3)(i)) are behavioral (not biomedical) interventions in conjunction with collecting information from an adult subject. It includes the collection of oral or written responses (including data entry) or audiovisual recording and poses little risk to the subject. Subjects must prospectively agree to the intervention and information collection. This research is exempt and must meet at least one of the following criteria:

      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 (addressing privacy and confidentiality safeguards) to make the determination required by §46.111(a)(7).
         1. For the purpose of this provision, benign behavioral interventions are 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. Provided all such criteria are met, examples of such benign behavioral interventions would include having the subjects play an online game, having them solve puzzles under various noise conditions, or having them decide how to allocate a nominal amount of received cash between themselves and someone else.
         2. If the research involves deceiving the subjects regarding the nature or purposes of the research, this exemption is not applicable unless the subject authorizes the deception through a prospective agreement to participate in research in circumstances in which the subject is informed that he or she will be unaware of or misled regarding the nature or purposes of the research.

   4. Research with publicly available biospecimens or information (secondary research)

      Secondary research refers to “re-using identifiable information and identifiable biospecimens that are collected for some other ‘primary’ or “initial’ activity” (82 FED. Reg. at 7191). Secondary research for which consent is not required: Secondary research uses of identifiable private information or identifiable biospecimens, if at least one of the following criteria is met is exempt:

      1. The identifiable private information or identifiable biospecimens are publicly available;
      2. Information, which may include information about biospecimens, 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, the investigator does not contact the subjects, and the investigator will not re-identify subjects;
      3. The research use of identifiable private information and identifiable biospecimens when the research involves only information collection and analysis and the use of such information is subject to the protections of HIPAA. It is expected that these protections will include, where appropriate, the individual’s authorization for future, secondary research uses of protected health information, or waiver of the authorization requirement by an IRB. Notably, this exemption does not apply where the information originates at an entity subject to HIPAA but is disclosed to an investigator who is not subject to HIPAA for use in the research.
      4. The research is conducted by, or on behalf of, a Federal department or agency using government-generated or government-collected information obtained for nonresearch activities, if the research generates identifiable private information that is or will be maintained on information technology that is subject to and in compliance with section 208(b) of the E-Government Act of 2002, 44 U.S.C. 3501 note, if all of the identifiable private information collected, used, or generated as part of the activity will be maintained in systems of records subject to the Privacy Act of 1974, 5 U.S.C. 552a, and, if applicable, the information used in the research was collected subject to the Paperwork Reduction Act of 1995, 44 U.S.C. 3501 et seq.

   5. Research supported by a federal departments or agency

      Research and demonstration projects that are conducted or supported by a Federal department or agency, or otherwise subject to the approval of department or agency heads (or the approval of the heads of bureaus or other subordinate agencies that have been delegated authority to conduct the research and demonstration projects), and that are designed to study, evaluate, improve, or otherwise examine public benefit or service programs, including procedures for obtaining benefits or services under those programs, possible changes in or alternatives to those programs or procedures, or possible changes in methods or levels of payment for benefits or services under those programs. Such projects include, but are not limited to, internal studies by Federal employees, and studies under contracts or consulting arrangements, cooperative agreements, or grants. Exempt projects also include waivers of otherwise mandatory requirements using authorities such as sections 1115 and 1115A of the Social Security Act, as amended.

      1. Each Federal department or agency conducting or supporting the research and demonstration projects must establish, on a publicly accessible Federal website or in such other manner as the department or agency head may determine, a list of the research and demonstration projects that the Federal department or agency conducts or supports under this provision. The research or demonstration project must be published on this list prior to commencing the research involving human subjects.

   6. Taste and food quality evaluations

      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 FDA or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

*The following exemptions 7 and 8 pertain specifically to Broad Consent and therefore will not be used at USC.

1. Storage and maintenance for secondary research with broad consent*

   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. The IRB conducts a limited IRB review and makes the determinations required by §46.111(a)(8).

   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 requirements for informed consent (§46.116(a)(1) through (4), (a)(6), and (d));
   2. Documentation of informed consent or waiver of documentation of consent was obtained in accordance with §46.117;
   3. An IRB conducts a limited IRB review and makes the determination required by §46.111(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

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.

General Restrictions on Exempt Review

For research involving prisoners, exemption categories DO NOT apply [45 CFR 46.101(i)].

46.104(a)(2) Subpart C. The exemptions at this section do not apply to research subject to subpart C, except for research aimed at involving a broader subject population that only incidentally includes prisoners.

For research involving children, exemption category 2 DOES NOT apply unless research only involves observation of public behavior when the investigator(s) do not participate in the activities being observed.

FDA does not recognize exemption categories 1 through 5. Only exempt category 6 may qualify as exempt.

Deception in exempt research is discussed in Section 17.9 – Research Using Deception.

Duration of Project Approval

Exempt studies do not expire and do not require annual IRB review of the project. However, if changes to the study are proposed that may affect the risk/benefit ratio of the study or a change in funding, investigators must inform the IRB. Additionally, when a study is completed or terminated, investigators should update the status of the IRB application (refer to Section 9.3 – Project Closure).

The IRB may use expedited review of research provided that research activities do not fall under any of the general restrictions. Expedited review may be used for minor changes in approved research and when limited IRB review is a condition of exemption. The research must present no more than minimal risk to human subjects, and involve procedures listed in one or more of the following categories (45 CFR 46.110(a)/21 CFR 56.110(a)):

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:
      1. an investigational device exemption application 21 CFR Part 812 is not required, or
      2. 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, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an eight- week period and collection may not occur more frequently than two times per week, or
   2. From other adults and children*, when 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 are considered. For these participants, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an eight-week period and collection may not occur more frequently than two times per week.*Children are defined in the federal regulations as “persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted” see 45 CFR 46.402(a).
3. Prospective collection of biological specimens for research purposes by noninvasive means.Examples: (a) Hair and nail clippings in a non-disfiguring 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 gum base 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 before 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 scrapping or swab, skin swab, or mouth washings; (j) Sputum collected after saline mist nebulization; (k) Vaginal swabs that do not go beyond the cervical os; (l) Rectal swabs that do not go beyond the rectum; and/or (m) Nasal swabs that do not go beyond the nares.
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.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 subject’s 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.
5. Research involving materials (data, documents, records, or specimens) that have been collected or will be collected solely for non-research purposes (such as medical treatment or diagnosis). (NOTE: Some research in this category may meet exemption under 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 meet exemption under 45 CFR 46.101(b) (2); this listing refers only to research that is not exempt.)
8. Continuing review of research previously approved by a full IRB as follows:
   1. 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
   2. Where no subjects have ever been enrolled and no additional risks have been identified; or
   3. 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 (2) through (8) do not apply but the IRB has determined and documented at a convened full IRB meeting that the research involves no greater than minimal risk and no additional risks have been identified.

The list of categories for research eligible for expedited review is to be reevaluated by Federal regulators at least every 8 years.

Unless the IRB determines otherwise, continuing review will no longer be required for: projects under expedited categories, or projects that have progressed to data analysis (including analysis of identifiable private information or identifiable biospecimens). For more information, refer to Section 8.2 – Continuing Review.

General Restrictions on Expedited Review

• • Expedited review procedures may not be used for research involving prisoners unless the research is minimal risk and meets the criteria of expedited review as indicated in the federal regulations (45 CFR 46, Subpart C). In most cases, expedited review procedures are not appropriate for research involving prisoners. However, if a project meets the criteria for expedited review, the IRB Chair or designee will consult with the prisoner representative of the IRB to determine if the submission could be reviewed by expedited procedures. If the prisoner representative agrees that expedited procedures are appropriate, the representative will be assigned as one of the designated reviewers. For more information on prisoner research, refer to Section 13.3 – Prisoners in Research.
  • 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.

The expedited review process may not be used in the review of classified research (such as DOD projects).

Duration of Project Approval for FDA Regulated Studies

FDA regulated studies require that every approved study receive continuing review “not less than once per year.” Accordingly, an approval period of an FDA regulated study cannot exceed 364 days.

Each IRB approval letter notes an initial approval date and an expiration date. The initial approval date is the date all contingencies are satisfied.

For additional information, refer to
http://www.hhs.gov/ohrp/policy/continuingreview2010.html#section-g2 and http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf

All human subjects research projects involving more than minimal risks to subjects (or involving minimal risk to subjects but do not qualify for expedited review) are reviewed at a fully convened IRB meeting. A majority of IRB members must be present to conduct the meeting and to satisfy voting requirements. At least one member whose primary concern is in nonscientific areas and at least one member who is not affiliated with USC must be present.

Duration of Project Approval

Federal regulations require that every approved study receive continuing review “not less than once per year.” Accordingly, an approval period cannot exceed 364 days. In some cases, the IRB may grant a shorter approval period if the complexity or risk level merits more frequent continuing review. Examples include: the nature of risks posed by the study, the degree of uncertainty regarding the risks involved, the vulnerability of the subject population, the experience of the clinical investigator in conducting clinical research, the IRB’s previous experience with the investigator and/or sponsor, the projected rate of involvement and whether the study involves novel therapies. Alternatively, the IRB may grant an approval period based on a number of subjects accrued, rather than a specific time period. This type of approval period is usually assigned when there are questions regarding the potential risks of participation.

Each IRB approval letter notes an approval date and an expiration date. The initial approval date is the date all contingencies are satisfied. The procedure for setting the effective approval date and the duration of protocol approval are based on guidance from the Office for Human Research Protections (OHRP) and from the Food and Drug Administration (FDA:
http://www.hhs.gov/ohrp/policy/continuingreview2010.html#section-g2 and http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf

Activities deemed NOT to be research include scholarly and journalistic activities, public health surveillance activities by a public health authority*, literary criticism and legal research, and authorized operational activities of national security agencies (46.102(l)). Studies are considered “Not Research” when they do not meet the 45 CFR 46 definitions of human subjects and/or research. If a study does not meet the definition of human subjects and/or research, and a researcher requires a determination from the IRB, submit an application via iStar (iStar item 1.1). In response to the application, the IRB can issue a letter stating that the study does not qualify as human subjects research and therefore does not need to be approved by the IRB. A non-human subjects, or human subjects research, determination cannot be made retroactively.

Projects that involve FDA-regulated products are required to be submitted as an IRB application.

* “Public health authority” means an agency or authority that is responsible for public health matters as part of its official mandate.

Private information, or specimens are not identifiable when they cannot be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. Study of specimens or data that meet this criterion is considered as not human subject research. (Guidance on Research Involving Coded Private Information or Biological Specimens). This type of study submission is applicable when both of the following conditions are met:

1. The private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with individuals; and
2. The investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example:
   1. The investigators and the holder of the key enter into an agreement prohibiting the release of the key to the investigators under any circumstances, until the individuals are deceased (note that the HHS regulations do not require the IRB to review and approve this agreement); or
   2. There are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of the key to the investigators under any circumstances, until the individuals are deceased; or
   3. There are other legal requirements prohibiting the release of the key to the investigators.

Urgent Review procedures may be requested in response to a requirement from a funder/sponsor who is demanding IRB approval prior to the issuance of a funding award and has an impending deadline. Supporting documentation from the funding agency must be submitted with the iStar application.

Urgency that is a result of negligence or delay on the part of the investigator or staff to submit an iStar application in time for the regular review process to be completed does not meet the criteria for Urgent Review.

A Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4,000 individuals in the United States per year. FDA developed this regulation to provide an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting these populations.

An approved Humanitarian Device Exemption (HDE) application authorizes marketing of the HUD.

Use of a HUD for its approved indication does not constitute human subjects research. However, FDA regulations require that the Institution’s IRB review and approve the use of the HUD at the Institution. The IRB’s responsibility in this case is to conduct a special limited review to verify that the proposed (non-research) use of the device is consistent with the HDE’s FDA-approved indication (21 CFR 814.124(a)). After granting initial approval, the IRB may use expedited procedures for conducting subsequent continuing reviews, which must be performed at least annually. FDA regulations do not require an informed consent form for clinical use of a HUD. However, sponsors often provide a sample consent form and the IRB or the Institution may require the investigator to use an informed consent form specific for HUDs. For additional information, refer to Section 16.6- Humanitarian Use Devices (HUD).

USC faculty or students who intend to conduct human subjects research abroad must obtain USC IRB approval prior to commencing research activities. Research conducted outside the U.S. must respect applicable national laws as well as U.S. regulatory expectations.

If a study involves more than minimal risk, investigators will be required to obtain approval from preferably a government regulatory agency, or with IRB approval, approval from one of the following – a Research Ethics Board, IRB equivalent, or a ministry of health from within the country where the research is being conducted. Research may be restricted in certain countries based on different privacy and/or data security rules, or rules pertaining to the export of personally identifiable data. As determined by the IRB, a member of or, expert in, the culture of the other country may be used in lieu of the IRB equivalent.

USC IRB has no oversight responsibility when research with human subjects is performed at another site by USC faculty members who are on an unpaid leave of absence, or are otherwise not conducting research in connection with their USC responsibilities. If the faculty member brings back identifiable private or intends to continue the research at USC, a new USC IRB application must be submitted.

Many international universities have Ethics Committees that review and approve research. HHS provides a resource to identify federally assured sites that is updated annually.

If a study involves minimal risk, the principal investigator is responsible for obtaining approval or permission from the research site. For research that is HHS funded, the investigator must obtain approval from an Ethics Committee at the international site or an IRB Authorization Agreement.

Consent and recruitment materials must be in the language that is readable and understandable by the subjects, or the short form and translator method may be used when applicable.

International research must also conform to USC’s policy on International Collaborations and Export Controls, as applicable.

Additional International Research Guidance

In accordance with federal regulations, the USC IRB requires that ongoing research protocols undergo continuing review by the convened IRB at intervals appropriate to the degree of risk. FDA regulated research must be reviewed not less than once per year. The frequency and extent of continuing review for each study is based upon the nature of the study, the degree of risk involved, the novelty of the research procedures, the experience of the clinical investigator in conducting clinical research, the IRB’s previous experience with the investigator and/or sponsor, the projected rate of enrollment and the vulnerability of the study subject population. When warranted, the IRB may choose to grant an approval period based less than a year or when a given number of subjects are accrued.

Each investigator must abide by the approval period imposed by the IRB at the time of the most recent IRB approval. No research project may continue to recruit, enroll, or treat subjects or analyze data after the IRB approval expiration date. Continuation of the research after the date of expiration of IRB approval is a violation of federal regulations.

To promote compliance with continuing review, the IRB sends expiration notices at 60, 45, and 30 days prior to expiration to the investigator, faculty advisor, and study coordinator. If investigators do not submit a completed application for continuing review at least 30 days before the protocol expiration date, the IRB cannot guarantee that the application will be reviewed before the date of expiration.

It is the investigator’s responsibility to maintain IRB approval. The IRB expiration date can be found on the main study page in the iStar online submission system, in the IRB approval letter, and in the expiration notices.

For more information, refer to Section 8.2 – Continuing Review.

Investigators must submit and obtain approval from the IRB before implementing any changes to an approved study. Amendments of exempt research are not required unless the changes alter the risk to participants. When changes are necessary to eliminate apparent, immediate hazards to subjects, the change may be implemented immediately but an amendment must be initiated.

The mechanism for proposing modifications to a previously approved research is an amendment application in iStar. The amendment process involves a “summary” that explains all proposed changes in the application followed by the modified study application. IRB review of amendment submissions focuses on the effect of the proposed changes on human subjects. The IRB analyzes whether or not the amendment poses additional risks to subjects or represents a significant change in study procedures. When the IRB approves the amendment, the modified study replaces the previously approved study.

Edit Study Personnel

Study personnel changes, with the exception of changes to the Principal Investigator, Co- Investigator(s), Faculty Advisor, or anyone obtaining informed consent, can be made to the IRB application without submitting an amendment. To do this, research staff can select the “Edit Study Personnel” activity in iStar for the specific study and add or delete study personnel. Study personnel added to a study must have current human subjects training.

For more information, refer to Section 8.1 – Amendments – Changes to Research after Approval

USC investigators are required to inform the IRB about certain events that occur in a study. These are called reportable events. An overview of reportable events including definitions and reporting timeline is provided here. For detailed information about reportable events, refer to Section 8.8 – Reportable Events and Chapter 18 – Reportable Events, Noncompliance, Suspensions, and Terminations.

Adverse Events

Adverse events (AEs), a type of reportable event, are defined as “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related” by the Federal Drug Administration (FDA). In contrast, the Office for Human Research Protections, (OHRP), defines adverse events as “any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.”

At USC, only AEs that are unexpected, related or possibly related, and are either serious or place subjects or others at a greater risk of harm than was previously known or recognized, must be reported to the IRB through iStar, using the Reportable Event application. Reporting to the USC IRB must be as soon as possible, but not later than 10 working days after the investigator becomes aware of the event.

Additional requirements are in effect for investigators who are also sponsors (sponsor- investigators). Refer to Section 12.2 – Investigator-Initiated Research and Sponsor- Investigators and Section 16.4 – Sponsor-Investigators for additional information.

Adverse Device Effects

An unanticipated adverse device effect (UADE) is “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects”.

UADEs must be reported by the clinical investigator to the sponsor and the reviewing IRB as soon as possible, but no later than 10 working days after the investigator first learns of the event. Investigators must report the UADE to the IRB through the Reportable Event application in the iStar system.

Additional requirements are in effect for investigators who are also sponsors (sponsor- investigators). Refer to Section 12.2 – Investigator-Initiated Research and Sponsor- Investigators and Section 16.4 – Sponsor-Investigators for additional information.

Unanticipated Problems Involving Risk to Subjects or Others (UPX)

An unanticipated problem involving risks to subjects or others (UPX) includes any incident, experience, or outcome that meets all of the following criteria:

• unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB- approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied
• related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research), and
• possibly places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized

UPXs should be reported to the IRB using the Reportable Event application in iStar, as soon as possible, but not later than 10 working days after the investigator becomes aware of the event. For sponsored research, the terms of the contract may define a shorter reporting timeframe.

PIs conducting research reviewed by the NCI CIRB are responsible for reporting any potential UPXs occurring at the local site. The PI will submit a reportable event to the CIRB and to the USC IRB. If the PI is unsure whether the specific event meets UPX criteria, the event should be submitted for determination by the CIRB.

Noncompliance in Research

Noncompliance is the failure to follow federal, state, local, or institutional regulations and policies governing human research or failure to comply with the determinations of the IRB. Noncompliance may involve any individual conducting research.

Additionally, if any reasonable individual would foresee the event as compromising the rights and welfare of a subject or others, the noncompliance may be considered serious. If the noncompliance recurs after a report of the activity has been evaluated and corrective action has been mandated, noncompliance may be deemed to be continuing noncompliance.

Protocol Deviations

A protocol deviation refers to those occasions when protocol required procedures are accidentally or intentionally not met. The determination as to which deviations or errors must be reported to the IRB is driven by sponsor/monitor requests or concerns of the principal investigator or study staff, it is not defined by regulation. When the determination is made to report a deviation, it should be submitted through iStar as a reportable event.

Participant Complaints

A participant complaint is an expression of dissatisfaction by the participant (or his/her representative) that may or may not involve a breach in human subjects rights or research ethics. Participants may choose to report complaints to the study team, the IRB, or to a third party (such as hospital administration). Therefore, it is important that during the consent process, subjects receive consent forms and information sheets that include investigator and IRB contact information so that participants have resources to ask questions about the study and report complaints.

Subject complaints must be reported using “Participant Complaint” form in the iStar “Reportable Events” application for IRB review and resolution.

In addition to routine, continuing review by the IRB, some clinical trials must submit periodic reports to the IRB, particularly those related to safety progress reports including data safety monitoring reports and annual reports for Investigational Device Exemption studies.

Data Safety Monitoring Reports

A data safety monitoring report is an interim analysis in a clinical trial, conducted by a committee independent of the research team and the IRB, such as a Data Safety Monitoring Board or a Data Monitoring Committee. The report is submitted to the IRB through the iStar reportable event application. For additional information about Data Safety Monitoring, refer to Section 19.2 – Data Safety Monitoring Board.

Investigational Device Exemption (IDE) Annual Report

Investigators conducting research with a device subject to Investigational Device Exemption (IDE) regulations must submit annual progress reports to the IRB. The annual IDE report is submitted to the IRB through the iStar reportable event application.

Investigators who are also sponsors of an IDE study must comply with additional regulations (refer to Section 16.4 – Sponsor-Investigators). For additional information about Investigational Device Exemptions, refer to Section 16.3 – Investigational Medical Devices.

The term “quality improvement” is the process of reviewing, analyzing, or evaluating patient and/or provider data that may indicate (the need for) changes in systems or procedures that would improve the quality of care.

The distinction between quality improvement and human subjects research is intent. When an activity is specifically initiated with a goal of evaluating and possible improving the performance of institutional practice in relation to an established standard, the activity is called quality improvement.

If a project is originally initiated as a quality improvement project but the findings may be of interest beyond the institution, publishing the findings does not make it human subjects research. When there are mixed aims involving quality improvement activities and research, IRB review is required. If the individual who conducted a quality improvement project chooses to expand the findings into a research study, IRB review is required at that time.

In order to distinguish research from quality improvement, use the following criteria:

• Intent- the purpose/aim statement should be clear. In general, quality improvement projects are aimed at improving local systems of care (nongeneralizable). If the intent is to promote “betterment” of a process of care or a clinical outcome, then the project is quality improvement.

If any of the following criteria are met, the study may require IRB review:

• if the primary intent of the study is to generate generalizable results
• if the study will impose risks or burdens on the subject/patient beyond the standard of practice it may be human subjects research
• if a study involves randomization or procedures that may be considered not standard of care

Institutional research is research conducted for internal use, or to evaluate programs or to inform management practice and decision-making. Institutional research falls outside the federal definitions [45 Part 46] of “research” or “human subjects” and therefore does not need to undergo review by the IRB.

Institutional research involves data collection, analysis, or reporting about educational, administrative, or other aspects of a college or university for either institutional self- improvement or external reporting. In most universities, institutional research informs such issues as enrollment management; program evaluation; student outcomes assessment; space planning and utilization; financial analysis; and faculty or staff planning. Data most often include institutional databases, surveys, focus groups, interviews, tests, work samples, and archival materials.

While the term “institutional research” is most often used in an academic setting, the function is found in a wide array of educational, service, and other organizations. Many health care providers and service organizations have offices of Quality Assurance, Organizational Effectiveness, Planning and Assessment, or Evaluation.

Oral history is not considered research as defined by the U.S. Department of Health and Human Services (DHHS) regulations (46.102(l)(1)). The DHHS Office for Human Research Protection does not consider oral history to meet the regulatory definition of “research” and therefore is excluded entirely from IRB review, without seeking formal exemption. If oral history projects do not meet the regulatory definition of research, they do not require IRB review. However, oral historians are encouraged to consult the IRB if they have questions.

Pilot studies must be submitted for IRB review and approval. IRB submissions should be identified as pilot studies. This helps the committee to contextualize the research, particularly when it comes to justification for the sample size and/or research design. Data from pilot studies is used to refine and support the expansion of a protocol that will be submitted for future IRB review and approval. Data from pilot studies may be saved for later inclusion with data from an IRB approved pilot study.

• Pilot Testing

  Pilot testing most commonly refers to the process of evaluating the usefulness or credibility of a test instruments to be used in a research study. The information collected in pilot testing assists in refining instruments, surveys and data collection procedures. This aids in minimizing instrument error and development of more precise research design. Pilot testing to validate questionnaires, surveys and instruments as described above does not constitute a pilot study and does not require IRB approval.

Deception is a technique that may be used in some research despite a general ethical concern about fully informed consent. For certain kinds of less than fully informed consent, exceptions to this prohibition are allowed primarily because there is not expectation of harm that will result. Examples of deception include studies in which the investigator does not disclose the true purpose of the research to subjects, does not explain the ultimate use of the subjects’ data, or uses a “confederate” acting on behalf of the study team, unbeknownst to the subject. Studies using deception routinely receive expedited or Full Board review when the conditions of deception would be problematic for the subjects and pose risk of physical or emotional stress. For these studies, there should be a prompt and complete debriefing of the subjects. A debriefing statement for IRB review should be submitted along with the informed consent form. Debriefing may include explaining the research, and if possible, providing the opportunity for withdrawal of personal responses or withdrawal from participation in the study.

Deception Qualifying for Exempt Review

Deception in exempt research is only allowed if the subject authorizes the deception through a prospective agreement to participate in research and the subject is informed that he or she will be unaware of or misled regarding the nature or purposes of the research.

• • The omission of minor facts is not equivalent to deception.
  • Exempt studies using deception in surveys/games/focus groups where the
    deception is of no risk can receive the Exempt determination.
  • Psychological research often justifies a need for use of deception to reduce biased responses that subjects may feel will reflect poorly on them. Study findings suggest that such deception is not harmful to subjects.