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Operations Manual - Part 4

Activities Subject to the HRPP

[Operations Manual Table of Contents]

I. Determining What is Human Research and What is Not

Research is defined under the Common Rule as "a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." (See 45 CFR 46.102(d).)

For purposes of human research at the University of Michigan, a “systematic investigation” is an activity conducted in pursuit of answering a specific research question or to permit conclusions to be drawn. The research is described in a formal protocol that sets forth an objective and a set of procedures to reach that objective, and results in the formulation of generalizable knowledge based on conclusions drawn. In turn, “generalizable knowledge” is knowledge based on the findings of a particular research study (or studies) that may be applied more broadly with the expectation of predictable outcomes.

This definition of research might seem clear and simple. However, determining what is and what is not human research is often a difficult task, in part because the distinction between research and clinical practice, non-research evaluation, journalism, and other activities involving interactions with living individuals or use of their private information may be blurred. The Belmont Report illustrates the difference between research and practice in the clinical realm.

In the clinical realm, the term, “practice” generally refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment, or therapy to particular individuals.  By contrast, the term “research” designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is “experimental,” in the sense of new, untested, or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, the activity should undergo review for the protection of human subjects.

A "clinical investigation" under U.S. Food and Drug Administration (FDA) regulations generally refers to any experiment that involves: (i) a test article (defined in turn as a drug, biological product, medical device, human food additive, color additive, electronic product, or any other article subject to regulation under the Food, Drug and Cosmetic Act or the Public Health Service Act); and (ii) one or more human subjects; and (iii) that is subject to FDA oversight or whose results are intended to be submitted to FDA as part of an application for a research or marketing permit.

Section III below describes who has the authority to make a determination about whether or not a particular activity constitutes human research subject to the HRPP, provides illustrations, and describes the process for notifying an investigator of the determination.

II. Determining Whether Research Involves Human Subjects

The fact that an activity is research does not mean that it is "human subjects" research under the Common Rule or a clinical investigation under corresponding FDA regulations.

The Common Rule (45 CFR 46.102(f)) defines a human subject (or human participant) as "a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information." The definition at 45 CFR 46.102(f) continues:  "Intervention includes both physical procedures by which data 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, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record)."

The definition of "human subject" is similar under FDA regulations. FDA regulations (21 CFR 56.102(e)) define a "human subject" as an individual who is or becomes a participant in research, either as a recipient of a test article (drug, biologic, or device) or as a control; it also includes individuals on whose specimen a device is used. A subject may be either in normal health or may have a medical condition or disease.

It is not always readily apparent that a research project involves human subjects. For example, research on specimens derived from living individuals may be considered human subjects research under both the Common Rule and FDA regulations and, therefore, for purposes of the University's HRPP. Guidance on whether or not a project involving human specimens may be considered regulated research is available on the following federal web sites:

Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information being collected) in order for obtaining or using the information to constitute research involving human subjects. The following illustrations may assist researchers in determining whether their activities constitute human research:

  • A researcher requests a University department to release individually identifiable private information to the researcher for use in a research project. Because the information is individually identifiable, the research is considered "human research" and the investigator must obtain Institutional Review Board (IRB) approval or certification of exemption before initiating the protocol.
  • A researcher obtains a completely de-identified dataset from an institution or agency outside of the University. The researcher will not make any attempt to re-identify the information contained in the dataset. The researcher has not received identifiable private information and, therefore, the project is not subject to University IRB approval or HRPP oversight. However, the originating institution may impose additional requirements.

Determining when information may be considered "de-identified" can be difficult. Privacy regulations issued under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) require that nineteen specific fields be eliminated from a data set to render it "de-identified" or that a statistician verify that the recipient of the dataset will not, based on the dataset and any other information to which the recipient may have access, be able to re-identify an individual, see 45 CFR 164.514(b); see also National Association for Public Health Statistics and Information Systems, Release of Individual-Level Vital Statistics Records for Research.

The National Institutes of Health (NIH) has developed additional guidance in its grant application instructions to help determine when research involves human subjects.

III. Determining Whether The University is Engaged in Human Research

The University of Michigan is considered to be “engaged” in human research (defined to include research involving human subjects under the Common Rule and clinical investigations under corresponding FDA regulations), and thus the research is considered “University research” and is subject to the requirements of the HRPP, if the person conducting or supervising the research is a University faculty or staff member, trainee, or other agent acting in connection with his/her University responsibilities.

“University responsibilities” refers to the activities and obligations of faculty, staff, and trainees in their roles as employees or students. Thus, for example, a faculty member who performs outside activities for unrelated institutions and not as part of his U-M appointment is not involved in “University responsibilities” in that context. Conversely, a faculty member who provides professional services at an outside institution under a contract between the University and the outside institution, and who is paid for his work by the University, is performing “University responsibilities.”

IV. Determining When Research Begins and Ends

Research begins when a researcher first “obtains data through intervention or interaction,” or otherwise obtains “private information,” as described above. For example, biomedical research begins when a researcher first collects individually identifiable private information about potential subjects, contacts those subjects, or performs eligibility testing solely for research purposes. Because the initial data access and contact constitute research, an IRB must review and approve the proposed data access and communication in advance. However, this preliminary effort to enhance future participation in a project may be eligible for a waiver of consent or documentation of consent. Additional information on consent and waiver requirements is provided in Part 6 of this Operations Manual (OM).

Research is considered to continue and IRB approval must remain active through data collection, while personally-identifiable data are being analyzed or as long as there is intent to conduct long-term follow-up on subjects of the currently approved research. When IRB approval lapses, expires, or is terminated, no interventions or interactions may occur and no identifiable data may be collected or analyzed, until the project is re-approved by the IRB. See Part 3 of this OM regarding lapse in IRB approval.

Once all personal-identifiers and links to identifiers are destroyed, the research is no longer regulated under federal regulations or the University’s HRPP. 

To formally close a study, the PI should submit a termination report via eRRM requesting closure. The PI must describe plans for secure storage of data and specify whether or not data will be de-identified.

Secondary analysis of data collected in a closed study that still retains identifiers must submitted to the IRB for approval. The language of the original consent is a factor in the IRB’s determination of whether secondary data analysis may be conducted.

V. Authority to Make Regulated/Not Regulated Determinations (Per the Common Rule and FDA) and Notification of Decisions

A. Authority to Make Regulated/Not Regulated Determinations

The Vice President for Research (VPR) has delegated to the IRBs and their staffs the authority to make regulated/not-regulated determinations in a manner consistent with their approved standard operating procedures. The VPR also has the authority to make a regulated/not-regulated determination for any specific project or category of projects.

The University does not require investigators to seek a formal “Not Regulated” determination from the IRB when the activity falls outside of the Common Rule and FDA definitions of human subjects research or where the University is not engaged in the research. Some types of project that are not regulated under the Common Rule may require review only for the purpose of assessing compliance with HIPAA or other regulations or institutional policies.  Investigators may consult informally with IRB staff or members to facilitate a self-determination. To obtain formal documentation of a “Not Regulated” determination, an eRRM “Activities not regulated as human subjects research” application must be submitted. This application allows the PI to self-generate a determination letter that may be used for funding or publication purposes or to request an IRB review to confirm the status of the project. 

B. Illustrations

The VPR has developed the following list of common activities for which categorical regulated/not-regulated determinations have been made. See also Part 5 of this OM for additional examples of research-related activities considered to constitute “engagement” or “non-engagement” in research. Selected activities that often are particularly difficult to categorize are discussed in further detail below.

Table 6: Regulated vs. Not Regulated Human Research. Activities Requiring or Not Requiring UM IRB Review and Approval Prior to Initiation


Clinical Investigations

Experiments using a test article (e.g., investigational drug, device, or biological) on one or more human subjects, or on the specimen of a human subject, that are regulated by the Food and Drug Administration (FDA) or support applications for research or marketing permits for products regulated by the FDA. Products regulated include foods, including dietary supplements that bear a nutrient content claim or a health claim, infant formulas, food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products that aid in diagnosis or treatment of injury or illness.


Medical Practice

Standard practice, innovative care, or off-label use of FDA-approved drugs, biologics, devices and other articles or substances that are used in the normal course of medical practice, provided the activity does not involve systematic collection of safety or efficacy data, and is limited to prevention, diagnosis, mitigation, treatment, or cure of disease in affected individuals.


Standard Diagnostic or Therapeutic Procedures

The collection of data about a series of established and accepted diagnostic or therapeutic procedures, or instructional methods for dissemination or contribution to generalizable knowledge.


An alteration in patient care or assignment for research purposes.


A diagnostic procedure added to a standard treatment for the purpose of research.


An established and accepted diagnostic, therapeutic procedure or instructional method, performed only for the benefit of a patient or student but not for the purposes of research. (See Case Studies)


Standard Public Health Surveillance Activities

The collection and analysis of identifiable health data through public health efforts that primarily involve surveillance; prevention or control of known or suspected diseases, or injuries or other conditions; to promote the health of a particular community. HIPAA compliance review may be required.

Case Studies - Clinical

Report about one or two clinical experiences or observations identified in the course of clinical care, provided that FDA regulations requiring IRB approval do not apply such as use of: articles (e.g., drugs, devices, biologics) that have not been approved for use in humans; articles requiring exemption from FDA oversight; articles under an Investigational New Drug Application (IND)/Investigational Device Exemption (IDE).


Case Studies - Other

Report about experiences or observations associated with one or two individuals.
Innovative Procedures, Treatment, or Instructional Methods

Systematic investigation of innovations in diagnostic, therapeutic procedure or instructional method in multiple participants in order to compare to standard procedure. The investigation is designed to test a hypothesis, permit conclusions to be drawn, and thereby develop or contribute to generalizable knowledge.


The use of innovative interventions that are designed solely to enhance the well being of an individual patient or client and have a reasonable expectation of success. The intent of the intervention is to provide diagnosis, preventive treatment, or therapy to the particular individual. (See Case Studies)


Pilot Testing

Preliminary activities typically designed to help the investigator refine data collection procedures. The data are to be included in the publication.

Repositories (e.g., data, specimen, etc.)

A storage site or mechanism by which identifiable human tissue, blood, genetic material or data are stored or archived for research by multiple investigators or multiple research projects.

Pre-Review of Clinical Data Sets

Activities (e.g., review of medical data, queries, etc.) intended only to assess the feasibility of future research. Note that the UMHS or other “covered entity” might need to obtain researcher representations for a review preparatory to research for HIPAA compliance purposes.
(but HIPAA compliance review processed through eRRM)
Research involving Coded Biological Specimens/Coded Private Information

Analysis of coded human specimens or coded private human data where:

  • The specimens/data were not collected specifically for the proposed study through an interaction or intervenion with living individuals,
  • The investigators cannot readily ascertain the identities of the individuals from whom the specimens/data were obtained either directly or indirectly through a coding system and,
  • The investigator is not a researcher or collaborator on the specimen or data provider's research.

For use of specimens, the research must not be testing a drug or biologic in support of an IND application.

Use of specimens or data may require HIPAA compliance review.

(but HIPAA compliance review processed through eRRM)

U-M functioning as the Coordinating Center for a Multi-Center Research Project

U-M is not an enrolling site and the U-M Principal Investigator (PI) has agreed to serve as the coordinating center for a multi-center project, which may include activities such as data collection, data analysis, reporting of adverse events to regulatory authorities, and/or oversight of the research at participating sites.


U-M is an enrolling site and the U-M PI has agreed to serve as the coordinating center for the multi-center project, which may include activities such as data collection, data analysis, reporting of adverse events to regulatory authorities, and/or oversight of the research at participating sites.


Emergency Use of an Investigational Drug or Device

Institutional Policies do not permit research activities to be started, even in an emergency, without prior IRB acknowledgement.

  1. This does not limit the physician's ability to deliver emergency care. The physician may deliver such care, but the data derived from such care may not be used in any prospectively conceived research.
  2. Emergency care involving investigational drugs, devices or biologics must meet the Food and Drug Administration (FDA) requirements and data from such use may not be used in any manner of research.

Classroom Assignments/ Research Methods Classes

Activities designed for educational purposes that teach research methods or demonstrate course concepts. The activities are not intended to create new knowledge.

(but instructors have an obligation to protect students and others)
Research Using Publicly Available Data Sets Use of publicly available data sets that do not include information that can be used to identify individuals. "Publicly available" is defined as information shared without conditions on use. This may include data sets that require payment of a fee to gain access to the data.
Research on Organizations Information gathering about organizations, including information about operations, budgets, etc. from organizational spokespersons or data sources. Does not include identifiable private information about individual members, employees, or staff of the organization.

Oral History

Interviews that collect, preserve and interpret the voices and memories of people, communities, and participants in past events as a method of historical documentation. The intent is to document a particular past or unique event in history.
(but exercise of professional ethics is expected)


Activities focused on the collection, verification, reporting, and analysis of information or facts on current events, trends, newsworthy issues or stories about people or events. There is no intent to test a hypothesis

(but exercise of professional ethics is expected)

Quality Assurance and Quality Improvement Activities - Clinical or Procedures

Systematic, data-guided activities designed to implement promising ways to improve clinical care, patient safety and health care operations. The activity is designed to bring about immediate positive changes in the delivery of health care, programs, or business practices in the local setting.
Quality Assurance and Quality Improvement Activities - Non-Clinical Data collected with the limited intent of evaluating and improving existing services and programs or for developing new services or programs. Examples include teaching evaluations or customer service surveys.

Research Involving Only Decedents

Research involving only data or tissue obtained from individuals who are deceased prior to the conduct of the research. There must not be any interaction or intervention with living individuals, or collection of private data or specimens associated with living individuals. Note that the UMHS or other "covered entity" might need to obtain researcher representations for research involving decedents' data for HIPAA compliance purposes.

(but HIPAA compliance review processed through eRRM)

C. Student Practicums and Internships

Many of the professional schools within the University actively seek opportunities for their students to become involved in “real world” activities or work assignments that will introduce them to and, in some cases, provide practical experiences in their chosen profession. This involvement may take the form of an internship requirement. In other situations, the opportunities may come in the form of a “practicum” in which students are assigned to work “in the field” (for example, in a government agency or in industry) to see first hand how problems are addressed by professionals in their chosen field. The student intern is under the day-to-day direction of the sponsoring organization, may be given specific work assignments, and may work side-by-side with regular employees of the organization. A faculty member, in turn, provides the “bridge” between the work experience and the learning experience – giving guidance to the student and striving to place the fieldwork into the broader context of the student's educational program.

In general, the development and acceptance of formal University agreements for student practicums or internships are acceptable when, in the opinion of the head of the department in which the practicum would be conducted, the activity may be of educational value or lead to an extension of knowledge, or increase effectiveness in teaching, or increase effectiveness in research. Some student practicums/internships are designed to contribute to generalizable knowledge and, thus, are research and reviewable by the IRB. Some are not. The following table illustrates the distinctions between activities that do and do not require IRB review.

Table 7: When is U-M IRB approval required for student practicums or internships?

U-M IRB Review Required?
A practicum/internship that falls within the work scope of a local, state, or federal agency (e.g. Public Health Agency) or employment by private industry involving data collection for non-research purposes. No a priori research design or intent.
(But professional
standards apply.)
Use of or access to human subjects data previously collected for non-research purposes (perhaps through a circumstance like the one above) in a systematic investigation designed to contribute to generalizable knowledge, one indicator of which is publication.
Participation with or providing services to a UM PI conducting IRB-approved research. No work outside the scope of the IRB approval. Student is providing research assistance at the level not normally requiring an IRB project amendment.

Student is providing research assistance at the level of key personnel.

(Amendment required.)
Participation with or providing services to a non-UM research project. Research is approved by a nonU-M IRB. Student is providing research assistance at a level not normally requiring an IRB project amendment. Requires letter from non-U-M PI attesting to non-UM IRB approval, and providing assurances that the non-U-M IRB does not require an amendment in accord with its own Standard Operating Procedures (SOPs). A letter should be maintained in the student file by the student’s U-M faculty mentor.
But professional standards apply.
U-M IRB Authorization Agreement ceding oversight to non-U-M IRB or IRB review at U-M is necessary.
Independent research project not falling within the scope of a previously approved project.
(Faculty member assigned
as faculty advisor is ultimately responsible.)

If a student or faculty member is unsure whether a particular activity requires U-M IRB approval, they should contact the U-M IRB that traditionally monitors research conducted within their academic unit. See Part 5 of this OM to determine the correct IRB.

D. Notification of Decisions

When a human research/not human research determination is made within eResearch, the person requesting the determination is informed by electronic confirmation.


A. Introduction

Under certain circumstances, human research activities subject to the HRPP may be granted exempt status (45 CFR 46.101). This means a study is considered research but meets certain exemption categories. In a practical sense it means the study must be reviewed by the IRB but does not require ongoing IRB oversight. If the research changes and the scope of the original exemption is exceeded, the investigator should submit an amendment to the IRB. Exempt status does not, however, lessen the ethical obligations to subjects as articulated in the Belmont Report and in disciplinary codes of professional conduct.

It is the policy of the University that to be deemed to be exempt, human research activities must be reviewed and determined to fall within one or more of the explicit exemption categories listed in the federal regulations or, for some non-federally supported research, fall under exemption categories described in UM policy (see HRPP Innovation and Demonstration Initiative).

With the exception of research involving certain vulnerable populations and for FDA-regulated research (and consistent with IRB-specific SOPs), research may be granted exempt status if all proposed research activities involve procedures listed in one or more of the specific categories listed below. IRB SOPs require that requests for exemption be submitted via the eResearch application, which includes specific questions to determine eligibility under each exemption category listed in section B. The application also includes questions about the proposed research protocol which allows the IRB to evaluate the protection of human subjects participating in the exempt research project, including information about risk to subjects, subject selection, and provisions for protecting the privacy interests of subjects and the confidentiality of subject data.

While the informed consent process and documentation do not require review as part of this screening, the application reminds researchers of their ethical obligation to ensure that participants are fully informed about the nature of a research project so that they can make an informed decision to participate. These standards also apply to research exempted by all IRBs.

When research is granted exempt status, the category or categories allowing exempt determination must be recorded by the entity making the judgment.

B. Categories of Eligibility for Exempt Determination

Research involving prisoners may not be granted exempt status, even if it falls into one or more of the categories listed below.

There are special limitations in the application of exempt status to research with children. Those exemption categories with limitations for research involving children are noted below.

1. Federal Exemption Categories

  1. Research conducted in established or accepted educational settings involving normal educational practices, such as research on regular and special education instructional strategies, or research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
  2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observations of public behavior, unless: (i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects outside of the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation.
    • Application of this exemption category to research with children is limited to the use of educational tests or to observation of public behavior where the investigator does not participate in the activities being observed.  It cannot be applied to projects involving surveys or interviews with children.
  3. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior not exempt under the previous category but if the human subjects are elected or appointed public officials or candidates for public office; or federal statutes require without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.
  4. Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available; or the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.
  5. Research and demonstration projects that are conducted by or subject to the approval of federal department or agency heads, and that are designed to study, evaluate, or otherwise examine: public benefit or service programs; 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. This exemption is for federally supported projects and is most appropriately invoked with authorization or concurrence by the funding agency. The following criteria must be satisfied to invoke this exemption:
    • The program under study must deliver a public benefit (e.g., financial or medical benefits as provided under the Social Security Act) or service (e.g., social, supportive, or nutritional services under the Older Americans Act);
    • It must be conducted pursuant to specific federal statutory authority;
    • There must be no statutory requirements that the project be reviewed by an IRB;
    • The project must not involve significant physical invasions or intrusions upon the privacy of participants.
    Non-federally supported research and demonstration projects conducted by or subject to the approval of state department or agency heads, and that otherwise meet the above requirements, are also eligible for exemption.
  6. Taste and food quality evaluation and consumer acceptance studies if wholesome foods without additives are consumed; or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, by the Food and Drug Administration or approved by the Environmental Protections Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

2.  U-M Exemption Categories

The following exemptions are defined by U-M policy HRPP Innovation and Demonstration Initiative):

  • U-M Exemption 2a: Minimal risk research that involves a non-invasive intervention followed by data collection via survey, interview (including focus groups), or observation, unless: (i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of human subjects’ responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation. Research that is federally funded, FDA-regulated or was issued a Certificate of Confidentiality is not eligible for this category.

  • U-M Exemption 5: Research and demonstration projects sponsored by the State of Michigan. All other criteria parallel those described for federal exemption 5 (above).

  • U-M Exemption 7: Research in which study activity is limited to analysis of identifiable data. For purposes of this research study, all research subject interactions and interventions have been completed and the data continues to contain subject identifiers or links. Research that is federally funded, FDA-regulated or was issued a Certificate of Confidentiality is not eligible for this category

C. Authority to Grant Exempt Status

The Institutional Official (IO) has granted to the University IRBs the authority to invoke federal exemptions 1-4 and 6, the demonstration projects, U-M exemptions 2a, 5 and 7. How and to whom the IRBs in turn distribute the authority to issue exemptions is described in their SOPs. IRB SOPs will ensure that individuals issuing exemptions receive initial and continuing training in the details of the exemption process.

The IO delegated the authority to grant exemption 5 to the HRPP Director. Any project that may be eligible for exemption 5 will be forwarded to the HRPP Director for review, either by the PI or by the IRB. The PI does not need to request exemption 5 in an application to the IRB for it to be deemed a legitimate candidate for such an exemption.

D. Notification and Documentation of Exempt Status

Exempt determination notices include the exemption category assigned to the project by the reviewer.  The exemption notice to the PI includes a statement that an amendment must be submitted to the IRB for any change in the research that might affect exempt status.  The amendment must be submitted to the IRB before the change is initiated.