Part 4 - Activities Subject to the HRPP (January 2008)

The conduct of human research triggers a broad array of regulatory and institutional requirements, including advance approval from IRBs and other review units.  To determine whether a particular activity is subject to the University’s HRPP or when the requirements of the HRPP are triggered, four questions must be answered: (i) is it human research under the Common Rule  (ii) is it human research under FDA regulations; (iii) is the University of Michigan engaged in the research; and (iv) when does the research begin and end.  Analysis of these questions is described below and in the decision aids attached to the Appendix and posted at http//www.research.umich.edu/hrpp/index.html.

Determining What is 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 C.F.R. § 46.102(d).)  At first blush, this definition of research seems clear and simple.  Yet determining what is human research and what is not is often a difficult task, in part because the distinction between research, on one hand, and clinical practice, non-research evaluation, journalism and other activities involving interactions with living individuals or use of their private information, on the other, is blurred.  The Belmont Report illustrates the difference between research and practice in the clinical realm.   

For the most part, the term, “practice” 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 an 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 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.

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 46.202(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 56.1029(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. 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 in Decision Trees posted on the HRPP Website and as follows:

Office for Human Research Protections: http://www.hhs.gov/ohrp/humansubjects/gidance/cdebiol.htm
NIH Office for Extramural Research:  http://rants.nih.gov/grants/plicy/hs/fags_specimens.htm

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:

• 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 IRB approval or certification of exemption before initiating the protocol.
• Researcher obtains a completely deidentified dataset from an institution or agency outside of the University.  The researcher will not make any attempt to reidentify 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 “deidentified” 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 the information it contains.  45 C.F.R. § 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 has developed additional guidance in its grant application instructions to help determining when research involves human subjects.

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, subject to the requirements of the HRPP) if it is funded or administered by the University; 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; or if the research involves the use of any University property or facilities, or private information created or maintained by the University.

“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 UM 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.”

Determining When Research Begins and Ends

Research begins long before the interventions or data collection central to a given project occur.  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.  Survey research also begins when a researcher first collects individually identifiable private information about potential subjects and contacts them, for example to let them know that a project is underway and they may soon be asked to participate.  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.

Research is considered to continue and, therefore, to require continuing (i.e., at least annual) IRB approval and oversight, through data collection and completion of data analysis. IRB approval must remain open as long as data are being collected or analysis is being conducted or as long as there is an 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. See Part 3 of this Operations Manual regarding lapse in IRB approval.

If, however, all links and identifiers are destroyed, the research may not be regulated under federal regulations or the University’s HRPP.  To analyze any data or to undertake secondary data analysis of a lapsed, expired or terminated study, the study must be resubmitted to the IRB.  An IRB application to conduct data analysis on a study previously closed may be determined to be exempt or may qualify for expedited review.  The language of the original consent is a factor in the IRB’s determination of whether secondary data analysis may be conducted.

To formally close a study, the PI must submit an application to the IRB.  In requesting closure, the PI must describe plans for secure storage of data and specify whether or not data will be deidentified.

Authority to Make Human Research/Not Human Research Determinations

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

The University does not require Investigators to seek a formal determination of “Not Human Subjects Research” from a University IRB when the activity falls outside Common Rule and FDA definitions of human subjects research.  Investigators may consult informally with IRB staff or members to facilitate a self-determination.  Investigators may alternatively request from an IRB or IRB staff member, or from the Vice President for Research or designee, formal human research/not human research determinations in cases that do not fall clearly into the category of non-research activities, rather than making an assumption that may later be determined to be incorrect.  With the implementation of eResearch, requests to an IRB or IRB staff member for a formal determination will be made through the eResearch application.

Illustrations

Generally

The Vice President for Research has developed the following list of common activities for which categorical human research/not human research determinations have been made.  See also Part 5 of this Operations Manual 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 3: Research vs. Not Research.  Activities Requiring or Not Requiring UM IRB Review and Approval Prior to Initiation

ACTIVITIES	DESCRIPTION	IRB REVIEW REQUIRED
Clinical Investigations	Experiments using a test article (e.g., investigational drug, device, or biological) on one or more human subjects that are regulated by the Food and Drug Administration or support applications for research or marketing permits for products regulated by the Food and Drug Administration.  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.	YES
Medical Practice	Innovative care or off-label use of FDA-approved drugs, biologics and devices in the normal course of medical practice, where the purpose is not research or collection of safety or efficacy data, but instead is limited to diagnosis, cure, mitigation, treatment, or prevention of disease in humans.	NO
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.	YES
	An alteration in patient care or assignment for research purposes.	YES
	A diagnostic procedure added to a standard treatment for the purpose of research.	YES
	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.	NO
Standard Public Health Surveillance Activities	[RESERVED]	NO
Innovative Procedures, Treatment, or Instructional Methods	A 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.	YES
	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 medical or behavioral science practitioner is to provide diagnosis, preventive treatment, or therapy to the particular individual.	NO
Repositories (e.g., data, specimen, etc.)	Preliminary activities typically designed to help the Investigator refine data collection procedures.  This data is to be included in the publication.	YES
	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.	YES
	Storage of human tissue, blood, genetic material or data that has been de-identified by UM personnel at the time of collection.	YES (may qualify as non-human research)
	Review of clinical datasets to determine the feasibility of studies by determining whether necessary information is collected in the datasets, whether adequate numbers of subjects might be available, etc.  Note that a “covered entity” might need to obtain researcher certifications for a review preparatory to research for HIPAA compliance purposes.	NO
U-M functioning as the Coordinating Center for a Multi-Center Research Project	UM is not an enrolling site and the UM 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.	YES
	UM is an enrolling site and the UM 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.	YES
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. 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. 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.	IRB NOTIFICATION
Classroom Assignments/ Research Practicums/ Research Methods Classes	Activities designed for educational purposes only.  The data will not contribute to generalizable knowledge or be published outside the classroom, will not result in an article, master’s thesis, doctoral dissertation, poster session, abstraction or result in any other publication or presentation.	NO (but instructors have an affirmative obligation to protect students and others)
Case Studies	A single subject study with clear intent before recruiting or interacting with the participant, to use data that would not ordinarily be collected in the course of daily life.  The intent is to report and publish the case study.	YES
	Analysis and publication of treatment provided in a single case where research is not prospectively planned, and no procedures are performed or information collected beyond what would be done for regular (or innovative) clinical care and treatment.	NO
	A single subject case study that involves an FDA-regulated test article and the results of which are intended to be submitted to FDA by the researcher or sponsor/manufacturer.	YES (see 21 CFR § 56.102(c))
Oral History	Interviews with sources (knowledgeable people) to supplement written documents and artifacts in attempting to preserve information about past events so long as: (i) they focus exclusively on past events; (ii) they are conducted to understand or explain a particular past or unique event in history; and (iii) the anonymity of the narrators is not preserved.  Social Scientists other than historians may conduct research that meets these criteria and historians may conduct research that does not meet these criteria.	NO (but exercise of professional ethics is expected)
Journalism	Projects consisting of collecting, verifying, reporting, and analyzing information regarding current events including trends, issues, and people.	NO (but exercise of professional ethics is expected)
Organization Research	Information gathering about organizations, operations, budgets, etc. from organizational spokespersons.  Does not include identifiable private information about individual members, employees or staff of the organizations.	NO
Quality Assurance and Quality Improvement Activities	Practice of evidence-based medicine; quality assurance or quality improvement projects designed to improve clinical care, patient safety, health care operations, etc.  The design does not include comparison or control groups but may include measuring outcomes of the initiative.  Secondary publication of project results is permissible.	NO
	Practice of program evaluation, self-assessment of programs or business practices, and other quality improvement projects where methods rather than humans are the subject of the study. Publication of project results is permissible.	NO
	Quality assurance or quality improvement projects conducted, at least in part, for research purposes.  Design may feature comparison or control groups.	YES
Health Services Research/ Outcomes Research	[RESERVED]	YES
Pilot Studies, Feasibility Studies and Research Development	Activities including those involving only one individual may be subject to the same scrutiny as a full-scale research project.  Although the data derived from a pilot activity may not be included in the full-scale research project, the activity would still need IRB review prior to conducting the activity.	YES

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.

The University Policy on Student Practicums provides guidelines on the development and acceptance of formal University agreements for student practicums or internships.  In general, 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 4: When is UM IRB approval required for student practicums or internships?

Circumstance		UM 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.		NO (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.		YES
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.	NO
	Student is providing research assistance at the level of key personnel.	YES (Amendment required.)
Participation with or providing services to a non-UM researcher.  Research is approved by a non-UM IRB.  Student is providing research assistance at a level not normally requiring an IRB project amendment.  Requires letter from non-UM PI attesting to non-UM IRB approval, and providing assurances that the non-UM IRB does not require an amendment in accord with its own SOPs.  Letter maintained in the student file by the student’s UM faculty mentor.		NO (But professional standards apply.)
Student is providing research assistance at the level of key personnel.  No different from standard collaborative research situation.	As part of its review, the UM IRB receives assurances that the project has been approved by a non-UM IRB at the non-UM location.	YES
	Official memorandum to make the non-UM IRB the IRB-of-Record for the student’s participation.  Standard form signed in OVPR.  Kept in OVPR. See Part 5 of this Operations Manual for additional information on IRB-of-Record arrangements.	NO
Independent research project not falling within the scope of a previously approved project.		YES (Faculty member assigned as faculty advisor is ultimately responsible.)

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

Quality Improvement Activities vs. Human Research

When the primary purpose of a project is quality assessment or improvement, outcomes evaluation, or development of clinical guidelines (and not the development of generalizable knowledge), then the study may be subject to the HRPP and the Common Rule, but not to HIPAA.  See Part 11 of this Operations Manual for additional information on HIPAA.

Public Health Not Human Research

[RESERVED]

Notification of Decisions

When a formal human research/not human research determination is made, the person requesting the determination should be informed in writing or electronically.  A verbal communication should be followed by written or electronic confirmation.

POLICY ON EXEMPT RESEARCH

Introduction

Under certain circumstances, human research activities subject to the HRPP may be granted exempt status.  The significance of exempt status, which may be requested by an investigator when submitting an application to an IRB and may be granted by the IRB Chair or designee or the Vice President for Research, as further provided below, is that the research activity is not monitored by the IRB.  Assuming the project does not change, it also is not subject to continuing IRB oversight.  Exempt status does not, however, lessen the ethical obligations to subjects as articulated in the Belmont Report and in disciplinary codes of professional conduct.  Thus, depending on the circumstances, researchers performing exempt studies may need to make provisions to obtain informed consent, protect confidentiality, minimize risks, and address problems or complaints.

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.  This policy does not apply to FDA-regulated test articles used in emergencies as provided in Part 8 of this Operations Manual.

With the exception of research involving certain vulnerable populations and of 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.  When research is granted exempt status, the category or categories allowing exempt determination must be recorded by the entity making the judgment.

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.

FDA-Regulated research may not be granted exempt status under categories 1-5 below, however certain emergency research is exempt from FDA regulation. See Part 8 of this Operations Manual.   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.  Finally, IRBs may institute procedures barring exemptions in designated categories of cases.  For example, an IRB might not grant exemptions to projects involving deception research or the use of student subjects.

1. Research conducted in established or commonly 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.  If the research involves children as participants, the research must be limited to educational tests (cognitive, diagnostic, aptitude, achievement), and observation of public behavior when the investigator(s) do not participate in the activities being observed.  Research that uses survey procedures, interview procedures, or observation of public behavior with the investigator(s) participate in the activities being observed cannot be granted an exemption.
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.

Authority to Grant Exempt Status

The Institutional Official has granted to the University IRBs the authority to invoke exemptions 1-4 and 6-7, above.  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 Institutional Official retains exclusive authority to grant exemption 5.  Any project that may be eligible for exemption 5 will be forwarded to the Institutional Official for review, either by the principal investigator or by the IRB.  The principal investigator 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.

Notification and Documentation of Exempt Status

Documentation of exempt status will include the exempt category relied upon.  Notification to a principal investigator that exempt status is granted will include a statement to the effect that any change in the research plan might affect exempt status and, therefore, the principal investigator should apply to the IRB for approval to continue the research under exempt status before the change is initiated.