Glossary

The definitions provided below are specific to the "IRBMED Reporting Instructions for Adverse Events and Other Reportable Events/Information."

Abnormal Preclinical Finding : A finding in a pre-clinical animal or in-vitro study that suggests a significant risk for human subjects, including reports of mutagenicity, tetratogenicity, or carcinogenicity (21 CFR 312.32 (c)(2)); or findings of contamination in vaccines or other administered agents. Sometimes referred to as an "abnormal laboratory finding," this reportable event does not refer to a value outside the normal range of values for routine clinical laboratory tests . Such lab results that refer a particular subject should be reported to the extent that they are a part of an event that would be categorized as an adverse event overall and/or when unexpected patterns are noted across subjects.

Adverse Drug Reaction (ADR): All harmful and unintended responses to a research use of a medicinal product (drug) related to any dose should be considered adverse drug reactions. The phrase "responses to a medicinal product" means that a causal relationship between the drug and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.

Adverse Event (AE): Any experience or abnormal finding that has taken place during the course of a research project and was harmful to the subject participating in the research, or increased the risks of harm from the research, or had an unfavorable impact on the risk/benefit ratio. Note that the Food and Drug Administration also includes in its definition abnormal preclinical or laboratory findings which may not yet have resulted in direct harm to subjects (e.g. a bacteria is identified in a culture from the same batch of cells used to produce a vaccine which has been administered, even if no cases of infection have been reported). (See also Serious Adverse Event , Adverse Drug R eaction, and abnormal preclinical finding .)

Any untoward medical occurrence in a clinical investigation with subject administered a test article or undergoes a test procedure and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory value), symptom, or disease temporally associated with the use of a test article, whether or not related to the test article (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

An undesirable, unintended - although not necessarily unexpected - event occurring during therapy or other intervention. The event may or may not be caused by the intervention (e.g., headache following spinal tap or intestinal bleeding associated with aspirin therapy, death from the underlying disease, car collision). (CTO Glossary)

Appointment/Visit Deviation: A scheduling deviation is a reportable occurrence if and when a procedure or intervention did not take place in accordance with the time frame established in the protocol for safety and/or scientific purposes of testing and evaluation . Note: protocol descriptions of treatment(s) to be administered, dosing schedule(s), treatment period(s), and follow-up period(s) should reflect reasonable flexibility in accordance with sound experimental design. (See ICH guidelines, section 6.6.1.)

Assent of a child: Assent means a child's affirmative agreement (verbal or written) to participate in a clinical investigation. Mere failure to object may not, absent affirmative agreement, be construed as assent. Children age 10 and up are generally able to provide their assent. (FDA) [ FDA Guidance ]

Attribution: A determination made by the investigators about the cause of an adverse event, specifically whether an adverse event is or is not related to a test article or other research intervention. (see also cause , relatedness )

Belmont Report: A document that is part of the Federal Register that sets forth fundamental ethical principles that form the foundation for rules for all government funded research involving human subjects. The three basic ethical principles that are particularly relevant to the protection of human participants in biomedical and behavioral research are respect for persons, beneficence (obligation to protect persons from harm), and justice. ( http://ohsr.od.nih.gov/mpa/belmont.php3 )

Biologics: A biological product subject to licensure under the Public Health Service Act is any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, applicable to the prevention, treatment or cure of diseases or injuries to humans. Examples include, but are not limited to, bacterial and viral vaccines, human blood and plasma and their derivatives, and certain products produced by biotechnology, such as interferons and erythropoietins. ( http://www.fda.gov/cber/faq.htm -Center for Biologics, Evaluation, and Research)

Blinded Study: A study in which one party, either the investigator or participant, is unaware of what medication or study arm the participant is assigned to (Single-Blind study). A clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental drug and which are receiving a placebo or another therapy (Double-Blind study). Double-blind trials are thought to produce more objective results, since the impact of expectations of the doctor and the participant about the experimental drug are minimized. (http://www.clinicaltrials.gov/) Also referred to as a "masked" study.

Cause: An assessment made by the investigator and/or sponsor regarding the proper attribution of an adverse event (See also Attribution and Relatedness). Examples:

CFR: See Code of Federal Regulations

45 CFR 46: Title 45, Part 46 of the Code of Federal Regulations, Protection of Human Subjects. Most recently updated in June 1991 (Subpart B in 2002), these regulations govern human subjects research conducted by all federal agencies. Together, this body of regulations governs the conduct of human subjects research today. (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm ) (CTO Glossary)

Characteristics of the subject population being studied: The traits, behaviors, symptoms, diseases, life experiences, or other qualities typically found in the persons comprising those eligible to participate in the study. Examples:

Children : Persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted. In Michigan, the legal age is 18 years old with some exceptions. Also see the HRPP OM, part 11, "Who May Give Consent".

Clinical Trial: A prospective study involving human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions; these may include drugs, treatments, surgical procedures, devices behavioral or nutritional strategies. (Note that not all human research studies are clinical trials-see human subjects research .)

Code of Federal Regulations: The Code of Federal Regulations is an annual codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government. The CFR is divided into 50 titles representing broad areas subject to Federal regulation. Each Title is divided into chapters that are assigned to agencies issuing regulations pertaining to that broad subject area. Each chapter is divided into parts and each part is then divided into sections -- the basic unit of the CFR. The purpose of the CFR is to present the official and complete text of agency regulations in one organized publication and to provide a comprehensive and convenient reference for all those who may need to know the text of general and permanent Federal regulations. (National Archives)

Cognitively Impaired: A person having either a psychiatric disorder (e.g., psychosis, neurosis, personality or behavior disorders, or dementia) or a developmental disorder (e.g., mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is significantly diminished. Others, including persons under the influence of or dependent on drugs or alcohol, those suffering from post-traumatic or degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps, may also be compromised in their ability to make decisions in their best interests. (OHRP) [ OHRP Guidance ]

Co-investigator: Any individual member of the clinical trial team designated and supervised by the principal investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions. See also Investigator . (ICH Guidelines)

Compliance: (in relation to research) Adherence to all relevant trial-related requirements, good clinical practice (GCP) requirements, and the applicable institutional, state and federal regulatory requirements. (ICH Guidelines)

Concurrent Standard Therapy : Treatment (e.g. surgery, drug) a subject is receiving while participating in a research study that is not the treatment under investigation; treatment the subject would be offered even if not enrolled in the research study. For example, in a comparison study of two anti-nausea drugs in cancer patients, the chemotherapy would be the "concurrent standard therapy" and the anti-nausea drugs would be the "investigational therapy."

Concurrently: (in relation to reporting) Reporting should occur simultaneously or in parallel to all oversight bodies (at the same time as).

Confidentiality: Pertains to the treatment of information that an individual has disclosed in a relationship of trust and with the expectation that it will not be divulged to others without written permission in ways that are inconsistent with the understanding of the original disclosure. (OHRP) Prevention of disclosure, other than to authorized individuals, of a sponsor's proprietary information or of a subject's identity. (ICH Guidelines)

Data and Safety Monitoring Board or Data and Safety Committee (DSMB/DSC): A board or committee comprised of scientists and other individuals familiar with the study therapy that evaluates adverse events and research progress in order to promote subject safety and scientific integrity of the study. (OHRP)

Data and Safety Monitoring Plan (DSMP): Data and Safety Monitoring Plan: A defined process to protect the safety of human subjects and maintain the scientific integrity of human subject research and the validity of the data.

A DSMP may be a stand-alone document or the section of a protocol that describes the steps to identify physical, social, or psychological occurrences that may result from participation in the research study and explains in detail how such occurrences will be handled and reported.

A DSMP describes the timing, tools and/or method(s) for monitoring and evaluation, procedures for treatment or resolution (including circumstances which would result in halting or terminating research). It includes procedures for and timing of reports to oversight bodies, and description of oversight bodies involved with the study (e.g. study team, FDA, IRB, or Data and Safety Monitoring Board). It describes the frequency with which each oversight group reviews the collected information.

A study does not need to have a Data and Safety Monitoring Board to have a DSMP.

The purpose of a DSMP is to minimize risks for subjects to the extent possible by explicating procedures for monitoring their safety. A DSMP would formalize action items such as:

•  methodology for notifying an attending physician of emergent events

•  obtaining psychiatric consults for findings of suicidality

•  procedures and education for staff regarding protection of private information

•  procedures to follow when subjects experience significant social or emotional upset in response to the research interaction (e.g. a panic attack after an interview and questionnaire)

(Note that data collected for safety monitoring (or for research purposes) does not necessarily have to be submitted to IRB as an adverse event report.)

Death : Deaths occurring within 30 days of the last study intervention are reportable events regardless of whether or not the investigators deem the death to be related to the study. If death occurs later than 30 days after the last study intervention AND the subject is still on-study (i.e. subject would have had further follow-up or intervention/interaction had death not occurred), then the death may still be a reportable event. If the subject is NOT still on-study and there is no long-term follow-up, a late death does not need to be reported the IRBMED even if the investigator learns that the subject died. Reports generally refer to the death of a research subject but also death of another (a person not enrolled in the study) that is definitely, probably, or possibly related to the study must be reported (e.g. in a study of anti-psychotic medications, the study drug is found to increase irritability and the research subject commits murder).

Declaration of Helsinki: A code of ethics for clinical research approved by the World Medical Association in 1964 and widely adopted by medical associations in various countries. It was revised in 1975 and 1989, and 2000.

Definitely related: An adverse event that is clearly related to the investigational agent(s) or research intervention: the adverse event has a temporal relationship to the administration of the investigational agent(s) or research intervention, follows a known pattern of response, and no alternative cause is present. (NCI/CTC Common Toxicity Criteria v.2.0) (see also cause , attribution , relatedness )

Device Study: See Medical Device, IDE, HDE, HUD

Department of Health and Human Services: The Department of Health and Human Services is the United States government's principal agency for protecting the health of all Americans and providing essential human services. Sometimes referred to as HHS or DHHS. ( http://www.os.dhhs.gov/ ) (CTO Glossary)

DHHS: See Department of Health and Human Services

Documentation: All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records; and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. (ICH Guidelines)

DSMB/DSC: See Data and Safety Monitoring Board or Data Safety Committee

DSMB/DSC Reports: Reports issued by a DSMB or DSC.

DSMP: See Data and Safety Monitoring Plan

Emergency and/or Urgent Treatment: (for purposes of adverse event reporting) An event that was not life-threatening but still warranted urgent professional treatment for physical or psychological trauma or injury such as treatment in an emergency room, urgent care center, psychiatrist's office, psychologist office, or other facility providing immediate care (e.g. battered women's shelter).

Every day event : As used in the context of particular subject populations, this term refers to the magnitude or frequency of events that would be expected in that population (i.e. broken hips in geriatric population).

Every day life: As used in the reporting of mild adverse events only, this term refers to the magnitude or frequency of an otherwise mild untoward occurrence (e.g. a headache) that is outside the expected norm for subjects in the study.

Exclusion Criteria: See inclusion/exclusion criteria

Expected Event: – An event that is expected in that it has been addressed or described in one or more of the following: Informed consent document(s) for this study, IRB application for this study, grant application or study agreement, protocol or procedures for this study, investigators' brochure or equivalent (for FDA regulated drugs or devices), DSMB/DSC Reports, published literature, other documentation, or characteristics of the study population.. NOTE: If an 'expected' event is of unexpected duration, magnitude, or frequency then the occurrence(s) should be reported within the timeframe of an unexpected adverse event.

Familial/social relations: Relationships of significance in the life of the research subject such as parent-child, spousal, employer-employee relations. Harms to these relationships (associated with the research study) are adverse events. When relevant, the study protocol or DSMP should address protection of such relations (e.g. in a genetic study, a plan for how discovery of non-paternity of the assumed father would be handled by the researchers).

Fatal Event: The subject's life ended in conjunction with the event (FDA). A fatal event is considered Grade V using NCI/CTC Common Toxicity Criteria (v. 2.0) (see also Death and Severity ).

Federal Wide Assurance : A standing agreement on file with the Office for Human Research Protections that is describes in detail the procedures it will use to protect the rights and welfare of the human subjects. The University of Michigan's FWA number is 00004969.

FDA : See Food and Drug Administration

FDA oversight: The FDA has oversight over clinical trials involving investigational drugs, devices, and biologics, and some trials involving approved drugs, devices and biologics. Contact the IRBMED Office or the UMHS Office of General Counsel for guidance if there is any question regarding whether FDA oversight of a clinical trial is required.

14 days : The IRBMED office should receive reports within 14 calendar days of the event or investigator's receipt of notification of the event. ( Because the reporting of adverse events can be a time-sensitive issue researchers are encouraged to establish a system for logging or date-stamping information related to adverse event notifications and reports from subjects, sponsors and other sources.)

Follow up report: A supplemental report from a sponsor or investigator providing additional information, clarification, or corrections to a previously reported (to IRBMED) adverse event.

Food and Drug Administration (FDA): The federal agency charged with overseeing the safety of food, drugs and cosmetics. FDA regulations confer protections on human subjects in research when a drug, device, biologic, food additive, color additive, electronic product, or other test article subject to FDA regulations is involved. ( http://www.fda.gov/cdrh/manual/appendb.html ) (CTO Glossary)

Food and Drug Administration (FDA)-Regulated Drug, Biologic, or Device : Any drug, biologic, or device regulated by the FDA. If you are uncertain about whether or not a particular drug, biologic, or medical device is regulated, please contact the Health System Legal Office at 764-2178 and ask to speak with an attorney assigned to IRB issues.

Form 483: The FDA-483 is the written notice of objectionable practices or deviations from the regulations that is prepared by the FDA investigator at the end of an inspection. The items listed on the form serve as the basis for the exit discussion with the researcher at which time the PI can either agree or disagree with the items and can offer possible corrective actions to be taken. The PI may also respond to the district office in writing after it has had sufficient time to properly study the FDA-483 (see the FDA website for more information). The receipt of and PI response to the Form 483 is an ORIO. Please click here for guidance.

FWA : See Federal Wide Assurance .

Gene Therapy: Treatment of a disease caused by malfunction of a gene, by introducing the normal gene into cells, either directly (in vivo) or in vitro and reintroducing those cells into the human subject. (CTO Glossary) Also referred to as "gene transfer," particularly for research applications in which it is unknown whether the introduction of the gene will actually result in a therapeutic effect (see also recombinant DNA ).

The treatment of genetic disease accomplished by altering the genetic structure of either somatic (nonreproductive) or germline (reproductive) cells. (OHRP)

Good Clinical Practice (GCP): A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. (ICH Guidelines)

Grade I: Mild adverse event (National Cancer Institute Common Toxicty Criteria, NCI/CTC v.2.0)

Grade II: Moderately severe adverse event

Grade III: Severe adverse event

Grade IV: Life-threatening or disabling adverse event

Grade V: Death related to adverse event

HDE: See Humanitarian Device Exemption

HUD: See Humanitarian Use Device

Human Subject:
1) A living individual about whom an investigator (whether professional or student) conducting research obtains:
a) Data through intervention or interaction with the individual, or
b) Identifiable private information.
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). 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) in order for obtaining the information to constitute research involving human subjects. Also see the UMHS HIPAA website for further information.

2) 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 individual or a patient. (FDA)

Human Subjects Research : This term applies to federally regulated research in which human subjects (see definition above), their data, tissue, genetic material or other is investigated in a systematic fashion. It includes clinical trials , retrospective studies (subject to IRB oversight or exempt from continuing IRB oversight), outcome studies, surveys, etc.

Humanitarian Device Exemption : An HDE is a premarket approval application submitted to the FDA (see also Investigational Device Exemption , Medical Device , Humanitarian Use Device )

Humanitarian Use Device : An FDA regulated medical device intended to benefit patients in the treatment or diagnosis of a disease or condition, but not yet approved for unrestricted use. The use of a HUD is subject to IRB oversight. Contact IRMBED Office for guidance.

ICH : International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH guidance was published in the Federal Register on May 9, 1997 (62 FR 25692).

IDE : See Investigational Device Exemption

Immediately: Page an IRBMED co-chair and email the IRBMED office as soon as possible (same day as the event/enrollment/incident).

IND: See Investigational New Drug

Incidence/Frequency: How often an event or effect occurred in a population.

Inclusion/Exclusion Criteria: The medical or other standards determining whether a person may or may not be allowed to enter a research study. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. (NIH; http://www.clinicaltrials.gov/ )

Informed Consent: A process by which a subject voluntarily confirms his or her willingness to participate in a particular research project, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form unless such documentation is waived by the IRB. (ICH Guidelines 45 CFR 46)

A person's voluntary agreement, based upon adequate knowledge and understanding of relevant information, to participate in research or to undergo a diagnostic, therapeutic, or preventive procedure. In giving informed consent, subjects may not waive or appear to waive any of their legal rights, or release or appear to release the investigator, the sponsor, the institution or agents thereof from liability for negligence [Federal Policy §116; 21 CFR 50.20 and 50.25]. (OHRP)

Institution: Any public or private entity or agency (including Federal, State, and other agencies). The term facility as used in section 520(g) of the act is deemed to be synonymous with the term institution for purposes of this part. (FDA)

Institutional Review Board (IRB):
1) An independent body constituted of medical, scientific, and nonscientific, members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trials, of protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects. (ICH Guidelines)

2) Any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects. The term has the same meaning as the phrase institutional review committee as used in section 520 (g) of the act. (FDA)

3) A specially constituted review body established or designated by an institution to protect the welfare of human subjects recruited to participate in biomedical or behavioral research (OHRP)

Institutional Review Board (IRB) Approval: The determination of the IRB that the proposed clinical investigation has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and Federal requirements. On IRBMED studies, approval is communicated to the investigator by a document called a " Notice of Outcome " which is faxed to an investigator.

Interaction: A research related communication or interface between an investigator and a research subject other than those that involve an investigational agent or procedure as it relates to a disease or disorder (an intervention ). Interactions may occur in person, by phone, computer, fax, or mail. Examples include surveys, focus groups, fMRI, and tests on healthy normal subjects.

Intervention: A research related interaction between an investigator and a research subject that involves an investigational agent or procedure as it relates to a disease or disorder (and is in this way is distinguished from other types of research interactions ). Interventions may occur in person, by phone, computer, fax, or mail. Examples include clinical trials, behavioral or nutritional counseling, and surgeries.

Investigational: Experimental. Clinical investigation means any experiment in which a test article, even an approved drug, is administered or dispensed to, or used involving, one or more human subjects. (FDA) The use of a marketed drug in the course of medical practice that is outside the label indications ("off-label" use or innovative care) does not in and of itself constitute investigational use of a drug, unless that use is part of an experiment or systematic investigation meeting the criteria for human subjects research .

Investigational Device: A device permitted by FDA to be tested in humans but not yet determined to be safe and effective for a particular use in the general population and not yet licensed for marketing. (FDA). Devices are classified as significant and non-significant risk . A significant risk device means an investigational device that presents a potential for serious risk to the health, safety, or welfare of a subject. (FDA)

Investigational Device Exemption : Approval by FDA for investigational device exemption (IDE) permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully across state and international boundries for the purpose of conducting investigations of that device. (FDA) Most devices under investigation should have an IDE. (see also Medical Device , HDE , HUD )

Investigational New Drug ( IND ) : A drug permitted by FDA to be tested in humans but not yet determined to be safe and effective for a particular use in the general population and not yet licensed for marketing. Use of investigational drugs requires application to the FDA and is usually limited to subjects enrolled in clinical studies covered by an Investigational New Drug agreement with the Food and Drug Administration. For research involving an investigational new drug, the IND number must be reported to the IRBMED.

Investigational Product : A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. (ICH Guidelines)

Investigator :
1) As used in the Reporting Timetables, investigator or PI means the University of Michigan researcher named as the principal investigator on the IRBMED application and the informed consent document for the study.

2) A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Co-investigator. (ICH Guidelines)
3) An individual who actually conducts a clinical investigation (i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject) or, in the event of an investigation conducted by a team of individuals, is the responsible leader. (FDA)

Investigator's Brochure : A compilation of the clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s) in human subjects. (ICH Guidelines)

Investigator Response : An assessment made by the investigator and/or sponsor regarding whether or not an adverse event, or DSMB/DSC or other Report, necessitates a change to the study protocol, informed consent document or process, or investigator's brochure in order to promote subject safety and/or autonomy.

IRBMED : Acronym for the multiple research ethics review committees comprising the Institutional Review Board (IRB) of the UM Medical School and its administrative support staff. The University of Michigan has four other IRBs-IRB-Behav-Sci, IRB-Health, IRB-Dearborn, and IRB-Flint. For guidance regarding which IRB has jurisdiction over a project, refer to http://www.research.umich.edu/

Legally Authorized Representative : An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial. (ICH Guidelines) OR
Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. (FDA)

Life Threatening Event : The subject's life was endangered by the event. (FDA) A life threatening event is considered Grade IV using NCI/CTC Common Toxicity Criteria (v.2.0) (see also Severity).

Local Event : UM Event. An event which occurs in a study under the supervision of the UM IRBMED and whose principal investigator is a UM faculty or staff member. The event is a UM Event when it occurs at The University of Michigan (including any UM hospital, health center, or other facility) or any other site where the UM principal investigator has oversight , even when the PI is physically in another location. It does not matter where the subject experiences or is treated for the adverse event. (See also Off-site Event ). If interventions take place at several different UM locations (e.g. the CCRB and the GCRC), please specify at which location the event occurred.

Medical Device : A diagnostic or therapeutic article that does not achieve any of its principal intended purpose through chemical action within or on the body (that is, not a drug or biologic). Such devices include diagnostic test kits, crutches, electrodes, pacemakers, arterial grafts, intraocular lenses, and orthopedic pins or other orthopedic equipment. (OHRP)

MedWatch : The voluntary FDA Safety Information and Adverse Event Reporting Program that both healthcare professionals and the medical product-using public use to report adverse events involving FDA regulated products. MedWatch provides important and timely clinical information about safety issues involving medical products, including prescription and over-the-counter drugs, biologics, medical and radiation-emitting devices, and, special nutritional products (e.g., medical foods, dietary supplements and infant formulas). (FDA) IRBMED monitors MedWatch reports and may notify investigators of MedWatch information and/or request changes to research protocols or consent documents based on MedWatch reports.

Mild Adverse Event : An event which does not pose any significant or permanent risk of harm to the subject. A mild adverse event is considered Grade I using CTC Common Toxicity Criteria (v 2.0). (see also Severity).

Minimal Risk : The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (OHRP) Research that poses no more than minimal risk to subjects is eligible for certain streamlined IRB oversight procedures termed "expedited review."

Moderate Adverse Event: An event which causes discomfort and perhaps requires treatment, but does not pose any significant or permanent risk or harm to the subject or require in-patient hospitalization. An event that is Grade II by CTC Common Toxicity Criteria.

Monitoring : The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), GCP, and the applicable regulatory requirement(s). (ICH Guidelines)

Monitoring Report : A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor's SOP's. (ICH Guidelines)

Multicenter Trial : A clinical trial conducted according to a single protocol but at more than one site, and, therefore, carried out by more than one set of investigators. (ICH Guidelines)

Non-physiological Adverse Event : An adverse event involving social or psychological trauma, insult or injury rather than physiological or biomedical harm. (See Social or Psychological Trauma .)

Notice of Outcome: Written acknowledgement from the IRBMED, faxed to the study coordinator and/or investigator at the fax number provided in the submission application, regarding the outcome of the review of that application. Outcomes may be "approved," "acknowledged," or "disapproved." Adverse event and ORIO reports are generally acknowledged, but if accompanying changes to the protocol or consent form are requested these require approval in order to take effect .

OBA : See Office of Biotechnology Activities

Office of Biotechnology Activities: Part of the National Institutes of Health. OBA monitors scientific progress in human genetics research in order to anticipate future developments, including ethical, legal, and social concerns, in basic and clinical research involving recombinant DNA, genetic testing, and xenotransplantation. (CTO Glossary) (see recombinant DNA )

Office for Human Research Protections (OHRP): An administrative unit within the Department of Health and Human Services (DHHS), with responsibilities that include implementation of the DHHS Regulations for the Protection of Human Subjects (45 CFR 46), and the provision of guidance on ethical issues in biomedical and behavioral research. OHRP has oversight and educational responsibilities wherever DHHS funds are used to conduct research involving human participants. It can order investigation, review remedies to problems and authorize shutdown of research protocols or programs. It was formerly known as the Office for Protection from Research Risks. ( http://ohrp.osophs.dhhs.gov/ )

Off-Label Use: A drug prescribed for conditions other than those approved by the FDA. (NIH; http://www.clinicaltrials.gov/ ). The off-label use of a marketed drug in the course of medical practice does not in and of itself constitute investigational use of a drug, unless that use is part of an experiment or systematic investigation meeting the criteria for human subjects research .

Off-site Event: In multi-center studies, an event that does not occur at UM or under the supervision of a UM principal investigator or the IRBMED (see also Local Event ).

OHRP: See Office for Human Research Protections

ORIO: Other Reportable Information or Occurrence .

Orphan Drugs: An FDA category that refers to medications used to treat diseases and conditions that occur rarely. There is little financial incentive for the pharmaceutical industry to develop medications for these diseases or conditions. Orphan drug status, however, gives a manufacturer specific financial incentives to develop and provide such medications. (NIH; http://www.clinicaltrials.gov/ )

Phase I Trial: Initial introduction of an investigational new drug into humans. These studies typically involve seriously ill patients for whom no effective standard therapies are available, but sometimes test new agents in healthy volunteers. Phase I trials are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of effectiveness; they are typically closely monitored. The ultimate goal of Phase I trials is to obtain sufficient information about the drug's pharmacokinetics and pharmacological effects (including safety and maximal tolerated dose) to permit the design of Phase II trials.

Phase II Trial: Clinical studies conducted to evaluate an investigational new drug's effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks (safety & efficacy) associated with the drug.

Phase III Trial: Controlled trial conducted after preliminary evidence suggesting effectiveness of the drug has been obtained, and intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide an adequate basis for marketing and labeling. (NIH; http://www.clinicaltrials.gov/ ). (See also randomization , blinded studies , placebo )

Placebo: A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or treatment. (NIH; www.clinical trials.gov )

Previously Unreported Adverse Event: A specific adverse event that has not yet been reported to the IRBMED . For example, the hospitalization of a subject due to infection after the second dose of a study medication would be a "previously unreported adverse event" even if there had been an earlier report submitted to IRBMED when that same subject had been previously hospitalized due to similar infection after the first dose. All previously unreported adverse events are reported to IRBMED using section 6 of the Previously Approved Project Application .

Principal Investigator (PI): Clinical researcher who prepares a protocol or treatment plan and implements it with subjects. Primary/lead clinical researcher of a clinical trial, ultimately responsible for all aspects in the conduct of a study.

Prisoner :Federal Regulations define "prisoner" as "any individual involuntarily confined or detained in a penal institution .  The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing ." See OHRP website for more information.

Protocol :
1) As referred to in the IRBMED's AE guidance : A document submitted to the IRBMED that describes the objective(s), design, methodology, statistical considerations, and organization of the research study. To report AEs using the IRBMED's "Study Specific Plan" Timetable, the protocol must include detailed and specific information about subject safety and adverse events, how they are evaluated (e.g. graded), and when and to which oversight bodies they are reported. "Protocol" does not refer to the routine (or otherwise specified) guidelines or department/sponsor/other directives for operations or procedures ( unless these are submitted to the IRBMED and approved for AE reporting purposes).

2) A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guidance, the term protocol refers to protocol and protocol amendments. (ICH Guidelines)

3) The formal design or plan of an experiment or research activity; specifically, the plan submitted to a Scientific or Peer Review committee for review and to an agency for research support. The protocol includes a description of the research design or methodology to be employed, the eligibility requirements for prospective participants and controls, the treatment regimen(s), and the proposed methods of analysis that will be performed on the collected data.

Protocol Amendment : A written description of any change(s) to or formal clarification of a protocol. (Submit protocol amendments to the IRBMED using sections 1-3, and 11 of the Previously Approved Project Application . Except to avoid the possibility of immediate harm to subjects, protocols should not be changed without prior IRB authorization. When changes for safety are made, an amendment should be submitted to the IRBMED within 7 days of the decision.

Protocol Deviation : Departure from the IRBMED approved research protocol without prior IRBMED approval for the variation. Reportable as an ORIO to IRBMED . Also see Protocol Exception .

Protocol Exception : Term used by FDA and some sponsors to refer to a departure from the protocol that receives approval from the IRB before implementation (a one-time exception as distinguished from an amendment to the protocol). Approval requests for a protocol exception should be submitted using sections 1-3, and 10 of the Previously Approved Project Application . Investigator should specify the extent of the exception (e.g. one-time only for patient X and note if data will be included in the study analysis).

Psychological Trauma : See Social or Psychological Trauma .

Randomization : A method based on chance by which study participants are assigned to a treatment group. Randomization minimizes the differences among groups by randomly distributing people with unknown or unrecognized characteristics that might affect outcome among the trial arms. Randomization is an appropriate research tool when the investigators do not know which treatment is better. Hence, any one of the treatments chosen at random could be appropriate for the participant (NIH; http://www.clinicaltrials.gov/ ).

Assignment of subjects to different treatments, interventions, or conditions according to chance rather than systematically (e.g., as dictated by the standard or usual response to their condition, history, or prognosis, or according to demographic characteristics). Random assignment of subjects to conditions is an important element of some experimental research because it makes more likely the probability that differences observed between subject groups are the result of the experimental intervention. (OHRP)

Randomized Trial : A study in which participants are randomly (i.e., by chance) assigned to one of two or more treatment arms of a clinical trial.

Research Study : See Human Subjects Research.

Recombinant DNA : In the context of the NIH Guidelines, recombinant DNA molecules are defined as either: (i) molecules that are constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell, or (ii) molecules that result from the replication of those described in (i) above. (NIH guidelines including OBA and Recombinant DNA Advisory Committee (RAC))

Regulatory Compliance: Following the rules set by a governing body.

Regulatory Concern: As it relates to the need to report to the IRB, this would be an issue or incident of non-compliance with laws and regulation or to an incident or information that regulations require an IRB consider. In the ORIO guidance the term is used as a criterion for determining what kinds of submission should be sent to the IRB within 7 days. Examples include but are not limited to:

Related Event : Any adverse event that has a temporal relationship to the administration of the investigational drug or research intervention, follows a known or suspected pattern of response, and for which an alternative cause may not be present, is definitely, probably, or possibly associated with the investigational drug/agent. Investigator needs to judge relatedness and be prepared to justify the judgment. See also Relatedness and Cause .

Relatedness : An assessment regarding the causal relationship between a drug or intervention and an adverse event (see also Related Event , Unrelated Event and Cause ). (NCI-CTEP) Regardless of r elatedness , unless otherwise approved in the protocol data safety monitoring plan, all adverse events should be reported to the IRBMED whether or not they are in any way related to the investigational agent or intervention.

Research : A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge . Activities which meet this definition constitute research. (OHRP)

Risk Benefit Ratio : The risk to individual participants versus the potential benefits to the individual and/or society. The risk/benefit ratio may differ depending on the condition being treated. (NIH; http://www.clinicaltrials.gov/ ) The IRB must determine that the risk benefit ratio of a research project is sufficiently favorable in order to approve the research, and reexamines that determination in light of adverse event, other reportable incidents, and unanticipated problems.

Serious : Refers to the outcome of an adverse event. See Serious Adverse Event , Severity and Severe-Serious Distinction.

Serious adverse event (SAE) or Serious Adverse Drug Reaction (Serious ADR) :

1) Any untoward occurrence that:

2) An unexpected result of therapy or other intervention that is severe, life threatening, or fatal, corresponding to grades III, IV, or V using NCI/CTC Common Toxicity Criteria.

3) Severe Social or Psychological Trauma: Loss of job, insurance, benefits; criminal prosecution, stigmatization of community/group, destruction of familial/social relations .

7 days : The IRBMED office should receive reports within seven calendar days of the event or investigator's receipt of notification of the event. ( Because the reporting of adverse events can be a time-sensitive issue researchers are encouraged to establish a system for logging or date-stamping information related to adverse event notifications and reports from subjects, sponsors and other sources.)

Severe-Serious Distinction : Serious adverse events result in death, disability, hospitalization (or prolongation of a hospital stay), or birth defects. Therefore, an adverse event that in and of itself would be graded as mild or moderately severe, becomes a serious adverse event if it leads to one of those outcomes. For example, a case of myelosuppression could require prolongation of an existing hospitalization, making it a "serious adverse event" for reporting purposes even if the myelosuppression was itself only moderately severe (Grade II). . Compare to a subject experiencing a migraine after a hormone injection-the patient might consider the migraine to be severe, but if it did not result in hospitalization or other serious problems, it is not reported as a serious adverse event . See Serious Adverse Event Severe , and Severity .

Severe Adverse Event : An event which causes significant discomfort and requires treatment, and which poses a significant or permanent risk of harm to the subject or requires in-patient hospitalization or prolongation of hospitalization. A severe adverse event is considered Grade III using CTC Common Toxicity Criteria (v 2.0). (see also Severity ).

Severity : An assessment regarding the intensity of an adverse event (rating the event mild, moderately severe, severe, life threatening or fatal; or Grade I, II, III, IV or V).

Significant Risk device : See Investigational device .

Site : This term refers to the location of the RESPONSIBLE oversight investigator and IRB. If the event occurred on a study directed/supervised by UM faculty or staff, it is local. (See also Local Event and Off-site Event ).

Social or Psychological Trauma : Harm, insult, or injury affecting social status or standing, or relationships, or psychological health/well-being. Such harms include but are not limited to: invasion of privacy; breach of confidentiality; significant embarrassment; stigmatization; anxiety; fear; effects of stereotyping; loss of insurance or other benefits; criminal prosecution; effects on employment including job loss or demotion; interruption, disruption, or destruction of familial/social relations .

Sponsor :
1) An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. (ICH Guidelines)

2) A person or other entity that initiates a clinical investigation, but that does not actually conduct the investigation, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate direction of another individual. A person other than that individual (e.g., a corporation or an agency) that uses one or more of it's own employees to conduct an investigation that it has initiated is considered to be a sponsor ( not a sponsor-investigator), and the employees are considered to be investigators. (FDA)

Sponsor-Investigator:
1) An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor, and those of an investigator. (ICH Guidelines)

2) An individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include any person other than an individual, e.g., it does not include a corporation or agency. The obligations of a sponsor-investigator under this part include both those of a sponsor and those of an investigator. (FDA) [ COI guidance ]

Standard Treatment : A treatment currently in wide use and/or approved by the FDA, considered to be effective in the treatment of a specific disease or condition.

Study Drug : The drug under investigation in a research study (includes approved and unapproved drugs).

Subject Confidentiality : Right and understanding of a subject that private data or protected health information will be divulged only as noted in the informed consent document, and/or as necessary for subject's health and safety, and/or as necessary by law. Investigators should take steps to protect subjects' confidentiality including where appropriate removal of patient specific identifiers (patient name, registration number, social security number, etc.) in reports to the IRBMED. Subject initials, unique coding specific to a study, and/or age are acceptable alternatives to names and registration numbers in IRBMED reports, and useful in correlating subject/patient specific information.

Subject : An individual who participates in research, either as a recipient of the investigational product (s) or as a control. (ICH Guidelines) (See also Human Subject ) Individuals can be the subject of research without being aware of their participation when informed consent is waived.

Summary Format : Tabulations, charts, or other analyzed system used to report to the IRBMED all Adverse Events occurring during a study (regardless of relatedness or severity) noted in the Timetables as reportable with the Scheduled Continuation Application. Frequency, expectedness, etc. of number of events in relation to number of subjects enrolled, locally and at all sites, should be readily discernible to the IRBMED.

Test Article : Any drug, biological product, medical device, human food additive, color additive, electronic product, or any other article under investigation in a research study (included approved and unapproved drugs, biologics and devices). (FDA)

Test Procedure : Any investigational method (other than test articles ) being developed, tested and evaluated, designed to develop or contribute to generalizable knowledge. Examples include surgical techniques and psychological therapy.

UM Event : An event which occurs in a study under the supervision of the UM IRBMED and whose principal investigator is a UM faculty or staff member. The event is a UM Event when it occurs at The University of Michigan (including any UM hospital, health center, or other facility) or any other site where the UM principal investigator has oversight , even when the PI is physically in another location. It does not matter where the subject experiences or is treated for the adverse event. (See also Off-site Event ). If interventions take place at several different UM locations (e.g. the CCRB and the GCRC), please specify at which location the event occurred.

Unanticipated problem : An unanticipated problem may be either an actual harmful or unfavorable occurrence or any development that potentially increased the likelihood of harm occurring in the future. Assessment Criteria:

1. The nature, severity, or frequency of the event(s) or information was NOT expected, given descriptions in the study documents or the characteristics of the subject population being studied.

2. There is a reasonable possibility that the procedures involved in the research caused the problem.

3. The event(s) or information suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized (including physical, psychological, economic, or social harm).

Click here for detailed information investigators are required to understand and follow .

Underlying condition : A disease or other circumstance affecting the research subject that is not a result of the intervention or experimental design of a research study.

Unexpected Adverse Drug Reaction : A term used by some sponsors to refer to an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochures for an unapproved investigational product or package insert/summary of product characteristics for an approved product).

Unexpected Event : An event or side effect that is not described in any of the following:

(see also Expected Event and Unexpected Magnitude, Duration or Frequency ).

Unexpected Magnitude, Duration or Frequency : An event or occurrence(s) should be reported to the IRBMED according to the Timeline for unexpected events when the intensity (severity), how long the event takes or persists, or the rate of occurrence is different than described in the informed consent document (ICD), even if the event is otherwise described in the ICD. For example, the ICD notes that some subjects experience mild, brief ringing in the ears following an fMRI. If a subject experiences ringing of significant intensity (such that she cannot work or attend classes) or the ringing persists for several weeks, the event would be reportable as an unexpected event. Likewise, if elevated liver enzymes were described in the ICD as expected at statistical rate of 2% but monitoring revealed 10% of subjects experienced such elevations, this should be reported as an unexpected adverse event.

Unrelated Event : Any adverse event for which there is evidence that it was definitely related to a cause other than the investigational drug/agent/therapy (e.g. disease progression). Investigators must be able to provide such evidence upon request. (See also Cause , attribution , relatedness ).

Vulnerable Subjects :
1) Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. (ICH Guidelines)

2) Vulnerable populations can be defined as children, prisoners, pregnant women, handicapped or mentally disabled persons, or economically or educationally disadvantaged persons. If vulnerable individuals are involved in clinical trials, Institutional Review Boards must ensure that additional safeguards have been included to protect the vulnerable group. Safeguards may include the presence of interpreters or social workers to explain the research and ensure informed consent. IRBs have a specific obligation to protect those individuals who are particularly susceptible to coercion or undue influence (21 CFR 56.11). Studies involving vulnerable groups often pose difficult ethical questions. For example, vulnerable subjects may not be allowed to participate in research that involves more than minimal risk but conveys no benefits directly to the subects. (21 CFR 56.11 and 45 CFR 46 subparts B & C).

This page is maintained by UMHS Public Relations & Marketing Communications. Contact UMMS
(c) copyright 2008 Regents of the University of Michigan