DEPARTMENT OF RESEARCH
Institutional Review Board
Evaluating and Monitoring Risk in Human Subjects Research
Guidelines
This document was designed to assist Institutional Review Board (IRB) members and principal
investigators in determining the level of risk and the type of monitoring that will be required for a
research study involving human subjects.
A. Risk of Study
The Code of Federal Regulations (45 CFR 46.102(i), 46.111, & 46.406) only defines minimal risk, and
defines it as:
“The probability and magnitude of harm or discomfort anticipated in the research are not greater than
those ordinarily encountered in daily life or during the performance of routine physical and
psychological examinations or tests.”
The LBH IRB further defines minimal risk and defines other risk levels as follows:
Minimal Risk: Involves no more risk than expected in daily life. There are no serious adverse
events anticipated. Examples of minimal risk studies include but are not limited to:
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Observation studies
Behavior studies
Nutrition studies
Survey/Questionnaire studies
Routine psychological testing
Anthropomorphic evaluations
Exercise testing
Oral glucose tolerance tests
Intravenous glucose tolerance tests
Venipuncture
Intravenous catheter insertion
EKGs
Ultrasound scans
DEXA scans
Note: Survey research and questionnaires may present more than minimal risk to subjects if they
address highly sensitive information. Inclusion of vulnerable populations (children,
prisoners, pregnant women, mentally disabled persons, or economically and/or
educationally disadvantaged persons) who may be more sensitive or vulnerable to the risks
posed by the research, regardless of the study, may increase the level of risk.
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Low Risk: Involves a minor increase over minimal risk. There is medium to high probability of the
occurrence of a low-severity event that is completely reversible (e.g., headache from lumbar
puncture) or the likelihood of serious harm occurring is low (e.g., fatal anaphylaxis from allergy skin
testing). Examples of low risk studies include but are not limited to:
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Studies that might meet requirements for minimal risk but include vulnerable populations or
invasive procedures.
Studies that involve sensitive information or a potential risk of breach of confidentiality
Interventions or invasive procedures that present low risks, reasonably commensurate with
those expected in medical or dental practice.
Studies of normal volunteers using well-described research procedures such as an
intravenous infusion, euglycemic clamp, indirect calorimetry and/or single dose of
experimental agent.
Post marketing studies - phase IV drug studies or device studies (as defined by FDA) with
minor safety concerns.
Studies involving MRI scans
Studies involving CT or PET scans
Category I radiation risk (HE (mrem) < 500 mrem and organ limit of HT < 150/W T)
Note: 10 CFR § 20.1003 defines HT (Dose equivalent) as the product of the absorbed dose in
tissue, quality factor, and all other necessary modifying factors at the location of interest.
HE equals the effective dose equivalent, which is the sum of the products of the dose
equivalent to the organ or tissue (HT) and the weighting factors (WT) applicable to each of
the body organs or tissues that are irradiated (HE = ΣWTHT). [Average background
exposure is about 360 mrem per year. Maximum safe occupational whole body radiation
exposure is 5000 mrem per year.]
Moderate Risk: Involves risks that are reasonable in relation to anticipated benefits (if any) to
subjects and the importance of the knowledge that may reasonably be expected to result. There is
a medium to high probability of a moderate-severity event occurring as a result of study
participation (e.g., reversible worsening of a non-fatal disease such as seasonal allergy while
receiving placebo or pneumonia from a bronchoscopy), but there is adequate surveillance and
protections to identify adverse events promptly and to minimize their effects. Examples of
moderate risk studies include but are not limited to:
1.
Minimal risk studies involving vulnerable populations (e.g. subjects with impaired capacity to
give informed consent)
2. Studies involving subjects with serious viral, autoimmune, and malignant illness
3. Studies involving subjects treated with a placebo for a recognized disease
4. Protocols in which there is substantial risk (>5%) of a serious adverse event originating from
the underlying condition of the enrolled subject
5. Phase I or II clinical trials with available safety data in humans
6. Industry sponsored phase III clinical trials
7. Studies using drugs for use not indicated
8. Studies that use invasive hemodynamic monitoring with arterial lines
9. Studies in which blood and tissue specimens are stored
10. Studies in which blood and tissue specimens are collected for genetic studies
11. Category II radiation risk [HE (mrem) 500 < HE < 5000 mrem or organ limit of 150/ W T < HT <
750/W T]
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High Risk: Involves risks that are greater due to a high probability of an event that is serious and
prolonged or permanent occurring as a result of study participation. Examples of high risk studies
include but are not limited to:
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Studies that have potential for high (significant) levels of risk that may result in permanent
physical and/or mental changes, hospitalization, and/or death
Clinical trials of interventions to prevent or treat diseases that lead to death or irreversible
morbidity
Phase I or II clinical trials with no available safety data in humans, and blinded Phase II
studies
Investigator-initiated IND (investigational new drug) or IDE (investigational device exemption)
trials
Investigator-initiated phase I, II or III clinical trials
Investigator-initiated multi-center trials
Studies involving an intervention or invasive procedure with substantial risk or potential for
severe toxicity
Implantation of a device with an IDE
FDA-approved agents for non-approved indications
The use of a new chemical or drug for which there is little or no toxicology data in humans
Clinical trials using investigational agents, gene therapy, or recombinant DNA molecules (gene
transfer)
Studies involving the manufacturing of agents on campus
Studies having has provisions to waive consent in emergency circumstances
Category III radiation risk [HE (mrem) > 5000 mrem or organ limit of HT > 750/W T]
Note: A Data Safety Monitoring Board (DSMB) may be required for high risk studies.
B. Monitoring of Study
All protocols presenting the potential of risk to subjects, even minimal risk, should address how the
investigator will monitor risk and report adverse events.
Monitoring Recommendations Based on Level of Risk:
Safety monitoring for a protocol must be appropriate for the level of risk identified. The
combination of factors used in assessing the level of risk drives the intensity of monitoring required
for a protocol. The requirements outlined below represent the minimum amount necessary to
assure subject safety. The LBH IRB may require more frequent and/or additional periodic
monitoring provided by an IRB Audit Subcommittee. Standard reporting to the IRB of unanticipated
problems and adverse events is required regardless of the level of monitoring.
Minimal Intensity Monitoring – The PI or co-investigator will monitor the study with prompt
reporting of adverse events and other study related information to the IRB, sponsor, and other
agencies as described in the LBH IRB Guide # 3: Adverse Event Reporting. A Modified Safety
Monitoring Plan that describes appropriate safety-monitoring procedures will be reviewed and
approved by the LBH IRB.
Low Intensity Monitoring –The PI or co-investigator will monitor the study with prompt reporting
of adverse events and other study related information to the IRB, sponsor, and other agencies as
described in the LBH IRB Guide # 3: Adverse Event Reporting. Team meetings by the PI and
his/her staff will be conducted on a routine basis to discuss protocol issues and review adverse
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events. The Safety Monitoring Plan approved by the LBH IRB will be revised and updated if the
risk/benefit ratio changes.
Moderate Intensity Monitoring – The PI or co-investigator monitors the study on a day-to-day
basis and includes all monitoring activities described above in low intensity monitoring. In addition,
most protocols will require well-described criteria for dose escalation, criteria defining maximum
tolerated dose (MTD), and/or criteria for stopping the trial or involvement of a subject. Surveillance
and protections are in place to adequately identify adverse events promptly. An independent
medical monitor or safety monitoring committee may also be utilized to review adverse events as
they occur and make recommendations to the protocol team.
High Intensity Monitoring – The PI or co-investigator monitors the study on a day-to-day basis
and includes all monitoring activities described above under Low Intensity Monitoring. Most highrisk protocols will also require a Data Safety Monitoring Committee (DSMC) to monitor the safety
and efficacy of the study. An independent Data Safety Monitoring Board (DSMB) is required by
NIH Guidelines for all Phase III clinical trials. Based on the level of risk, the complexity of the
protocol, and the patient population, the LBH IRB may determine that a clinical trial or protocol
requires an independent DSMB or DSMC. Some single institution, investigator initiated, clinical
trials or protocols deemed of significant risk may also fit these criteria. If no other DSMB is in place
for a single institution clinical trial, the PI may ask the LBH IRB to appoint an independent board to
fulfill this function.
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