IRB APPLICATION INSTRUCTIONS
The Mount Auburn Hospital Institutional Review Board (IRB) reviews protocols
according to the level of risk to research subjects involved and categories of
research as defined by federal regulations 45 CFR Part 46 and 21 CFR Part 50.
The proposed research may present more than minimal risk to subjects (full
board review), minimal risk (expedited review), or the research may qualify as
exempt under specific categories 46.101(b)(1-6), 46.201(b), 46.301(a),
46.401(b), 21 CFR 50.104.
The type of review will determine the research application requirements.
For all protocols that involve any contact with human subjects whether
through procedures, questionnaires, surveys, interviews, focus groups, sample
tissue, cell lines or any material or data that may or may not be linked to
human subjects, a determination must be made through the IRB office whether
the proposal meets the definition of research with human subjects and whether
subsequent IRB review is required.
The IRB Administrator pre-reviews all application submissions and determines
whether the research project meets the definition of research involving human
subjects. The IRB Administrator is available to consult informally in
preparation of a protocol. However, if an investigator would like to consult with
the Administrator to determine whether a research project fits a specific
category of research, a detailed protocol with all relevant attachments will be
required. The IRB Administrator may request additional documents as
necessary to make an appropriate recommendation.
Please review the categories of research, expedited, full board, exempt, to
determine the level of review and application submission requirements.
EXPEDITED REVIEW
ONLY protocols that satisfy the federal requirements for expedited review may
be reviewed in a pre-meeting of the IRB as an expedited study. Expedited
reviews are conducted by the IRB Co-Chairs in accordance with 45 CFR
46.110(b), the reviewer “may exercise all of the authorities of the IRB except
that the reviewer may not disapprove research.” The Co-Chair may approve
the application, require modifications to the application, or defer the study to
the convened board for review. Expedited procedures may be used for initial
and continuing review of research, and amendments to previously approved
research under 45 CFR 46.110 and 21 CFR 56.110.
Research activities that:
1. present no more than minimal risk to human subjects, and
2. involve only procedures listed in one or more of seven specific categories
permitted by the federal regulations are eligible for expedited review.
“minimal risk” is defined as 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 or routine physical
or psychological examinations or tests.”
Risks to subjects may include physical or psychological risks, risks associated
with breach of privacy and confidentiality, risk of criminal or civil liability, or
negative impact to subject’s financial standing, employability, insurability, or
reputation.
An expedited review application may require an informed consent form and
authorization. The investigator may request a waiver of consent and waiver of
authorization provided the criteria for waiver are met.
LINK – Section M, Expedited Review Instructions revising expedited review form
Forms required for Expedited Review: Section A - Research Application;
Section B – Study Description; Section C – Medical Records Review (if not
applicable do not submit); Section D – Informed Consent Form;
If requesting a waiver of consent requirement, please complete Section A-12 of
the application. If requesting a waiver of authorization, please complete
Section A-12 of the application and submit a Waiver of Authorization Form
FULL BOARD REVIEW
The convened IRB may approve research only after it has determined that
all of the following requirements are satisfied:
1. Risks to subjects are minimized by using procedures that are
consistent with sound research design, and that do not
unnecessarily expose subjects to risk. Whenever appropriate,
researchers should employ procedures that are being performed on
subjects for diagnostic or treatment purposes.
2. Risks to subjects are reasonable relative to
1. anticipated benefits, if any, to subjects, and
2. the importance of the knowledge that may reasonably be
expected to result.
3. The selection of subjects is equitable. In making this assessment
the IRB must take into account the purposes of the research and
the setting in which it will be conducted. The IRB must be
particularly attentive to the special problems that may arise when
research involves vulnerable populations, such as children,
pregnant women, prisoners, mentally disabled persons, or
economically or educationally disadvantaged persons. If any of the
subjects is likely to be susceptible to undue influence or coercion,
the IRB may require additional safeguards in the study to protect
such subjects.
4. Informed consent will be sought from each prospective subject, or
the subject's legally authorized representative, generally by means
of a written consent document. The IRB will carefully review these
documents to assure that they contain the required elements of
informed consent (see 45 CFR 46.116) and that they are
understandable to a lay person.
5. The research plan makes adequate provisions for ensuring the
safety of subjects.
6. There are adequate provisions to protect the privacy of subjects
and to maintain the confidentiality of data.
Forms required for Full Board Review: Section A - Research Application;
Section B – Study Description; Section C – Medical Records Review if
applicable; Section D – Informed Consent Form;
If requesting a waiver of consent requirement, please complete section A-12 of
the application. If requesting a waiver of authorization please complete section
A-12 of the application and submit a Waiver of Authorization Form
EXEMPT RESEARCH
The six categories of research that qualify for exemption from ongoing IRB
review are:
1. research conducted in established or commonly accepted educational
settings, involving normal educational practices
2. research involving the use of educational tests, (cognitive, diagnostic,
aptitude, achievement), survey procedures, interview procedures or
observation 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' responses
outside the research could reasonably place the subjects at risk of
criminal or civil liability or be damaging to the subjects' financial
standing, employability, or reputation.
3. behavioral and social science studies that present little or no risk to
participants;
4. research involving the collection or study of existing data, documents,
records, pathological specimens, or diagnostic specimens, if these
sources are publicly available
5. research and demonstration projects which are conducted by or subject
to the approval of department or agency heads, and which are designed
to study, evaluate, or otherwise examine:
(i) Public benefit or service programs; (ii) procedures for obtaining
benefits or services under those programs; (iii) possible changes in or
alternatives to those programs or procedures; or (iv) possible changes in
methods or levels of payment for benefits or services under those
programs.
6. taste and food quality evaluation and consumer acceptance studies
Exempt research must have little, if any, associated risk. In rare
circumstances, the IRB may review periodic reports on an exempt study.
Forms required for Exempt Review: revising the exempt review form.
The research may not begin until the IRB has issued an approval.
AMENDMENTS
Amendments are changes to the currently approved research application. The
Mount Auburn Hospital IRB also processes and reviews as amendments
recruitment materials, information sheets, advertisements,
surveys/questionnaires, investigator brochures, changes to informed consent
forms, partial waiver of consent requirements, and changes to study status
prior to annual review.
Some amendments or changes may be minor. Studies deemed to be minimal
risk amendments may be reviewed by an IRB Co-Chair using the expedited
review process.
The IRB determines that the information or activity described in an
amendment could place subjects at increased risk and, it will require that the
amendment go to the full board for review.
INVESTIGATORS MAY NOT INCLUDE UNAPPROVED AMENDMENT INFORMATION OR
ACTIVITIES IN THE PROTOCOL OR INFORMED CONSENT FORM WITHOUT PRIOR IRB
APPROVAL. If you believe that an amendment is necessary to eliminate
immediate potential harm to subjects contact the IRB Co-Chair for emergency
approval
The PI is responsible for submitting the amendment to the IRB office with all
supporting revisions and any additional information related to the amendment.
The Research Administrator is responsible for reviewing and determining
whether the risks to subjects is minor and, therefore can be approved through
expedited review procedure.
Forms required: Amendment form; if amending the informed consent form
(ICF), please include a copy of the IRB approved ICF along with the revised
copy; if amending any other forms, please include the original with the
amended copy.
CONTINUING REVIEW
The timeframe for IRB continuing review is based on the level of risks to
subjects [45 CFR 46.103(b)(4) and 46.109(e)] and will occur at least annually.
Investigators who do not submit a continuing review before the study
expiration date must stop all research activities until the IRB receives and
approves the continuing review. In circumstances where risks to subjects may
be compromised by halting study procedures, the investigator is required to
contact the IRB Co-Chair and inform him of the reasons why the study can not
be stopped, provide a written explanation to the IRB, and submit a continuing
review form.
Forms required for continuing review: Continuing Review Form; a copy of the
IRB approved informed consent form.
THIS SECTION, ADVERSE EVENTS, IS STILL UNDER REVIEW
ADVERSE EVENTS & UNANTICIPATED PROBLEMS INSTRUCTIONS AND REPORTING GUIDE
RELEVANT DEFINITIONS: LINK THRU TO “END OF DEFINITIONS”
Serious adverse event:
Any adverse event temporally associated with the subject’s
participation in research that meets any of the following criteria:
1. results in death;
2. is life-threatening (places the subject at immediate risk of death
from the event as it occurred);
3. requires inpatient hospitalization or prolongation of existing
hospitalization;
4. results in a persistent or significant disability/incapacity;
5. results in a congenital anomaly/birth defect; or
6. any other adverse event that, based upon appropriate medical
judgment, may jeopardize the subject’s health and may require
medical or surgical intervention to prevent one of the other
outcomes listed in this definition (examples of such events
include allergic bronchospasm requiring intensive treatment in
the emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or
the development of drug dependency or drug abuse).
UNEXPECTED ADVERSE EVENTS:
Any adverse event occurring in one or more subjects participating in a
research protocol, the nature, severity, or frequency of which is not
consistent with either:
 The known or foreseeable risk of adverse events associated with
the procedures involved in the research that are described in (a)
the protocol related documents, such as the IRB-approved
research protocol, any investigator brochure, and the current
IRB-approved informed consent document, and (b) other
relevant sources of information, such as product labeling and
package inserts; or
 The expected natural progression of any underlying disease,
disorder, or condition of the subject(s) experiencing the adverse
event and the subject’s predisposing risk factor profile for the
adverse event. (Modified from the definition of unexpected
adverse drug experience in FDA regulations at 21 CFR
312.32(a)).
External Adverse events: From the perspective of one particular
institution engaged in a multi-center clinical trial, external adverse
events are those adverse events experienced by subjects enrolled by
investigators at other institutions engaged in the clinical trial.
Internal Adverse events: From the perspective of one particular
institution engaged in a multi-center clinical trial, internal adverse
events are those adverse events experienced by subjects enrolled by
the investigator at that institution.
In the context of a single-center clinical trial, all adverse events would
be considered internal adverse events.
Possibly related to the research: There is a reasonable possibility that
the adverse event, incident, experience or outcome may have been
caused by the procedure involved in the research (modified from the
definition of associated with use of the drug in FDA regulations at 21
CFR 312.32(a). END OF DEFINITIONS.
WHAT ARE ADVERSE EVENTS?
The term adverse event is used very broadly and includes any event
meeting the following definition:
Any untoward or unfavorable medical occurrence in a human subject,
including any abnormal sign (for example, abnormal physical exam or
laboratory finding), symptom, or disease, temporally associated with
the subject’s participation in the research, whether or not considered
related to the subject’s participation in the research.
Adverse events may be caused by one or more of the following:
1. the procedures involved in the research;
2. an underlying disease, disorder, or condition of the subject; or
3. other circumstances unrelated to either the research or any
underlying disease, disorder, or condition of the subject.
WHAT ARE UNANTICIPATED PROBLEMS?
Office of Human Research Protection (OHRP) considers unanticipated
problems, in general, to include any incident, experience, or outcome
that meets all of the following criteria:
1. unexpected (in terms of nature, severity, or frequency) given (a)
the research procedures that are described in the protocolrelated documents, such as the IRB-approved research protocol
and informed consent document; and (b) the characteristics of
the subject population being studied;
2. related or possibly related to participation in the research (in
this guidance document, possibly related means there is a
reasonable possibility that the incident, experience, or outcome
may have been caused by the procedures involved in the
research); and
3. suggests that the research places subjects or others at a greater
risk of harm (including physical, psychological, economic, or
social harm) than was previously known or recognized.
An incident, experience, or outcome that meets the three criteria
above generally will warrant consideration of substantive changes in
the research protocol or informed consent process/document or other
corrective actions in order to protect the safety, welfare, or rights of
subjects or others. Examples of corrective actions that might need to
be considered in response to an unanticipated problem include:
 changes to the research protocol initiated by the investigator
prior to obtaining IRB approval to eliminate apparent immediate
hazards to subjects
 modification of inclusion or exclusion criteria to mitigate the
newly identified risks;
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implementation of additional procedures for monitoring
subjects;
suspension of enrollment of new subjects;
suspension of research procedures in currently enrolled
subjects;
modification of informed consent documents to include a
description of newly recognized risks; and
provision of additional information about newly recognized risks
to previously enrolled subjects.
EXAMPLES OF UNANTICIPATED PROBLEMS THAT DO NOT INVOLVE ADVERSE EVENTS AND
NEED TO BE REPORTED TO THE IRB
1. As a result of a processing error by a pharmacy technician, a subject
enrolled in a multi-center clinical trial receives a dose of an experimental
agent that is 10-times higher than the dose dictated by the IRB-approved
protocol. While the dosing error increased the risk of toxic
manifestations of the experimental agent, the subject experienced o
detectable harm or adverse effect after an appropriate period of careful
observation. Nevertheless, this constitutes an unanticipated problem for
the institution where the dosing error occurred that must be reported to
the IRB, appropriate institutional officials, and OHRP because the
incident was (a) unexpected; (b) related to participation in the research;
and (c) placed subject at a greater risk of physical harm than was
previously known or recognized.
2. Subjects with cancer are enrolled in a phase 2 clinical trial evaluating
an investigational biologic product derived from human sera. After
several subjects are enrolled and receive the investigational product, a
study audit reveals that the investigational product administered to
subjects was obtained from donors who were not appropriately screened
and tested for several potential viral contaminants, including the human
immunodeficiency virus and the hepatitis B virus. This constitutes an
unanticipated problem that must be reported because the incident was
(a) unexpected; (b) related to participation in the research; and (c) placed
subjects and others at a greater risk of physical harm than was
previously known or recognized.
This unanticipated problem example may have presented unanticipated
risks to others (e.g., the sexual partners of the subjects) in addition to
the subjects and should be promptly reported to the IRB, appropriate
institutional officials, and the OHRP in accordance with HHS regulations
at 45 CFR 46.103(a) and 46.103(b)(5).
3.
An investigator conducting behavioral research collects
individually identifiable sensitive information about illicit drug use and
other illegal behaviors by surveying college students. The data are stored
on a laptop computer without encryption, and the laptop computer is
stolen from the investigator’s car on the way home from work. This is an
unanticipated problem that must be reported to the IRB, appropriate
institutional officials, and the OHRP in accordance with HHS regulations
at 45 CFR 46.103(a) and 46.103(b)(5) because the incident was (a)
unexpected (i.e., the investigators did not anticipate the theft); (b) related
to participation in the research; and (c) placed the subjects at a greater
risk of psychological and social harm from the breach of confidentiality of
the study data than was previously known or recognized.
UNANTICIPATED PROBLEMS MAY REQUIRE SUBSTANTIVE CHANGES IN THE RESEARCH
PROTOCOL OR INFORMED CONSENT PROCESS/DOCUMENT OR OTHER CORRECTIVE
ACTIONS IN ORDER TO PROTECT THE SAFETY, WELFARE, OR RIGHTS OF SUBJECTS.
END OF LINK #1 EXAMPLES OF UNANTICIPATED PROBLEMS
LOCAL ADVERSE EVENT REPORTS - SUBMISSION INSTRUCTIONS:
 Complete the ADVERSE EVENT REPORT FORM with original PI signature
 Signature of responsible treating physician, if different from the PI
 Include supporting Medical reports
 Discharge summary, if applicable
 If revising informed consent form, include:
o Revised ICF with changes highlighted
o 1 clean copy of revised ICF
EXAMPLES OF ADVERSE EVENTS THAT REPRESENT UNANTICIPATED PROBLEMS AND
NEED TO BE REPORTED UNDER THE HHS REGULATIONS AT 45 CFR PART 46
1. A behavioral researcher conducts a study in college students that
involves completion of a detailed survey asking questions about
early childhood experiences. The research was judged to involve
no more than minimal risk and was approved by the IRB
chairperson under an expedited review procedure. During the
completion of the survey, one student subject has a transient
psychological reaction manifested by intense sadness and
depressed mood that resolved without intervention after a few
hours. The protocol and informed consent document did not
describe any risk of such negative psychological reactions. Upon
further evaluation, the investigator determines that the subject’s
negative psychological reaction resulted from certain survey
questions that triggered repressed memories of physical abuse as a
child. The investigator had not expected that such reactions
would be triggered by the survey questions. This is an example of
an unanticipated problem that must be reported in the context of
social and behavioral research because, though not serious, the
adverse event was (a) unexpected; (b) related to participation in the
research; and (c) suggested that the research places subjects at a
greater risk of psychological harm than was previously known or
recognized.
2. Subjects with essential hypertension are enrolled in a phase 2,
non-randomized clinical trial testing a new investigational
antihypertensive drug. At the time the clinical trial is initiated,
there is no documented evidence of gastroesophageal reflux
disease (GERD) associated with the investigational drug, and the
IRB approved protocol and informed consent document do not
describe GERD as a risk of the research. Three of the first ten
subjects are noted by the investigator to have severe GERD
symptoms that began within one week of starting the
investigational drug and resolved a few days after the drug was
discontinued. The investigator determines that the GERD
symptoms were most likely caused by the investigational drug and
warrant modification of the informed consent document to include
a description of GERD as a risk of the research. This is an
example of an adverse event that, although not serious, represents
an unanticipated problem that must be reported because it was (a)
unexpected in nature; (b) possibly related to participation in the
research; and (c) suggested that the research placed subjects at a
greater risk of physical harm than was previously known or
recognized.
3. The fifth subject enrolled in a phase 2, open label, uncontrolled
clinical study evaluating the safety and efficacy of a new oral agent
administered daily for treatment of severe psoriasis unresponsive
to FDA-approved treatments, develops severe hepatic failure
complicated by encephalopathy one month after starting the oral
agent. The known risk profile of the new oral agent prior to this
event included mild elevation of serum liver enzymes in 10% of
subjects receiving the agent during previous clinical studies, but
there was no other history of subjects developing clinically
significant liver disease. The IRB-approved protocol and informed
consent document for the study identifies mild liver injury as a
risk of the research. The investigators identify no other etiology for
the liver failure in this subject and attribute it to the study agent.
This is an example of an unanticipated problem that must be
reported because although the risk of mild liver injury was
foreseen, severe liver injury resulting in hepatic failure was (a)
unexpected in severity; (b) possibly related to participation in the
research; and (c) serious.
EXAMPLES
OF ADVERSE EVENTS THAT DO NOT REPRESENT UNANTICIPATED PROBLEMS
AND DO NOT NEED TO BE REPORTED UNDER THE HHS REGUALTIONS AT 45 CFR PART
46.
1. A subject enrolled in a phase 3, randomized, double-blind,
placebo-controlled clinical trial evaluating the safety and efficacy of
a new investigational anti-inflammatory agent for management of
osteoarthritis develops severe abdominal pain and nausea one
month after randomization . Subsequent medical evaluation
reveals gastric ulcers. The IRB-approved protocol and informed
consent document for the study indicated that there was a 10%
chance of developing mild to moderate gastritis and a 2% chance
of developing gastric ulcers for subjects assigned to the active
investigational agent. The investigator concludes that the subject’s
gastric ulcers are within the expected frequency. This example is
not an unanticipated problem because the occurrence of gastric
ulcers – in terms of nature, severity, and frequency – was expected.
2. A subject is enrolled in a phase 3, randomized clinical trial
evaluating the relative safety and efficacy of vascular stent
placement versus carotid endarterectomy for the treatment of
patients with severe carotid artery stenosis and recent transient
ischemic attacks. The patient is assigned to the stent placement
study group and undergoes stent placement in the right carotid
artery. Immediately following the procedure, the patient suffers a
severe ischemic stroke resulting in complete left-sided paralysis.
The IRB-approved protocol and informed consent document for the
study indicated that there was a 5-10% chance of stroke for both
study groups. To date, 25 subjects have been enrolled in the
clinical trial, and 2 have suffered a stroke shortly after undergoing
the study intervention, including the current subject. The DSMB
responsible for monitoring the study concludes that the subject’s
stroke resulted from the research intervention. This example is
not an unanticipated problem because the occurrence of stroke
was expected and the frequency at which strokes were occurring in
subjects enrolled so far was at the expected level.
3. An investigator is conducting a psychological study evaluating the
factors that affect reaction times in response to auditory stimuli.
In order to perform the reaction time measurements, subjects are
placed in a small, windowless soundproof booth and asked to wear
headphones. The IRB-approved protocol and informed consent
document describe claustrophobic reactions as one of the risks of
the research. The twentieth subject enrolled in the research
experiences significant claustrophobia, resulting in the subject
withdrawing from the research. This example is not an
unanticipated problem because the occurrence of the
claustrophobic reaction – in terms of nature, severity, and
frequency – was expected.