Using the short
form and reporting
adverse events
Erin Coons, Senior IRB Specialist, COMIRB
1
The short form
2
…the consent form may be either of the following:
1.
A written consent document that embodies the elements of informed
consent required by [regulation]. This form may be read to the subject or the
subject's legally authorized representative, but in any event, the investigator
shall give either the subject or the representative adequate opportunity to
read it before it is signed; or
2.
A short form written consent document stating that the elements of informed
consent required by [regulation] have been presented orally to the subject or
the subject's legally authorized representative. When this method is used,
there shall be a witness to the oral presentation. Also, the IRB shall approve
a written summary of what is to be said to the subject or the representative.
Only the short form itself is to be signed by the subject or the representative.
However, the witness shall sign both the short form and a copy of the
summary, and the person actually obtaining consent shall sign a copy of the
summary. A copy of the summary shall be given to the subject or the
representative, in addition to a copy of the short form.
21 CFR 50.27(b) and 45 CFR 46.117(b)
3
COMIRB Policy
Non-English speaking subjects may not be enrolled with a short form process of
consent documentation unless reviewed and approved in advance by the
COMIRB. For studies reviewed by COMIRB, if a non-English-speaking subject is
enrolled unexpectedly, researchers may rely on an oral translation of the English
language consent form or the COMIRB template short consent form, but should
take extra care in the informed consent process to ensure that the subject has
understood the project. A statement in the research records (and on the English
language consent form) should indicate that the translation took place, identify the
translator, and document the translator‘s belief that the subject understands the
study and the consent process. If the subject is a patient, a note about the
translation should be made in the patient‘s medical records as well. Researchers
should try to provide a written translation of the vital emergency contact
information.
4
COMIRB Policy…
A study is permitted to utilize the short form up to three times in the same
language. If a 4th subject is to be enrolled then a translation of the entire consent
form should be provided to COMIRB for approval.
For studies with a separate HIPAA B form, the HIPAA B form in English (unless
the Spanish translation is being used) must also be translated by the interpreter
as part of the summary and the HIPAA B form must be signed and dated by the
subject or representative.
5
Short forms available on COMIRB web site
• Amharic
• Arabic​
• Burmese
• Chinese​​
• French​
• Hindi​
• Korean​
• Laotian​
• Mandarin​
• Nepali (Coming soon)
• Polish
• Portuguese​
• Punjabi​
• Russian​
• Serbian​
• Spanish Adult​
• Swahili
• Tagalog​
• Thai​
• Urdo​
• Vietnamese​​
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• English example:
http://gcrc.ucdenver.edu/comirb/Short-Form-AdultEnglish.doc
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Reporting adverse
events to COMIRB
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• Unanticipated Problem Involving Risks to Participants or
Others (Unanticipated Problem): Any event or information
that was unforeseen and indicates that the research
procedures caused harm (including physical, psychological,
economic, or social harm) to participants or others or indicates
that participants or others are at increased risk of harm than
was previously known or recognized.
• Unanticipated event: Any adverse experience where the
nature, severity or frequency is not identified in the
investigational brochure described in the application form or
detailed in the consent form. This can also include noncompliance issues such as over enrollment of subjects without
prior COMIRB approval.
• Adverse Event: Any unfavorable and unintended sign
(including abnormal laboratory finding), symptom, or disease
temporally associated with the use of a medical treatment or
procedure, regardless of whether it is considered related to the
medical treatment or procedure (attribution of unrelated,
unlikely, possible, probable or definite).
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• Possibly related: In the opinion of the PI, the
adverse event is unlikely to be related to the study
intervention, drug or device.
• Probably related: In the opinion of the PI, it is more
likely than not that the adverse event is related to
the study intervention, drug or device.
• Definitely related: In the opinion of the PI, it is very
likely that the adverse event is related to the study
intervention, drug or device.
• Related to the research: An event is related to the
research procedures if in the opinion of the principal
investigator, it was more likely than not [probably] to
be caused by the research procedures or if it is
more likely that not [probably] that the event affects
the rights and welfare of current participants.
10
Adverse events that are
•
unexpected
AND
•
probably or definitely related to the study
procedures, drug, or device
must be reported to COMIRB within 5 days
11
Adverse events that are
•
expected
OR
•
not related or possibly related to the study
procedures, drug, or device
must be reported in summary form at the next
continuing review
12
External events
http://gcrc.ucdenver.edu/comirb/Decision-Tree-SafetyReport-Received-from-Sponsor.xls
13
COMIRB policy: Other events that require immediate reporting
•
•
•
An actual unforeseen harmful or unfavorable occurrence to participants or others
that relates to the research protocol (injuries, psychological events, drug errors).
An unforeseen development that potentially increases the likelihood of harm to
participants or others in the future.
Information that indicates a change to the risks or potential benefits of the research.
For example:
An interim analysis or safety monitoring report indicates that frequency or
magnitude of harms or benefits may be different than initially presented to
the COMIRB.
A paper is published from another study that shows that the risks or
potential benefits of your research may be different than initially
presented to the COMIRB.
•
A problem involving data collection, data storage, privacy or confidentiality.
•
Incarceration of a participant in a protocol not approved to enroll prisoners.
•
Pregnancy of a participant or spouse in a protocol that specifically exclude
pregnancy due to the potential risks of the intervention or treatment on the fetus.
14
COMIRB policy: Other events that require immediate reporting
• Change to the protocol taken without prior COMIRB review to
eliminate an apparent immediate hazard to a research participant.
• Complaint of a participant when the complaint indicates
unexpected risks or cannot be resolved by the research team.
• Protocol violation (meaning an accidental or unintentional change
to the COMIRB approved protocol) that harmed participants or
others or that indicates participants or others may be at increased
risk of harm.
• Study related event that requires prompt reporting to the sponsor.
• Sponsor imposed suspension for risk.
• Non compliance by the PI or research team
• Any other problem that caused a risk to the participant or others
15
The unanticipated problem form should also be used
to submit the following documents to COMIRB for
prompt review if they meet the criteria for an
unanticipated problem:
• Medwatch reports
• IND reports
• DSMB or other safety review reports
• Investigational Brochures changes
• Changes to Package Inserts
• Audit reports
• Complaints
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What does not require immediate reporting to
COMIRB?
• Out of window visits that do not affect subject safety
• Death due to disease progression
• IND Safety Reports that do not meet the definition of
an unanticipated problem
• Drug side effects listed in the risk section of the
consent form
17
Reporting adverse
events to the
sponsor and FDA –
drug studies
18
• Sponsor (not the investigator) determines causality
• For this reason, investigators must immediately
report any serious adverse event to the sponsor,
without regard to causality (21 CFR 312.64(b))
• However, it is also important for the sponsor to
consider the investigator’s view when assessing the
safety of the drug
• Nonserious adverse events reported to sponsor per
protocol
• Follow the protocol!
19
An adverse event or suspected adverse reaction is
considered “serious” if, in the view of either the
investigator or sponsor, it results in any of the
following outcomes: Death, a life-threatening adverse
event, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant
incapacity or substantial disruption of the ability to
conduct normal life functions, or a congenital
anomaly/birth defect. Important medical events that
may not result in death, be life-threatening, or require
hospitalization may be considered serious when,
based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the
outcomes listed in this definition.
20
Examples
• allergic bronchospasm requiring intensive treatment
in an emergency room or at home
• blood dyscrasias or convulsions that do not result in
inpatient hospitalization
• the development of drug dependency or drug abuse
21
The sponsor [including an investigator who holds an IND] must
report to FDA and all participating investigators any suspected
adverse reaction that is both serious and unexpected. Before
submitting this report, the sponsor needs to ensure that the event
meets all three of the definitions contained in the requirement:
• Suspected adverse reaction
• Serious
• Unexpected
If the adverse event meets all three of the definitions, it should be
submitted as an expedited IND safety report (Medwatch report for
drug studies without an IND, or VAERS report for vaccine studies
without an IND) within 15 days.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegul
atoryInformation/Guidances/UCM227351.pdf
22
Suspected adverse reaction means any adverse event
for which there is a reasonable possibility that the drug
caused the adverse event. For the purposes of IND
safety reporting, ‘reasonable possibility’ means there
is evidence to suggest a causal relationship between
the drug and the adverse event.
23
Examples of types of evidence that would suggest a
causal relationship between the drug and the adverse
event
• A single occurrence of an event that is uncommon and
known to be strongly associated with drug exposure
(e.g., angioedema, hepatic injury, Stevens-Johnson
Syndrome)
• One or more occurrences of an event that is not
commonly associated with drug exposure, but is
otherwise uncommon in the population exposed to the
drug (e.g., tendon rupture)
• An aggregate analysis of specific events observed in a
clinical trial (such as known consequences of the
underlying disease or condition under investigation or
other events that commonly occur in the study
population independent of drug therapy, e.g., MI in an
elderly population) that indicates those events occur
more frequently in the drug treatment group than in a
concurrent or historical control group
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An adverse event or suspected adverse reaction is
considered “unexpected” if it is not listed in the
investigator brochure or is not listed at the specificity
or severity that has been observed; or, if an
investigator brochure is not required or available, is
not consistent with the risk information described in
the general investigational plan or elsewhere in the
current application.
25
Examples:
• hepatic necrosis would be unexpected (by virtue of
greater severity) if the investigator brochure referred
only to elevated hepatic enzymes or hepatitis
• cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater
specificity) if the investigator brochure listed only
cerebral vascular accidents
• adverse events or suspected adverse reactions that
are mentioned in the investigator brochure as
occurring with a class of drugs or as anticipated
from the pharmacological properties of the drug, but
are not specifically mentioned as occurring with the
particular drug under investigation (e.g.,
angioedema with ACE inhibitors)
26
Reporting adverse
events to the
sponsor and FDA –
Device studies
27
An investigator shall submit to the sponsor a report of
any unanticipated adverse device effect occurring
during an investigation as soon as possible, but in no
event later than 10 working days after the investigator
first learns of the effect.
28
Sponsors (including investigators who hold an IDE or
lead a trial of a Non-significant Risk or exempt device)
must immediately evaluate the reported unanticipated
adverse device effect and report to FDA, responsible
IRBs, and participating investigators within 10 working
days.
29
Unanticipated adverse device effect means any
serious adverse effect on health or safety or any lifethreatening problem or death caused by, or associated
with, a device, if that effect, problem, or death was not
previously identified in nature, severity, or degree of
incidence in the investigational plan or application
(including a supplementary plan or application), or any
other unanticipated serious problem associated with a
device that relates to the rights, safety, or welfare of
subjects.
30
Summary of adverse event reporting
• Unexpected and probably / definitely related, regardless of
severity - to COMIRB within 5 days
• Local events: Expected or unrelated events – to COMIRB in
summary form at continuing review
• External events: See decision tree
• IND studies: Serious adverse events, regardless of causality or
expectedness – to the sponsor immediately
• All drug studies: Serious adverse events, reasonable
probability related to drug, and unexpected – to the FDA and
participating investigators by the sponsor within 15 days
• IND studies: Nonserious adverse events per protocol
• Device studies: Serious adverse events, related to or
associated with device, and unexpected – to the sponsor
within 10 days, and to the FDA and participating investigators
by the sponsor within 10 days
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References
• COMIRB Policies and Procedures
http://www.ucdenver.edu/academics/research/AboutUs/c
omirb/forms/comirb%20forms/01COMIRB%20Policy%20and%20Procedures%20Docume
nt.pdf
• FDA Guidance – Adverse Event Reporting to IRBs (From
2009 - Drug information is outdated, use for devices
only)
http://www.fda.gov/downloads/drugs/guidancecomplianc
eregulatoryinformation/guidances/ucm079753.pdf
• FDA Guidance - Safety Reporting Requirements for INDs
and BA/BE Studies
http://www.fda.gov/downloads/Drugs/GuidanceComplian
ceRegulatoryInformation/Guidances/UCM227351.pdf 32
Erin Coons
Senior IRB Specialist, COMIRB
erin.coons@ucdenver.edu
303-724-1551
http://www.ucdenver.edu/academics/research/AboutU
s/comirb/Pages/comirb-home.aspx
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