Transcript Informed Consent, Adverse Events, and Protocol Deviations

Adverse Events
Shannon Simmons
Vanderbilt Human Research
Protections Program
July 11, 2014
Outline

Review key terms and federal definitions used in the
context of adverse event reporting

Review federal and local information on adverse event
reporting requirements

Summarize information and identify main points

Present list of Resources

Present example scenarios for evaluation
Everyone Wants Something
Different
IRB
FDA
Sponsor
OHRP
Disclaimer Regarding the
Differences

You are responsible to keep track of each involved
agencies reporting policy and report accordingly.

Often different requirements imposed by:

FDA

OHRP

IRB

Funding agencies

Collaborating Institutions
Accurate AE Reporting and Documentation is Important

It is the law per Federal Regulations and applies to all
research involving human subjects, conducted, supported or
otherwise subject to regulation by any federal department or
agency

For FDA regulated studies, it is a contractual obligation of all
physicians who sign the FDA 1572 investigator registration
form

Ensures human subject safety

Facilitates accurate analysis of effects from investigational
interventions
DEFINITIONS
OHRP
OHRP Reporting Regulations

45 CFR 46.103(a) and (b)(5) require that institutions
have written procedures to ensure the following
incidents related to research conducted under an OHRP
approved assurance is promptly reported to OHRP.
These incidences include:
o
Any unanticipated problems involving risks to subjects or
others
o
Any serious or continuing noncompliance with this policy
or the requirements or determinations of the IRB
Unanticipated Problems Involving Risk to
Participants or Others
 Any incident, experience, or outcome that
meets ALL of the following criteria:
 1.
Unexpected (nature, severity and
frequency AND
 2.
Related or Possibly related -reasonable
possibility that the adverse event 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 than was
previously known or recognized.
OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others
and Adverse Events
Unanticipated Problems Involving
Risk to Participants or Others

Have all three criterion answered yes.

Incidents, experiences, or outcome that meets the three criteria
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 such as:

Modification of the inclusion/exclusion criteria

Implementation of additional monitoring
procedures

Suspension of enrollment of new subjects or
research procedures in enrolled subjects

Providing additional information about newly
recognized risks to enrolled subjects
OHRP and Adverse Events

45 CFR part 46 does not define or use the term adverse
event, nor is there a common definition of this term across
government and non-government entities.

Adverse event according to the regulations, in general 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 (modified from the definition of
adverse events in the 1996 International Conference on
Harmonization E-6 Guidelines for Good Clinical Practice).”
FDA
No Wonder We Are Confused

FDA regulations use different terms when referring to
an adverse event.

adverse effect is used in 21 CFR 312.64;

adverse experience is used in 21 CFR 312.32;

adverse reactions /adverse event (used interchangeably)
in 21 CFR 312.32 ;

unanticipated problems is used in 21 CFR 312.66.

with qualifiers/descriptors to specifically identify: lifethreatening, suspected and/or unexpected.
Adverse Event
(adverse experience)

Any untoward medical occurrence associated with the use
of a drug in humans, whether or not considered drug
related.

Can be any unfavorable and unintended sign (e.g., an
abnormal laboratory finding), symptom, or disease
temporally associated with the use of a drug, without any
judgment about causality.
21CFR 312.32
Unexpected Adverse Event

FDA defines this as any event where:
o
the specificity or severity of which is not consistent with
the current Investigator Brochure (IB);
or
o
if an IB is not required or available, the specificity or
severity of which is not consistent with the risk
information described in the general investigational plan
or elsewhere in the current application.
Serious Adverse Events

Any event resulting in the following outcome should be
reported to FDA :

Death

Life-threatening adverse event;

Inpatient hospitalization or prolongation of existing hospitalization;

A persistent or significant disability/incapacity or substantial
disruption of the ability to conduct normal life functions;

A congenital anomaly/birth defect; or

May jeopardize the subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.
Reporting Requirements

IRB Policy III.L Reporting of Adverse Events, Serious
Adverse Events and Unanticipated Problems Involving
Risk to Participants or Others
When VU is the IRB of Record
VU PI Responsible for Research

Any serious adverse event that in the Investigator’s
opinion:

Was unanticipated (not foreseeable at the time of the
occurrence) or unexpected (not previously seen), AND

Involved risk to participants or others AND

Was possibly related to the research procedures;
AND/OR

•
Any noncompliance with the IRB approved protocol that
increased the risk or affected the patients rights, safety or
welfare.
Any unanticipated problem that falls within the guidelines
listed above require reporting to the IRB even after the
participant has completed the study or after the participant has
withdrawn from the study including after study closure
When VU Is not the IRB of Record and the Study
Related Event does not occur at VU or a
Location that a VU PI is Responsible for
Research.

Does not need to be reported to the IRB unless, the event is :
o
Related,
o
Unanticipated,
And
o

Places subjects at greater risk then previously known
In these cases the PI will:
o
Submit the event to the VU IRB as an amendment Request

The Amendment Form should include: Sponsor and/or DSMB’s
assessment of the event and the VU PI’s assessment of the event;
and the amendment request form should outline the necessary
revisions to the VU IRB approved protocol and associated
documents needed to address the potential risk.
Flowchart for Reporting
Unanticipated Problems involving
risk to Others and Serious
Adverse Events
Reporting Requirements for
Unanticipated Problems and Adverse Events
Involving Risk to Participants and Others

Include:
 The
Investigator’s assessment of causality and
 A description of the actual event;
 An evaluation of whether the event meets the
following criteria:
 Unanticipated;
AND
 Related;
AND
 Serious-An event that suggests that the
research places subjects or others at a greater
risk of physical or psychological harm than was
previously known or recognized.
Other Safety Reporting
Requirements

Independent safety monitoring reports,

Interim analysis reports or

Data and Safety Monitoring Board reports.
VU IND Safety Reporting
Requirements

Outside Safety Reports are no longer reported to the VU
IRB

Unless it caused increased safety risk to subjects which
necessitated revising study documents such as the
protocol, IB and/or consent documents.
FDA Reporting Requirements
An investigator must immediately report to the sponsor any
serious adverse event, whether or not considered drug
related, including those listed in the protocol or
investigator brochure and must include an assessment of
whether there is a reasonable possibility that the drug
caused the event.
21CFR312.64
FDA Reporting ProgramMedWatch

The FDA Safety Information and Adverse Event
Reporting Program
o
Voluntary and Mandatory reporting
o
Used to report a serious adverse event, product quality
problem, product use error, or therapeutic
inequivalence/failure that is suspected to be associated
with the use of an FDA-regulated drug, biologic, medical
device, dietary supplement or cosmetic.
o
FDA uses the reporting of events to maintain safety
surveillance on FDA regulated products which may prompt
action needed to increase patient safety.
FDA Reporting Requirements
FDA has 3 reporting forms:
 Form FDA 3500A - Mandatory Reporting



o
For use by IND reporters, manufacturers, distributors, importers,
user facilities (Sponsors/Sponsor-Investigator),
o
Submitted as specified in the investigational new drug/biologic
regulations or investigational device exemptions.
o
For sponsored studies, may be required per the study protocol and
sent to the address and contact person listed in the study protocol.
Form FDA 3500 [voluntary]
o
For use by healthcare professionals, consumers, and patients.
o
Voluntary reporting of adverse events noted spontaneously in the
course of clinical care, not events that occur during clinical trials
under an IND application.
o
You can report even if:

You are not certain the product caused the event

You don’t have all the details
Form FDA 3500 B [Consumer voluntary]
o
Completed by non-health Professionals or consumers
o
New and easier version (4/2013)
MedWatch 3500A Form
Unanticipated Adverse Device
Effect

Definition: any serious adverse effect on the health or safety of
subjects, or any life-threatening problem or death caused by, or
associated with, a device, if that problem or death was not
previously identified in nature, severity or degree of incidence in
the investigational plan.
•
The sponsor and the VU IRB must be informed of any unanticipated
adverse device effect during a study within 10 days of the investigator
first learns of the effect.
•
A sponsor (the holder of the IDE) must immediately conduct an
evaluation of a unanticipated effect and report to the FDA and to all
investigators and the IRB within 10 days of the sponsors receiving
notice of the effect.
•
Investigators must send these reports to the IRB.
FDA: 21 CFR 812.150
IRB Policy: XI.C
How Will I Ever Get it Right?
Relationship Between Adverse Events and
Unanticipated Problems
The diagram illustrates not all adverse events are unanticipated
problems:

The vast majority of adverse events are not unanticipated
problems (area A).

A small proportion of adverse events are unanticipated problems
(area B).

Unanticipated problems include other incidents, experiences, and
outcomes that are not adverse events (area C).
http://www.hhs.gov/ohrp/policy/advevntguid.html
Stay or Become Organized

Print out and use adverse event flow charts available to you.

Check the VU IRB flow chart prior to any submission.

Create tip sheet of who to report to and when.
•
Discuss requirements with Sponsor
•
Understand the reporting requirements described in the
Protocol and Data Safety Plan

Call (IRB or FDA) if you have questions regarding whether to submit
or not submit.

Document who reports were submitted to
(FDA, IRB, Sponsor etc.) and when.

Stay current with regulations and Institution policies.
Summary

Although the regulations place the burden of
responsibility on the PI, the protection of human
research subjects is a shared responsibility among all
research professionals involved in the conduct of the
study.

We all have a common goal to keep participants safe
and have strict regulations to ensure drugs are safe
prior to FDA approval for use.
Resources

Office for Human Research Protections (OHRP) --45 CFR 46.103(b)(5)



http://www.hhs.gov/ohrp/
OHRP Guidance Document, “Guidance on Reviewing and Reporting Unanticipated
Problems Involving Risks to Subjects or Others and Adverse Events,” January 15, 2007
Food and Drug Administration (FDA)--45 CFR 46.103(b)(5)
http://www.fda.gov/
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM227351.pdf
 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126572.pdf



Instructions for completing Medwatch Form 3500A
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm149238.htm#send

Institutional Review Board (IRB)
IRB Policy III.L Reporting of Adverse Events, Serious Adverse Events and Unanticipated
Problems Involving Risk to Participants or Others
IRB Policy XI.C Investigational Devices



Good Clinical Practice

http://www.fda.gov/oc/gcp/guidance.html
Scenarios
Should this be Reported?

Event: A 52 year old female went to the oncologic clinic to
received Cycle 2 of A/C. The participant was seen and
reported fever, pain, redness and hardness of right breast.
She was treated with Cipro and a drainage catheter was
inserted. 120 ml of fluid was sent for culture. Other labs
were normal and cultures are pending. The plan for the
participant is to receive Cycle 2 on 10/22/03. The PI
determined that the event was related to the study and risk
is currently contained in the informed consent document.

No, this example is not an unanticipated problem because
the occurrence is currently listed in the consent document–
was expected.

What could make this an unanticipated problem that could
be reportable?
Should this be Reported?

A participant takes a new investigational anti-inflammatory
agent for management of osteoarthritis develops severe
abdominal pain and nausea one month after randomization.
Medical evaluation reveals gastric ulcers. The protocol and ICD
state there is a 10% chance of developing mild to moderate
gastritis and a 2% chance of developing gastric ulcers if
assigned to the active agent.

No, because the event is expected.
Should this be Reported?

Due to a processing error by a pharmacy technician, a
participant receives a dose of an experimental agent
that is 10-times higher than the dose stated in the IRB
approved protocol. While the dosing error increased the
risk of toxicity, the participant experienced no
detectable harm or adverse effects.

Yes, This is an unanticipated problem that needs to be
reported because the incident was:

Unexpected

Related to study participation

Placed the subject at a greater risk of physical harm
Should this be Reported?

An investigator is conducting a psychology 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.

No, this example is not an unanticipated problem
because the occurrence of the claustrophobic reactions
in terms of nature, severity, and frequency – was
expected.
Should this be Reported?

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.

Yes, this is an unanticipated problem that must be
reported 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 in confidentiality of
the study data than was previously known or
recognized.
Should This be Reported?

A study nurse realizes the consent form signed by the
participant is not the most recent version, however, the
consent form has not expired. There were no changes to
the consent document other than new expiration date.

No, This example is not an unanticipated problem
because it is not serious and does not place the subject
at greater risk than was previously known.
Questions
Shannon Simmons
Regulatory Compliance Analyst
Phone: 322-2918
Email: [email protected]