Transcript Slide 1

Reporting Adverse Events
What, When, How?
Cynthia Gross
Professor, College of Pharmacy and School of Nursing
The MN Center for Health Trajectory Research
Month, day, year
Presentation
12/3/09
Learning Objectives
Define key terms and acronyms as used in the context of
monitoring and reporting safety in clinical research studies:
•
•
•
•
adverse event
UPIRTSO
relatedness
seriousness and severity (and how these differ).
Identify what is to be reported to the UMN IRB and who reports,
and in what timeframe.
Evaluate case studies and determine whether they meet criteria
for expedited reported as UPIRTSOs.
Outline of Presentation
Regulatory background
Define terms
Describe systems for coding events
Present examples
Outline UMN IRB reporting procedures
List key resources
Regulatory Background:
Key Source Document
Guidance on Reviewing and Reporting Unanticipated
Problems involving Risks to Subjects or Others and
Adverse Events
from the OHRP - Office for Human Research Protections,
DHHS - Dept. of Health and Human Services
Guidance document, January 2007
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm
Topics in the Guidance
What are unanticipated problems?
What are adverse events?
How do you determine which adverse events are
unanticipated problems?
What are other important considerations regarding the
reviewing and reporting of unanticipated problems
and adverse events?
What is the appropriate time frame for reporting
unanticipated problems to the IRB and others?
Plus topics related to the policies and conduct
of IRBs in these processes.
The Role of the IRB
Each IRB interprets and implements the Guidance with
its own policies, procedures and forms. The
University of Minnesota’s guidelines are at:
http://cflegacy.research.umn.edu/irb/ae/
The Mayo Clinic guidelines are at:
http://mayoresearch.mayo.edu/mayo/research/irb/upirtso_reporti
ng_policy.cfm
There will be differences across IRBs – where one IRB
defines expedited or prompt reporting as 10 days another
may use a 5 day rule.
What are adverse events
(AEs)?
Any unfavorable or unintended sign (including an
abnormal exam or lab finding), symptom or disease,
temporally associated with the subject’s participation
in the research, regardless of whether it is
considered related to the subject’s participation in
the research.
*AEs includes physical and psychological harms.
(definition modified from on the 1996 ICH E-6 Guidelines
for Good Clinical Practice).
What is serious?
1 of 2
Clearly defined
A problem/event that results in:
In-patient hospitalization, or prolongation of
hospitalization;
Life-threatening adverse experience;
A persistent or significant disability or incapacity;
Death;
Birth defect or congenital anomaly; or
Protocol-defined condition/event.
What is serious?
2 of 2
Less clearly defined
An event/problem is also serious if it is:
“deemed by the investigator to have adversely affected
the rights, safety or welfare of the subjects or others;
including compromising the research data.”
from the IRB website
Rights, safety, welfare and
data problems
Rights
1. Confidential records made public
2.
Safety
1. Contaminant in drug supply
2.
Welfare
1. Alternative treatment options not shared
2.
Data Integrity
1. Corrupted data file, no backup, data lost
2.
Determination of Problem may not be clear-cut
What are unanticipated
problems?
Unanticipated Problem Involving Risk to Subjects or
Others = UPIRTSO
1. Serious AND
2. Unanticipated AND
3. At least possibly related to the research procedures.
All 3 conditions must be present.
What is unanticipated?
Not in the protocol
Not in the consent form
Not in the investigators brochure
Not common in the study populations (e.g., part of the
disease process)
“An unforeseeable problem or one which occurred at a
higher frequency or greater severity than
anticipated”
What is related?
Possibly
Probably
Definitely related
to the research
Determination of relatedness rests with the
study investigators and their monitors (site
investigator, independent monitor, overall
protocol PI, Data Safety Committee, etc.)
Classification of relatedness
What is related may not be immediately apparent
or may remain uncertain
Attribution
Description
Unrelated
The AE is clearly NOT related to the
intervention.
Unlikely
The AE is doubtfully related to the intervention.
Possible
The AE may be related to the intervention.
Probable
The AE is likely related to the intervention.
Definite
The AE is clearly related to the intervention
from NCI, CTEP guidelines
Consequences of
unanticipated problems
Unanticipated problems will generally
warrant consideration of substantive
changes in:
•
•
•
•
•
research protocol
informed consent process/document
staff training
monitoring plan
or other corrective actions
Example 1
1 of 3
The Event
Routine safety monitoring identified more
incidences of tooth discoloration than anticipated in
an ongoing clinical trial.
Example 1
1 of 3
The Evaluation by the Investigator:
Seriousness: Yes. Condition was deemed potentially
serious since some patients view this as a
disfigurement.
Unanticipated: Yes. Based on the higher than
expected frequency, tooth discoloration was
deemed an unanticipated problem.
Related: Yes. The research protocol and informed
consent documents mentioned tooth discoloration
but implied it was a relatively rare problem.
Example 1
3 of 3
Decision and action:
The Protocol Investigator notified all site investigators,
all current participants and IRBs, OHRP, FDA, and
other sponsors and relevant parties were notified of
this problem.
The protocol and wording of the informed consent
were revised.
As the condition being studied was disabling and severe, this
notification had little impact on recruiting or continuation of
participants.
Serious versus Severe
‘Severity’ is not the same as ‘serious’. Serious is based
on event/outcome or actions meeting criteria for
posing a threat to rights, safety or welfare. ‘Severe’
is usually a description of intensity (as in mild,
moderate or severe headache). Some events rated
as ‘severe’, may not be deemed ‘serious’ in the
context of a particular study and vice versa.
Adapted from NCI, CTEP guidelines
Determining which adverse
events are unanticipated
problems.
Most AEs are not unanticipated
problems; not all problems are AEs.
Sources of Adverse Event
Data
Lab tests
Patient
comments
AE
checklist
Examinations
Study
Subject
Imaging
reports
Other
Interviews
Letters
The
Obituaries
Systems for recording adverse events:
MedDRA
The Medical Dictionary for Regulatory Activities (MedDRA) is a medical
terminology system for classifying adverse events for drugs and
devices, reporting and drug labeling.
MedDRA was developed by the International Conference on
Harmonization (started by the US, EU and Japan) and is owned by
the International Federation of Pharmaceutical Manufacturers.
Current version is MedDRA 12.1. MedDRA is available by subscription
and has coding and training classes.
MedDRA does not determine severity or establish relatedness.
http://www.meddramsso.com/
NCI Common Terminology Criteria
for Adverse Events (CTCAE)
A standard system for eliciting, grading and reporting adverse
events in cancer clinical trials. Each AE has a grading
(severity scale). CTCAE terms map to MedDRA.
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic
observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated;
limiting age-appropriate instrumental activities of daily living (ADL).
Grade 3
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling;
limiting self care ADL.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf
Cancer Adverse Event Reporting System (caAERS)
• An open-source software tool that is used to collect, process, and
report AEs
• Tool supports regulatory compliance and allows local collection,
management, and querying of routine and expedited AEs
(UPIRTSOs)
https://cabig.nci.nih.gov/tools/caAERS#tools
Investigator Responsibility
• Investigators have the primary responsibility for AE
identification, documentation, evaluation/grading
and assignment of attribution.
• Investigators have to report to their IRB, sponsors
and others.
• MedDRA and CaAERS assist by providing common
terminology and classification systems, but the
determination of severity, attribution (relatedness)
require the direct involvement and judgment of the
investigators – ultimately the study principal
investigator.
What to report to the UMN IRB
1 of 3
Reported within 10 days:
UPIRTSOs:
1. Any serious event (including on-site and off-site adverse
events, injuries, side effects, deaths or other problems) which
in the opinion of the local investigator was unanticipated,
involved risk to subjects or others, and was possibly related to
the research procedures.
Plus….
What to report, continued
2 of 3
2. Serious accidental or unintentional protocol change
that involves risk or potential to recur.
3. Protocol deviation to eliminate immediate hazard to
a research subject.
4. Publications, safety reports or interim results that
indicate an unexpected change to the risk/benefit
ratio
Plus…
What to report, continued
3 of 3
5. Breach in confidentiality that may involve risk to the
subject or others.
6. Complaint of a subject that indicates an
unanticipated risk or that cannot be resolved by the
research staff.
7. Any other serious and possibly related event which
in the opinion of the investigator constitutes an
unanticipated risk.
UMN form to
report UPIRTSOs
What about nonUPIRTSOs?
Non-UPIRTSO events/problems are reported with the
annual continuation report.
Example 2
from Guidance Document
1 of 3
The Event:
A behavioral study in college students involves
completion of a detailed survey asking questions
about early childhood experiences.
During the completion of the survey, one subject has a
transient psychological reaction manifested by
intense sadness and depressed mood that resolved
without intervention after a few hours.
Case Example 2
from Guidance Document
2 of 3
The Evaluation by the Investigator:
Serious: Yes. The events suggested that the research places
subjects at a greater risk of psychological harm than was
previously known or recognized.
Unanticipated: Yes. The investigator had not expected that
such reactions would be triggered by the survey questions.
The protocol and informed consent document for the research
did not describe any risk of such negative psychological
reactions.
Related: Yes. 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.
Case Example 2
from Guidance Document
3 of 3
Actions:
What would you do?
Note for additional examples see Guidance document and
Mayo IRB website.
Summary of Investigator
Responsibilities
Continually monitor and track adverse events and potential
problems;
Maintain current knowledge of issues (e.g., new publications, FDA
rulings) relevant to the risk/benefit of the study interventions;
Report any UPIRTSOs within the 10 days of learning of the event
using the UMN IRB form. Include proposed changes to protocol,
consent or other procedures, and relevant documentation
(identified only by study ID #) of the event and its
consequences.
Comply with all other reporting requirements ( the DSMB, study
sponsors, the NIH, FDA, etc.).
The IRB will evaluate UPIRTSOs and notify the OHRP/DHHS,
university officials and others; and take actions as per its
policies.
Reminder from the
Guidance
The Guidance expects that only a small subset of
adverse events occurring in human subjects
participating in research will be unanticipated
problems that must be reported under 45 CFR
part 46.*
* HHS regulations for protection of human subjects.
Who can answer my
questions?
Patrice Webster, CIP
Assistant Director, Human Research Protection Program (UMN IRB)
[email protected]
612.626.5654 (HRPP main line)
612.626.5941 (direct line and voice mail) 612.626.6061 (fax)
www.research.umn.edu/subjects/
Clinical and Translational Science Institute (CTSI)
phone number:(612)625-2874
e-mail: [email protected]
and suggest that the inquiry to be directed to a Research Project
Manager(RPM) or to a Clinical Research Associate (CRA).
Main Resources used in this talk:
Reporting Unanticipated Problems, Institutional Review Board (IRB),
University of Minnesota
http://cflegacy.research.umn.edu/irb/ae/
UPIRTSO Reporting Policy, Office for Human Research Protection,
Mayo Clinic
http://mayoresearch.mayo.edu/mayo/research/irb/upirtso_reporting_poli
cy.cfm
Guidance Document: Office for Human Research Protections (OHRP)
Department of Health and Human Services (DHHS)
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm