New Adverse Event Reporting Policy

1
New Adverse Event Reporting Policy

• Effective September 1, 2007

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Local adverse event reporting

• Local adverse events are those experienced by
  subjects enrolled by the investigator(s) at this
  institution or in the local community area
• Local investigator typically becomes aware of the
  event directly from the subject, another
  collaborating investigator at the same site, the
  subjects healthcare provider, or an affiliated
  hospital (MMC, SJH, etc.)

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• Serious adverse event is any adverse event
  that
• results in death
• is life-threatening (places the subject at
  immediate risk of death from the event as it
  occurred)
• results in inpatient hospitalization or
  prolongation of existing hospitalization
  results in a persistent or significant
  disability/incapacity
• results in a congenital anomaly/birth defect or
• based upon appropriate medical judgment, may
  jeopardize the subjects health and may require
  medical or surgical intervention to prevent one
  of the other outcomes listed in this definition.

4

• Unexpected adverse event - any adverse
  experience, the nature, severity, or frequency of
  which is not consistent with the current
  investigator's brochure, risk information
  described in the investigational plan, or consent
  form. Expected Adverse Event- any adverse
  experience, the nature, severity or frequency of
  which is consistent with the current
  investigator's brochure, risk information
  described in the general investigational plan, or
  consent form.

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Keep in mind, the SCRIHS reporting schedule does
not relieve investigators of sponsor requirements
to report earlier.
6
NIH funded cooperative group studies

• Often include lifetime or long-term follow-up for
  enrolled subjects.
• A subject who has completed on-study therapy can
  be a subject that completed the protocol
  required therapy, a subject that was removed from
  active treatment, a subject that chose to stop
  treatment
• New SCRIHS reporting guidelines for long-term
  adverse event reporting as it relates to subjects
  that are no longer receiving active study therapy
  but continue to have long-term follow-up
  completed as per NIH protocol guidelines and
  requirements

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guidelines

• Subject must be gt30 days from the last dose of
  any protocol therapy.
• Adverse event reporting should be consistent with
  the protocol guidelines. Individual protocol
  guidelines will mandate the required expedited
  reporting requirements.
• Expedited Report Special reporting of an
  adverse event or events directly to CTEP/NCI/NIH
  within a shorter/specified time frame, usually
  ranging from 24 hours up to 10 calendar days
  based on the severity of the event(s). This does
  NOT include routine follow-up or reporting to the
  cooperative group, although the cooperative group
  will receive copies of the expedited reports.

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continued

• If expedited reporting is required for any
  subject in long-term follow-up- a report to
  SCRIHS must be submitted within 5 working days of
  the completion of the expedited report along with
  a copy of the submitted expedited report.
• Deaths of subjects in long-term follow-up if
  unrelated to prior protocol therapy no report
  to SCRIHS required.
• All deaths deemed at least possibly related to
  prior protocol therapy require reporting under
  Serious, Unexpected guidelines regardless of
  length of time from last protocol therapy

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Minimal Risk studies

• For studies involving no risk or minimal risk,
  report adverse event only if the event is
  directly related to the study.
• Minimal risk studies exempt and expedited
  studies that do not involve an invasive
  procedures, drug or device.

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Non-local Adverse Event Reporting Policy

• Those adverse events experienced by subjects
  enrolled by investigators at other institutions
  engaged in a multi-center clinical trial.
•  
• Investigators at all participating institutions
  learn of such events via reports that are
  distributed by the sponsor or coordinating center
  of the multi-center clinical trials. 
• Reports of non-local adverse events represent the
  majority of adverse event reports currently being
  submitted by investigators to SCRIHS.

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Individual non-local adverse events should only
be reported to SCRIHS when a determination has
been made that the adverse event meets the
criteria for an unanticipated problem.
12
Ideally, these AEs should be submitted for review
and analysis to a monitoring entity such as a
Data Safety Monitoring Board or Committee
(DSMB/DMC), a coordinating statistical center or
the research sponsor in accordance with a
monitoring plan described in the SCRIHS-approved
protocol. In cases when there is no monitoring
entity charged with this responsibility, it will
be the responsibility of the local PI to review
all of the non-local adverse events and determine
which ones meet the criteria of an unanticipated
problem (UP) and subsequently report that UP to
SCRIHS.
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Okay, so what is an Unanticipated Problem (UP)?

• Any incident, experience, or outcome that meets
  all of the following criteria
• unexpected (in terms of nature, severity, or
  frequency) given (a) the research procedures that
  are described in the protocol-related documents,
  such as the IRB-approved research protocol, IB
  and ICF and (b) the characteristics of the
  subject population being studied
• related or possibly related to participation in
  the research (possibly related there is a
  reasonable possibility that the incident,
  experience, or outcome may have been caused by
  the procedures involved in the research)
• 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

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A UP will likely warrant consideration of
substantive changes in the research protocol
and/or informed consent process/document or other
corrective actions in order to protect the
safety, welfare and rights of subjects or others

• changes to the protocol initiated by the
  investigator prior to obtaining SCRIHS approval
  to eliminate apparent immediate hazards to
  subjects
• modification of inclusion or exclusion criteria
  to mitigate the newly identified risks
• implementation of additional procedures for
  monitoring subjects
• suspension of enrollment of new subjects
• suspension of research procedures in currently
  enrolled subjects
• modification of ICF to include a description of
  newly recognized risks
• re-consenting

15
Some UPs involve social or economic harm instead
of the physical or psychological harm associated
with adverse events Some UPs place subjects or
others at increased risk of harm, but no harm
occurs
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Unexpected adverse event

• 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) protocol,
  applicable IB, and the current ICF, 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
  subjects predisposing risk factor profile for
  the adverse event.

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Majority of AEs are expected and thus--do not
meet criteria of unexpected--are not UPs--are
not reportable
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Does the event suggest that the research places
subjects or others at a greater risk of harm than
was previously known or recognized ?

• Is it serious?
• If event is unexpected, related or possibly
  related to participation in research, and serious
  
• always suggests that the research places
  subjects or others at a greater risk of physical
  or psychological harm than was previously known
  or recognized

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Timeframe?

• UPs should be reported to SCRIHS within 5
  working days of the investigator becoming aware
  of the event.

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What if sponsor says they require reporting?

• What if AE does not meet the criteria for a UP
  and is non-reportable, per SCRIHS, but the
  sponsor requirements are inconsistent with our
  reporting policy? It would be acceptable for the
  PI/Study Coordinator to refer the company to the
  SIU policy located on the SCRIHS website. It
  would also be acceptable for the PI/Study
  Coordinator to indicate in the Case Report Form
  and AE log "...that the AE was not reported to
  the IRB per institutional policy."

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Consequences of reporting out of timeframe or
incomplete reporting

• PI and research staff will receive an email from
  SCRIHS staff reminding them of the reporting
  time-frame requirements (mainly for local AEs of
  less serious nature)
• PI receive a letter from the SCRIHS Chairman
• Review by the full SCRIHS committee who will
  decide on the course of action which can include
  but is not limited to requesting written
  response from the PI, requesting presence of PI
  at next SCRIHS meeting to address the issue with
  the committee, scheduling an audit of the PIs
  research, suspension of enrollment into one or
  more of the PIs ongoing studies, and report of
  non-compliance to OHRP and/or the FDA

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What needs to be on a UP report?

• protocol title, PI name, and the SCRIHS protocol
  number
• a detailed description of the adverse event,
  incident, or experience, and the outcome
• an explanation of the basis for determining that
  the adverse event, incident, or experience
  represents an UP and
• a description of any changes to the protocol, ICF
  or other corrective actions that have been taken
  or are proposed in response to the UP (these
  changes must be submitted on an Amendment Summary
  Form with all of the necessary documents)

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• What happens if a local PI independently
  proposes changes to the protocol or informed
  consent document in response to an unanticipated
  problem?
• SCRIHS requires that the local PI provide
  documentation of the communication with the
  sponsor and the outcome of such communication to
  SCRIHS.

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SCRIHS review process

• Chairman will review all UP reports
• Is this indeed a UP?
• Further review by SCRIHS subcommittee or full
  SCRIHS committee at convened meeting
• Does research still meet requirements for IRB
  approval?
• Are risks to subjects still minimized and
  reasonable in relation to the anticipated
  benefits?
• As a condition of continued approval of the
  research study, does SCRIHS need more detailed
  information from the investigator(s), the
  sponsor, the study coordinating center, or
  DSMB/DMC?
• Are we satisfied with the corrective action taken?

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Changes to protocol and/or consent as a result of
a UP

• Most likely will require full-board approval
• If SCRIHS requires additional changes in a
  multi-center trial, SCRIHS will request in
  writing that the local PI discuss the proposed
  modifications with the study sponsor or
  coordinating center and submit a response or
  necessary modifications for review by SCRIHS

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For multi-center studies, only the institution at
which the subject(s) experienced an adverse event
determined to be an UP (or the institution at
which any other type of UP occurred) must report
the event to OHRP and/or the FDA.
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Requirements for initial SCRIHS approval

• Sufficient information regarding the risk
  profile of the proposed study, including the
  type, probability, and expected level of severity
  of the adverse events that may be caused by the
  procedures involved in the research, and how the
  risks of the research will be minimized
• The IRB is responsible for determining if a
  study needs formal ongoing monitoring of data to
  ensure that research subjects will be protected.
  If the study presents greater than minimal risks
  to subjects or risks that are unforeseeable,
  SCRIHS will likely require adequate provisions
  for monitoring the adverse event data collected
  to ensure the safety of subjects

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Adequate monitoring provisions for research
involving greater than minimal risk must include

• The type of data or events that are to be
  captured under the monitoring provisions.
• The entity responsible for monitoring the data
  collected, including data related to
  unanticipated problems and adverse events, and
  their respective roles (e.g., the investigators,
  the research sponsor, a coordinating or
  statistical center, an independent medical
  monitor, a DSMB/DMC, and/or some other entity). 
• The required time frames in which investigators
  must report adverse events and unanticipated
  problems to the monitoring entity.

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continued

• The frequency of assessments (e.g., how often the
  sponsor, DSMB/DMC, etc. will meet to review the
  information) of data or events captured by the
  monitoring provisions.
• Definition of specific triggers or stopping rules
  that will dictate when some action is required by
  the monitoring entity to ensure patient safety.
•  
• As appropriate, procedures for communicating to
  the IRB(s), the study sponsor, the
  investigator(s), and other appropriate officials
  the outcome of the reviews by the monitoring
  entity.
• Added to the Application

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Requirements for continuing review approval

• Confirm that any provisions under the previously
  approved protocol for monitoring study data to
  ensure safety of subjects have been implemented
  and are working as intended
• A report from the monitoring entity described in
  the approved protocol including 
• 1) A statement indicating what information
  (e.g., study- wide AEs, interim findings, and any
  recent literature that may be relevant to the
  the research) was reviewed by the monitoring
  entity
• 2) The date of the review(s)
• 3) The monitoring entitys assessment of the
  information reviewed

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What if there is no monitoring entity?

• The local PI is responsible for reviewing and
  assessing all adverse events (local and
  non-local) and he/she is required to document all
  adverse events, whether reportable to SCRIHS or
  not.

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What does the local PI need to submit with the
continuing review?

• Two spreadsheets (one for local AEs and one for
  non-local AEs) with the following information
  about each event
• Description of the AE
• Date the event occurred
• Outcome of the event
• Determination of serious vs non-serious
• Determination of causality (relatedness to the
  research procedures)

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Since, prior to this policy, SCRIHS did not
review data monitoring plans for any of the
currently approved SCRIHS studies, a review of
such plans will be done at the time of CR for all
studies. Therefore, it will be the
responsibility of the PI to obtain the data
monitoring plan (including all of the required
elements) from the monitoring entity, along with
the most current report, and include these items
in the continuing review submission