EAE Training PROTOCOLSPECIFIC

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EAE TrainingPROTOCOLSPECIFIC

• 2009

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Objectives

• Definitions
• Assessment of Adverse Events
• EAE Reporting

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EAE Reporting Materials

• EAE Manual
• EAE Reporting Form
• EAE Reporting FormCompletion Instructions
• AE Grading Table
• Protocol

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Expedited Adverse Event (EAE)

• An adverse event that meets the criteria for
  expedited reporting to Division of AIDS (DAIDS).

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Adverse Event

• Any untoward medical occurrence in a patient or
  clinical investigation subject administered a
  pharmaceutical product and which does not
  necessarily have to have a causal relationship
  with this treatment.
• (ICH E2A)

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Serious Adverse Event (SAE)

• A serious adverse event (experience) or reaction
  is any untoward medical occurrence that at any
  dose
• Results in death,
• Is life-threatening,
• Requires inpatient hospitalization or
  prolongation of existing hospitalization,
• Results in persistent or significant
  disability/incapacity, or
• Is a congenital anomaly/birth defect.
• In addition, important medical events that may
  not be immediately life-threatening or result in
  death or hospitalization but may jeopardize the
  patient or may require intervention to prevent
  one of the other outcomes listed in the
  definition aboveshould also usually be
  considered serious.
• (ICH E2A)   

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Adverse Event vs. Event Outcome

• Death
• Death is an outcome and is not usually considered
  to be an AE.
• Example If death due to myocardial infarction
  is reported, myocardial infarction can be
  selected and death should be captured as the
  outcome.
• If the only information reported is death, then
  the most specific death term available should be
  selected.
• Example If a reporter states only that a study
  subject was found dead, found dead can be
  selected.
• Example If the autopsy report states, the cause
  of death was natural, Death from natural
  causes can be selected.

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Adverse Event vs. Event Outcome

• Hospitalization
• Hospitalization is a consequence and is not
  usually considered an AE.
• Example If hospitalization due to congestive
  heart failure is reported, congestive heart
  failure can be selected and hospitalization
  should be captured as the consequence of the
  event.
• If the only information reported is the outcome
  term, then the most specific term available
  should be selected.
• Example If a reporter states only that a study
  subject was hospitalized, hospitalization can
  be selected.

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Hospitalization Exemptions from expedited
reporting

• Hospitalization in the absence of a medical AE is
  not in itself an AE and does not need to be
  reported in an expedited time frame.
• Admission unrelated to an AE (e.g. for
  labor/delivery, aging-related cosmetic surgery,
  administrative or social admission)
• Protocol-specified admission (e.g. for procedure
  required by protocol)
• Admission for diagnosis or treatment for
  pre-existing condition (unless it is worsening or
  increasing in frequency)
• A new AIDS-defining event in HIV-infected subject
  would be considered worsening of pre-existing
  condition of HIV infection

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Severity

• Describes the intensity of the event
• Events are graded on a severity scale
• Events are graded on a severity scale of 1-5
• 1 Mild
• 2 Moderate
• 3 Severe
• 4 Potentially Life-threatening
• 5 Death

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Grading Severity of Events

• Division of AIDS (DAIDS) Table for Grading the
  Severity of Adult and Pediatric Adverse Events
  (Version 1.0) December 2004 (Clarification August
  2009)
• Web Site http//rcc.tech-res.com

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EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR
GRADING THE SEVERITY OF ADULT AND PEDIATRIC
ADVERSE EVENTS
Death Grade 5
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EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR
GRADING THE SEVERITY OF ADULT AND PEDIATRIC
ADVERSE EVENTS
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EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR
GRADING THE SEVERITY OF ADULT AND PEDIATRIC
ADVERSE EVENTS
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Severity vs. Serious

• Severity is not the same as Serious
• Severity Intensity
• e.g., chest pain, moderate severity
• Serious (SAE) Based on patient/event outcome or
  action criteria
• Used to define regulatory reporting obligations
• AE classification must divorce usage of serious
  in a clinical sense from serious in a regulatory
  sense
• For clinical connotations, use severity
  descriptors

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Action Taken with Drug

• Action Taken with Drug
• O Course completed or Subject OFF study agent at
  AE
• C Continued without change
• R Dose or schedule reduced
• T Temporarily held
• D Permanently discontinued
• U unknown
• DAIDS EAE Form

• Action Taken with Drug
• Withdrawn
• Dose reduced
• Dose increased
• Dose not changed
• Unknown
• Not applicable
• ICH E2B (R3)

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Outcome

• Outcome of reaction/event at the time of last
  observation
• Recovered/resolved
• Recovering/resolving
• Not recovered/not resolved
• Recovered/resolved with sequelae
• Fatal
• Unknown
• Outcome of subject in study
• Remains in Study
• Withdrawn
• Lost to follow-up
• Death

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Expectedness

• Pertains to whether an event is expected or
  unexpected (on the basis of previous observation,
  not what might be anticipated from the
  pharmacological properties of the product)
• Unexpected the nature or severity of the adverse
  event is not consistent with the applicable
  product information (e.g. Investigators Brochure
  for unapproved product, Package Insert for
  approved product)

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Relatedness (Causality)

• No standard international nomenclature
• Conveys that a causal relationship between the
  study product and the adverse event is at least
  a reasonable possibility ICH E2A
• Facts (evidence) exist to suggest the
  relationship
• Judged by
• Reporting health professional
• Sponsor

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Determination of Relatedness

• Standard determinations include
• Is there Drug Exposure and Temporal
  Association?
• Is there Dechallenge/Rechallenge or Dose
  Adjustments?
• Any known association per Investigators
  Brochure or Package Insert?
• Is there Biological Plausibility?
• Any other possible Etiology?

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Relatedness

• Judgment of a relationship between AE and study
  agent.
• An event is assessed as
• Definitely related
• Probably related
• Possibly related
• Probably not related
• Not related
• Pending relationship
• to the study agent

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Narrative

• Comprehensive, stand-alone medical story
• Written in logical time sequence
• Include key information from supplementary
  records
• Include relevant autopsy or post-mortem findings
• Summarize all relevant clinical and related
  information, including
• Study subject characteristics
• Therapy details
• Medical history
• Clinical course of the event(s)
• Diagnosis (workup, relevant tests/procedures, lab
  results)
• Other information that supports or refutes an AE
• gt ICH E2D

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Assessment

• Study physician listed on the1572 / Investigator
  of Record (IoR)
  Agreement assesses the
  events
• Seriousness
• Severity
• Relationship
• Expectedness(only applies to Targeted)

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Review and Assessment of EAE/SAE

• Assemble all information available and use
  medical judgment
• Standard for each AE
• Select Seriousness Criteria
• Grade Severity per DAIDS Toxicity Table
• Specify Actions Taken on Study Product
• Specify Outcome of SAE/EAE. If Outcome is not
  resolved at time of evaluation, follow until
  resolution or stability at each study visit
• Is it Expected?
• Is it Related?

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New vs. Follow-up reports

• New
• A reportable event first occurs.
• An ongoing event increases in severity to a
  higher grade than previously reported.
• An event fully resolves to baseline status and
  then recurs at a reportable level.

• Follow-up
• DAIDS requests additional information.
• Study physician changes assessment of
  relationship to study agent.
• Additional significant information becomes
  available (e.g. autopsy report, death
  certificate).
• Results of rechallenge.

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Levels of Expedited AdverseEvent Reporting

• The protocol will specifyone level ofadverse
  event reporting
• Standard
• Intensive
• Targeted
• Other SAE (added 2008)

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Levels of Expedited AdverseEvent Reporting -
Summary
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EAE Reporting Period

• Entire study duration for an individual subject
  (from enrollment until study completion or
  discontinuation for that particular subject).
• or as specified in the protocol.

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EAE Reporting Period

• After the EAE Reporting Period, only the
  following should be reported
• Unexpected, Serious, Clinical SADRs
  If the study staff becomes aware of
  their occurrence on a passive basis (i.e. through
  publicly available information, not active follow
  up)
• Example Obituary in the newspaper

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EAE Study Physician signature

• Physician signature signifies physician review
  and sign off
• The EAE report may be sent in without the study
  physician signature, if necessary.
• BUT
• The completed signature page must be submitted to
  the RCC Safety Office within 3 business days of
  submitting the original EAE.

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EAE Reporting Timeframe

• Within 3 business days of site awareness that an
  event has occurred at a reportable level.

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Confirmation Of Receipt

• The RCC Safety Office sends a confirmation email
  for all new reports.
• It is the sites responsibility to follow-up if
  they do not receive a confirmation email.

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How to Report EAEs

• Reports must be submitted on theEAE form
  available on the RCC Web sitehttp//rcc.tech-res.
  com/.
• DAERS DAIDS AE Reporting System web-based
  electronic submission https//daidses.niaid.nih.g
  ov/Phoenix
• If reporting via DAERS, no paper form needed

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How to Report EAEs

• Reports may be submitted via FAX, E-mail or
  DAERS
• FAX [phone] or 1-800-275-7619 (USA
  only)
• Email RCCSafetyOffice_at_tech-res.com
• If e-mailing, scan or FAX signature page
• DAERS https//daidses.niaid.nih.gov/Phoenix

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Where to Get Help

• RCC Safety Office
• E-mail RCCSafetyOffice_at_tech-res.com
• Telephone [phone] or 1-800-537-9979
  (US Only)
• Fax [phone] or 1 -800-275-7619 (US
  Only)
• DAERS help DAIDS-ESSupport_at_niaid.nih.gov
• Phone [phone] (outside US), 866-337-1605
  (US)
• Fax [phone] (outside US), 866-337-1606 (US)
• Live assistance is available from 830 am to 530
  pm EST, Monday to Friday (Excluding US Holidays)

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Overview of Reporting Timelines
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ProtocolSpecific Information
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Case Study