Reportable Events

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Reportable Events

• Guidance from the Emory IRB

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Objectives

• Understand the types of reportable events
• Review regulatory and Emory requirements for
  reporting events
• Understand roles and responsibilities of study
  staff for reporting events

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Emory IRBs Reportable Events

• The IRB processes, on average, 90-110 reportable
  events per month

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Why Do We Have to Report?

• The Food and Drug Administration (FDA) and the
  Office of Human Research Protections (OHRP)
  require reporting for their studies
• Emory IRB requires reporting for studies that it
  approves to ensure subjects are protected

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What Does the PI Have to Report to the IRB?

• Some Internal External Adverse Events
• Unanticipated Problems Involving Risks to
  Participants or Others (UPs)
• Other Reportable Events

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What are Other Reportable Events?

• New information that indicates a change in
  risk/benefit
• Protocol deviations or violations
• Complaints

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What are Other Reportable Events?

• Unanticipated adverse device event
• Some issues of non-compliance
• Changes made to the research without prior IRB
  approval in order to eliminate apparent immediate
  harm.

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What Does the IRB Have to Report to OHRP FDA?

• Unanticipated problems involving risks to
  participants or others
• Serious and continuing non-compliance
• Suspensions and terminations

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Adverse Event Reporting Common FDA Audit Finding

• FDA often cites study investigators for not
  properly reporting to study sponsors and/or the
  IRB

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Unanticipated Problems Involving Risks to
Participants or Others

• Any incident, experience, or outcome that meets
  all of the following criteria
• Is unexpected
• Is related or possibly related to participation
  in the research and
• Suggests that the research places subjects or
  others at a greater risk of harm than was
  previously known

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Emory Standard Operating Procedure

• Affects rights, safety or welfare of subjects or
  others or significantly impacts integrity of the
  research data.

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Some Points about UPs

• UPs are not always considered adverse events.
• Some UPs involve social or economic harm instead
  of physical harm (such as a breach of
  confidentiality or harm to reputation)
• Some UPs place subjects at increased risk of
  harm, but no harm actually occurs

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Significance of UPs

• UPs may warrant consideration of substantive
  changes in the research protocol or informed
  consent (IC), or other corrective actions in
  order to protect the safety of the subjects.

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Examples of UPs

• Breach of confidentiality from theft of laptop
  computer containing study data
• Protocol violations
• Complaints about research procedures or treatment
  by study staff
• Falsification of research data

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Unanticipated Problems Tell the IRB.

• Advise on the relationship between the problem
  and the intervention or study protocol
• Explain whether or not a protocol change is
  necessary to reduce risk
• Tell us whether the information about the problem
  affects the informed consent process

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Internal/External Events

• Internal - events that are experienced by the
  subjects enrolled in your own site
• External events that are experienced by
  subjects enrolled in the same study at another
  site (for multi-center sites)

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Internal versus External

• Unless we state otherwise, in this talk we are
  referring to internal events

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Prompt Reporting

• UPs that are serious should be reported to the
  IRB within 10 days
• Any other UPs should be reported to the IRB
  within 30 days
• SOP may be revised soon, we will post
  notification when we do

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Reporting UPs to IRB

• Please report any UPs that occur at a site over
  which our IRB has jurisdiction.

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Investigator Initiated Research

• If the study is investigator initiated and a
  multicenter study, then the PI must act as the
  sponsor and report UPs to all of the other
  participating sites. See our SOP 64 on
  Investigator Reporting for more information.

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Adverse Event - Definition

• Any unfavorable or unintended (but not
  necessarily unexpected)
• Sign
• Abnormal lab
• Symptom
• Disease

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Adverse Event Definition

• The event occurs while subject is associated with
  the research, whether or not considered related
  to the research.

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The PI should ask him/herself

• Is the adverse event unexpected?
• Is the AE related or possibly related to the
  participation in the research
• Does the AE change the risk level to other
  subjects?

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Ask Is it Expected?

• Anticipated events should be listed in the
  informed consent document and the investigators
  brochure.
• Often the frequency of the events will be
  described as well

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Ask Is It Related to the Research?

• The PI can look at the causes of the AEs for
  this answer

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AEs May Be Caused By

• (1) The procedures involved in the research
• If this is even partially true, then the AE is
  related to the research.

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Cause of the AE?

• 2) An underlying disease, disorder, or condition
  of the subject or
• 3) Other circumstances unrelated to either the
  research or any underlying disease, disorder, or
  condition of the subject.
• If solely related to 2 and 3, it is not
  considered a related AE.

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Ask Is it Anticipated?

• The vast majority of AEs are expected in light of
• The known toxicities and side effects of research
  procedures
• The expected natural progression of subjects
  underlying diseases, disorders, and conditions
  and
• Subjects predisposing risk factor profiles for
  the AEs. Thorough patient histories are
  important.

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Ask Does it change the risk level to other
subjects?

• Do other subjects need to know about this to be
  properly informed of their risk?
• Might this change their mind about participating
  in the study?
• Should changes be made to the informed consent
  process?
• Does it affect rights, safety or welfare of
  subjects or others or significantly impact
  integrity of research data

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When to Report Internal AEs

• So.Report an AE if it is unexpected, and related
  to the research.

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Reporting External AEs

• For multi-center studies, individual AEs should
  be reported to all participating sites (PIs and
  IRBs) when a determination has been made that the
  event is a UP
• Sponsor usually does this, but if Investigator
  initiated, will be PI

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Reporting External AEs

• AEs occurring in subjects enrolled in a
  multi-center study should be submitted for review
  and analysis to a monitoring entity (e.g. the
  sponsor or DSMB) in accordance with the
  monitoring plan described in the protocol
• Again, sponsor will do this, if investigator
  initiated, PI will need a data safety monitoring
  plan

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OHRPs Reporting Diagram
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What Does the Diagram Show?

• The vast majority of AEs are not unanticipated
  problems (Area A)
• Small proportion of AEs are unanticipated
  problems.
• Unanticipated problems include other things that
  are not AEs

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UP vs AE?

• Is the AE unexpected?
• Is the AE related or possibly related to
  participation in the research?
• Does the AE suggest that the research places
  subjects or others at a greater risk of harm that
  was previously known?

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UP vs. AE?

• If the answer to all three questions is yes, then
  the AE is a UP and must be reported to the IRB
  (and then to the federal regulatory agencies if
  FDA regulated or federally funded trial)

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Serious Adverse Events

• Any adverse event that
• (1) results in death
• (2) is life-threatening
• (3) results in inpatient hospitalization or
  prolongation of existing hospitalization
• (4) results in a persistent or significant
  disability/incapacity
• (5) results in a congenital anomaly/birth defect
  or

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Serious Adverse Events (cont)

• (6) 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

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Internal SAEs

• If it is a UP, report immediately.
• If not a UP, report at the time of continuing
  review.

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Internal SAEs

• Internal SAEs that are unexpected should be
  reported to the IRB, sponsor and/or FDA
  immediately but no later than 10 days following
  the event.
• A description of the SAE and treatment, if any,
  must accompany the form.

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Death of a Subject

• Deaths If possibly, probably or definitely
  associated with study procedures, drug or device
  report immediately report immediately
• Automatically an SAE
• If not related to study, report at renewal

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External SAEs

• You must report external SAEs to the IRB, or any
  external AEs which are unanticipated problems
  involving risks to participants or others.
• FDA regulations require the reporting of SAEs.

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IND Reporting to IRB

• The safety reports notify the sponsor of any
  adverse effects noted in the study as possibly
  associated with the drug.

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INDs - Emergency Use

• Report emergency use without consent to the IRB
  (see our SOP).

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External Safety Reports

• The external safety reports that are given to the
  PI by the sponsor should be provided to the IRB
  for their continuing review of the study.
  (requested at that time)

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Investigational Device Exemption (IDE)

• PI should report to the device sponsor and the
  IRB unanticipated adverse device effect (UADE)
  within 10 days
• Sponsor notifies the FDA

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IDEs

• Progress Reports and Final
• Report
• When PI provides these to sponsor, should also
  give a copy to the IRB

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A Note About Source Docs

• Source Documents are the first recordings of
  information about the subject such as
• Nurses notes, progress notes, all laboratory
  results, concomitant meds, IRB approval, medical
  history, memoranda, x-rays, subject diaries,
  dispensing records

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More on Source Documents

• Sometimes your case report form (CRF) is the
  source document if protocol asks that data be
  recorded directly into the CRF and no other
  source exists (check w/ sponsor monitor first!)

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A Note About Source Documentation

• Make sure that your source documentation matches
  your CRF and read your source documents closely

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Actual FDA Warning Letters

• For Subject , the medical records for the
  visit indicate that the subject developed ,
  but the Physical Exam case report from indicates
  that there were no complications.
• For Subject , the medical records for the
  visit document pain in the but the Physical
  Exam CRF indicates there were not complications.

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More Warning Letters

• The discharge summary for subject indicates
  that the subject was considered unstable and was
  placed under an Emergency Order of Detention and
  transferred to a hospital for psychiatric care
  on , 6 days after subject completed study.
  This was not reported as an SAE to the sponsor
  until 6/21/05. (did not follow protocol)

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More Warning Letters

• The protocol required that all adverse events
  (AEs) that occur between the first study-related
  procedure and the last study-related procedure
  were to be reportedThe protocol also required
  that all AEs, regardless of seriousness,
  severity, or presumed relationship to the study
  therapy were to be recorded in the source
  document and the CRF. The following subjects had
  laboratory results that you determined to be
  clinically significant however, these AEs were
  not reported to the sponsor as required by the
  protocol

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Final Note on Letters

• We find your April response inadequate because
  it does not explain why these AEs were not
  promptly reported to the sponsor. Timely,
  accurate and complete reporting of required
  safety information from clinical studies is
  crucial for the protection of subjects.

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Protocol Deviations

• The PI must report to the IRB when there is a
  substantive deviation from the process and
  procedures in the approved protocol

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Protocol Deviations/Non-Compliance

• This is to ensure that the research that is
  performed on subjects is being performed as it
  was approved by the IRB.

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What Does Emory IRB Expect You to Report?

• Protocol Modifications but we have some new
  procedures

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What should the report include?

• The relationship between the problem and the
  intervention or protocol
• Whether or not a protocol change is necessary to
  reduce the risk and
• Whether the problem affects the informed consent
  process.

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Reporting of Pediatric Studies

• There are no differences in the requirements for
  pediatric study reporting obligations or
  procedures than those for adult studies

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Medwatch

• FDA has a Safety Information and Adverse Event
  Reporting Program
• Voluntary Reporting System for approved
  FDA-Regulated drugs, biologics, medical devices
  and special nutritional products and cosmetics
• http//www.fda.gov/medwatch/

63
Case Study 1

• An investigator conducting behavioral research
  collects identifiable information about illicit
  drug use by surveying college students. The data
  is stored on a laptop computer without
  encryption, and the laptop computer is stolen
  from the investigators car overnight.

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Case Study 1

• Is the event unexpected?

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Case Study 1

• Yes, the PI did not anticipate the theft

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Case Study 1

• Is the event related to participation in the
  research?

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Case Study 1

• Yes, the participants data was stored on the
  laptop because they were participating in the
  research

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Case Study 1

• Does the event place the subjects at a greater
  risk of harm?

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Case Study 1

• Yes, it places the subjects at a greater risk of
  social and psychological harm from the breach of
  confidentiality of the study data

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Case Study 1

• Is this a UP?

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Case Study 1

• Yes

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Case Study 1

• How will the PI report this to the IRB?

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Case Study 1

• Submit through eResearch or paper system

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Case Study 1

• Does it need to be reported to federal agencies?

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Case Study 1

• Yes, all UPs need to be reported to federal
  agencies regardless if they involve an AE or not

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Case Study 2

• A subject with multiple myeloma participates in a
  phase 3, randomized, double-blind, controlled
  clinical trial comparing a new chemotherapy agent
  combined with the current standard chemo regimen
  versus placebo combined with the

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Case Study 2

• Current standard chemo regimen. The subject
  develops neutropenia, sepsis, and then dies.

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Case Study 2

• Prolonged bone marrow suppression resulting in
  neutropenia is a known complication of the chemo
  regimens and these risks are described in the IC.

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Case Study 2

• Is it unexpected?

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Case Study 2

• No, it is a known side effect of the chemo
  regimen.
• Dont have to ask any other questions, because we
  already know this is not a UP, but instead an SAE

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Case Study 3

• Subjects with cancer and enrolled in a phase 2
  clinical trial evaluating an investigational
  biologic product derived from human serum. After
  several subjects are enrolled, a study audit
  reveals that the investigational product..

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Case Study 3

• ..administered to subjects was obtained from
  donors who were not appropriately tested for
  several potential viral contaminants, including
  HIV and Hepatitis B.

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Case Study 3

• Is this unexpected?

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Case Study 3

• Yes

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Case Study 3

• Is it related to participation in the research?

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Case Study 3

• Yes

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Case Study 3

• Does it place the subjects and others at greater
  risk of harm?

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Case Study 3

• Yes, it places participants and other at harm
  (e.g. the sexual partners of the subjects)

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Contact Us with your Questions!

• Stephanie deRijke
• Stephanie.derijke_at_emory.edu
• 404-712-0724
• Marie Mathews
• Marie.mathews_at_emory.edu
• 404-712-0766