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Reportable Events

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Understand the types of reportable events. Review regulatory and Emory requirements for reporting events ... UPs are not always considered adverse events. ... – PowerPoint PPT presentation

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Title: Reportable Events


1
Reportable Events
  • Guidance from the Emory IRB

2
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

3
Emory IRBs Reportable Events
  • The IRB processes, on average, 90-110 reportable
    events per month

4
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

5
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

6
What are Other Reportable Events?
  • New information that indicates a change in
    risk/benefit
  • Protocol deviations or violations
  • Complaints

7
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.

8
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

9
Adverse Event Reporting Common FDA Audit Finding
  • FDA often cites study investigators for not
    properly reporting to study sponsors and/or the
    IRB

10
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

11
Emory Standard Operating Procedure
  • Affects rights, safety or welfare of subjects or
    others or significantly impacts integrity of the
    research data.

12
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

13
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.

14
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

15
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

16
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)

17
Internal versus External
  • Unless we state otherwise, in this talk we are
    referring to internal events

18
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

19
Reporting UPs to IRB
  • Please report any UPs that occur at a site over
    which our IRB has jurisdiction.

20
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.

21
Adverse Event - Definition
  • Any unfavorable or unintended (but not
    necessarily unexpected)
  • Sign
  • Abnormal lab
  • Symptom
  • Disease

22
Adverse Event Definition
  • The event occurs while subject is associated with
    the research, whether or not considered related
    to the research.

23
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?

24
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

25
Ask Is It Related to the Research?
  • The PI can look at the causes of the AEs for
    this answer

26
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.

27
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.

28
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.

29
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

30
When to Report Internal AEs
  • So.Report an AE if it is unexpected, and related
    to the research.

31
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

32
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

33
OHRPs Reporting Diagram
34
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

35
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?

36
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)

37
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

38
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

39
Internal SAEs
  • If it is a UP, report immediately.
  • If not a UP, report at the time of continuing
    review.

40
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.

41
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

42
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.

43
IND Reporting to IRB
  • The safety reports notify the sponsor of any
    adverse effects noted in the study as possibly
    associated with the drug.

44
INDs - Emergency Use
  • Report emergency use without consent to the IRB
    (see our SOP).

45
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)

46
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

47
IDEs
  • Progress Reports and Final
  • Report
  • When PI provides these to sponsor, should also
    give a copy to the IRB

48
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

49
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!)

50
A Note About Source Documentation
  • Make sure that your source documentation matches
    your CRF and read your source documents closely

51
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.

52
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)

53
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

54
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.

55
Protocol Deviations
  • The PI must report to the IRB when there is a
    substantive deviation from the process and
    procedures in the approved protocol

56
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.

57
What Does Emory IRB Expect You to Report?
  • Protocol Modifications but we have some new
    procedures

58
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.

59
Reporting of Pediatric Studies
  • There are no differences in the requirements for
    pediatric study reporting obligations or
    procedures than those for adult studies

60
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62
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.

64
Case Study 1
  • Is the event unexpected?

65
Case Study 1
  • Yes, the PI did not anticipate the theft

66
Case Study 1
  • Is the event related to participation in the
    research?

67
Case Study 1
  • Yes, the participants data was stored on the
    laptop because they were participating in the
    research

68
Case Study 1
  • Does the event place the subjects at a greater
    risk of harm?

69
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

70
Case Study 1
  • Is this a UP?

71
Case Study 1
  • Yes

72
Case Study 1
  • How will the PI report this to the IRB?

73
Case Study 1
  • Submit through eResearch or paper system

74
Case Study 1
  • Does it need to be reported to federal agencies?

75
Case Study 1
  • Yes, all UPs need to be reported to federal
    agencies regardless if they involve an AE or not

76
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

77
Case Study 2
  • Current standard chemo regimen. The subject
    develops neutropenia, sepsis, and then dies.

78
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.

79
Case Study 2
  • Is it unexpected?

80
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

81
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..

82
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.

83
Case Study 3
  • Is this unexpected?

84
Case Study 3
  • Yes

85
Case Study 3
  • Is it related to participation in the research?

86
Case Study 3
  • Yes

87
Case Study 3
  • Does it place the subjects and others at greater
    risk of harm?

88
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
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