UPIRTSO and NonUPIRTSO Examples Roles and Responsibilities

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UPIRTSO and Non-UPIRTSO ExamplesRoles and
Responsibilities

• Mayo Clinics Office for Human Research
  Protection Institutional Review Board (IRB)
• March 19, 2007
• Reference OHRP Guidance Document

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Federal Regulations

• Investigators must report any unanticipated
  problems/events involving risk to subjects or
  others (UPIRTSO).
• 45 CFR 46,103(b)(5) and 21 CFR
  56.108(b)(1)

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New Mayo Terminology

• UPIRTSO
• Unanticipated Problems Involving Risk to Subjects
  or Others
• Non-UPIRTSO
• Problems/Events that do not meet the IRBs
  definition

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UPIRTSOUnanticipated Problems Involving Risk
to Subjects or Others

• UPIRTSO is any problem/event that was
• 1) serious AND
• 2) unanticipated AND
• 3) at least possibly related to the research
  procedures.
• The problem/event must meet all three criteria in
  the IRBs definition.

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Two Definitions of Serious
Well-defined

• 1. Serious problems/events
• Death
• Life-threatening adverse experience
• Hospitalization inpatient, new or prolonged.
• Disability/ incapacity persistent or significant
  
• Birth defect/anomaly
• Per-protocol

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Two Definitions of Serious
Subjective

• 2. A problem/event that
• in the opinion of the investigator may have
  adversely affected the rights, safety or welfare
  of the subjects or others, or substantially
  compromised the research data.

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UPIRTSOAdversely affected.
Subjective

• Rights
• Safety
• Welfare
• Data integrity

• Confidentiality breached
• Monitoring equipment failed
• Info on new treatment alternative not shared
• Data lost

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Definitions Unanticipated problem/event

• Unforeseeable
• Occurred at an increased frequency or increased
  severity than expected.
• not already described in the consent form
• not listed in the Investigators Brochure
• not part of the underlying disease

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Definitions Related

• Possibly
• Probably
• Definitely
• occurred due to participation in the research
  study.

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Example 1

• An Investigator conducting behavioral research
  collects individually identifiable sensitive
  information about illicit drug use and other
  illegal behaviors by surveying college students.
  
• The data are stored on a laptop computer without
  encryption, and the laptop computer is stolen
  from the Investigators car on the way home from
  work.

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Example 1 Decision

• This is a problem/event that meets Mayo Clinics
  IRB definition of UPIRTSO.
• The incident was
• SERIOUS - placed the subjects at a greater risk
  of psychological and social harm from the breach
  in confidentiality of the study data than was
  previously known or recognized
• UNANTICIPATED - the Investigator did not
  anticipate the theft AND
• RELATED the problem/event was related to
  participation in the research.

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Example 2

• Subjects with cancer are enrolled in a phase 2
  clinical trial evaluating an investigational
  biologic product derived from human sera.
• After several subjects are enrolled and receive
  the investigational product, a study audit
  reveals the investigational product administered
  to subjects was obtained from donors who were not
  appropriately screened and tested for several
  potential viral contaminants, including HIV and
  Hepatitis B virus.

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Example 2 Decision

• This is a problem/event that meets Mayo Clinics
  IRB definition of UPIRTSO.
• The incident was
• SERIOUS - placed the subjects at a greater risk
  of physical / psychological harm than was
  previously known or recognized
• UNANTICIPATED - the Investigators did not
  anticipate this problem/event AND
• RELATED the problem/event was related to
  participation in the research.

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Investigator Responsibilities in Example 1 2

• In example 1 2, the problem/event resulted in
  new circumstances that increased the risk of harm
  to subjects (serious), unanticipated, and related
  to participation in the research.
• In example 1 and 2, the UPIRTSO warrants
  consideration of substantive changes in the
  research protocol informed consent process
  consent document and/or other corrective actions
  in order to protect the safety, welfare, or
  rights of subjects.

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Investigator Responsibilities in Example 1 2

• In example 2, there may be unanticipated risks
  to others (e.g. sexual partners of the subjects)
  in addition to the subjects that may necessitate
  substantive changes.
• In both examples, while these problems/events may
  not have caused any detectable harm or adverse
  effect to subjects or others, they nevertheless
  are UPIRTSOs and shall be reported to Mayos IRB
  within 5 working days.

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Mayos IRB Responsibilities in Example 1 and 2

• The IRB is required to report UPIRTSOs according
  to Federal regulations and Mayo Clinic IRB Policy
  (See IRB Policy II.C) to
• appropriate Mayo Clinic institutional officials
• OHRP
• FDA (if applicable)
• the head of any Department or Agency that
  provides support for the study 45 CFR 46.103(a)
  and 45 CFR 46.103(b)(5).

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Example 3

• A subject enrolled in a phase 3, randomized,
  double-blind, controlled clinical trial comparing
  the relative safety and efficacy of a new
  chemotherapy agent combined with the current
  standard chemotherapy regimen, versus placebo
  combined with the current standard chemotherapy
  regimen, for the management of multiple myeloma
  develops neutropenia and sepsis.
• The subject subsequently develops multi-organ
  failure and dies.

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Example 3

• Prolonged bone marrow suppression resulting in
  neutropenia and risk of life-threatening
  infections is a known complication of the
  chemotherapy regimens being tested in the
  clinical trial and these risks are described in
  the IRB-approved protocol and consent document.
• The Investigator concludes that the subjects
  infection and death are directly related to the
  research interventions.

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Example 3 Decision

• This problem/event does NOT meet Mayo Clinics
  IRB definition of a UPIRTSO.
• The incident was
• SERIOUS Yes multi-organ failure, death
• UNANTICIPATED No the Investigators review of
  study data reveals that the incidence of severe
  neutropenia, infection, and death are within the
  expected frequency
• RELATED Yes the Investigator concluded that
  the subjects infection and death were directly
  related to research interventions.

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Example 3 Decision

• This example is not a UPIRTSO because the
  occurrence of severe infections and death in
  terms of nature, severity, and frequency was
  expected.
• The Investigator is reminded that while a
  problem/event may not initially meet the
  definition of a UPIRTSO, it can transform (based
  on severity and frequency) to a UPIRTSO.
• (A problem / event must meet all 3 criterion to
  meet the IRB definition of UPIRTSO)

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Example 4

• A subject is enrolled in a phase 3, randomized
  clinical trial evaluating the relative safety and
  efficacy of vascular stent replacement versus
  carotid endarterectomy for the treatment of
  patients with severe carotid artery stenosis and
  recent transient ischemic attacks.
• The patient is assigned to the stent placement
  study group and undergoes stent replacement in
  the right carotid artery.

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Example 4

• Immediately following the procedure, the patient
  suffers a severe ischemic stroke resulting in
  complete left-sided paralysis.
• The IRB-approved protocol and consent document
  for the study indicated there was a 5-10 chance
  of stroke for both study groups.

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Example 4 Decision

• This is a problem/event that does NOT meet Mayo
  Clinics IRB definition of UPIRTSO.
• The incident was
• SERIOUS Yes ischemic stroke resulting in
  left-sided paralysis
• UNANTICIPATED No the occurrence of stroke was
  expected the Investigators review of study data
  reveals that 25 subjects have been enrolled in
  the clinical trial 2 have suffered a stroke
  shortly after undergoing the study intervention
  (including the current subject)
• RELATED Yes the DSMB concludes the subjects
  stroke resulted from the research intervention.

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Example 4 Decision

• This example is a non-UPIRTSO because the
  occurrence of stroke was expected and frequency
  at which strokes were occurring in subjects
  enrolled so far was at the expected level.
• The Investigator is reminded that while a
  problem/event may not initially meet the
  definition of a UPIRTSO, it can transform (based
  on severity and frequency) to a UPIRTSO.
• (The problem / event must meet all 3 criterion to
  meet the IRB definition of UPIRTSO)

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Investigator Responsibilities in Example 3 4

• In example 3 4 the problem/event was serious
  and determined to be related to participation in
  the study.
• Both examples describe a problem/event that was
  anticipated. In both situations the problem/event
  needs to be monitored by the Investigator for any
  changes in nature, severity and/or frequency.
• Investigators are reminded that while a
  problem/event may not meet Mayos IRB definition
  of UPIRTSO, they must also comply with
  requirements for reporting to other reviewing
  entities (e.g. sponsors, funding agencies,
  DSMBs).

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Investigator Responsibilities in Example 3 4

• Example 3 and 4 demonstrate the Investigator
  responsibility inherent in study management.
• Standard Operating Procedures (SOPs) are
  essential as they set forth 1) the
  Investigators documentation / tracking system
  for tracking problems/events and 2) frequency of
  study team meetings to assess study data for any
  changes in nature, severity and/or frequency of
  problems/events.

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Investigator Responsibilities in Example 3 4

• In both examples, while these problems/events may
  not meet Mayos IRB definition of a UPIRTSO, they
  are monitored by the study team.
• The Investigator is reminded that while a
  problem/event may not initially meet the
  definition of a UPIRTSO, it can transform (based
  on severity and frequency) to a UPIRTSO.
• In example 3 and 4, the Investigator will provide
  a narrative summary of these problems/events
  (non-UPIRTSOs) at the time of IRB continuing
  review.

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Mayos IRB Responsibilities in Example 3 and 4

• Problems/events that meet the definition of a
  UPIRTSO are referred to an IRB Chair or Vice
  Chair to make the determination for appropriate
  decision-making and triage.
• Problems/event that are determined to be a
  non-UPIRTSO are returned to the Investigator with
  instructions to submit a brief narrative summary
  at the time of IRB continuing review.
• See IRB Policy and Procedure III.J

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Example 5

• A subject with chronic gastroesophageal reflux
  disease enrolls in a randomized,
  placebo-controlled, double-blind, phase 3
  clinical trial evaluating a new investigational
  agent that blocks acid release in the stomach.
• Two weeks after being randomized and started on
  study intervention, the subject develops acute
  kidney failure (serum creatinine increase from
  1.0mg/dl to 5.0mg/dl).
• The known risk profile of the investigational
  agent does not include renal toxicity the IRB
  approved protocol and consent form does not
  identify kidney damage as a risk of the research.

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Example 5 Decision

• This is a problem/event that meets Mayo Clinics
  IRB definition of UPIRTSO.
• The incident was
• SERIOUS Yes acute kidney failure
• UNANTICIPATED the known risk profile does not
  include renal toxicity IRB approved protocol and
  consent form do not identify kidney damage as a
  risk of the research AND
• RELATED the Investigator concluded that the
  episode of acute renal failure probably was due
  to the investigational agent.

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Investigator Responsibilities in Example 5

• In example 5, the problem/event was serious,
  unanticipated, and related to participation in
  the research.
• The UPIRTSO warrants consideration of substantive
  changes in the research protocol informed
  consent process consent document and/or other
  corrective actions in order to protect the
  safety, welfare, or rights of subjects.
• The Investigator shall report this UPIRTSO to
  Mayo Clinics IRB within 5 working days.

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Mayos IRB Responsibilities in Example 5

• The IRB is required to report the UPIRTSOs
  according to Federal regulations and Mayo IRB
  Policy (See IRB Policy II.C) to
• appropriate Mayo Clinic institutional officials
• OHRP
• FDA (if applicable)
• the head of any Department or agency that
  provides support for the study 45 CFR 46.103(a)
  and 45 CFR 46.103(b)(5).

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Additional Questions??

• Contact the IRB Service Center at
• (77) 6-4000 or off campus at [phone].
• Email IRB Service Center