CasesAn EBAA, FDA and Legal Perspective

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Cases-An EBAA, FDA and Legal Perspective

• EBAA June 2009
• Jayne S Weiss MD, Program Director
• Seattle, Washington

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Case 1

• Eye bank used tissue on a medical examiners
  case.
• History
• Patient had the usual negative lab work, but when
  autopsy results came back several months later,
  she had signs of active hepatitis on pathology.

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Case 1

• Medical Director spoke to Medical Examiner who
  was surprised at this finding. He couldn't say
  whether this was infectious or autoimmune.
• How should Medical Director proceed?
• Suggested by James Caudill MD MIB- West Virginia

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CASE 1 EBAA MEDICAL STANDARDS
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Case 1 Infectious hepatitis?

• Eye bank used tissue on ME case
• Infectious disease testing was negative
• Several months later, autopsy report indicates
  signs of active hepatitis
• ME unable to say if hepatitis was infectious or
  autoimmune

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Case 1 Medical Standards

• D1.120 Contraindications for donors
• Active viral hepatitis
• Hepatitis B surface antigen positive
• Hepatitis C seropositive
• G1.280 Non-required laboratory results
• Medical director must review and act on them
• B1.000 Membership
• Compliance with Federal, State regulations

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Case 1 Adverse reaction report?

• G1.000 Adverse reaction reporting
• Distributing bank notifies source bank
• Source bank investigates and
• Notifies EBAA within 30 days
• Notifies FDA within 15 days if relevant
  communicable disease agent or disease involved
• Has an adverse reaction been reported?

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Case 1 Recall?

• G1.290 Tissue recall or withdrawal
• Positive test results of information about
  behavioral risks or medical history, received
  after release of tissue, that indicate a risk for
  transmission of a relevant communicable disease
  must be reported to the medical director,
  consignee, EBAA, and FDA
• Does the information received indicate a risk for
  transmission of a relevant communicable disease?

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CASE 1 FDA
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Case 1 Summary
FDA

• Cornea donor is a medical examiners (ME) case
• Information obtained for donor eligibility,
  including donor screening and testing
  information, is all negative prior to
  distribution
• Autopsy results received 3 months after
  distribution of corneas showed active hepatitis
  on pathology slides
• ME cannot verify whether hepatitis is infectious
  or autoimmune
• How does medical director proceed?

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Case 1 Discussion
FDA

• Donor Eligibility (DE) Determination based upon a
  review of donor screening and testing is required
  ( 1271.50)
• Donor screening includes a review of relevant
  medical records ( 1271.75)
• Some relevant medical records are records that
  must be reviewed, and
• Others must be reviewed if available
• ( 1271.3(s))

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Case 1 Donor Eligibility (DE) Determination
FDA

• 1271.50 requires a DE determination, based on
  screening and testing
• Donor is eligible if free from risk factors for
  or clinical evidence of relevant communicable
  diseases, free from risks associated with
  xenotransplantation, and tests negative or
  nonreactive
• A responsible person must determine and document
  the eligibility of a donor
• Risks/risk factors specifics of testing
  discussed in guidance

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Case 1 Relevant Medical Records
FDA

• Under 1271.75(a) donor screening includes
  review of relevant medical records (as defined in
  1271.3(s))
• Relevant medical records are a collection of
  documents that includes
• Current donor medical history interview
• Current report of physical assessment or physical
  exam
• Other records, if available

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Case 1 Relevant Medical Records
FDA

• If available records include the following
• ( 1271.3(s))
• Laboratory test results
• Medical records
• Coroner and autopsy reports and
• Records or other information received from any
  source pertaining to risk factors for relevant
  communicable disease (e.g., social behavior,
  clinical signs and symptoms, treatments).
  Examples include
• Medical examiner reports
• Police records
• Records from other establishments

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Case 1 Relevant Medical Records
FDA

• In the DE Guidance, we explain that we define
  available to mean that a record or information
  exists, or is pending, and can be obtained
  through due diligence, within a reasonable amount
  of time.
• A reasonable amount of time is a period of time
  that would allow for the collection of important
  information without compromising the utility of
  the tissue.
• One example was given in the guidance regarding
  corneas and autopsy reports.

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Case 1 Example from DE Guidance
FDA

• You know that an autopsy report will be prepared
  on a cadaveric donor, but the report will not be
  complete for several weeks.
• If waiting several weeks to review the autopsy
  report would compromise the utility of the
  tissue, perhaps because your HCT/P (e.g., cornea)
  needs to be released within a limited timeframe,
  then the report could not be obtained in a
  reasonable time period.
• Under these circumstances, it might not be
  necessary to wait to review the final report of
  autopsy results before distribution of the HCT/P.

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Case 1 Example from DE Guidance
FDA

• If this is the case, you should use the available
  information when considering the donors
  eligibility, including the presumed cause of
  death and other relevant preliminary autopsy
  findings and all other information obtained about
  the donor.
• Also, you should review the final autopsy report
  when it becomes available.
• If any new information in the final report
  indicates that the donor is ineligible, you
  should consider notifying the consignees of the
  distributed HCT/Ps and submit to FDA an HCT/P
  deviation report within 45 days, if applicable.

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Case 1 Discussion
FDA

• While HCT/Ps may be distributed prior to
  obtaining the if available relevant medical
  records if waiting for those records would
  compromise the utility of the HCT/P, relevant
  information obtained after distribution still
  must be considered by the responsible person in
  determining donor eligibility
• If the newly obtained information adversely
  affects the Donor Eligibility Determination, an
  HCT/P deviation report must be submitted to FDA
  (1271.350(b))

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CASE 1 LEGAL

• ARETA KUPCHYK

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CASE 2

• 80 year old woman had PKP in 2005 for PBK. Graft
  did well.

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Case 2

• HistoryFeb 2008-Rapid Neurological Degeneration
  March 2008-Surgeon/medical notified by
  Neurologist of Clinical DX of CJD
• What Is Appropriate Investigation of Case?
• Suggested by Alan Sugar MD, Ann Arbor, Michigan

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CASE 2 EBAA MEDICAL STANDARDS
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Case 2 CJD?

• 80 year old female had penetrating keratoplasty
  in 2005 for pseudophakic bullous keratopathy,
  graft doing well
• Feb 2008 Rapid neurological degeneration
• Mar 2008 Neurologist makes clinical diagnosis of
  CJD
• Discuss investigation

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How is CJD diagnosed?

• Clinical criteria?
• Prion protein in spinal fluid, blood, tissue?
• Genetic testing?
• Brain biopsy?

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Ideal investigation

• Brain biopsy of donor
• Tissue not typically available at time CJD
  diagnosis is considered years later
• Brain biopsy of recipient
• Tissue may or may not be available upon death of
  recipient

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What else can be done

• Review available donor records
• Medical Standard M1.100 requires permanent
  retention of minimum information for tracking
• Test corneal tissue for prion protein
• May be more accessible than brain biopsy
• Look for all potential sources
• Family history, genetic testing for familial form
• Exposure consistent with variant form

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Get Help National Prion Disease Pathology
Surveillance Center

• NPDPSC
• www.cjdsurveillance.com
• 216 368-0587
• Tests for sporadic, familial, or variant CJD
• Western blot (frozen tissue)
• Immunohistochemistry, histology (fixed tissue)
• Genetic analysis (blood or frozen tissue)

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CJD In Cornea Recipients

• 1 proven case of transmission in 1974
• CJD confirmed by biopsy in donor and recipient
• Not eye bank tissue
• Prior to current screening standards
• Whole globe present in OR with recipient
• 9 additional cases
• 8 probably, 1 possibly due to corneal tissue

Duffy P. NEJM 290692, 1974
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CJD In Cornea Recipients
Maddox RA. Cornea 27851, 2008
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CJD CDC Analysis

• Based on
• US eye banking statistics
• Age-stratified annual CJD mortality rates
• Age stratified annual mortality other than CJD

Maddox RA. Cornea 27851, 2008
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CJD CDC Conclusions

• Sporadic, coincidental CJD unrelated to donor
  tissue is expected to occur in one cornea
  recipient in the USA every 1.5 years
• It is unlikely that the possible and probable
  cases are due to corneal tissue
• There are additional unrelated, coincidental
  cases that remain unreported
• EBAA screening criteria minimize risk

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Maddox RA. Cornea 27851, 2008
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CASE 2 FDA
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Case 2 Summary
FDA

• 80 year old woman had penetrating keratoplasty in
  2005 for pseudophakic bullous keratopathy. Graft
  did well.
• Feb 2008Rapid neurological degeneration
• March 2008Surgeon/medical notified by
  neurologist of clinical DX of CJD
• Discuss appropriate investigation of case

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Case 2 Adverse Reaction Investigation
FDA

• 1271.350(a) You must investigate any adverse
  reaction involving a communicable disease related
  to an HCT/P that you made available for
  distribution.
• 1271.160(b)(2) Ensure that procedures exist for
  receiving, investigating, evaluating, and
  documenting information relating to core GTP
  requirements, including complaints, and for
  sharing any information pertaining to the
  possible contamination of the HCT/P or the
  potential transmission of a communicable disease
  by the HCT/P

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Case 2 Adverse Reaction Investigation
FDA

• 1271.200(e) You must document and maintain
  records of all equipment maintenance, cleaning,
  sanitizing, calibration, and other activities
  performed in accordance with section 1271.200.
  (s.a. records related to recovery instruments)
• 1271.320(b) You must maintain a record of
  complaints that you receive in a file designated
  for complaints. (c) You must review and evaluate
  each complaint relating to core GTP requirements
  to determine if the complaint is related to an
  HCT/P deviation or to an adverse reaction

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Case 2 Information to Review (from GTP Draft
Guidance)
FDA

• Pre- and post-processing culture results
• Donor screening records
• Donor testing results
• Donor eligibility determination
• Donor identification code
• Lot number
• Receipt of complaints involving recipients of
  other HCT/Ps from the same donor
• Occurrence of any processing deviations from your
  established SOPs

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Case 2 Examples of Additional Info (from GTP
Draft Guidance)
FDA

• Date of implantation
• Symptoms of infection in the recipient and dates
  of onset
• Pathology reports
• Recipients risk factors
• Physicians impression about the cause of the
  adverse reaction
• Recipients clinical records

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CASE 2 LEGAL

• ARETA KUPCHYK

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CASE 3

• Medical Director CaseHistory 19 year old, COD
  Multiple Trauma D/T MVANo significant PMHSocial
  History- 2 years in Juvenile Detention w/
  Homemade Tattoos involving shared needles and ink
  (not within last 12 months)

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Case 3

• NOK (Mother) has not had any contact with son
  within last 3 years many risk questions answered
  "I don't know".Cannot reach Father or Girlfriend
  for medical/social questionnaire

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Case 3

• Medical examiner-External exam notes the Homemade
  Tattoos Donor's EMA cited state at the time of
  exam.
• Can this tissue be used?

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CASE 3 EBAA MEDICAL STANDARDS
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Case 3 Suspicious social history

• 19 year old male dies in MVA
• No significant illnesses
• History of 2 years in juvenile detention, had
  non-professional tattoos done with shared
  needles, but not within last 12 months
• Medical/social interview with mother, who has not
  had contact with son in 3 years, results in many
  I dont know responses
• Unable to contact father or girlfriend

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Case 3 Medical Standards

• D1.000 Donor eligibility
• Medical and social histories are important
  aspects of donor evaluation.
• Donor history must include information from at
  least one of the following pathologist or ME
  report, family interview, medical record or
  treating physician interview, and
• Medical director oversight to review donor
  information where questions arise in the above
  areas

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Case 3 Does it pass muster?

• Incarceration and needle-sharing tattoos were
  greater than 12 months ago.
• There is a family interview.
• Is the family interview adequate?
• Would you consider this donor eligible?

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CASE 3 FDA
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Case 3 Summary
FDA

• 19 y/o died of multiple trauma secondary to motor
  vehicle accident
• No significant Past Medical History
• Social History gt 12 months ago
• Was in juvenile detention center, and
• Has homemade tattoos involving shared needles and
  ink
• NOK (mother) has not had contact with the donor
  for the past 3 years, answers many risk questions
  with I dont know
• Cannot reach father or girlfriend for
  medical/social questionnaire
• Medical Examiner notes on exam the homemade
  tattoos

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Case 3 Donor Eligibility (DE) Determination
FDA

• 1271.50 requires a DE determination, based on
  screening and testing
• Donor is eligible if free from risk factors for
  or clinical evidence of relevant communicable
  diseases, free from risks associated with
  xenotransplantation, and tests negative or
  nonreactive
• A responsible person must determine and document
  the eligibility of a donor
• Risks/risk factors specifics of testing
  discussed in guidance

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Case 3 Discussion
FDA

• Donor Eligibility (DE) Determination based upon a
  review of donor screening and testing is required
  ( 1271.50)
• Donor screening includes a review of relevant
  medical records for risk factors for, and
  clinical evidence of, relevant communicable
  disease agents and diseases ( 1271.75)
• Relevant medical records are a collection of
  documents that includes ( 1271.3(s))
• Current donor medical history interview
• Current report of physical assessment or physical
  exam
• Other records, if available

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Case 3 Relevant Risk Factors
FDA

• The DE Guidance provides information regarding
  risk factors for relevant communicable diseases
• Following is a list of conditions and behaviors
  that increase the donors relevant communicable
  disease risk. Except as noted in this section,
  and in accordance with 1271.75(d), you should
  determine to be ineligible any potential donor
  who exhibits one or more of the following
  conditions or behaviors.

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Case 3 Donor Screening
FDA

• 1271.75 states that you must screen a donor of
  cells or tissue by reviewing the donors relevant
  medical records for risk factors for, and
  clinical evidence of, relevant communicable
  disease agents and diseases
• It further states that you must determine
  ineligible a donor who is identified as having
  either risk factors for, or clinical evidence of,
  any of the relevant communicable disease agents
  or diseases for which screening is required or
  communicable disease risk associated with
  xenotransplantation

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Case 3 Relevant Risk Factors (from DE Guidance)
FDA

• 8. Persons who have been in juvenile detention,
  lock up, jail or prison for more than 72
  consecutive hours in the preceding 12 months
  (Refs. 29, 67, and 68) (risk factor for HIV,
  Hepatitis B and Hepatitis C).
• 10. Persons who have undergone tattooing, ear
  piercing or body piercing in the preceding 12
  months, in which sterile procedures were not
  used, e.g., contaminated instruments and/or ink
  were used, or shared instruments that had not
  been sterilized between uses were used (Ref. 69).

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Case 3 Discussion
FDA

• The histories regarding incarceration and
  tattooing, both occurring/ending gt12 months ago,
  in and of themselves do not necessitate
  determining the donor to be ineligible under
• 1271.75
• In this case, it seems that the responsible
  person cannot complete a DE determination as
  required under 1271.50 without obtaining
  answers to all questions in the donor medical
  history interview, since these questions identify
  risk factors for relevant communicable diseases
• Would need to seek an alternate historian who can
  provide the additional information in order to
  complete the DE determination

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CASE 3 LEGAL

• ARETA KUPCHYK