Donors as Research Subjects: Algorithm Training

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Donors as Research Subjects Algorithm Training

• Christina Jobe
• Program Specialist, Research Administration

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Agenda

• Background
• Historical context of donors as research subjects
• Challenges
• WMDA and NMDP approaches
• Data provided to TC as part of donor selection
  process
• How to analyze a protocol using the algorithm
• Process for completion and submission of analysis
  worksheet
• Conclusion donor is a research subject or a
  third party in research. What next?
• Maintenance
• Audit program
• Subsequent training
• Q A

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Historical Context

• Transplant centers asked to review research
  protocols to identify where donor is a research
  subject emphasis on solid tumor protocols
• 2001 NMDP creates list of donor research
  categories
• donor-derived cell lines
• product manipulated as part of IND/IDE
• Ancillary lab studies with donor cells/product
• Transplant for non-standard indication
• 2005 Tandem initiatives implemented in NMDP and
  WMDA to formally address this question

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WMDA Donors as Research Subjects

• Surveyed WMDA Registries on national regulations
  and four categories for donor research
• No consensus on when a donor is a research
  subject
• Many differing national regulations
• Discussed topic within the WMDA Ethics Committee
• Many differing opinions

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Challenges

• Differing opinions on when to consider a donor as
  a research subject
• Complicated in an international setting with
  differing national regulations
• Research protocols often mix therapy and research
• Standard transplant followed by experimental
  anti-fungal drug
• Standard transplant followed by an experimental
  DLI

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• Belmont Report
• Practice interventions that are designed
  solely to enhance the well being of an individual
  patient that have a reasonable expectation of
  success
• Research activity designed to test an
  hypothesis, permit conclusions to be drawn, and
  thereby contribute to generalizable knowledge
• Research and practice/therapy may be carried on
  together in the same protocol, but if there is an
  element of research in an activity, that activity
  should undergo review for the protection of human
  subjects.

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WMDA International Approach

• Developed internationally acceptable criteria for
  determining when a donor is a research subject
• Criteria are based on the statement in the WMAs
  Helsinski Declaration
• Medical research involving human subjects
  includes research on identifiable human material
  or identifiable data
• Criteria for recipient-only research that
  increases donor risk (third party research)
• Created algorithm and a process based on those
  criteria

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WMDA and NMDP Tandem Initiatives

• WMDA algorithms patterned after NMDP U.S.
  specific algorithms
• Processes in development for international donor
  research closely align with NMDP processes
• WMDA criteria in development that will be brought
  to WMDA Board for approval in Spring 2008

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NMDP Approach

• Formed committee that included a range of
  specialties (ethical, legal, medical)
• Set out to answer the question in five scenarios
• Transplant for indication where efficacy is not
  established
• Experimental manipulation of the product
• Donor-derived cell lines created for experimental
  therapy
• Prospectively collected cells for laboratory
  research
• Patient transplanted on a research protocol with
  some experimental intervention but transplant
  efficacy for the disease is proven and donation
  is standard

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NMDP Approach

• Examined the U.S. regulatory definitions of human
  research subject
• Research intervention
• Identifiable data
• Concluded it depends on specific protocol
  circumstances
• Developed algorithm to which protocol specific
  circumstances could be applied

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Basis for Algorithm

• U.S. regulatory definition of research
• U.S. regulatory definitions of human subject
• Concept of third party research

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U.S. Regulatory Definition of Research

• A systematic investigation designed to develop or
  contribute to generalizable knowledge
• 45 CFR 46.102(d)
• Definition implies that
• Investigation plan is formulated in a research
  protocol
• More than one subject will be involved

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U.S. Regulatory Definitions of Human Subject

• OHRP
• A living individual about whom an investigator
  conducting research obtains
• 1) data through intervention or interaction with
  the individual, or
• 2) identifiable private information.
• 45 CFR 46.102(f)(1),(2)
• FDA
• An individual who is or becomes a participant in
  research, either as a recipient of the test
  article or as a control. A subject may be either
  a healthy individual or a patient. 21 CFR
  56.111(e)
• A human who participates in an investigation
  either as an individual on whom or on whose
  specimen an investigational device is used or as
  a control. A subject may be in normal health or
  may have a medical condition or disease. 21
  CFR 812.3(p)

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Third Party in Research

• Individuals whose rights or welfare may be
  adversely affected by research procedures in
  which others are involved
• No U.S. regulatory requirement for IRBs to
  address risk to third parties
• Ethical obligations to inform third parties of
  research risks

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Donor a Third Party in Research

• Research protocols where
• Recipient is a human subject but donor isnt
• Donor at risk because of recipients
  participation in research
• Examples of third party research risk
• Increased risk of second donation
• Increased risk of donating for a futile transplant

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Donor data provided to TC as part of donor
selection process

• Race
• Age
• Gender
• HLA typing
• Infectious disease markers
• ABO type
• Rh type
• Previous transfusions
• of pregnancies
• Weight

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Donor data provided to TC as part of donor
selection process (cont.)

• These data can be used on a research protocol
  without putting the protocol through the NMDP
  IRB.
• OHRP Guidance on Research Involving Coded Private
  Information or Biological Specimens (10-Aug-2004)
• Data were not collected specifically for the
  research protocol
• Investigator cannot readily identify the
  individual to whom the data pertain (Even though
  a link to donors identity is maintained at DC,
  federal laws exist to prohibit release of
  identity.)

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Is the Donor a Human Research Subject or a Third
Party in Research?
Is the activity research? A systematic
investigation that is clearly formulated in an
experimental protocol and designed to develop or
contribute to generalizable knowledge. This
includes clinical investigations for which the
investigator holds an Investigational Device
Exemption (IDE) or an Investigational New Drug
Application (IND). 45 CFR 46.102(d) 21 CFR
50.3(c)
Activity Is not research. Therefore, donor is
not a research subject.
no
yes
Donor is not a research subject. Is the donor a
third party in research? Does the research
activity in which the patient is involved put the
donor at greater risk for a second donation or
donating for a futile transplant? NOTE 2
Activity is research. Is the donor a research
subject? Does the activity involve Obtaining
NMDP donor data specifically for research
purposes? OR Obtaining NMDP donor material
(e.g., cells) specifically for research purposes?
OR Using an investigational device on an NMDP
donors specimen (marrow, peripheral blood stem
cells or other tissue)? OR Giving an NMDP donor
an investigational drug or device? If you
answered yes to any of these, then the donor is
a research subject. 45 CFR 46.102(f)(1), (2)
21 CFR 812.3(p) 21 CFR 56.111(e) NOTE 1
no
yes
no
Donor is not a third party in research. Patient
research does not impact donor. NMDP does not
need to be informed of patients research
activity.
Donor is a third party in research. Donor must
be allowed to weigh his/her risks against the
benefit to the patient. Inform NMDP IRB Office
of the patients research activity.
yes
Donor is a Research Subject Activity is research
involving donors as human subjects. 45 CFR
46.101(a)(1) Submit NMDP IRB Application
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EXAMPLE Transplant for Renal Cell Carcinoma
Is the activity research? A systematic
investigation that is clearly formulated in an
experimental protocol and designed to develop or
contribute to generalizable knowledge. This
includes clinical investigations for which the
investigator holds an Investigational Device
Exemption (IDE) or an Investigational New Drug
Application (IND). 45 CFR 46.102(d) 21 CFR
50.3(c)
Activity Is not research. Therefore, donor is
not a research subject.
no
YES, there is a research protocol with the intent
to contribute to generalizable knowledge.
yes
Donor is not a research subject. Is the donor a
third party in research? Does the research
activity in which the patient is involved put the
donor at greater risk for a second donation or
donating for a futile transplant? NOTE 2
Activity is research. Is the donor a research
subject? Does the activity involve Obtaining
NMDP donor data specifically for research
purposes? OR Obtaining NMDP donor material
(e.g., cells) specifically for research purposes?
OR Using an investigational device on an NMDP
donors specimen (marrow, peripheral blood stem
cells or other tissue)? OR Giving an NMDP donor
an investigational drug or device? If you
answered yes to any of these, then the donor is
a research subject. 45 CFR 46.102(f)(1), (2)
21 CFR 812.3(p) 21 CFR 56.111(e) NOTE 1
no
yes
no
Donor is a third party in research. Donor must
be allowed to weigh his/her risks against the
benefit to the patient. Inform NMDP IRB Office
of the patients research activity.
Donor is not a third party in research. Patient
research does not impact donor. NMDP does not
need to be informed of patients research
activity.
YES, the transplant itself is a research
activity. The stem cell donation is a donor
intervention done for research purposes.
Identifiable donor stem cells will be used for
research.
yes
Donor is a Research Subject Activity is research
involving donors as human subjects. 45 CFR
46.101(a)(1) Submit NMDP IRB Application
Conclusion Donor is a research subject. Donor
stem cells will be used for a research
transplant the donor intervention occurred
explicitly for research purposes. Although the
stem cells are coded, a link to the donors
identity does exist at the donor center.
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EXAMPLE Study uses a conditioning regimen that
allows for older AML patients with co-morbidities
to receive a transplant
Is the activity research? A systematic
investigation that is clearly formulated in an
experimental protocol and designed to develop or
contribute to generalizable knowledge. This
includes clinical investigations for which the
investigator holds an Investigational Device
Exemption (IDE) or an Investigational New Drug
Application (IND). 45 CFR 46.102(d) 21 CFR
50.3(c)
Activity Is not research. Therefore, donor is
not a research subject.
no
YES, there is a research protocol with the intent
to contribute to generalizable knowledge.
yes
Donor is not a research subject. Is the donor a
third party in research? Does the research
activity in which the patient is involved put the
donor at greater risk for a second donation or
donating for a futile transplant? NOTE 2
Activity is research. Is the donor a research
subject? Does the activity involve Obtaining
NMDP donor data specifically for research
purposes? OR Obtaining NMDP donor material
(e.g., cells) specifically for research purposes?
OR Using an investigational device on an NMDP
donors specimen (marrow, peripheral blood stem
cells or other tissue)? OR Giving an NMDP donor
an investigational drug or device? If you
answered yes to any of these, then the donor is
a research subject. 45 CFR 46.102(f)(1), (2)
21 CFR 812.3(p) 21 CFR 56.111(e) NOTE 1
no
YES, patients research activity increases the
donors chance of making a donation for a futile
transplant
yes
no
NO, the transplant is therapy and not research.
Transplant already shown to be efficacious for
AML. The research activity is the conditioning
regimen for the patient. No donor data or donor
cells will be included in the research.
Donor is a third party in research. Donor must
be allowed to weigh his/her risks against the
benefit to the patient. Inform NMDP IRB Office
of the patients research activity.
Donor is not a third party in research. Patient
research does not impact donor. NMDP does not
need to be informed of patients research
activity.
yes
Donor is a Research Subject Activity is research
involving donors as human subjects. 45 CFR
46.101(a)(1) Submit NMDP IRB Application
Conclusion Donor is a third party in research.
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EXAMPLE Patient with Severe Aplastic Anemia
will be given prophylactic drug post-transplant
for fungal infections.
Is the activity research? A systematic
investigation that is clearly formulated in an
experimental protocol and designed to develop or
contribute to generalizable knowledge. This
includes clinical investigations for which the
investigator holds an Investigational Device
Exemption (IDE) or an Investigational New Drug
Application (IND). 45 CFR 46.102(d) 21 CFR
50.3(c)
Activity Is not research. Therefore, donor is
not a research subject.
no
YES, there is a research protocol with the intent
to contribute to generalizable knowledge.
yes
Donor is not a research subject. Is the donor a
third party in research? Does the research
activity in which the patient is involved put the
donor at greater risk for a second donation or
donating for a futile transplant? NOTE 2
Activity is research. Is the donor a research
subject? Does the activity involve Obtaining
NMDP donor data specifically for research
purposes? OR Obtaining NMDP donor material
(e.g., cells) specifically for research purposes?
OR Using an investigational device on an NMDP
donors specimen (marrow, peripheral blood stem
cells or other tissue)? OR Giving an NMDP donor
an investigational drug or device? If you
answered yes to any of these, then the donor is
a research subject. 45 CFR 46.102(f)(1), (2)
21 CFR 812.3(p) 21 CFR 56.111(e) NOTE 1
no
NO, the patients research activity does not
increase the donors risk for a second donation
or donating for a futile transplant
yes
no
NO, the transplant is therapy and not research.
The research activity is the anti-fungal drug for
the patient. No donor data or donor cells will
be included in the research.
Donor is a third party in research. Donor must
be allowed to weigh his/her risks against the
benefit to the patient. Inform NMDP IRB Office
of the patients research activity.
Donor is not a third party in research. Patient
research does not impact donor. NMDP does not
need to be informed of patients research
activity.
yes
Donor is a Research Subject Activity is research
involving donors as human subjects. 45 CFR
46.101(a)(1) Submit NMDP IRB Application
Conclusion Donor is neither a research subject,
nor a third party in research.
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Process for Algorithm Analysis Worksheet

• New Research Protocols
• TCs test protocols against the algorithm on every
  new research protocol submitted to local IRB for
  initial review
• TC determines if unrelated donor is a research
  subject, third party in research, or neither
• TC submits the completed analysis worksheet and
  cover memo to local IRB along with submission for
  initial review
• Regardless of conclusion, TC submits Algorithm
  Analysis Worksheet to NMDP IRB office
• If donor is a research subject, TC submits NMDP
  IRB application materials to NMDP IRB for review
• If donor is a third party in research, TC submits
  protocol to NMDP IRB office so an information
  sheet for donors can be developed

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Process for algorithm analysis worksheet (cont.)

• Current, Active Research Protocols
• TCs test protocols against the algorithm on every
  current, active research protocol approved by
  local IRB
• TC determines if unrelated donor is a research
  subject, third party in research, or neither
• TC submits the completed analysis worksheet and
  cover memo to local IRB along with submission for
  continuing review
• If donor is a research subject, TC immediately
  submits NMDP IRB application materials to NMDP
  IRB for review
• If donor is a third party in research, TC
  immediately submits protocol to NMDP IRB office
  so an information sheet for donors can be
  developed
• Submit all Algorithm Analysis Worksheets
  (regardless of conclusion) to NMDP IRB office by
  June 30, 2008
• Random selection will be audited

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Submission to NMDP IRB Office

• Submit all completed Algorithm Analysis
  Worksheets to the NMDP IRB Office
• If donor is a human research subject
• Submit NMDP IRB Application, protocol and other
  required documents to NMDP IRB Office
• If donor is a third party in research
• Submit protocol and recipient consent form to
  NMDP IRB Office
• The following documents can be found on
  www.nmdpresearch.org under the Institutional
  Review Board page
• Algorithm Analysis Worksheet (4 pages)
• Transplant Center Procedures
• Cover memo for your local IRB
• NMDP IRB Application for Initial Review

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NMDP IRB Office Contacts

• Christina Jobe Roberta King, M.P.H
• Program Specialist IRB Administrator
• Ph 612-627-8164 Ph 612-627-5807
• cjobe_at_nmdp.org rking_at_nmdp.org
• IRB Fax [phone]
• www.nmdpresearch.org

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Requesting donors on research studies

• If donor is a human research subject, and study
  has been approved by NMDP IRB
• Submit Request for NMDP Donor to Participate in a
  Research Study form along with the workup request
• Form provided to transplant center upon NMDP IRB
  approval
• If donor is a third party in research
• Submit NMDP Donor as a Third Party in Research
  form along with the workup request
• Form provided to transplant center upon NMDP IRB
  staff administrative review of protocol

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Maintenance

• TCs should develop a system to ensure that the
  Algorithm Analysis Worksheet is completed on all
  new research protocols.
• Example Create a new SOP or update an existing
  SOP
• Example Add to submission checklist for local
  IRB

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Audit program

• IRB staff will audit a random selection of
  completed Algorithm Analysis Worksheets that are
  received on current, active protocols between now
  and June 30, 2008.
• After June 30, IRB staff will audit 1 to 2 TCs
  each week
• TC will be asked for a completed Algorithm
  Analysis Worksheet on a recipient research
  protocol where the donor was deemed to be neither
  a human research subject nor a third party in
  research.
• TC will submit Worksheet, protocol and recipient
  consent form.
• NMDP IRB staff will perform algorithm analysis to
  verify analysis was done correctly by TC.

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Subsequent training

• TCs should ensure new staff who will be using the
  algorithm are trained on the process
• This training presentation will be made available
  online
• Record of training should be kept in staff files

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Summary

• Background
• How to use algorithm
• Process for completion and submission of analysis
  worksheet
• Next steps depending on algorithm conclusion
• Maintaining process at TC
• NMDPs audit program

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Questions