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Title: Research Involving Human Specimens


1
Research Involving Human Specimens
  • Marianna Bledsoe, M.A.
  • HRPP 201
  • March 24, 2011

2
Overview of Presentation
  • Applicable federal regulations
  • Determining when human specimen research is human
    subjects research
  • Applying relevant federal regulations
  • Considerations for secondary use of
    specimens/data
  • Special considerations for banking
  • VA tissue banking guidelines
  • Current hot topics
  • Tools and Resources

3
Human Biological Specimens
  • Any material derived from a human subjectsuch as
    blood, urine, tissues, organs, hair, nail
    clippings, or any other cells or fluids
  • Whether collected for research purposes or as
    residual specimens from diagnostic, therapeutic,
    or surgical procedures
  • Does not include fungi, viruses, bacteria, etc.

4
Applicable Federal Regulations
  • Common Rule 38 CFR part 16
  • FDA Regulations
  • 21 CFR Part 50, 56, 812
  • HIPAA Privacy and Security Rules
  • 45 CFR Part 160 Subparts A, C E of Part 164
  • Privacy Act of 1974
  • HITECH Breach Notification Interim Final Rule

5
When is Specimen Research Human Subjects Research?
  • Is it research?
  • Research means a systematic investigation,
    including research development, testing and
    evaluation, designed to develop or contribute to
    generalizable knowledge.
  • OHRP considers creation of repositories for
    research purposes a research activity

6
When is Specimen Research Human Subjects Research?
  • Is it human subjects research?
  • Human subject A living individual about whom an
    investigator (whether professional or student)
    conducting research obtains a) data through
    intervention or interactions with the individual,
    or b) identifiable private information. 38 CFR
    16.102(f)
  • Common Rule definition of identifiable the
    identity of the subject is or may readily be
    ascertained by the investigator or associated
    with the information

7
When is Specimen Research Human Subjects Research?
  • Is it human subjects research (contd)?
  • For VA, research must meet both the Common Rule
    and Privacy Rule definitions of identifiable.

8
When is Specimen Research Exempt?
  • (4) Research involving the collection or study of
    existing data, documents, records, pathological
    specimens, or diagnostic specimens, if these
    sources are publicly available or if the
    information is recorded by the investigator in
    such a manner that subjects cannot be identified,
    directly or through identifiers linked to the
    subjects.

9
OHRP Guidance on Coded Private Information or
Biological Specimens
  • Definition of Coded
  • (1) identifying information (such as name or
    social security number) that would enable the
    investigator to readily ascertain the identity of
    the individual to whom the private information or
    specimens pertain has been replaced with a
    number, letter, symbol, or combination thereof
    (i.e., the code) and
  • (2) a key to decipher the code exists,
    enabling linkage of the identifying information
    to the private information or specimens.

10
OHRP Guidance on Coded Private Information or
Biological Specimens
  • In general, OHRP considers private
    information or specimens to be individually
    identifiable as defined at 45 CFR 46.102(f) when
    they can be linked to specific individuals by the
    investigator(s) either directly or indirectly
    through coding systems.
  • However, the OHRP coded specimens policy
    allows exceptions under certain conditions.

11
OHRP Guidance on Coded Private Information or
Biological Specimens
  • Research involving only coded information or
    specimens is not considered to involve human
    subjects if the following conditions are both
    met
  • (1) the private information or specimens were not
    collected specifically for the currently proposed
    research project through an interaction or
    intervention with living individuals AND
  • (2) the investigator(s) cannot readily ascertain
    the identify of the individual(s) to whom the
    coded private information or specimens pertain.

12
OHRP Guidance on Coded Private Information or
Biological Specimens
  • Examples of When Coded Data/Biologic Specimens
    Are Not Individually Identifiable to
    Investigators
  • the investigators and the holder of the key enter
    into an agreement prohibiting the release of the
    key to the investigators under any circumstances,
    until the individuals are deceased

13
OHRP Guidance on Coded Private Information or
Biological Specimens
  • Examples of When Coded Data/Biologic
    Specimens Are Not Individually Identifiable to
    Investigators
  • (b) there are IRB-approved written policies
    and operating procedures for a repository or data
    management center that prohibit the release of
    the key to the investigators under any
    circumstances, until the individuals are
    deceased or
  • (c) there are other legal requirements
    prohibiting the release of the key to the
    investigators, until the individuals are
    deceased.

14
OHRP Guidance on Coded Private Information or
Biological Specimens
  • Only applies if
  • 1. Person(s) doing coding of data/specimens and
    person(s) holding codes are not part of the
    research team AND
  • 2. Specimens/data are not being obtained for the
  • specific research in question by an interaction
    or intervention with living individuals.

15
Informed Consent
  • Informed consent required when there is
    intervention/interaction with a living individual
    or private identifiable information is being
    collected and/or used, unless waived by the IRB
  • Should be clear and understandable

16
Additional Informed Consent Content
  • Must meet requirements of human subjects
    regulations
  • In addition, should also include
  • Description of specimens/data and process used
    for collecting them
  • Risks, including risks to privacy and
    confidentiality, and methods to protect risks
  • Description of the purpose of the collection and
    conditions for sharing
  • Types of research to be conducted

17
Additional Informed Consent Content
  • Statement of the right to withdraw
  • Whether results will be returned
  • Commercial use, if any, and plans, if any, for
    sharing profits
  • Plans for re-contact, if any
  • As appropriate
  • Details about where and how long the specimens
    will be stored
  • Genetic uses and information on the consequences
    of DNA typing

18
Additional Informed Consent Content
  • As appropriate (contd)
  • Conditions for sharing with other researchers
  • What will happen to specimens when no longer
    useful, when repository loses support, or is
    transferred to others

19
IRB Waivers of Consent
  • The research involves no more than minimal risk
    to the subjects
  •  (2) The waiver or alteration will not adversely
    affect the rights and welfare of the subjects
  •  (3) The research could not practicably be
    carried out without the waiver or alteration and
  •  (4) Whenever appropriate, the subjects will be
    provided with additional pertinent information
    after participation.

20
Secondary Use of Specimens
  • Research use for a purpose other than that
    described in the protocol
  • Research should be compatible with the informed
    consent under which the specimens were collected
  • See discussion of the Secretarys Advisory
    Committee for Human Research Protections

21
Special Considerations for Repositories
  • How does the Common Rule apply? Three paths to
    human subjects research
  • Creating a research repository/database through
    intervention or interaction with individual
  • Creating a research repository/database by
    obtaining identifiable private information
  • Obtaining identifiable private information from a
    research repository/database

22
Special Considerations for Repositories
  • Need for review and oversight of repository
    operating procedures and policies for protecting
    subject privacy and confidentiality, access and
    dissemination
  • Need for mechanism for ensuring specimen use is
    consistent/compatible with informed consent
  • Need to address custodianship issues
  • Material Transfer Agreements CRADAs
  • Plans if repository/bank closes
  • Plans for transfer if PI leaves institution

23
HIPAA Privacy and Security Rules
  • HIPAA does not apply to specimens per se, but may
    apply to information associated with the specimen
  • HIPAA authorization for use and disclosure of
    protected health information generally required
    but there are certain exceptions

24
HIPAA Privacy Rule
  • Use or Disclosure of PHI for Research
  • With an individuals Authorization
  • Must be study specific
  • Authorization NOT required if one of the
    following applies
  • IRB or Privacy Board waiver
  • Preparatory to research (with certain
    representations)
  • Limited data set (with data use agreement)
  • De-identified dataset
  • Research solely on decedents (with certain
    representations and documentation)
  • IC, waiver of IC, or express legal permission
    prior to compliance date (and other conditions of
    transition provisions met)

25
VA Policies
  • VHA Handbook 1200.05--Requirements for the
    Protection of Human Subjects in Research
  • VHA Handbook 1200.12Use of Data and Data
    Repositories in VHA Research
  • VHA Handbook 1605.1--Privacy and Release of
    Information
  • VHA Handbook 1605.2Minimum Necessary Standard
    for Protected Health Information
  • VA Handbook 6500--Information Security Program
  • VHA Handbook 1106.01Pathology and Laboratory
    Medicine Service Procedures

26
VA Specimen Banking Guidelines
  • Current requirements found on ORD web site
    http//www.research.va.gov/programs/tissue_banking
    /default.cfm

27
VA Definition of De-identified
  • De-identified data is health or other
    information about an individual that
  • Does not contain any of the 18 HIPAA identifiers
  • AND
  • Is de-identified according to the Common Rule

28
HIPAA Identifiers
  • Names or initials
  • All geographic subdivisions smaller than a state
  • All elements of dates except the year and all
    ages over 89
  • Telephone numbers
  • Fax numbers
  • E-mail addresses
  • Social Security numbers (or scrambled SSNs)
  • Medical record numbers
  • Health plan beneficiary numbers

29
HIPAA Identifiers (contd)
  1. Account numbers
  2. Certificate or license numbers
  3. Vehicle identifiers
  4. Device identifiers and serial numbers
  5. URLs
  6. IP addresses
  7. Biometric identifiers, including finger and voice
    prints
  8. Full-face photographs and any comparable images
  9. Any other unique identifying number,
    characteristic, or code

30
Specimens for a Single Research Protocol
  • .
  • A waiver from ORD must be obtained if
  • If specimens are stored off-site at a non-profit
    institution ?5 years
  • If specimens are stored off-site at a
    non-academic, for-profit institution for gt3
    months
  • If the specimens are sent to a non-VA institution
    for testing as defined in the protocol, once the
    specific analyses are performed, the remainder of
    the specimens must be destroyed or returned to
    the VA for destruction.

31
Collecting and Storing Specimens for Secondary or
Future Research
  • A tissue bank established at a VA site by a
    VA-paid investigator does not require ORD
    approval.
  • The ACOS/R or research office should maintain
    records of all tissue banks within the facility.

32
Collecting and Storing Specimens for Secondary or
Future Research
  • The researcher must obtain a waiver from ORD
    before banking human biological specimens for
    future research use at an off-site location.
  • Specimens may not be banked for future research
    use at a non-academic, for-profit institution.
  • Off-site tissue banks are approved on a per
    protocol basis.

33
Collecting and Storing Specimens for Secondary or
Future Research
  • Exception National Cancer Institute
    (NCI)-sponsored cooperative tissue banks listed
    on the next slide. As a result of a letter of
    understanding with the NCI, these banks are
    designated as VA-approved if they are used for
    one of their protocols (for example, the
    SWOG-supported tissue bank can be used for SWOG
    protocols without ORD approval).

34
VA-Approved NCI Tissue Banks
  • Clinical Trials Cooperative Groups Tissue
    Resources
  • American College of Surgeons Oncology Group
    (ACOSOG)
  • Cancer and Leukemia Group B (CALGB)
  • Eastern Cooperative Oncology Group (ECOG)
  • Gynecologic Oncology Group (GOG)
  • North Central Cancer Treatment Group (NCCTG)
  • National Surgical Adjuvant Breast and Bowel
    Project (NSABP)
  • Radiation Therapy Oncology Group (RTOG)
  • Southwest Oncology Group (SWOG)
  • National Cancer Institute of Canada Clinical
    Trials Group (NCIC CTG)
  • Cooperative Breast Cancer Tissue Resource
  • Cooperative Human Tissue Network
  • Gynecologic Oncology Group Tissue Network
  • Cancer Prevention Network

35
Storage of Specimens
  • Specimens must be labeled with a code that does
    not contain any of the 18 HIPAA identifiers.
  • In the case of storage at non-profits, the key to
    the code must be maintained at the VA unless
    there is a compelling reason otherwise. If the
    storage is at a for-profit institution, then it
    is mandatory that the code be maintained at the
    VA.

36
Additional Requirements for Specimens Stored at
For-Profit Sites
  • Only analyses/tests listed in the protocol and
    informed consent may be performed.
  • The code must be maintained at the VAMC.
  • All specimens must be de-identified to meet both
    Common Rule and HIPAA requirements.
  • Limited DNA/RNA analyses may be performed.

37
Additional Requirements (contd)
  • HIPAA authorization must be a separate stand
    alone document and expire at the end of the
    study.
  • Use of initials outside of VA is generally not
    permitted.
  • Before company personnel may view files at the
    VA, they must complete VA security and privacy
    training.
  • Specimens must be destroyed within 1 year of the
    study completion date. The company should inform
    the PI in writing when samples are destroyed.

38
Data Linked to Banked or Stored Specimens
  • If data linked to the sample leaves the VA, then
    it should be de-identified or stored in a
    database that is encrypted according to FIPS
    140-2 standards.
  • See VA Handbook 6500 Information Security

39
Application Process
  • The investigator must complete VA form 10-0436.
    This is a pdf form that can be filled in and
    saved using Acrobat Reader version 7 or higher
    (http//www.va.gov/vaforms/medical/pdf/vha-10-0436
    -fill.pdf).
  • The additional required information can be
    scanned and attached to the pdf or to the e-mail.
  • Research protocol
  • Tissue bank manual /SOPs non-profits
  • VA consent form
  • HIPAA authorization

40
Application Process (contd)
  • The application should be e-mailed to Kristina
    Hill (Kristina.Hill_at_va.gov). It should be sent
    from the research office.
  • Alternatively, the form and requested information
    can be faxed to (202) 495-6156.

41
Application Process (contd)
  • After the application is reviewed, the PI and
    ACOS/R will receive a memo listing any issues
    that need to be addressed.
  • Frequent issues with applications include
    informed consent issues, use of identifiers,
    long term storage, and mandatory banking or
    genetic testing which is not permissible except
    when integral to study design.

42
Multi-Site Trials
  • If several VAMCs are planning to participate in
    the same clinical trial, then only one of the VA
    sites needs to apply for a waiver.

43
In the Works
  • Changes to the HIPAA Privacy Rule
  • HITECH Breach Notification Requirements Final
    Rule
  • New VA Handbook on Specimen Research

44
Current Hot Topics
  • Return of Research Results and Incidental
    Findings
  • Group Harms
  • Intellectual Property/Ownership/Custodianship
  • Identifiability
  • Differing definitions
  • Impact of emerging genetic technologies and
    extent and availability of databases containing
    patient/subject information

45
Current Policy Discussions
  • Secretarys Advisory Committee on Human Research
    Protections
  • http//www.hhs.gov/ohrp/sachrp
  • FAQs on Specimen Research (October 2008 October
    2010)
  • Implications of the Havasupai Case (July 21,
    2010)
  • Discussion of Identifiability (October 20, 2010)
  • Subcommittee on Harmonization exploring secondary
    use of specimens, HITECH

46
Biorepository Best Practices
  • International Society for Biological and
    Environmental Repositories (ISBER) 2008 Best
    Practices for Repositories http//www.isber.org/P
    ubs/BestPractices2008.pdf
  • National Cancer Institute Best Practices for
    Biospecimen Resources (June 2007)
    http//biospecimens.cancer.gov/global/pdfs/NCI_Bes
    t_Practices_060507.pdf

47
Other Resources
  • Report of the Public Responsibility in Medicine
    and Research (PRIMR) Human Tissue/Specimen
    Banking Working Group (March 2007)
    http//www.primr.org/uploadedFiles/PRIMR_Site_Home
    /Public_Policy/Recently_Files_Comments/Tissue20Ba
    nking20White20Paper203-7-0720final20combined.
    pdf

48
Contact Information
  • Marianna Bledsoe, M.A.
  • Senior Program Manager for Biorepositories and
    Biobanking
  • E-mail Marianna.Bledsoe_at_va.gov
  • Phone 202-443-5781
  • Fax 202-495-6156

49
Acknowledgements
  • Marilyn Mason, PhD.
  • Kristina Hill, MPH

50
Selected SACHRP FAQs
51
FAQ 1Approved by SACHRP July 22, 2009
  • Tissue biopsies were obtained for clinical
    diagnostic purposes, which have now been
    satisfied. The hospital pathology department is
    willing to provide a portion of the remaining
    biopsy specimens to an investigator who will
    perform research assays. In order to allow
    matching with relevant clinical information, the
    specimens will be provided with identifiers such
    that the investigator can readily ascertain the
    identity of subjects.
  • Is consent of the patient from whom the biopsy
    was taken (or waiver of consent) required for the
    secondary research use?

52
Response 1Approved by SACHRP July 22, 2009
  • Yes. Under this scenario, informed consent of
    the subjects should either be obtained or waived
    under 45 CFR 46.116(d) because the samples are
    identifiable to the recipient investigator.

53
HIPAA Issues for FAQ 1Approved by SACHRP
October 27, 2009
  • Assuming the hospital is a HIPAA covered entity,
    the use or disclosure of patient identifiers for
    the research purpose would also require a HIPAA
    authorization from the patient or a waiver of
    authorization by an IRB or Privacy Board.

54
FAQ 2Approved by SACHRP July 22, 2009
  • Tissue biopsies were obtained for clinical
    diagnostic purposes, which have now been
    satisfied. The hospital pathology department is
    willing to provide a portion of the remaining
    biopsy specimens to an investigator who will
    perform research assays. The specimens will be
    coded such that the investigator will not be able
    to readily ascertain the identity of individuals.
  • Is consent of the patient from whom the biopsy
    was taken (or waiver of consent) required for the
    secondary research use?

55
Response 2Approved by SACHRP July 22, 2009
  • No. Under this scenario, neither consent nor
    waiver is required, because the activity is not
    considered to be research involving human
    subjects.

56
HIPAA Issues for FAQ 2Approved as modified by
SACHRP October 27, 2009
  • If the information associated with the specimens
    is de-identified in accordance with the HIPAA
    Privacy Rule, neither authorization nor waiver of
    authorization is required, because it would no
    longer be considered Protected Health
    Information.
  • Note, however, that information associated with
    the specimens that is not individually
    identifiable per OHRP guidance (i.e., coded) may
    not necessarily be de-identified for HIPAA
    Privacy Rule purposes. For example, the coded
    information may not be considered to be
    de-identified under the Privacy Rule if the code
    is derived from a patient identifier or certain
    data elements, such as dates of service or zip
    codes, remain with the information. Thus, the
    use or disclosure of the information for research
    may still require a form of HIPAA permission,
    such as a HIPAA authorization, IRB or Privacy
    Board waiver of authorization, or, if the
    information constitutes a limited data set a
    data use agreement with the recipient of the
    information.

57
FAQ 6Approved by SACHRP October 27, 2009
  • Blood samples were obtained for research
    purposes, with informed consent of the subjects,
    and the original study has been completed. The
    samples remain under the control of the original
    investigator. Another investigator wants to use
    a portion of the remaining samples to perform
    research unrelated to the original study.
  • If the sample is identifiable to the secondary
    user, is this considered to be human subjects
    research under the purview of the IRB? If so,
    what are the consent considerations ?

58
Response 6Approved by SACHRP October 27, 2009
  • Yes. This is human subjects research under the
    purview of the IRB. The IRB should consider
    whether the secondary use is compatible with the
    original terms of consent given by the subjects.

59
HIPAA Issues for FAQ 6Approved by SACHRP
October 27, 2009
  • A HIPAA authorization for research must be
    research-study specific. Thus, assuming a HIPAA
    covered entity is involved, a new HIPAA
    authorization would be required for the
    subsequent unrelated research use or disclosure,
    or another form of HIPAA permission obtained
    (e.g., waiver of authorization).

60
FAQ 7Approved by SACHRP October 27, 2009
  • Blood samples were obtained for research
    purposes, with informed consent of the subjects,
    and the original study has been completed. The
    samples remain under the control of the original
    investigator, who now wants to collaborate with
    another investigator to perform research
    unrelated to the original study.
  • If the original consent was silent on the
    question of subsequent uses, is informed consent
    (or waiver of consent) required before the sample
    can be used for other purposes?

61
Response 7Approved by SACHRP October 27, 2009
  • Yes. Under these circumstances, the IRB should
    consider the original terms of consent, and
    determine whether a waiver might be appropriate
    or whether additional consent is required.
  • The criteria for waiver of consent under 45 CFR
    46.116(d) include that the research involves no
    more than minimal risk the waiver would not
    adversely affect the rights and welfare of
    subjects the research could not practicably be
    carried out without the waiver and whenever
    appropriate, the subjects will be provided with
    pertinent information after participation.
  • Points to consider in applying these criteria
    include the nature of the research the
    protections in place to maintain privacy and
    confidentiality (e.g., coding, limited/controlled
    access, honest broker mechanisms) the change in
    level of risk, if any the ability to locate or
    contact subjects risk of introducing bias into
    the research potential anxiety or confusion for
    subjects the number of subjects the length of
    time since specimens were first collected and
    the likelihood that subjects would object to the
    proposed secondary use, based on the nature of
    original collection.

62
FAQ 9Approved by SACHRP October 27, 2009
  • Patients undergoing surgery agree to donate any
    excess tissue (i.e., beyond that needed for
    clinical purposes) to a tissue bank. The
    creation of the bank is reviewed as human
    subjects research and approved by the IRB. The
    consent form makes it clear that the specimens
    and associated clinical data will be used for
    research, but does not specify or limit that use.
  • If specimens are provided to the researchers
    with clinical information that allows the
    researcher to readily ascertain the identity of
    the subjects, do those researchers need separate
    IRB approval of the proposed research use of the
    specimens and data?

63
Response 9Approved by SACHRP October 27, 2009
  • Yes, the provision of identifiable information
    with the specimen means the research to be
    conducted with the specimen is a separate human
    subjects research protocol and separate IRB
    approval would be required.

64
FAQ 10Approved by SACHRP October 27, 2009
  • Patients undergoing surgery agree to donate any
    excess tissue (i.e., beyond that needed for
    clinical purposes) to a tissue bank. The
    creation of the bank is reviewed and approved by
    the IRB. The consent form makes it clear that
    the specimens and associated clinical data will
    be used for research, but does not specify or
    limit that use.
  • If specimens are provided to the researchers
    with clinical information that allows the
    researcher to readily ascertain the identity of
    the subjects, is a new consent from the
    patient/subject or IRB waiver of informed
    consent required?

65
Response 10Approved by SACHRP October 27, 2009
  • Yes, a new consent is required unless IRB
    determines that the original consent was adequate
    to allow the subsequent research use, or the IRB
    determines a waiver is appropriate.
  • The criteria for waiver of consent under 45 CFR
    46.116(d) include that the research involves no
    more than minimal risk the waiver would not
    adversely affect the rights and welfare of
    subjects the research could not practicably be
    carried out without the waiver and whenever
    appropriate, the subjects will be provided with
    pertinent information after participation.
  • Points to consider in applying these criteria
    include the nature of the research the
    protections in place to maintain privacy and
    confidentiality (e.g., coding, limited/controlled
    access, honest broker mechanisms) the change in
    level of risk, if any the ability to locate or
    contact subjects risk of introducing bias into
    the research potential anxiety or confusion for
    subjects the number of subjects the length of
    time since specimens were first collected and
    the likelihood that subjects would object to the
    proposed secondary use, based on the nature of
    original collection.

66
  • A Real Life Example

67
Real Example
  • A non-VA researcher approaches a VA
    ophthalmologist wanting to obtain residual fluid
    that is used to wash eyes during treatment for
    cataracts. This fluid is waste that would
    ordinarily be discarded. The non-VA researcher
    will use the material to study the mechanisms of
    cataract formation in mice. No identifying
    information is sought.
  • Is this human subjects research?
  • Is an FWA and IRB approval required at the VA
    site?
  • What if the VA opthalmologist were providing
    identifiers along with the specimens? Would a
    FWA or IRB approval be required at the VA site?
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