developing a repository protocol kathleen t. uscinski. mba, cip april 25, 2006

Developing A Developing A Repository Repository

ProtocolProtocolKathleen T. Uscinski. MBA, Kathleen T. Uscinski. MBA,

CIPCIP

April 25, 2006April 25, 2006

AgendaAgenda

The Basics: Objective, Definitions, Key The Basics: Objective, Definitions, Key Terms Terms

Creation of Repositories and DatabanksCreation of Repositories and Databanks Regulations and GuidanceRegulations and Guidance IRB ConsiderationsIRB Considerations Attributes of a Repository ProtocolAttributes of a Repository Protocol Ownership of Tissue and DataOwnership of Tissue and Data

DefinitionsDefinitions Research:Research: A systematic investigation, including A systematic investigation, including

testing and evaluation, designed to develop or testing and evaluation, designed to develop or contribute to generalizable knowledge. [that may contribute to generalizable knowledge. [that may assist in improving the care of currently assist in improving the care of currently unknown beneficiaries in the future.]unknown beneficiaries in the future.]

Human Subject:Human Subject: a living individual about whom a living individual about whom an investigator conducting research obtains: an investigator conducting research obtains:

1)1) data through intervention or interaction data through intervention or interaction with the individual, orwith the individual, or2)2) identifiable private information. identifiable private information.

““Collections” and DatabanksCollections” and Databanks

Databases are often created not for a Databases are often created not for a specific research project but as resources specific research project but as resources for future research. for future research.

Tissue banks and “collections” of Tissue banks and “collections” of identifiable biologic materials containing identifiable biologic materials containing patient material with identifiable patient patient material with identifiable patient data are similarly created and maintained.data are similarly created and maintained.

Specific concern is the collection of data/biologicSpecific concern is the collection of data/biologicsamples and the secondary uses of thesamples and the secondary uses of theinformation/materials by:information/materials by:

1.1. Colleagues at the same or other Colleagues at the same or other institutions/hospitals that collect the institutions/hospitals that collect the data/tissues through clinical data/tissues through clinical interventions.interventions.

2.2. Researchers who collect the data/tissues as part of Researchers who collect the data/tissues as part of a primary study and who wish to conduct, or wish to a primary study and who wish to conduct, or wish to share the info with colleagues who wish to conduct, share the info with colleagues who wish to conduct, secondary research… eventually. secondary research… eventually.

3.3. Commercial or other research sponsors to which Commercial or other research sponsors to which data/tissues have been given during the course of data/tissues have been given during the course of primary research.primary research.

What May ApplyWhat May Apply Ethical Obligations Ethical Obligations Clinical Trial AgreementsClinical Trial Agreements HIPAAHIPAA Common Rule (OHRP Guidance Nov 1997 and Common Rule (OHRP Guidance Nov 1997 and

August 2004)August 2004) FDA Regulations and GuidanceFDA Regulations and Guidance State Laws and LitigationState Laws and Litigation Publication Requirements (ICMJE standards)Publication Requirements (ICMJE standards) Industry Codes (PhRMA)Industry Codes (PhRMA) Voluntary Accreditation Standards for IRBsVoluntary Accreditation Standards for IRBs

Data/Tissue Collector



Repository Storage

&

Data Manageme

nt

Recipient Investigator



Informed Consent and IRB Review: Informed Consent and IRB Review:

OHRP GuidanceOHRP Guidance

IRB Review

Informed Consent

Submittal Agreement

Assurance of Compliance

IRB Review

Sample Informed Consent

Certificate of Confidentiality

Assurance of Compliance

IRB Review

Informed Consent/Waiver

Recipient Agreement

Local Policies

IRB Considerations of Repository IRB Considerations of Repository ProtocolsProtocols

Key Questions:Key Questions:Is it appropriate for the HIC to approve a consent formIs it appropriate for the HIC to approve a consent formfor a study [repository] that is vague or broad withfor a study [repository] that is vague or broad withrespect to possible future uses by researchers?respect to possible future uses by researchers?

The HIC may not have enough information to adequately The HIC may not have enough information to adequately assess risks to subjects, or that information may not be assess risks to subjects, or that information may not be adequately conveyed in the ICF.adequately conveyed in the ICF.

The HIC The HIC couldcould approve a collection protocol that approve a collection protocol that contemplates unspecified future uses by institution’s contemplates unspecified future uses by institution’s investigators (if subject is so informed), but new HIC review investigators (if subject is so informed), but new HIC review (and consent or waiver) would be required before initiating (and consent or waiver) would be required before initiating any such future research.any such future research.

IRB Considerations of Repository IRB Considerations of Repository ProtocolsProtocols (cont.) (cont.)

Who will have access to the information for Who will have access to the information for future research purposes? Is it possible to future research purposes? Is it possible to even predict this?even predict this?

What identifiers will remain associated with What identifiers will remain associated with the data/materials? What coding will be the data/materials? What coding will be done?done?

Considerations for Future UsesConsiderations for Future Uses

Is the proposed use of the data or identified Is the proposed use of the data or identified biologic material consistent with the subject’s biologic material consistent with the subject’s likely understanding of how it would be used likely understanding of how it would be used under the terms of the consent form?under the terms of the consent form?

Is collection consent sufficient?Is collection consent sufficient?

Can consent be waived, or must it be Can consent be waived, or must it be obtained? obtained?

Research Regulations:Research Regulations: Informed Consent and HIC ReviewInformed Consent and HIC Review OPRR (OHRP) guidance for IRB review of OPRR (OHRP) guidance for IRB review of

consent for a collection study:consent for a collection study: Informed consent should include a clear description of:Informed consent should include a clear description of:

the operation of the repository;the operation of the repository; the specific types of research to be conducted; the specific types of research to be conducted; the conditions under which data and specimens will be the conditions under which data and specimens will be

released to recipient-investigators; andreleased to recipient-investigators; and procedures for protecting the privacy of subjects and procedures for protecting the privacy of subjects and

maintaining the confidentiality of datamaintaining the confidentiality of data Informed consent information describing the nature and purposes of the Informed consent information describing the nature and purposes of the

research should be as specific as possible.research should be as specific as possible. Where human genetic research is anticipated, informed consent Where human genetic research is anticipated, informed consent

information should include information about the consequences of DNA information should include information about the consequences of DNA typing (e.g., regarding possible paternity determinations)typing (e.g., regarding possible paternity determinations)

Repository Protocol Repository Protocol AttributesAttributes

University-wide vs. Departmental RepositoriesUniversity-wide vs. Departmental Repositories DurationDuration The IRB should review and approve a protocol that The IRB should review and approve a protocol that

describes the nature and purposes of the research as describes the nature and purposes of the research as “specifically” as possible:“specifically” as possible:

The purpose of this study is to create a Yale The purpose of this study is to create a Yale School of Medicine Neuro-Oncology data School of Medicine Neuro-Oncology data bank that will be used for future research bank that will be used for future research projects involving the study of brain cancer projects involving the study of brain cancer biology and brain biology and related biology and brain biology and related medical issues.medical issues.

Protocol Attributes: Banking DataProtocol Attributes: Banking Data Conditions under which data will be acceptedConditions under which data will be accepted The data bank will be created from adult patients The data bank will be created from adult patients

(age (age >>18) who are receiving on-going care for 18) who are receiving on-going care for brain tumors in the Departments of Neurosurgery, brain tumors in the Departments of Neurosurgery, Radiation Oncology and Section of Medical Radiation Oncology and Section of Medical Oncology. Oncology.

Subject info that will be entered into the database Subject info that will be entered into the database and may be used for future research purposes: and may be used for future research purposes: Name, age, medical record numbers, surgery Name, age, medical record numbers, surgery date, clinical test results (such as MRI, lab tests date, clinical test results (such as MRI, lab tests and neuropsychological results), the duration of and neuropsychological results), the duration of symptoms, risk factors for tumors and other symptoms, risk factors for tumors and other diseases, past medical history and other pertinent diseases, past medical history and other pertinent medical information.medical information.

Protocol Attributes: Banking Protocol Attributes: Banking

DataData The Protocol should state the conditions under The Protocol should state the conditions under which data will be sharedwhich data will be sharedData collected by the PI or other researchers listed onData collected by the PI or other researchers listed onthis protocol will be distributed for secondary researchthis protocol will be distributed for secondary researchpurposes only after the recipient investigator haspurposes only after the recipient investigator hasobtained IRB approval for the proposed research obtained IRB approval for the proposed research objective or after having received an IRB exemption orobjective or after having received an IRB exemption ora determination that research is not considered human a determination that research is not considered human subject research.subject research.

Data will be distributed for research projects of the Data will be distributed for research projects of the same nature and purpose specified in this protocol and same nature and purpose specified in this protocol and by the donor-subject in his/her ICF and HIPAAby the donor-subject in his/her ICF and HIPAAauthorization documents.authorization documents.

Protocol Attributes: Banking Protocol Attributes: Banking DataData The Principal Investigator is responsible for The Principal Investigator is responsible for

receiving appropriate attestation by recipient receiving appropriate attestation by recipient investigators prior to permitting access to the investigators prior to permitting access to the database for activities considered preparatory to database for activities considered preparatory to research. Attestation will be obtained by using theresearch. Attestation will be obtained by using the Request for Access to Protected Health Information Request for Access to Protected Health Information for a Research Purposefor a Research Purpose Form. Form. http://info.med.yale.edu/hic/hipaa/index.htmlhttp://info.med.yale.edu/hic/hipaa/index.html

Data released to collaborators for IRB approved Data released to collaborators for IRB approved research will be assigned a unique code, unless research will be assigned a unique code, unless permission is granted by the HIC to include specific permission is granted by the HIC to include specific identifiers. identifiers.

1996 OPRR Guidance “strongly recommends” that 1996 OPRR Guidance “strongly recommends” that collector-investigators not provide recipient-collector-investigators not provide recipient-investigators with access to the identities of donor-investigators with access to the identities of donor-subjects.subjects.

Research OversightResearch OversightFederal regulations require HIC review and approval of allFederal regulations require HIC review and approval of allresearch studies involving human subjects, unlessresearch studies involving human subjects, unless1.1. Research is determined to be Research is determined to be exemptexempt: involves the : involves the

collection or study of existing data, records, collection or study of existing data, records, pathological specimens, or diagnostic specimens, if pathological specimens, or diagnostic specimens, if sources are publicly available or if the information is sources are publicly available or if the information is recorded by the investigator so that subjects recorded by the investigator so that subjects cannot be cannot be identifiedidentified, either directly or through identifiers linked to , either directly or through identifiers linked to the subjects, orthe subjects, or

2.2. Research is determined to be Research is determined to be Not Human SubjectsNot Human Subjects Research or Research or not subject to IRB reviewnot subject to IRB review; ;

Use of coded private information or specimens, orUse of coded private information or specimens, or De-identified data/biologic samples.De-identified data/biologic samples.

Research OversightResearch Oversight

Federal regulations and Yale University Federal regulations and Yale University policy require that someone policy require that someone OTHER OTHER THAN THE PITHAN THE PI determine whether a determine whether a research project is exempt, considered not research project is exempt, considered not to be human subject research OR does to be human subject research OR does not require IRB oversight.not require IRB oversight.

Journals require a letter of IRB approval or Journals require a letter of IRB approval or oversight.oversight.

Protocol Attributes: Banking Protocol Attributes: Banking DataData

Risks to subjects are minimized, use procedures Risks to subjects are minimized, use procedures consistent with sound research design and which do consistent with sound research design and which do not unnecessarily expose subjects to risk.not unnecessarily expose subjects to risk.45 CFR 46.111(a)(1)45 CFR 46.111(a)(1) De-identificationDe-identification

““Risks to subjects are reasonable in relation to Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and anticipated benefits, if any, to subjects, and the importance of the knowledge that may the importance of the knowledge that may reasonably be expected to result.” 45 CFR reasonably be expected to result.” 45 CFR 46.111(a)(2). 46.111(a)(2).

What if the data is used for genetic testing?What if the data is used for genetic testing?


Adequate provisions to protect the privacy of Adequate provisions to protect the privacy of participants.participants.

Provisions to maintain the confidentiality of data.Provisions to maintain the confidentiality of data.

45 CFR 46.111(a)(7)45 CFR 46.111(a)(7) Information about the subject-donors will be Information about the subject-donors will be

maintained in a password-protected computer maintained in a password-protected computer and password-protected data files. Only and password-protected data files. Only researchers responsible for operating the data researchers responsible for operating the data bank, will be provided with access. bank, will be provided with access. Information resides on a server considered by Information resides on a server considered by ITS-Med to adhere to the HIPAA Security Rule.ITS-Med to adhere to the HIPAA Security Rule.

Should IRB should inquire about security?Should IRB should inquire about security?


Conditions whereby the subject can withdraw their participation:

Donor-subjects may withdraw their consent for the use of any data at any time. In this event, the Principal Investigator will indicate in the data base that consent from the donor-subject is no longer active and that data can no longer be used.

“Anonymize” vs. Destroy the data?


DSMP and provisions for reporting serious DSMP and provisions for reporting serious and unanticipated and related adverse and unanticipated and related adverse events. Examples; loss of lap top, break-events. Examples; loss of lap top, break-ins to data and servers.ins to data and servers. In the unlikely event of a serious adverse In the unlikely event of a serious adverse

event or breach in confidentiality, the event event or breach in confidentiality, the event will be reported to the HIC within 48 hours of will be reported to the HIC within 48 hours of it becoming known to the PI.it becoming known to the PI.

The PI will periodically review the collection, The PI will periodically review the collection, storage and distribution practices associated storage and distribution practices associated with this data bank and determine whether with this data bank and determine whether changes to enhance confidentiality and changes to enhance confidentiality and privacy are required. privacy are required.

Specific concern is the collection of data/biologicSpecific concern is the collection of data/biologicsamples and the secondary uses of thesamples and the secondary uses of theinformation/materials by:information/materials by:

1.1. Colleagues at the same or other Colleagues at the same or other institutions/hospitals, that collect the data/tissues institutions/hospitals, that collect the data/tissues through clinical interventions.through clinical interventions.

2.2. Researchers who collect the Researchers who collect the data/tissues as part of a primary data/tissues as part of a primary study and who wish to conduct, or study and who wish to conduct, or wish to share the info with colleagues wish to share the info with colleagues who wish to conduct, secondary who wish to conduct, secondary research… eventually. research… eventually.

3.3. Commercial or other research sponsors to which Commercial or other research sponsors to which data/tissues have been given during the course of data/tissues have been given during the course of primary research.primary research.

IRB ConsiderationsIRB Considerations What constitutes a new or different study as What constitutes a new or different study as

opposed to “future” uses that are really part of opposed to “future” uses that are really part of the primary research study?the primary research study?

Therapeutic trial with a banking component.Therapeutic trial with a banking component.

Is it appropriate for an IRB to approve a consent Is it appropriate for an IRB to approve a consent form for a study that is vague or broad with form for a study that is vague or broad with respect to possible future uses? respect to possible future uses?

____I hereby grant permission for…to be used for I hereby grant permission for…to be used for future trials related to lung cancerfuture trials related to lung cancer

____I hereby grant permission for…to be used for I hereby grant permission for…to be used for future trials related to cancer and other future trials related to cancer and other diseases.diseases.

____I hereby grant permission for…to be used for I hereby grant permission for…to be used for any future research purposeany future research purpose. .

IRB ConsiderationsIRB Considerations

Will multiple “primary” studies Will multiple “primary” studies support the repository? support the repository? One consent or two?One consent or two? Opt out or not?Opt out or not? Protocols (Consents documents) from Protocols (Consents documents) from

primary studies must be reapproved primary studies must be reapproved annually to permit the data to be stored annually to permit the data to be stored and used for future research projects.and used for future research projects.

HIPAA RAF limited to single purposeHIPAA RAF limited to single purpose..

Specific concern is the collection of data/biologicSpecific concern is the collection of data/biologic

samples and the secondary uses of thesamples and the secondary uses of the

information/materials by:information/materials by:1.1. Colleagues at the same or other Colleagues at the same or other

institutions/hospitals that collect the data/tissues institutions/hospitals that collect the data/tissues through clinical interventions.through clinical interventions.

2.2. Researchers who collect the data/tissues as part Researchers who collect the data/tissues as part of a primary study and who wish to conduct, or of a primary study and who wish to conduct, or wish to share the info with colleagues who wish to wish to share the info with colleagues who wish to conduct, secondary research… eventually. conduct, secondary research… eventually.

3.3. Commercial or other research Commercial or other research sponsors to which data/tissues have sponsors to which data/tissues have been given during the course of been given during the course of primary research.primary research.

IRB ConsiderationsIRB Considerations

Is it appropriate for the HIC to approve a Is it appropriate for the HIC to approve a consent form for a study that is vague or consent form for a study that is vague or broad with respect to possible future uses broad with respect to possible future uses by a sponsor? by a sponsor? G&C and HIC policies: de-identified use of G&C and HIC policies: de-identified use of

tissue/data for study on same drug or tissue/data for study on same drug or disease.disease.

Can researchers seek on behalf of Can researchers seek on behalf of sponsorssponsors a consent broader than the a consent broader than the consent that researchers could legally consent that researchers could legally seek for themselves?seek for themselves?

Commercialization of Commercialization of Data/MaterialsData/Materials: Who Has : Who Has Ownership and Control?Ownership and Control?

1996 OPRR (OHRP) Guidance1996 OPRR (OHRP) Guidance Unacceptable (Exculpatory) Language Unacceptable (Exculpatory) Language

By agreeing to this use, you should understand that you will By agreeing to this use, you should understand that you will give up all claim to personal benefit from commercial or other give up all claim to personal benefit from commercial or other use of these substances.use of these substances.

I voluntarily and freely donate any and all blood, urine, and I voluntarily and freely donate any and all blood, urine, and tissue samples to the U.S. Government and hereby relinquish tissue samples to the U.S. Government and hereby relinquish all right, title, and interest to said items.all right, title, and interest to said items.

By consent to participate in this research, I give up any By consent to participate in this research, I give up any property rights I may have in bodily fluids or tissue samples property rights I may have in bodily fluids or tissue samples obtained in the course of the research.obtained in the course of the research.

Acceptable LanguageAcceptable Language Tissue obtained from you in this research may be used to Tissue obtained from you in this research may be used to

establish a cell line that could be patented and licensed. There establish a cell line that could be patented and licensed. There are no plans to provide financial compensation to you should are no plans to provide financial compensation to you should this occur.this occur.

By consenting to participate, you authorize the use of your By consenting to participate, you authorize the use of your bodily fluids and tissue samples for the research described bodily fluids and tissue samples for the research described above.above.

OwnershipOwnership

Washington University v. William Washington University v. William CatalonaCatalona Tissue is property of Washington Tissue is property of Washington

University.University. Subject forfeits ownership upon Subject forfeits ownership upon

donation [signing informed consent].donation [signing informed consent]. Voluntary withdrawal from the research Voluntary withdrawal from the research

[repository] does not equate to [repository] does not equate to directing use or transferring ownership.directing use or transferring ownership.

On The HorizonOn The Horizon

April 16, 2006 NYT Magazine Article: April 16, 2006 NYT Magazine Article: Taking the Taking the Least of YouLeast of You (by Rebecca Skloot) (by Rebecca Skloot)

Proprietary rights belong to subject if cells are Proprietary rights belong to subject if cells are still within the subject.still within the subject.

““Anonymization” and use of tissue and data Anonymization” and use of tissue and data violates the intent of the Belmont Report.violates the intent of the Belmont Report.

Bio-ethicists may be more conservative on the Bio-ethicists may be more conservative on the issue than the general public.issue than the general public.

Sharing results back with subjects.Sharing results back with subjects.

ConclusionConclusion

Collect information under a protocol Collect information under a protocol approved by the HIC and via subject approved by the HIC and via subject consent.consent.

Think broadly.Think broadly. Keep abreast of changing guidelines and Keep abreast of changing guidelines and

policies.policies.

developing a repository protocol kathleen t. uscinski. mba, cip april 25, 2006

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