Developing A Repository Protocol

1. Developing A Repository Protocol Kathleen T. Uscinski. MBA, CIP April 25, 2006

2. Agenda • The Basics: Objective, Definitions, Key Terms • Creation of Repositories and Databanks • Regulations and Guidance • IRB Considerations • Attributes of a Repository Protocol • Ownership of Tissue and Data

3. Definitions • Research: A systematic investigation, including testing and evaluation, designed to develop or contribute to generalizable knowledge. [that may assist in improving the care of currently unknown beneficiaries in the future.] • Human Subject: a living individual about whom an investigator conducting research obtains: 1) data through intervention or interaction with the individual, or 2) identifiable private information.

4. “Collections” and Databanks • Databases are often created not for a specific research project but as resources for future research. • Tissue banks and “collections” of identifiable biologic materials containing patient material with identifiable patient data are similarly created and maintained.

5. Specific concern is the collection of data/biologic samples and the secondary uses of the information/materials by: • Colleagues at the same or other institutions/hospitals that collect the data/tissues through clinical interventions. • Researchers who collect the data/tissues as part of a primary study and who wish to conduct, or wish to share the info with colleagues who wish to conduct, secondary research… eventually. • Commercial or other research sponsors to which data/tissues have been given during the course of primary research.

6. What May Apply • Ethical Obligations • Clinical Trial Agreements • HIPAA • Common Rule (OHRP Guidance Nov 1997 and August 2004) • FDA Regulations and Guidance • State Laws and Litigation • Publication Requirements (ICMJE standards) • Industry Codes (PhRMA) • Voluntary Accreditation Standards for IRBs

7. Informed Consent and IRB Review: OHRP Guidance Recipient Investigator Recipient Investigator Recipient Investigator Data/Tissue Collector Data/Tissue Collector Data/Tissue Collector Repository Storage & Data Management IRB Review Sample Informed Consent Certificate of Confidentiality Assurance of Compliance IRB Review Informed Consent Submittal Agreement Assurance of Compliance IRB Review Informed Consent/Waiver Recipient Agreement Local Policies

8. IRB Considerations of Repository Protocols • Key Questions: Is it appropriate for the HIC to approve a consent form for a study [repository] that is vague or broad with respect to possible future uses by researchers? • The HIC may not have enough information to adequately assess risks to subjects, or that information may not be adequately conveyed in the ICF. • The HIC could approve a collection protocol that contemplates unspecified future uses by institution’s investigators (if subject is so informed), but new HIC review (and consent or waiver) would be required before initiating any such future research.

9. IRB Considerations of Repository Protocols (cont.) • Who will have access to the information for future research purposes? Is it possible to even predict this? • What identifiers will remain associated with the data/materials? What coding will be done?

10. Considerations for Future Uses • Is the proposed use of the data or identified biologic material consistent with the subject’s likely understanding of how it would be used under the terms of the consent form? • Is collection consent sufficient? • Can consent be waived, or must it be obtained?

11. Research Regulations:Informed Consent and HIC Review • OPRR (OHRP) guidance for IRB review of consent for a collection study: • Informed consent should include a clear description of: • the operation of the repository; • the specific types of research to be conducted; • the conditions under which data and specimens will be released to recipient-investigators; and • procedures for protecting the privacy of subjects and maintaining the confidentiality of data • Informed consent information describing the nature and purposes of the research should be as specific as possible. • Where human genetic research is anticipated, informed consent information should include information about the consequences of DNA typing (e.g., regarding possible paternity determinations)

12. Repository Protocol Attributes • University-wide vs. Departmental Repositories • Duration • The IRB should review and approve a protocol that describes the nature and purposes of the research as “specifically” as possible: The purpose of this study is to create a Yale School of Medicine Neuro-Oncology data bank that will be used for future research projects involving the study of brain cancer biology and brain biology and related medical issues.

13. Protocol Attributes: Banking Data • Conditions under which data will be accepted • The data bank will be created from adult patients (age >18) who are receiving on-going care for brain tumors in the Departments of Neurosurgery, Radiation Oncology and Section of Medical Oncology. • Subject info that will be entered into the database and may be used for future research purposes: Name, age, medical record numbers, surgery date, clinical test results (such as MRI, lab tests and neuropsychological results), the duration of symptoms, risk factors for tumors and other diseases, past medical history and other pertinent medical information.

14. Protocol Attributes: Banking Data • The Protocol should state the conditions under which data will be shared Data collected by the PI or other researchers listed on this protocol will be distributed for secondary research purposes only after the recipient investigator has obtained IRB approval for the proposed research objective or after having received an IRB exemption or a determination that research is not considered human subject research. Data will be distributed for research projects of the same nature and purpose specified in this protocol and by the donor-subject in his/her ICF and HIPAA authorization documents.

15. Protocol Attributes: Banking Data • The Principal Investigator is responsible for receiving appropriate attestation by recipient investigators prior to permitting access to the database for activities considered preparatory to research. Attestation will be obtained by using theRequest for Access to Protected Health Information for a Research Purpose Form. http://info.med.yale.edu/hic/hipaa/index.html • Data released to collaborators for IRB approved research will be assigned a unique code, unless permission is granted by the HIC to include specific identifiers. • 1996 OPRR Guidance “strongly recommends” that collector-investigators not provide recipient-investigators with access to the identities of donor-subjects.

16. Research Oversight Federal regulations require HIC review and approval of all research studies involving human subjects, unless • Research is determined to be exempt: involves the collection or study of existing data, records, pathological specimens, or diagnostic specimens, if sources are publicly available or if the information is recorded by the investigator so that subjects cannot be identified, either directly or through identifiers linked to the subjects, or • Research is determined to be Not Human Subjects Research or not subject to IRB review; • Use of coded private information or specimens, or • De-identified data/biologic samples.

17. Research Oversight • Federal regulations and Yale University policy require that someone OTHER THAN THE PI determine whether a research project is exempt, considered not to be human subject research OR does not require IRB oversight. • Journals require a letter of IRB approval or oversight.

18. Protocol Attributes: Banking Data • Risks to subjects are minimized, use procedures consistent with sound research design and which do not unnecessarily expose subjects to risk. 45 CFR 46.111(a)(1) • De-identification • “Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.” 45 CFR 46.111(a)(2). • What if the data is used for genetic testing?

19. Protocol Attributes: Banking Data • Adequate provisions to protect the privacy of participants. • Provisions to maintain the confidentiality of data. 45 CFR 46.111(a)(7) • Information about the subject-donors will be maintained in a password-protected computer and password-protected data files. Only researchers responsible for operating the data bank, will be provided with access. Information resides on a server considered by ITS-Med to adhere to the HIPAA Security Rule. • Should IRB should inquire about security?

20. Protocol Attributes: Banking Data • 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?

21. Protocol Attributes: Banking Data • DSMP and provisions for reporting serious and unanticipated and related adverse events. Examples; loss of lap top, break-ins to data and servers. • In the unlikely event of a serious adverse event or breach in confidentiality, the event will be reported to the HIC within 48 hours of it becoming known to the PI. • The PI will periodically review the collection, storage and distribution practices associated with this data bank and determine whether changes to enhance confidentiality and privacy are required.

22. Specific concern is the collection of data/biologic samples and the secondary uses of the information/materials by: • Colleagues at the same or other institutions/hospitals, that collect the data/tissues through clinical interventions. • Researchers who collect the data/tissues as part of a primary study and who wish to conduct, or wish to share the info with colleagues who wish to conduct, secondary research… eventually. • Commercial or other research sponsors to which data/tissues have been given during the course of primary research.

23. IRB Considerations • What constitutes a new or different study as opposed to “future” uses that are really part of the primary research study? • Therapeutic trial with a banking component. • Is it appropriate for an IRB to approve a consent form for a study that is vague or broad with respect to possible future uses? __I hereby grant permission for…to be used for future trials related to lung cancer __I hereby grant permission for…to be used for future trials related to cancer and other diseases. __I hereby grant permission for…to be used for any future research purpose.

24. IRB Considerations • Will multiple “primary” studies support the repository? • One consent or two? • Opt out or not? • Protocols (Consents documents) from primary studies must be reapproved annually to permit the data to be stored and used for future research projects. • HIPAA RAF limited to single purpose.

25. Specific concern is the collection of data/biologic samples and the secondary uses of the information/materials by: • Colleagues at the same or other institutions/hospitals that collect the data/tissues through clinical interventions. • Researchers who collect the data/tissues as part of a primary study and who wish to conduct, or wish to share the info with colleagues who wish to conduct, secondary research… eventually. • Commercial or other research sponsors to which data/tissues have been given during the course of primary research.

26. IRB Considerations • Is it appropriate for the HIC to approve a consent form for a study that is vague or broad with respect to possible future uses by a sponsor? • G&C and HIC policies: de-identified use of tissue/data for study on same drug or disease. • Can researchers seek on behalf of sponsors a consent broader than the consent that researchers could legally seek for themselves?

27. Commercialization of Data/Materials: Who Has Ownership and Control? • 1996 OPRR (OHRP) Guidance • Unacceptable (Exculpatory) Language • By agreeing to this use, you should understand that you will give up all claim to personal benefit from commercial or other use of these substances. • I voluntarily and freely donate any and all blood, urine, and tissue samples to the U.S. Government and hereby relinquish all right, title, and interest to said items. • By consent to participate in this research, I give up any property rights I may have in bodily fluids or tissue samples obtained in the course of the research. • Acceptable Language • Tissue obtained from you in this research may be used to establish a cell line that could be patented and licensed. There are no plans to provide financial compensation to you should this occur. • By consenting to participate, you authorize the use of your bodily fluids and tissue samples for the research described above.

28. Ownership • Washington University v. William Catalona • Tissue is property of Washington University. • Subject forfeits ownership upon donation [signing informed consent]. • Voluntary withdrawal from the research [repository] does not equate to directing use or transferring ownership.

29. On The Horizon April 16, 2006 NYT Magazine Article: Taking the Least of You (by Rebecca Skloot) • Proprietary rights belong to subject if cells are still within the subject. • “Anonymization” and use of tissue and data violates the intent of the Belmont Report. • Bio-ethicists may be more conservative on the issue than the general public. Sharing results back with subjects.

30. Conclusion • Collect information under a protocol approved by the HIC and via subject consent. • Think broadly. • Keep abreast of changing guidelines and policies.