1. Research Involving Human Specimens Marianna Bledsoe, M.A. 2011 VA Local Accountability for Research Meeting June 2, 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  Case studies 2

3. Human Biological Specimens  Any material derived from a human subject—such 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. 3

4. Applicable Federal Regulations May Include  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 4

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 5

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 6

7. When is Specimen Research Human Subjects Research?  Is it human subjects research (cont’d)? –For VA, research to be de-identified it must meet both the Common Rule and Privacy Rule definitions of de-identified. 7

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. 8

9. 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. 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. 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. 12 OHRP Guidance on Coded Private Information or Biological Specimens Examples of When Coded Data/Biologic Specimens Are Not Individually Identifiable to Investigators: (a) 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. 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. 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. 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. 16 Additional Informed Consent Content  Must meet requirements of human subjects regulations  In addition, should also include: –Description of the purpose of the collection –Types of research to be conducted –Description of specimens/data and process used for collecting them –Risks, including risks to privacy and confidentiality, and methods to protect risks

17. 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 (cont’d) –Conditions for sharing with other researchers –What will happen to specimens when no longer useful, when repository loses support, or is transferred to others 18

19. Secondary Use of Specimens  Research use for a purpose other than that described in the protocol  Research should be consistent or “compatible “ with the informed consent under which the specimens were collected –See discussion of the Secretary’s Advisory Committee for Human Research Protections (http://www.hhs.gov/ohrp/sachrp/) 19

20. 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 20

21. 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 21

22. 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 22

23. VA Policies  VHA Handbook 1200.05--Requirements for the Protection of Human Subjects in Research  VHA Handbook 1200.12—Use of Data and Data Repositories in VHA Research  VHA Handbook 1605.1--Privacy and Release of Information  VHA Handbook 1605.2—Minimum Necessary Standard for Protected Health Information  VA Handbook 6500--Information Security Program  VHA Handbook 1106.01—Pathology and Laboratory Medicine Service Procedures 23

24. VA Specimen Banking Guidelines  Current requirements found on ORD web site http://www.research.va.gov/programs/tissue_ banking/default.cfm http://www.research.va.gov/programs/tissue_ banking/default.cfm 24

25. 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 >3 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. 25

26. 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. 26

27. 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. 27

28. Collecting and Storing Specimens for Secondary or Future Research  Exception: Some National Cancer Institute (NCI)-sponsored tissue banks are exempt from the requirements as a result of a memorandum of understanding with the NCI. Protocols that involve collection for these banks do not require ORD approval. (See list on VA website) 28

29. 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. 29

30. 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. 30

31. Additional Requirements (cont’d)  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. 31

32. 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” 32

33. Application Process  The investigator must complete VA form 10-0436. (http://www.va.gov/vaforms/medical/pdf/vha-10-0436- fill.pdf).http://www.va.gov/vaforms/medical/pdf/vha-10-0436- fill.pdf  The following additional is required: –Research protocol –Tissue bank manual /SOPs [non-profits] –VA consent form –HIPAA authorization  The application should be e-mailed to Kristina Hill (Kristina.Hill@va.gov). It should be sent from the research office.Kristina.Hill@va.gov  Alternatively, the form and requested information can be faxed to: (202) 495-6156. 33

34. Application Process (cont’d)  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. 34

35. 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. 35

36. 36 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

37. Contact Information  Marianna Bledsoe, M.A.  Senior Program Manager for Biorepositories and Biobanking  E-mail: Marianna.Bledsoe@va.govMarianna.Bledsoe@va.gov  Phone: 202-443-5781  Fax: 202-495-6156 37

38. Acknowledgements  Marilyn Mason, PhD.  Kristina Hill, MPH 38

39. Case Examples

40. Case Example #1  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. 40

41. Case Example #1  Is this human subjects research? –Yes? –No?  Is an FWA and IRB approval required at the VA site?  What if the VA ophthalmologist were providing identifiers along with the specimens? Would a FWA or IRB approval be required at the VA site? 41

42. Case Example #2 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. (Reference FAQ #1 SACHRP, 2011) 42

43. Case Example # 2 Is consent of the patient from whom the biopsy was taken (or waiver of consent) required for the secondary research use? Yes? No? 43

44. Case Example #2 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. 44

45. Case Example # 3 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. (Reference FAQ#2 SACHRP, 2011) 45

46. Example #3 Is consent of the patient from whom the biopsy was taken (or waiver of consent) required for the secondary research use? Yes? No? 46

47. Case Example # 2 No. Under this scenario, neither consent nor waiver is required, because the activity is not considered to be research involving human subjects. 47

48. 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. (Reference FAQ #6, SACHRP 2011) Case Example #3 48

49. Case Example #3  If the sample is identifiable to the secondary user, is this considered to be human subjects research under the purview of the IRB?  Yes?  No? 49

50. Case Example #3 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. 50

51. Case Example #4 Identifiable 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. (Reference FAQ#7, SACHRP 2011) 51

52. Case Example #4 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? Yes? No? 52

53. Case Example #4  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. 53