1. Biobanking Research: Opportunities and Challenges Jody Harland, MS, CIP Lead Regulatory Advisor, Indiana CTSI Regulatory Knowledge and Support (RKS) Program IUSM Department of Pediatrics

2. Biobanks Objective: To consider a topic which presents challenges to researchers, IRBs, and the public – Biospecimen Banking – What it is and how it works – Special issues – Issues of informed consent – Attitudes of participants – Resources

3. Biobanks defined

4. Biobanks  Collections include:  Large generic tissue banks, repositories  Materials collected in longitudinal studies (e.g., Framingham)  Unique collections (e.g., brain, Alzheimer)  Pathology specimens collected for clinical use  Newborn screening tests  Forensic DNA banks  Materials include:  Biopsy tissue  Blood (and its parts)  Tumor material  Umbilical cord blood  DNA  Guthrie cards  Urine

5. Biobanks are key resource  Can be directed at specific medical conditions OR as general collections  Can be used to develop new therapy, diagnostic tests, and personalized therapy  One goal: contribute toward efficiencies in research.

6. Benefits of studies using human biological materials  Cancer  Studies of precancerous lesions of cervix lead to Pap smears  Infectious disease  Stored samples helped researchers sequence the SARS virus  Medical Devices  Artificial joints developed with research on stored blood, bone  Pacemakers developed with research on cardiac tissue

7. Ways to use specimens  Examples of ways in which samples may be used:  DNA: identify genes and their functions to learn the progression of a disease or to understand the response to certain treatment  Plasma : used to measure drug concentrations  Serum: used in metabolomics and proteomics studies  Urine: used to measure certain bone markers, drug clearance, etc.  What do researchers do with the sample?  Generally, aliquot and store in freezers until the time needed.

8. Biobanks: what makes them even more powerful?  Collection of samples is good.  To be better, we need to know something about the person who donated them.  Options:  Do nothing – just use the sample  Case report form – selected amount of demographic information presumably obtained at the time the sample is collected  Connect to the electronic medical record and obtain data about the individual.  Can require other safety measures, e.g., barcoding system; firewalls; prospective informed consent from subject

9. Vocabulary  Biobank = biorepository  De-identified vs. anonymized?  De-identified = no identifiers attached to samples; code is kept separate  Anonymized = after de-identification, code is destroyed.

10. Vocabulary  Collection/storage protocol is the protocol where samples/data are collected and stored.  Consent obtained from subjects for:  Future, unspecified uses  If doing this, linkage to EMR data in perpetuity (sometimes – at least )  Potential additional opportunity for subject to consent to be re- contacted in the future (not required though)  IRB approval required.

11. Vocabulary  Usage protocol is the protocol by which the samples/data will be used (e.g., the specific project).  Subject’s consent usually not needed again (e.g., ‘waived’ because already gave consent for sample/data to go into the biobank and to be used for future, unspecified research)  IRB approval required.

12. Vocabulary  Governance: how are the samples/data managed? Distributed for projects?  Structure should exist.  Committees which make determinations about usage of samples/data  Steering Committee  Scientific Review Committee  Consider issues of feasibility  Scientific merit of project  Is data there?  Is the amount of sample requested reasonable? Is there enough of the sample to distribute?  IRB will look for it to be described in the protocol.

13. Vocabulary  Certificate of Confidentiality (CoC)  Document that can be obtained from NIH which protects investigators and institutions from being compelled to release information that could be used to identify subjects with a research project.  CoC’s allow the investigator and others who have access to the research records to refuse to disclose identifying information in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level.  Examples of sensitive research activities include:  Collecting genetic information  Collecting info on psychological well-being of subjects  Collecting info on subjects’ sexual attitudes, preferences, or practices  Collecting data on substance abuse or other illegal risk behaviors

14. Vocabulary  Genetic Information Non- Discrimination Act (GINA)  Federal law which generally makes it illegal for health insurance companies, group health plans, and most employers to request the genetic information from this research and discriminate against individuals based on their genetic information.

15. Vocabulary  Genome-Wide Associations Studies (GWAS)  Purpose of GWAS is to discover genetic factors that contribute to the development, progression, or treatment options for a particular disease or trait.  Whole genome information, when combined with clinical and other phenotype data, offers the potential for increased understanding of basic biological processes affecting human health, improvement in the prediction of disease and patient care, and ultimately the realization of the promise of personalized medicine.  As a result, the NIH has established a centralized GWAS data repository to advance science for the benefit of the public.  Potential for public benefit to be achieved through sharing GWAS data is significant.  Results of such studies can be sensitive – INFORMED CONSENT IS KEY!

16. Vocabulary  Metabolomics  Scientific study of chemical processes involving metabolites, e.g., the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind."  Proteomics  Large-scale study of proteins, particularly their structures and functions. Proteins will vary with time and distinct requirements, or stresses, that a cell or organism undergoes.  Cellomics  Study of cell structure, function and generation and application of cellular products.

17. What do the regulations say?  Permits some forms of research involving specimens to be expedited and/or exempt  Still differs somewhat in requirements from those in HIPAA

18. VA-Specific Regulations  When involving VA patients in studies where specimens are collected and/or stored for future research purposes beyond the scope of the work in the original protocol/ICS or for those which are collected under a specific biobank protocol, certain regulations pertain. (VA Handbook 1200.12)  VA regulatory requirements will be based upon a variety of considerations, including:  Where/how/by whom samples are to be stored  HIPAA  Timelines for destruction of samples (e.g., outside of VA firewall? Can’t keep as long.)  For-profit (heavier restrictions) vs. Non-profit  Simple (1 or 2 PIs; VA owns it and manages) vs. Complex (multiple PIs on multiple sites; different databases/data-broker services) determinations

19. VA-Specific Regulations  Contact Marta Sears (marta.sears@va.gov) with any questions.marta.sears@va.gov  Reference VA Handbook (1200.12):  Use of Data and Data Repositories in VHA Research http://www.va.gov/vhapublications/ViewPublication.asp?pu b_ID=1851 http://www.va.gov/vhapublications/ViewPublication.asp?pu b_ID=1851

20. 5 major biobanks at IU BiobankHealthyAffectedArea Future unspecified use? Linked to medical records? NCRAD (Foroud) Yes Alzheimer'sNo CRC (Shekhar) Yes VarietyYes Pediatrics (Ragg/Schadow) Yes Neo; GI; Endo; Cardiology; Cancer Yes Komen (Storniolo/Clare) Yes BreastNo Indiana Biobank (Shekhar) Yes VarietyYes

21.  Questions at this point?

22. Special Issues Related to Biobanking Research  Issues of informed consent  Attitudes toward biobanking research

23. Special Issues Related to Biobanking Research  Issues of informed consent  Attitudes toward biobanking research

24. Belmont Principles Respect for persons Individuals should be treated as autonomous agents Persons with diminished autonomy are entitled to protection. Beneficence Human subjects should not be harmed Research should maximize possible benefits and minimize possible harms. Justice The benefits and risks of research must be distributed fairly. *The Belmont Report (1979) - National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

25. IRB SOP on Biospecimen Banking From the IUPUI/Clarian IRB SOP on “Biological Specimens in Research”, IRB review is required under 2 scenarios: – retrospective use of previously stored specimens, and – prospective studies requesting the collection, storage or use of specimens for current and/or future research. Two categories of specimens: – those obtained initially for clinical or diagnostic purposes only, and – those obtained solely for research purposes. IRB approval criteria (45 CFR 46.111) must be met for these projects (the same as any other human subjects research project) – unless the projects are reviewed as ‘exempt’. Collection Protocol Use Protocol

26. Criteria for IRB Approval (45 CFR 46.111) Risks to subjects are minimized. Risks to subjects are reasonable in relation to anticipated benefits. Selection of subjects is equitable. Informed consent will be prospectively obtained and documented (unless waived). Adequate provisions exist to monitor the data and ensure subject safety. Adequate provisions exist to protect privacy of subjects and maintain confidentiality of data. The influence of payments … is not coercive or do not present undue influence to potential subjects. If … subjects are likely to be vulnerable to coercion or undue influence, additional safeguards exist.

27. Biospecimen Banking - Issues of Consent Potential Challenges – Informed Consent – assure comprehension and voluntary participation Proposed use(s) Security and maintenance of sample Privacy and confidentiality of data attached to sample and results generated from sample analysis Obtaining results from analyses Possible future contact for additional studies? Impact of genetic studies and returning results Impact upon families, employability, insurability, etc. Potential third party access to samples – oversight

28. Issues of Consent: Henrietta Lacks 1951: 30 year-old poor, uneducated African-American woman visits Johns Hopkins and is diagnosed with cervical cancer. Required radiation treatments for next several months. During her first two-night stay at hospital, doctors removed several pieces of tissue from her tumor and placed them in a dish. Neither Lacks nor her family gave permission for her cells to be taken.

29. Issues of Consent: Henrietta Lacks Dr. George Gey (head of tissue-culture research at Hopkins) was interested in growing first ‘immortal’ human cells (a continuously dividing line of cells that all descend from one original sample). To date, he had been unsuccessful. Her cancer cells grew well and doubled in number every 24 hours. Dr. Gey named the cells “HeLa” cells after Lacks and began sending cells to scientists all over the world for research. Six months after her diagnosis, Lacks died.

30. Issues of Consent: Henrietta Lacks HeLa cells have been used to: help develop the polio vaccine (Tuskegee Institute) study cancer and viruses lead to advances like in vitro fertilization (IVF), cloning, and gene mapping HeLa cells piled onto a scale = more than 50 million metric tons (100 Empire State Buildings) HeLa cells have generated a multimillion dollar industry.

31. Issues of Consent: Henrietta Lacks Twenty years after cells were taken, family learned that they were being used. Family was living in poverty in Baltimore – could not afford health insurance and had limited education. Family struggled to understand what existence of her cells really meant. ………To date, family has not been compensated for this contribution; however, various foundations have been established to ensure access to healthcare and education, for example, for her grandchildren.

32. Issues of Consent: Henrietta Lacks Issues – gender, race, education: What if she had been presented with the opportunity to give permission? What topics should that conversation have covered?

33. Issues of Consent - Havasupai Case Havasupai Indian Tribe Case (Mello & Wolf, 2010; Harmon 2010) Havasupai Indians live at bottom of Grand Canyon. Beginning in the 1960’s, high incidence of diabetes leads to amputations – tribe members can’t hike out of the canyon – forced to leave to obtain dialysis. Late 1989, tribal member approaches ASU anthropologist who had gained the tribe’s trust to ask for help in preventing the spread of diabetes. Anthropologist approaches ASU geneticist for help (Pima Indians have genetic variant related to high rate of diabetes). 1990 diabetes study in which ASU researchers collected more than 200 blood samples from tribe members.

34. Issues of Consent – Havasupai Case Consent form (in simple English) described the project as studying “the causes of behavioral/medical disorders,” but pre-study communications with tribal leaders apparently focused on diabetes. Havasupai hoped that if found a cure to diabetes, their people wouldn’t have to leave the canyon. Students obtained consent (written and verbal).  Researchers used samples in multiple studies unrelated to diabetes, sharing them with other investigators. Examined several genes (schizophrenia, metabolic disorders, alcoholism and found little to pursue - also did not share the gene variant linked to diabetes similar to Pima)

35. Issues of Consent – Havasupai Case 2003 – grad student comes up with new technology to discern variations in the Havasupai DNA and wrote dissertation Carletta Tilousi stops by anthropologist’s office and he invites her to the doctoral presentation. His presentation doesn’t match what she and others thought they donated blood for. Two dozen publications based upon those blood samples. 2004 – tribe members filed a $50 million lawsuit alleging: Fraud Breach of fiduciary duty Negligence Trespass

36. Issues of Consent – Havasupai Case Tribe members objected to 3 uses: Study evaluating the genetic basis of schizophrenia Study examining inbreeding (stigmatization issues and concern related to cultural belief that inbreeding brings harm to one’s family) Evolutionary-genetics studies suggesting that, contrary to Tribe’s origin story, its ancestors migrated across the Bering Sea. Case law pretty clear – biospecimen donors do not retain property interests in samples collected and used in accordance with properly obtained informed consent. What is adequate informed consent?

38. Biospecimen Banking - Issues of Consent April 2010, ASU agrees to: Pay $700K to 41 members of the Havasupai Indian tribe to settle legal claims. Return all blood samples in its possession. Return documents like lab books, genealogy materials containing research derived from the samples. IRBs at universities in the suit cannot approve ongoing or new research involving the samples. Provide a list to the tribe of entities to which it previously transferred the samples.

39. Issues of Consent – Havasupai Case  What did individuals understand about what their blood samples were to be used for?  Community consultation?  What did the consent form say?  What was the IRB’s role?  Risks to participants – what about risks to entire communities?  Any parallels to studies at IU?

40. Special Issues Related to Biobanking Research  Issues of informed consent  Attitudes toward biobanking research

41. Informed Consent: What Do We Know? Physicians and Nurses—Pediatric Biobanking  MD and RN attitudes toward pediatric biobanks are similar  Broad support for a pediatric biobank from HCP, including support for unspecified use of samples  Denne, Wolf, Harland, Miller, Meslin et al (2008) [Unpublished] Women and Pregnant Mothers  77% felt predictive health research was worthwhile  Most supported consent for future use  Haas, Renbarger, Meslin, Drabiak, Flockhart (2008) IU Cancer Patients  ~85% agreed that stored tissue could be used in unspecified future research  60-70% would not require re-contact each time tissues were used  Helft, Champion, Eckles, Johnson, Meslin, (2007) Parental Attitudes-—Pediatric Biobanking 68% agree/strongly agree pts should have chance to be in research 81% somewhat/very likely to permit child’s blood to in biobank 91% have fair/great deal of trust in hospitals to protect confidentiality 62% oppose/strongly oppose commercialization  Harland, Miller, Meslin, Wolf, Denne (2010)

42. Biospecimen Banking - Assessing Attitudes Parental Attitudes Toward Pediatric Biobanks (Harland, Miller, Meslin, Wolf, and Denne)  Will parents/guardians have particular areas of concern about participation in a biobank? Areas of concern would relate to confidentiality and commercialization.  Because the point of contact for biobank entry will be the Hospital environment, we asked whether there would be any differences between the perspectives of parents/guardians of inpatients vs. outpatients? Parents/guardians of inpatients would be more in favor of biobanking research than parents of outpatients.

43. Biospecimen Banking - Parental Attitudes toward Participation  Methods  Survey questions developed by multi-disciplinary group.  MDs, RNs, survey research expert, hospital parent support representative, bioethicist, IRB regulatory expertise, parent.  Questions field-tested by a small group of parents/guardians.  Parents/guardians of pediatric inpatients and pediatric outpatients at Riley Hospital were offered paper-and-pencil surveys in person.  English and Spanish language versions of the survey were available.

44. Biospecimen Banking - Parental Attitudes toward Participation  General questions about child’s health  Attitudes toward medical research  Biobank questions Support for biobanking Use of samples Child’s health, age Future contact Confidentiality Commercialization

45. General Support for Medical Research “All Riley Hospital patients should have a chance to be in medical research.” 68% “strongly agree” or “agree” with this statement.

46. Support for Biobanking “In general, how likely would you be to allow your child’s blood to be included in the Riley Hospital biobank?” 81% are “very likely” or “somewhat likely” to do so.

47. Confidentiality “ If your child were to participate in a biobank study, how much do you trust Riley Hospital to maintain the confidentiality of your child's personal health information?” 91% have “a great deal” or “fair amount” of trust.

48. “Some biobanks are set up to allow the sale of samples for a profit. How much would you support or oppose such an arrangement at Riley Hospital?” 62% “strongly oppose” or “oppose” the sale of samples for a profit. Commercialization

49. Comments Received  “I want to learn more about it. Never heard about it ‘til now.”  “Extremely concerned--privacy, discrimination, misuse/abuse issues.”  “Would this child’s sample of blood be used to research cloning of any kind?”  “I believe that sometime in the future if a child was born with a genetic defect, like my child, it would help someone else to know what has happened.”  “My daughter has a rare disorder and more knowledge needs to be given to physicians.”  “Help get answers, cures, and some hope for other parents.”

50. Biospecimen Banking - Attitudes Toward Participation  Parents/guardians generally are supportive (80%) of biobanking initiatives and research activities.  Parents/guardians may not be as concerned about confidentiality issues in biobanking research. 91% expressed a ‘great deal’ or ‘fair amount’ of trust.  Parents/guardians are generally opposed (61%) or perhaps need more information (22% expressed ‘no opinion’) about commercialization issues.

51. Summary  Biobanking research promises to be extremely valuable research in an era of personalized medicine.  Very real ethical and regulatory concerns.  Ultimately, a question of how do we ensure adequate informed consent?  Do we talk with individuals, communities?  How do we describe the potential possibilities in a meaningful way?  How will case law and ethics evolve?

52. Summary  As researchers, we must be transparent in what we know to be true, what we expect to be true, and what we just don’t know.  Individuals need to trust in the “institution” (thus, we need to be trustworthy!)  Ultimately, biobanking research with adequate informed consent promises to be an immense opportunity to advance our understanding of human health.

53. Resources  Indiana Biobank (IB)  Indiana CTSI Recruitment Office  Regulatory Knowledge and Support (RKS) Program  Clinical Research Center (CRC)  Project Development Teams (PDTs) http://www.indianactsi.org/

54.  Questions? Contact info: Jody Harland, MS, CIP UH 5525 harlandj@iupui.edu