Current Topics in Human Subjects Research 2012

1. Current Topics in Human Subjects Research 2012 Sandra L. Alfano, Pharm.D, CIP Research Scientist, GIM Chair, HIC II and IV December 13, 2012

2. Objectives • Understand issues leading to problems with compliance, including lapses in protocol approval, and the need for clinical trials registration at inception of a protocol • Be cognizant of issues thought of as ‘hot topics’, including return of results from laboratory work on donated tissues, and COI disclosure issues • Be aware of proposed changes to the human subjects regulations embodied in the recent ‘Advanced Notice of Proposed Rule Making (ANPRM)

3. Yale University Human Research Protection Program (HRPP) Formally implemented in September 2009. Seeks to: • Create a culture of respect for, and awareness of, the rights and welfare of human research participants while advancing scientific knowledge and facilitating the highest quality research. • Facilitate compliance of researchers as they conduct research with the federal regulations, and protection of research participants. • Develop new approaches that serve the overarching mission, such as continuing education and training, ensuring scientific integrity, tracking and monitoring research activities and assessing the overall effectiveness of the HRPP. • Assess the effectiveness and independence of the IRBs.

4. Yale University HRPP

5. Recent HRPP Initiatives Achieved accreditation December, 2010 Enhanced website, including all policies, procedures, forms and guidance: http://www.yale.edu/hrpp/ Implemented every three year training requirements Harmonized COI policy with University’s Restructured HICs into team structure

6. Recent compliance issues Lapses in IRB approval • It is a violation of federal regulation and University policy to continue to conduct research activities once IRB approval for a study has lapsed unless permission is granted by the Yale IRB to continue research interventions.  Such permission will be granted by the IRB when discontinuing the research interventions may jeopardize the health or welfare of a participant.

7. Lapses, cont’d • Under no circumstances can federal funds be expended on research and research-related activities during a lapse period. If the study is federally funded, you must immediately contact your Grant and Contract Administration (GCA) and Grants and Contract Financial Administration (GCFA) representatives for more information.

8. Clinical Trial Registries • Instituted years ago in an effort to expand public knowledge of, and access to, clinical trials • Clinicaltrials.gov is an example, run by the NIH/NLM • Currently over 135,000 studies are registered, with locations in all 50 states and 182 countries

9. Clinical Trial Registries • Registration of trial before subject enrollment • Results posting now required as well • Differing definitions used by FDA and ICMJE • FDA required language for consent documents informing participants that the trial is registered and that additional information may be obtained at clinicaltrials.gov

10. Two compliance issues with registration • Nationally, very poor compliance with posting of results according to requirements • Some Yale researchers report being denied publication because the trial had not been registered prior to subject enrollment

11. FDA definition • ‘applicable clinical trial’: Controlled interventional studies with one or more arms of drugs, or biologics if the trial is a controlled clinical investigation, other than a phase I investigation, of a drug subject to FDA regulation For devices, the trial prospectively compares a device-based intervention against a control

12. ICMJE definition • Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes • Health-related interventions include any intervention used to modify a biomedical or health-related measure including PK and AEs

13. Tissue and/or Data Banking • Evolving issues related to informed consent, privacy, and definition of future research. • Attention to when donation is required for participation versus when it may be optional.

14. Ethical Issues in Tissue and Data Banking • Respect for Persons • Informed consent • Autonomy • Withdrawal • Privacy, confidentiality • Beneficence • Mostly indirect or societal benefit • Need to Minimize risk • Justice • Ownership issues

15. Informed consent • Purpose of collection, use and any future research must be specified • Access to information • What identifiers will be released • Who will receive the information and • Under what conditions • Where human genetic research is anticipated, consent must describe consequences • Conditions whereby subjects may withdraw their participation: destruction vs anonymization

16. Privacy/Confidentiality • What identifiers are linked to samples or retained in data sets? • If genetic testing is planned, can identities really be protected? • HIPAA RAF is limited to a single purpose • Government, law enforcement use of DNA biobanks (Patriot Act, Big Brother)

17. Risks • Mainly involve breach of confidentiality • Some public health data bases cite deductive disclosure risks where releasing 5 data fields (or more) has the potential to re-identify an individual.(Add Health, PSI, ARIS/REDS) • Coded sets with coded donor sites may also lead to deductive disclosure. • Effect on access to or retention of benefits or entitlements, perceived harm of discrimination or stigmatization. (health insurance, altered family relationships, etc.)

18. Ownership issues • Courts seem to say subject forfeits ownership upon donation (signing informed consent) (Moore) • Voluntary withdrawal from the research (repository) does not equate to directing use or transferring ownership (Catalona) • Proprietary rights belong to the subject if cells are still within the subject (Slavin) • Bioethicists may be more conservative on the issue than the general public

19. Unresolved issues • Return of information to subjects? • Re-consent for future uses that were unanticipated • When is waiver for future or secondary use not permissible? • Tiered consent (how to track?) • Assent/re-consent at age of majority for minors

20. Tissue Conclusions • Evolving scenario • Consent albeit broadly written should be obtained for future research uses • Put protections in place to minimize risks • Check with HIPAA Security when storing and sharing data sets • Deal with ownership honestly

21. Disclosure of External Interests • Individuals must disclose all interests required by University policy to the COI Office. • New regulations have prompted the University to institute a branched policy and branched on-line disclosure • Mandatory training is now required, and training has been built into the on-line disclosure

22. Significant Financial Interests (SFIs) • New PHS regulations used by NIH define an SFI as income over $5K from a for-profit entity or stock ownership • Many other entities are using the PHS rules, such as AHRQ, ACS, AHA, CDC, JDRF • Travel must be disclosed and considered for PHS • NSF still defines SFI as income over $10K from a for – profit entity • If a researcher has neither PHS or NSF funding, University threshold is $10K

23. Individual profile must be: • Updated at least annually and whenever a new interest is added, e.g., consulting for industry or new ownership interests (stock). • On file with COIC BEFORE applying for NIH funding • Kept current, especially when submitting a human research protocol to the IRB where there is a related interest.

24. HIC/COIC Harmonization Efforts • IRB will review annual disclosure status of PI, co-investigator and those obtaining consent for new studies (non exempt), • IRB will also review at time of renewal and when an amendment adds new PI, Co-I or “responsible person”. • No more disclosures to IRB, but must note to PI and IRB, the names of researchers with protocol-related interests

25. IRB will not process the submission when the PI’s disclosure is expired or is pending. • When the disclosure of a co-investigator or person obtaining consent is not current or is pending, then the person will be removed from the research team and cannot take part in the study until the COI disclosure is updated. • ENSURE DISCLOSURES ON FILE with COIC PRIOR TO SUBMITTING TO THE IRB!

26. IRB assesses the interest and determines if it is a COI that must be managed • IRB needs to distinguish the risks that may compromise the protection of subjects, a scientist’s objectivity or challenge the integrity of the research. • May require a plan to manage, reduce or eliminate the interest.

27. Disclosing Interests • Is it enough to inform research participants of the investigator’s financial or potential financial interests? • Will disclosing the information to a research volunteer affect their decision to participate? • Will it make the process any safer for them? • Can financial conflicts be managed or reduced in a way that doesn’t adversely affect patient safety or influence the objectivity of the research conclusions?

28. Physician Payments Sunshine Act • Applicable manufacturers of drugs, devices, biologicals or medical supplies must report annually to the secretary of health and human services certain payments or transfers of value to physicians or teaching hospitals. Government would then publish the reported data on a public website

29. IOM Initiative • Creation of a harmonized conflict of interest disclosure system that will be web-based to allow a single, flexible mechanism allowing physicians and researchers to disclose, and institutions and relevant entities to request, specific information • Business plan being developed, with deployment expected late 2013 or early 2014 JAMA 2012; 308:2093-4

30. Advance Notice of Proposed Rule Making (ANPRM) • First revision of human subjects protection regulations since they were written in 1981 • Advance notice published Summer of 2011 for comment • Next step in process is still awaited

31. Be careful what you wish for: It might come true!

32. Substantive changes proposed • Good news scenario: improvements on several fronts that may lead to increased efficiency (such as not requiring continuing review for studies involving minimal risk) • Bad news scenario: some proposals not thought through carefully and can have significant unplanned repercussions

33. Broad categories of proposed changes • Risk based protections: calibrate the type of review to the risk posed by the research, with resultant elimination of the need for annual review of minimal risk studies • Revamp of informed consent, including requiring consent up front for all samples • Mandate use of a single IRB for multisite studies

34. Single IRB for multisite studies • Great example of inadequate conceptualization of entire issue • No universal model proposed/adapted • Resultant myriad of models which all differ significantly and require new systems to be put in place • Researchers will need to understand and comply with multiple systems • Yale currently deals with 5 different models

35. Strengthening data protection • Streamlining adverse event reporting and cataloging via a website • Extension of Federal Regulations to all human subjects research regardless of funding source • Harmonization of guidance from myriad federal agencies

36. Conflicts of interest, and tissue banking, are evolving topics Lapses and clinical trials registration present challenges for compliance Evolving landscape in human subjects protections Conclusions