OHRP Doing it right … together! OFFICE FOR HUMAN RESEARCH PROTECTIONS, DHHS

1. OHRP Doing it right … together! OFFICE FOR HUMAN RESEARCH PROTECTIONS, DHHS (http://ohrp.osophs.dhhs.gov/) SBIR/STTR: HUMAN SUBJECT REQUIREMENTS (http://ohrp.osophs.dhhs.gov/educmat.htm) Clifford C. Scharke, D.M.D., M.P.H. Last Revised May 20, 2002

2. Introduction and Overview • Why - Concepts • When - Applicability • What - Process • How - Resources • Who - Human Assistance • Wow - Things That Can Go Wrong

3. Concepts • Volunteers - Human Subjects • Permission - Informed Consent • Oversight - Institutional Review Boards • Documentation - Assurance and Records • Self-Interest - What’s it to you?

4. Volunteers - Human Subjects • Other people and their private information don’t belong to the PI • The sheer value of the research does not automatically trump rights of people • Ask before you take unless IRB approves • Definition of a human subject

5. Definition of a Human Subject Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains: data through intervention or interaction with the individual, or identifiable private information

6. Permission - Informed Consent • From the Nuremberg Code on, the right to say “no” is the first right of a subject • Permission of a duly informed volunteer is required unless the IRB says otherwise • Volunteers who are not of legal age for the intended procedure must also grant permission (if they’re able to do so) • Definitions of consent and assent

7. Definitions of Consent and Assent • Consent - legally effective agreement of the subject or the subject's legally authorized representative based on information that is given to the subject or the representative in language that is understandable • Assent - child’s affirmative agreement to participate in research • Permission - agreement of parent(s) or guardian to the participation of their child or ward in research

8. Oversight - Institutional Review Boards • An objective review panel under 45 CFR 46 (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102) • Competent for review of science & ethics • Adequate in number and composition • Voting members are free of conflict • Suitably composed for involved human subjects • Sufficient knowledge of local context (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htm)

9. Documentation - Assurance and Records • Prior written promise to meet minimum Federal standards to protect subjects • IRB minutes in required detail • Ongoing IRB certification and enduring records of all required reportable events • If it isn’t documented, it didn’t happen • Definitions of Assurance and Records

10. Documentation - Assurance and Records • Assurance - a legally binding written document that commits a public or private entity to compliance with applicable Federal minimum standards for the protection of human subjects prior to engagement in Department or Agency conducted or supported research (i.e., prior binding promise to follow applicable rules) and includes citation of ethical principles, designated IRB, list of IRB members, IRB procedures, and institutional and investigator responsibilities

11. Documentation - Assurance and Records • Records - An institution, or when appropriate an IRB, shall prepare and maintain: • Copies of all research proposals reviewed, any scientific evaluations, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects • Minutes of IRB meetings which shall be in sufficient detail to show attendance; actions taken; the vote on these actions; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controverted issues and their resolution

12. Documentation - Assurance and Records • Records - An institution, or when appropriate an IRB, shall prepare and maintain: • Records of continuing review activities • Copies of all correspondence between the IRB and the investigators • A list of IRB members in the same detail as described in §46.103(b)(3) • Written procedures for the IRB in the same detail as described in §46.103(b)(4) and §46.103(b)(5).

13. Self-Interest - What’s it to you? • Defensible research must be ethical research • Rules that protect subjects protect the PI • PI integrity is measured by compliance • The reputation of the PI’s institution is at stake • Future funding can be jeopardized • Funding authority credibility can be questioned • As goes the public’s trust, so goes research

14. Applicability • Research - a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge (regardlesss of what it might be called) (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102) • 45 CFR 46 applies if Human Subjects + DHHS Research - Exemptions (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htm) • Awardees of DHHS-supported human subject research and all entities that interact with, intervene upon, or have potential access to private identifiable information of living persons are engaged and are required to possess an applicable Assurance prior to human subjects (http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm)

15. Process • Preparation - it’s never too early to consult with the population, institutions, and IRB Chair(s) when planning the research design • Pre-application - Assurance and IRB approvals are not required (needed prior to any award) • PHS 398 Application – complete instructions (http://grants.nih.gov/grants/funding/phs398/phs398.html)

16. Process • SBIR/STTR Application Instructions - don’t miss: • I.C.1 Face Page - Item 4 - Human Subjects • No Human Subjects • Human Subjects Involved • Exemptions from Regulations • Human Subject Assurance Number • NIH-Defined Phase III Clinical Trial* • I.C.1 Face Page - Item 15 - Organization Certification • Human Subjects • Transplantation of Human Fetal Tissue • NIH Women and Minority Inclusion Policy* • NIH Inclusion of Children Policy* • Use of Embryonic Stem Cells • I.C.8 Research Plan – 8.e - Human Subjects Research Note: These are policies to which questions are best addressed to NIH

17. Process • SBIR/STTR Application Highlights - don’t miss: • I.C.1. Item 4 - Face Page – enter “yes” or “no” for human subjects and exemptions; if yes for both, then enter E1-6 (http://grants1.nih.gov/grants/funding/phs398/section_1.html#e_humansubs) -see footnote to 46.101(b) for limitations to exemptions • I.C.1. Item 4 - Face Page - do not enter Assurance number for the institution with the designated IRB (enter “None”); if applicant possesses a Multiple Project Assurance (MPA) or Federalwide Assurance (FWA), then enter number - check OHRP Website if not sure (select link to MPA or FWA from http://ohrp.osophs.dhhs.gov/irbasur.htm)

18. Process • SBIR/STTR Application entries - don’t miss: • Research Plan/Item 8e – Human Subjects Research* Follow PHS 398 instructions carefully to avoid your application from being designated incomplete: • Human Subject/Exemption/Clinical/Clinical Trial Status • Exemption Categories – 1 through 6 (select as applicable) • Risks/Protections/Benefits/Importance • Certificates of Confidentiality (http://grants.nih.gov/grants/policy/coc/index.htm and http://ohrp.osophs.dhhs.gov/humansubjects/guidance/cert-con.htm) • Collaborating Sites • Engagement of sites in human subject research (http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm) *Note: Scenarios are given in the instructions to assist.

19. Process • Assurance to Comply with 45 CFR 46 Before Award • Applicant will be notified by NIH in writing of award • Award conditioned on Assurances to OHRP from: • Awardee • All sites engaged in human subject research • Funding authority identifies the need for and seeks Assurances through the awardee for all engaged sites • Each site without a Federal-wide Assurance files an FWA, designates a registered IRB; sends to OHRP (see instructions at http://ohrp.osophs.dhhs.gov/irbasur.htm) • OHRP advice required for options other than FWA • Awardee/PI may but need not contact OHRP

20. Specific Resources • OHRP Web-based FWA Filing and IRB Registration; review in detail and act when timely (http://ohrp.osophs.dhhs.gov/irbasur.htm) • Options to finding an IRB to designate: • Establish your own (potential conflicts) • Rely on suitable IRB of a collaborating site • Locate willing MPA institution near subjects (http://ohrp.cit.nih.gov/search/asearch.asp) • Identify suitable independent IRB (see next slide) • Designated IRB must perform “local” review (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htm)

21. General Resources • OHRP Website (http://ohrp.osophs.dhhs.gov/index.htm) - seek, find, and fill needs • Belmont Report (ethical principles) • IRB Guidebook and Investigator 101 CD • Training Videotapes and Workshops • Common Findings in Noncompliance • Links to Other Websites • Independent Institutional Review Boards (for a listing see http://www.advamed.org/solutions/reviewboards.shtml) - Note: URL not endorsed by OHRP - provided solely as a courtesy; not all listed IRBs necessarily conform to OHRP “local” IRB and conflict-free requirements (see previous slide)

22. Human Assistance • IRB Chair • Pre-protocol planning to enhance and prevent problems • Arrange for investigator training to preserve integrity • Advice on exemptions and expedited review • Expertise on human subject issues • Referral to other sources of expertise • OHRP Assurance Staff (http://ohrp.osophs.dhhs.gov/dpa-staff.htm#Table1) • General SBIR/STTR questions - Assurance Coordinators* • IRB Registration questions - Helen Gordon • Federalwide Assurance negotiations - Assurance Coordinators*(http://ohrp.osophs.dhhs.gov/dpa-staff.htm#Table2) *Note: Click on geographic location of awardee for correct AC

23. Things That Can Go Wrong • Doesn’t see PI and subject interests are same • Investigator waits too long for IRB input • Underestimates the value added by the IRB to the integrity of the process and reputation of all • PI’s unaware of accrual restrictions or is not informed by funding authority until it’s too late • PI falls victim to miscellaneous investigator shortcomings (e.g., special protections, protocol revisions, adverse events, and progress reports)(http://ohrp.osophs.dhhs.gov/references/findings.pdf)

24. Conclusions • Volunteers grant permission with IRB oversight that is assured in advance • Prepare early for human subject issues • Know when and from where to get help • Prepare your application with confidence • Let the system work for you; know when it isn’t & confirm with funding authority • What’s good for subjects is good for you!