Human Subjects Protections in NIH SBIR/STTR Applications Ann Hardy, DrPH NIH Extramural Human Research Protection Officer Office of Extramural Programs (OEP), OER SBIR Conference October 21-23, 2014

Learning Objectives After this presentation, you will: Understand the regulatory basis for human subjects protection in research Define human subjects research and apply the regulations to common research designs Distinguish exempt and non-exempt human subjects research Understand the human subjects requirements for NIH applications and awards

HHS Regulations 45 CFR part 46: Protection of Human Research Subjects Subpart A - Basic Requirements for Protection Subpart B, C, D – Additional protections for Pregnant Women/Fetuses/Neonates; Prisoners; Children Subpart E – IRB Registration Office for Human Research Protections (OHRP) is responsible for ensuring compliance

Sponsoring Agency Responsibilities 45 CFR 46 - Subpart A Applicability Key Definitions Sponsoring Agency Responsibilities Institutional Responsibilities Assurance (FWA) Institutional Review Board (IRB)

Do The Regulations Apply to My Project? Kevin L. Nellis, MS, MT(ASCP) February 8, 2008 Do The Regulations Apply to My Project? Does activity involve Research? Does research involve Human Subjects? If yes, is human subjects research Exempt? ASK QUESTIONS IN THIS ORDER! Human Subject Regulations Decision Chart: http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html 5 5

Definition of Research Research – a systematic investigation designed to develop or contribute to generalizable knowledge includes research development, testing, evaluation, pilot studies

Definition of Human Subject … a living individual about whom an investigator (professional or student) conducting research obtains Data through intervention or interaction with the individual Identifiable private information OR 7

Definition Deconstructed a living individual Regulations do NOT apply to research involving materials from deceased individuals 8

Definition Deconstructed about whom an investigator conducting research obtains Data through intervention or interaction Examples: Collect biological samples (blood) Administer a questionnaire Conduct MRI Manipulating environment and noting response OR Collected for THIS Research 9

Definition Deconstructed Identifiable Private Information Identity of subjects can be readily ascertained by ANY of the investigators Name or Unique # linked to name Who is an investigator? Anyone involved in conduct of the research (study, analysis, interpretation of research data, co- authorship). Does NOT include providing info or samples. OHRP guidance on coded info and specimens Collected for OTHER purpose

Definition Examples PI will use materials from a brain bank; donors consented prior to death for materials to be used for research Not human subjects research because the federal regulations only apply to living persons PI will purchase tissue from commercial vendor Not human subjects research because not collected for research and no identifiers

Definition Examples At time of clinical blood draw, an extra tube of blood is collected for research Yes, because this tube is being collected specifically for research. This is different from using left-over blood that was collected for clinical reasons.

Is the Human Subjects Research Exempt? Non-Exempt 6 categories of human subjects research activities that are so low risk, they are EXEMPT from the regulations All other human subjects research is classified as NON- EXEMPT HUMAN SUBJECTS RESEARCH About 13% of SBIR/STTR awards that involve human subjects are exempt

Categories of Exempt Human Subjects Research (1) Research in educational settings on educational practices (2) Educational Tests, Surveys, Interviews… (not if ID and info disclosure put subject at risk; parts not applicable to research w/ children) (3) Tests, Surveys, Interviews with public officials, or if federal law requires confidentiality (4) Collection/Study of existing data, specimens if recorded by investigator in way subjects cannot be identified (5) Research approved/conducted by Federal Agencies on public benefit programs (6) Evaluation of taste or food quality

Exemption 1 Research conducted in educational settings on educational practices such as instructional strategies, techniques, curricula …. Examples: Study to determine effectiveness of on-line training as supplement to regular instructional approach for teaching anatomy to medical students. Study to determine effectiveness of planned activities to increase the public’s awareness of oral health to be delivered at a community science museum.

Exemption 2 Research involving use of educational tests, surveys, interviews or observation of public behavior unless ID AND disclosure could harm Examples: Focus group to discuss general barriers to use of community health centers Some parts not applicable to research with children

Exemption 4 Research involving the study of existing data, documents, records, specimens if publicly available OR info recorded by the investigator in manner that subjects cannot be identified directly or indirectly

Research Involving Coded Data/Specimens OHRP Policy Guidance 2008: http://www.hhs.gov/ohrp/policy/cdebiol.html Research involving only use of coded data/spec from living individuals is NOT human subjects research IF Info/spec not collected for proposed research AND Investigator(s) cannot readily ascertain identity of subjects Provider will not to share ID w/ investigator Written policies prohibiting release of ID (repositories) Clarified that most research with existing data/specimens Not HS research (no one has ID’s) OR Non-exempt (investigator has ID’s) 18

Tricky Issues in Applying Guidance Who is an “investigator” Anyone involved in any aspect of the research Only providing data/spec is not “involvement” Assisting w/ data analysis or interpretation, authorship is involvement PI involved in primary collection or associated w/ repository NO circumstances where investigators could identify “Excess” clinical samples When is E4 applicable?

Exemption 4 Research involving the study of existing data, documents, records, specimens if publicly available OR info recorded by the investigator in manner that subjects cannot be identified directly or indirectly

When is E4 Applicable? For E4 Examples Investigator initially obtains identifiable info/specimens AND “Records the data in such a manner that subjects cannot be identified” – break link Examples PI accesses identifiable data but extracts research data w/o identifiers that can no longer be linked back. PI goes through set of existing excess clinical samples to identify those of interest. She removes label with identifiers and marks tubes with random number and basic non-identifiable clinical info.

Expert Advice and Product Testing Using expert consultants to improve research design or advise on research process – NOT research Persons to test a new product to identify flaws – NOT human subjects research Pilot test of new product May be human subjects research if collecting data about individuals and/or identifiable private info

Examples Computer design experts will review your software product to identify flaws and overall usability (colors, font, readability, navigation) Probably not research Conduct a small pilot study of your survey system with end users. It Depends You ask patients to wear your new prosthetic device and provide feedback Is HS research

Is it Human Subjects Research? Ask Questions in THIS ORDER 1/Does it meet the definition of human subjects research? Data through intervention or interaction OR Identifiable private information For secondary use of specimens/data Who are investigators; is provider an investigator? Who has access to identifiers or can link? If No, NOT Human subjects research (STOP) 2/If Yes, do any of the Exemptions apply? Yes: Exemption # No: Non-exempt human subjects research Living Subjects

Sponsoring Agency Responsibilities Regulations require Agencies to evaluate applications and proposals involving human subjects: Risks subjects Adequacy of protections Benefits Importance of knowledge to be gained The Department or Agency head will evaluate all applications and proposals involving human subjects submitted to the Department or Agency through such officers and employees of the Department or Agency and such experts and consultants as the Department or Agency head determines to be appropriate. This evaluation will take into consideration the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. (b) On the basis of this evaluation, the Department or Agency head may approve or disapprove the application or proposal, or enter into negotiations to develop an approvable one. Federal funds administered by a Department or Agency may not be expended for research involving human subjects unless the requirements of this policy have been satisfied. NIH evaluates through peer review No funds expended unless regulatory requirements are met; can withdraw funding for non-compliance 25 25

Human Subjects Section of Grant Application Risks to Human Subjects Human subjects involvement and characteristics Demographic and health characteristics Inclusion and exclusion criteria Rational for involvement of vulnerable populations Sources of materials What materials (specimens, records, data) How will materials be collected Who has access to information Potential Risks Physical, psychological, financial, legal or other risks Alternative treatments/procedures

Human Subjects Section (con’t) Adequacy of Protection Against Risks Recruitment Informed consent Children – assent; parental permission How consent will be obtained; info provided Protections against risk Procedures to minimize risk; protect privacy and confidentiality Additional protections for vulnerable populations Ensure necessary medical/professional intervention Data and safety monitoring 27

Human Subjects Section (con’t) Potential Benefits of Research to Human Subjects and Others May not be direct benefit to subjects Compensation is not a benefit Discuss risks in relation to anticipated benefits Importance of Knowledge to be Gained Discuss in relation to risks 28

Preparing the Human Subjects Section All proposed research will fall into one of six scenarios: A. No Human Subjects B. Non-Exempt Human Subjects Research C. Exempt Human Subjects Research D. Delayed-Onset of Human Subjects Research E. Clinical Trial F. NIH-defined Phase III Clinical Trial

Scenario A: No Human Subjects  Are Human Subjects Involved? ___ Yes ____ No Provide clear justification if using human specimens or data Only post-mortem samples will be used Samples will be purchased from a commercial vendor and will be provided without identifiers 30

Scenario B: Non-Exempt Research  Are Human Subjects Involved? ___ Yes ___ No Research Exempt? ___ Yes ___ No Clinical Trial? ___ Yes ___ No NIH-Defined Phase III CT? ___ Yes ___ No Human Subjects Section- no page limitations Address 4 required points (risk, protections, benefits, knowledge) Inclusion of Women and Minorities Planned Enrollment Tables Inclusion of Children    31

Scenario C: Exempt Research  Are Human Subjects Involved? ___ Yes ___ No Research Exempt ___ Yes ____No Exemption Number (mark all) __1 __2 __3 __4 __5 __6 Clinical Trial? ___ Yes ___ No NIH-Defined Phase III CT? ___ Yes ___ No Human Subjects Section Justify selection of exemption(s) Sources of research materials Inclusion of Women and Minorities* Targeted/Planned Enrollment Tables* Inclusion of Children* * Not required for Exemption 4    32

Scenario D: Delayed Onset HS Research  Are Human Subjects Involved? ____ Yes ___No Research Exempt? ____ Yes ___No Clinical Trial? ____ Yes ___No NIH-Defined Phase III CT ? ____ Yes ___No Delayed Onset: Human subjects research anticipated but Specific plans cannot be described (45 CFR 46.118) Human Subjects Section – explain why delayed onset If funded, you will have submit human subjects section, FWA and IRB approval before involving human subjects Mark as applicable 33

Scenarios E & F: Clinical Trial Clinical Trial: Prospective research study designed to answer questions about biomedical or behavioral interventions NIH Defined Phase III Trial: broad-based, prospective trial, often to provide scientific basis for change in health policy or standard of care (Scenario F) All other Phases (Scenario E) 34

Scenario E: Clinical Trial (not Phase III)  Are Human Subjects Involved? ___ Yes ___ No Research Exempt? ___ Yes ___ No Clinical Trial? ___ Yes ___ No NIH-Defined Phase III CT? ___ Yes ___ No Provide information required for Scenario B (Non- Exempt Human Subjects Research) Must have a Data and Safety Monitoring Plan May need Data and Safety Monitoring Board (DSMB)    35

Scenario F: NIH-defined Phase III Clinical Trial  Are Human Subjects Involved? ___ Yes ___ No Research Exempt? ___ Yes ___ No Clinical Trial? ___ Yes ___ No NIH-Defined Phase III CT? ___ Yes ___ No Provide information required for Scenario E Generally requires Data and Safety Monitoring Board (DSMB)    Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. Behavioral human subjects research involving an intervention to modify behavior 36 36

Minorities, and Children Inclusion of Women, Minorities, and Children By law, Women and Minorities must be included in clinical research studies; in Ph III CT in numbers adequate for valid analysis By NIH policy, children should also be included in human subjects research unless scientific/ethical reasons (NOTE: Children are < 21 years) NOTE: difference between children according to HS regulations and children according to inclusion policy

NIH Uses Two Definitions for Children For purposes of human subjects protection: Children are persons who have not attained the legal age of consent for research treatment/procedures where research will be conducted. For the purposes of inclusion: Children are individuals under the age of 21. 38

Minorities, and Children Inclusion of Women, Minorities, and Children Cost or convenience is NOT an acceptable reason for exclusion Inclusion should be tied to scientific goals of project Enrollment tables (recently revised) http://grants.nih.gov/grants/funding/women_min/women_min.htm http://grants.nih.gov/grants/funding/children/children.htm

Planned Enrollment Report For Internal NIH Use Only

Peer Review of HS and Inclusion Each reviewer assesses human subjects protections and inclusion Peer review group will determine overall rating of “acceptable” or “unacceptable”. May affect overall score 24% SBIR/STTR applications involving HS are deemed Unacceptable vs 18% overall Summary Statement: will note Unacceptable on front page; nacceptable for HS or inclusion is bar to funding Concerns are questions that must be answered, information that must be supplied, or issues that must be resolved, prior to funding. 41 41

What Happens to Grants with Unacceptable Code for Human Subjects? For grants in the fundable range: PI submits written response After Program Officer approves response, submit request to OEP for review and code change OEP reviews entire Human Subjects plan OEP concurs OEP may request additional information

Common HS Concerns Source of existing specimens/data; missing or inadequate justification for no human subjects research Risks -physical, psychological, reputation, employability, financial, etc. Missing/inadequate Data & Safety Monitoring Plans for Clinical Trials Confidentiality of data Inadequate protections for vulnerable populations Coercive recruitment Incidental findings not addressed In order from most to least common in FY2002

Institutional Responsibilities: FWA IRB Documents institution’s commitment to regulations Designate a registered Institutional Review Board (IRB) Reviews/approves proposed research and on-going research at least annually & FWA and IRB approval required for funded institutions and sites engaged in human subjects research (just-in time) (http://www.hhs.gov/ohrp/policy/engage08.html) For cooperative projects, may rely on single IRB (http://www.hhs.gov/ohrp/assurances/forms/irbauthorizpdf.pdf)

Additional NIH Award Requirements Certification that Key Personnel have completed appropriate human subjects research education Protecting Human Research Participants Tutorial: http://phrp.nihtraining.com/users/login.php Annual IRB approval Update Inclusion enrollment in annual progress report 45

Cumulative Inclusion Enrollment Report For Internal NIH Use Only

Human Subjects Resources Office of Extramural Research Human Subjects Web site: http://grants.nih.gov/grants/policy/hs/index.htm OHRP Web site: http://www.hhs.gov/ohrp/ Coded Information/Specimens Resources http://www.hhs.gov/ohrp/policy/cdebiol.html http://www.youtube.com/watch?v=yp5GzAmXlPM (VIDEO) OER Flow Chart Code Specimen Guidance http://grants.nih.gov/grants/policy/hs/PrivateInfoOrBioSpecimensDecisionChart.pdf

Contact Information Thank you Email: oer@od.nih.gov