1. 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

2. 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

3. 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

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

5. 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: 5 5

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

7. 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

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

9. 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

10. 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

11. 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

12. 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.

13. 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

14. 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

15. 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.

16. 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

17. 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

18. Research Involving Coded Data/Specimens
OHRP Policy Guidance 2008:
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

19. 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?

20. 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

21. 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.

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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 )
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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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)

40. Planned Enrollment Report
For Internal NIH Use Only

41. 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

42. 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

43. 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

44. 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) (
For cooperative projects, may rely on single IRB (

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

46. Cumulative Inclusion Enrollment Report
For Internal NIH Use Only

47. Human Subjects Resources
Office of Extramural Research Human Subjects Web site:
OHRP Web site:
Coded Information/Specimens Resources
(VIDEO)
OER Flow Chart Code Specimen Guidance

48. Contact Information
Thank you