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
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
• 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
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?
Does activity involve Research ?
Does research involve Human Subjects ?
If yes, is human subjects research Exempt ?
ASK QUESTIONS IN THIS ORDER!
5
Human Subject Regulations Decision Chart: http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html

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

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

8
•
8

9
•
– Data through intervention or interaction
Examples:
Collect biological samples (blood)
Administer a questionnaire
Conduct MRI
Manipulating environment and noting response
Collected for THIS
Research
OR
9

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, coauthorship). Does NOT include providing info or samples.
•
OHRP guidance on coded info and specimens
10
Collected for
OTHER purpose

• 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
11
• PI will purchase tissue from commercial vendor
Not human subjects research because not collected for research and no identifiers

12
• 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.

Exempt Non-Exempt
13
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

(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
14

15
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
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
• 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

• 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
18

19
• 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
• 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
• For E4
– 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
• 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

• 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
23

• 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?
Living
Subjects
If No, NOT Human subjects research (STOP)
2/If Yes, do any of the Exemptions apply?
• Yes: Exemption #
• No: Non-exempt human subjects research
24

Regulations require
Agencies to evaluate applications and proposals involving human subjects:
1.
Risks subjects
2.
Adequacy of protections
3.
Benefits
4.
Importance of knowledge to be gained
25
• NIH evaluates through peer review
• No funds expended unless regulatory requirements are met; can withdraw funding for non-compliance
25

26
• 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
• 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
• 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
• 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
• 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
Are Human Subjects Involved?
Research Exempt?
Clinical Trial?
NIH-Defined Phase III CT?

___ Yes
___ Yes
___ Yes


• 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

Are Human Subjects Involved?
Research Exempt

___ No
____No
Exemption Number (mark all) __1 __2 __3 __4 __5 __6
Clinical Trial? ___ Yes

NIH-Defined Phase III CT?
___ Yes

32
• 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
Are Human Subjects Involved?

Research Exempt?
____ Yes ___No
Clinical Trial?
NIH-Defined Phase III CT ?
____ Yes ___No
____ Yes ___No
Mark as applicable
• 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
33

34
• 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
Are Human Subjects Involved? ___ Yes ___ No
Research Exempt?
Clinical Trial?
NIH-Defined Phase III CT?
___ Yes

___ 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
Are Human Subjects Involved? ___ Yes ___ No
Research Exempt?
Clinical Trial?
NIH-Defined Phase III CT?
___ Yes


___ No
___ No
• Provide information required for Scenario E
• Generally requires Data and Safety Monitoring Board
(DSMB)
36

37
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
• 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

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

Planned Enrollment Report
40
40
For Internal NIH Use Only

• 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
41
• Summary Statement: will note Unacceptable on front page; nacceptable for HS or inclusion is bar to funding
41

• 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
42

43
• 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

44
FWA IRB
• Documents institution’s
Reviews/approves proposed commitment to regulations research and on-going
• Designate a registered
Institutional Review Board
(IRB)
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
)

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

Cumulative Inclusion Enrollment Report
46
46
For Internal NIH Use Only

• 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/PrivateInfoOrBioSpecimensDe cisionChart.pdf
47

48