Dawn Corbett (NIH/OER)

Protection of Human Participants in NIH Research

Goals

• Understand the regulatory basis and requirements for human subjects

protection and inclusion in research

• Define human subjects research and understand exempt and non-exempt

research involving human subjects

• Gain clarity about which requirements apply to different types of human

subjects studies;

• Recognize NIH post award reporting requirements for research involving

human participants

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HHS Regulations

45 CFR part 46: Protection of Human Research Subjects

• Subpart A (“Common Rule”) – Basic Requirements for Protection**

• Subpart B, C, D – Additional protections for Pregnant Women/Fetuses/Neonates; Prisoners; & Children

• Subpart E – IRB Registration

• The Office for Human Research Protections (OHRP) is responsible for ensuring compliance.

• Revisions to the Common Rule were published on 1/19/17, with a general implementation date of 1/19/18. After subsequent delays, general compliance date: 1/21/2019

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Three Pillars of Human Subjects Protections Under the Common Rule

1. Institutional Assurance of Compliance (Federalwideassurance – FWA)• Documents institution’s commitment to protecting the

rights and welfare of research subjects2. Institutional Review Boards (IRB) Review

• Oversees and reviews research by an independent committee with diverse knowledge and perspectives

• Reviews and approves non-exempt human subjects research according to criteria laid out in the regulations

3. Informed Consent• Respects research subjects’ autonomy to participate or

not• Helps protect subjects’ interests

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When Do the Regulations Apply?

To determine if your project is non-exempt human subjects research…

Ask these questions in this order:1) Does the activity involve research?

2) Does the research involve human subjects?

3) Is the research with human subjects exempt?

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Human Subjects Research

ResearchA systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge

Does not include: Certain scholarly and journalistic activities; certain public health

surveillance activities, collection and analysis of information, specimens, or records, by or for a criminal justice agency for certain criminal justice or investigative purposes, and certain authorized operational activities for national security purposes

A living individual about whom an investigator conducting research(1) Obtains information or biospecimens through intervention or

interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or

(2) Obtains, uses, studies, analyzes, or generates identifiableprivate information or identifiable biospecimens

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Unpacking the Definition of a Human Subject

• a living individual

• Regulations do NOT apply to research

involving materials from deceased individuals

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Who is An Investigator?Anyone involved in the conduct of the research (study, analysis, interpretation of research data, co-authorship).

**Does NOT include simply providing info or samples.

OHRP guidance on coded info and specimens

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Do The Regulations Apply to My Project?

Does the activity involve Research?

Does the 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

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Currently, about 10% of NIH awards are considered exempt.

Exempt Human Subjects Research

8 Exemptions

Meets the definition of human subjects research.Exempt studies involve human subjects research: research involving a living individual about whom

data or biospecimens are obtained/used/studied/analyzed through interaction/intervention, or identifiable, private information is used/studied/analyzed/generated

1

Meets the criteria of one of the following exemptions:2

Exemption 1: conducted in an educational setting using normal educational

practices*

Exemption 2: uses educational tests, surveys,

interviews, or observations of public behavior*

*Limited IRB review may be required

Exemption 3: uses benign behavioral interventions

*Limited IRB review may be required

Exemption 4: involves the collection or study of data or

specimens if publicly available or information

recorded such that subjects cannot be identified

Exemption 5: public service program or demonstration

project

Exemption 6: taste and food quality

Exemption 7: storage of identifiable information or

biospecimens for secondary research use. Broad consent is and limited IRB review are

required.

Exemption 8: secondary research use of identifiable

information or biospecimens. Broad consent and limited IRB review are required.

*Cannot include any other procedures, such as collection of clinical data or biospecimens

Exemption 1 addition: Cannot adversely impact student learning

of required content or

assessment of educators

Exemption 2 addition: NEW

concept- limited IRB review for privacy/

confidentiality when identifiable info is

recorded.

NEW Exemption 3:Replaces exemption for

specific types of research on public

officials & candidates. Includes verbal, written

or audiovisual data.

Must be brief in duration, harmless,

painless, not physically invasive, unlikely to

have adverse effect or be offensive and/or embarrassing to the subjects. Limited IRB

review required when identifiable info is

recorded.

Exemption 4 expanded:

No longer includes only existing

data/specimens. Added HIPAA-

regulated use as exempt. Exemption 5

expanded: Includes federally

supported research.

Requires list of E5 projects to be

published.

NEW exemptions 7 and 8. Includes new

concepts- broad consent and limited

IRB review

Consider

NIH Requirements:•HS education•Inclusion tracking for all except 4

45 CFR 46 Requirements:•Limited IRB review for 7 & 8, and some study designs under 2 & 3.•Broad consent for 7 & 8

Cannot involve prisoners, unless includes a broader population that happens to include prisoners.

Cannot involve children in:•Exemption 2 if investigators participate in the activity being observed or includes identifiable info. OR •Exemption 3.

For more information see the OER website for Research Involving Human Subjects.

Send questions/comments to OER-HS@nih.gov.

Exemption 1

Research conducted in educational settings on normal educational practices such as instructional strategies, techniques, curricula ….

May not be likely to adversely impact:

• Students’ opportunity to learn required educational content, or

• Assessment of educators who provide instruction

• 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.

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Exemption 2

• Research that only includes use of educational tests, surveys,

interviews or observation of public behavior

• Limited IRB review required if sensitive or identifiable

• Children can included only in observation of public behavior if

investigators not participating in activities

Examples

• Focus group of adult community members to discuss access to dental

care

• Questionnaire about outdoor exercise, including collection of

participants’ age and zip code (with limited IRB review)12

Research involving benign behavioral interventions with adults who

prospectively agree, when information collection is limited to verbal

or written (including data entry) or audiovisual recording

• Limited IRB review required if identifiable

• Intervention must be brief in duration, harmless, painless, not physically

invasive, not likely to have a significant adverse lasting impact on the subjects,

AND investigator has no reason to think the subjects will find the interventions

offensive or embarrassing

• Includes authorized deception research

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Exemption 3 (New)

Exemption 3 (Continued)

Examples

• Study among young adults evaluating preferred snack foods following

a television program.

• Study investigating text vs. voice message appointment reminders on

self-reported annual physical appointment attendance.

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Exemption 4

Research involving the study of existing data, documents, records, specimens if publicly available,

information recorded by the investigator in manner that subjects cannot be identified directly or

indirectly, or identifiable and regulated under HIPAA or conducted by federal agency under federal

privacy standards

• Investigator does not contact or re-identify the subjects

• No longer has to be existing under Revised Common Rule

• Examples

• PI accesses information from medical records. He records information for the study without recording identifiable info.

• PI goes through set of existing excess blood samples to identify those of interest. She removes label with identifiers and marks tubes with random number and basic non-identifiable clinical info.15

Do The Regulations Apply to My Project?

Does the activity involve Research?

Does the research involve Human Subjects?

If yes, is human subjects research Exempt?

45 CFR 46 applies to your research

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Federalwide Assurance (FWA)

• Required when institutions are engaged in non-exempt human subject research conducted or supported by a federal department/agency

• Documentation of institution’s commitment

• to protecting the rights and welfare of human research subjects;

• comply with applicable regulations

• Designate the IRB(s) to be used to review applicable human subjects research

• IRB must be registered w/ OHRP

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If you are awarded Federal funding, you must have your

own FWA

What Is An Institutional Review Board (IRB)?

A committee charged with the review of research involving human

subjects to assure that their rights and welfare are adequately

protected

An IRB will review submissions by:

• Full board review• Review by a fully convened IRB

• Expedited review• Review by IRB chair or experienced member(s)

• Meets one of categories eligible for expedited review

Options

• Set up own IRB

• Rely on other registered IRB

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Many institutions have procedures for determining exempt human subjects research

Full Board

Expedited

IRB Review of Projects

• Initial Review BEFORE start of Research

• Continuing Review may be required

• Specific Criteria for IRB Approval

• Consider subparts B, C, D when applicable

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Decision Tool: Am I Doing Human Subjects Research

SLIDE | 20 https://grants.nih.gov/policy/humansubjects/hs-decision.htm

NIH Human Subjects Research Policies

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When do NIH Human Subjects Polices Apply?

•Apply to Human Subjects research as defined in 45 CFR part 46: Protection of Human Research Subjects Subpart A (aka the Common Rule)• Includes exempt and non-exempt research• Inclusion policies apply only to clinical research• Some policies apply only to clinical trials

•NIH policies complementary or in addition to the Common Rule

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NIH’s Role in Human Research Protections

•Evaluate applications/proposals involving human subjects for• Risks• Adequacy of protections• Benefits• Importance of knowledge to be

gained (45 CFR § 690.120)

•NIH delegates to peer review

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Single IRB Policy

• Multi-site domestic studies which involve non-exempt human subjects research must use a

single Institutional Review Board (siRB)

• Applies to applications submitted for due dates January 25, 2018 or later

• Exclusions:• Foreign sites

• Career development (K), institutional training (T), and fellowship awards (F)

• Applies to applications submitted for due dates January 25, 2018 or later

• Some exceptions apply :• When Federal, State, Tribal, local requirements require local review

• Time-limited exception for ancillary studies

• Other cases with a compelling rationale (rare)

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Guide Notice: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-

094.html

Certificates of Confidentiality (CoC)

• What is a Certificate of Confidentiality?

• Prohibits disclosure of names or information, documents, or

biospecimens containing identifiable sensitive information

As a result of 21st Century Cures Act:

• To persons not connected to the research

• In any Federal, State, or local civil, criminal,

administrative, legislative, or other proceeding, (unless

with participants’ consent)

• For any other purpose, with some exceptions

• See (NOT-OD-17-109) published September 7, 2017

CoC

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Key Changes to Certificates of Confidentiality

Issue Previous Authority Current Authority

How to get oneIssued upon approval of

application• NIH-funded – automatic

DisclosurePI/ Institution could voluntarily

disclose

Disclosure is prohibited unless specifically allowed by statute or

with consent

Admissibility as evidence

Information protected by a CoC could be used in a legal proceeding if disclosed

Protected information cannot be used in a legal proceeding even if it

is disclosed elsewhere

Copies of information

Unclear; typically advised to amend or extend

All information, including copies, is protected

Applies to ongoing research as of December 13, 2016

Inclusion of Women and Minorities in NIH Research

Public Law (42 U.S. Code § 289a–2) requires:

• Women and minorities be included in all NIH-funded clinical research studies unless there is a compelling rationale for exclusion

• Analyses by sex/gender, race and ethnicity for NIH-defined Phase III clinical trials

• Applicable* NIH-defined Phase III trials awarded December 13, 2017 or later must report results of “valid” analyses to Clinicaltrials.gov. See NOT-OD-18-104

*Applicable clinical trials are drug and device trials subject to Clinicaltrials.gov registration and results reporting requirements under Title VIII of the Food and Drug Administration Amendments Act (FDAAA) of 2007

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Inclusion Across the Lifespan

• Revision to Inclusion of Children Policy; effective for

applications submitted for due dates on or after January

25, 2019 (and for contract solicitations and intramural

studies issued after that date).

• See NOT-OD-18-116

• Requires individuals of all ages be included in NIH

human subjects research unless there are scientific or

ethical reasons not to do so

• Requires submission of individual-level data on

participant age at enrollment in progress reports

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How Does NIH Define a Clinical Trial?

A research study in which one or more

human subjects are prospectively

assigned to one or more

interventions (which may include

placebo or other control) to evaluate

the effects of those interventions

on health-related biomedical or

behavioral outcomes.

SLIDE | 29

Helpful resources: https://grants.nih.gov/policy/clinical-trials/definition.htm

Funding Opportunity Announcement (FOA) Policy

• Applications involving clinical trials must be submitted to

clinical-trial specific FOAs

• Purpose is to:

• Improve NIH’s ability to identify proposed clinical trials

• Ensure key pieces of trial-specific information are submitted with

each application

• Uniformly apply trial-specific review criteria

https://grants.nih.gov/policy/clinical-trials/specific-funding-opportunities.htm

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Registration & Results Reporting

NIH Policy Requires:

Submit a plan in the application that outlines compliance with the expectations of the policy

Register the clinical trial no later than 21 days after enrolling the first participant

Submit summary results no later than one year after primary completion date

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Good Clinical Practice Training (GCP)

• All NIH-funded clinical investigators and clinical trial staff involved in the design, conduct, oversight, or management of clinical trials should be trained in GCP

• GCP training can be achieved through :

class or course

academic training program

certification from a recognized clinical research professional organization

• Training should be refreshed every 3 years

Learn more at https://grants.nih.gov/policy/clinical-trials/good-clinical-training.htm

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• Clinical trials must submit a Data and Safety monitoring plan

• Address overall data and safety monitoring framework

• Describe procedures for adverse event reporting

• Identify responsible entity (e.g. PI, independent safety

monitor, DSMB, etc.)

• Data and safety monitoring board generally required for NIH-

defined phase III trials

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Data and Safety Monitoring

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Review IC-Specific Guidelines at https://humansubjects.nih.gov/data_safety

Human Subjects and Clinical Trials Information Form

SLIDE | 34

Main Landing Page

• Some information prepopulated from

R&R Other Project Information Form

Study Record(s)

• Add ‘Study Record’ or ‘Delayed Onset

Study Record’ for each study in

application

See the Application Guide for detailed instructions

Research Strategy

Overall strategy, methodology,

and analyses of your proposed

research

Human Subjects/Clinical Trial Form

Detailed study information (e.g.,

eligibility, inclusion, protection

and monitoring plans)

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Developing Your Application

In the Research Strategy:

• Refer to information from the Human Subjects/Clinical Trial Form as

needed

• Do not duplicate information presented in the Human Subjects/Clinical

Trial Form

How Many Studies Does My Application Have?

• In some cases how to group or split studies is a judgement call

• Consider:

• What will be most clear for reviewers

• Not necessarily based on how aims are separated

• May be best to group studies if many of the study details are the same between studies

• Study Records live with award for duration of funding and used for post-award reporting

SLIDE | 36

“No” Human Subjects Involved• If research involves use of human materials, a

justification for the claim of “No Human Subjects” is

needed

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Key Points of Justification

• Material is NOT collected for your proposed research• Discuss source (repository, purchased commercially)

• NO investigator has access to ID, including access to code key)• Investigator = anyone involved in conduct of the research beyond providing

samples/data

Applying to a due date on/after January 25, 2018----------

Forms-E – PHS HS/CT Info Form; specific attachment to explain

Exempt Human Subjects Research

• Inclusion justification for the exemption in Protections of Human

Subjects attachment

• Be aware of changes to exemptions in Revised Common Rule

• Refer to current exemptions and definitions

• Described in section 46.101(b) of 45 CFR 46

• https://www.hhs.gov/ohrp/regulations-and-

policy/regulations/45-cfr-46/index.html#46.101

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Protection of Human Subjects Section (no page limits):

1. Risks

• Human subjects involvement and characteristics; meets regulary requirements for vulnerable populations

• Sources of materials – what, how, access to identifiers

• Potential Risks for ALL research interventions: physical, psychological, social, legal

2. Adequacy of Protection Against Risks

• The consenting process

• Procedures to minimize identified risks

• Additional protections for vulnerable subjects

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Non-exempt Human Subjects Research

3. Potential Benefits of Research to Human Subjects and

Others

• In some cases, no direct benefit to subjects

• Should not include monetary compensation

4. Importance of Knowledge to be Gained

• Discuss in relation to risks

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Non-exempt Human Subjects Research

3. Potential Benefits of Research to Human Subjects and Others

• May not be direct benefit to subjects

• Discuss risks in relation to anticipated benefits

• Should not include monetary compensation

4. Importance of Knowledge to be Gained

• Discuss in relation to risks

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Non-exempt Human Subjects Research

Clinical Trial Questionnaire

Answers determine:

Appropriate FOA type

Application form requirements

Review criteria for evaluation

Requirement for registration and results reporting

Requirement for GCP training

Does the study involve human participants?

Are the participants prospectively assigned to an intervention?

Is the study designed to evaluate the effect of the intervention of the

participants?

Is the effect that will be evaluated a health-related biomedical or

behavioral outcome?

If YES to all questions, study is a clinical trial SLIDE | 42

Using the Human Subjects and Clinical Trial Form

Form SectionIf answered “No” to anyquestions in Clinical Trial

Questionnaire

If answered “Yes” to allquestions in Clinical Trial

Questionnaire

Section 1Basic Information

Required Required

Section 2Study Population Characteristics

Required Required

Section 3Protection and Monitoring Plans

Some fields required; some fields optional

Required

Section 4Protocol Synopsis

Not permitted Required

Section 5Other Clinical Trial-related Attachments

Not permitted Required only if specified in FOA

SLIDE | 43

Trainees & Fellows Proposing “Clinical Trial Research Experience”:

• Answer ‘Yes’ to all 4 questions in Clinical Trial Questionnaire

• Complete form Sections 1-3

• Not permitted to complete Section 4 or 5

• Statement from Mentor or Sponsor:

• Role of fellow/trainee in proposed clinical trial

• Source of funding for the trial

• Mentor’s relevant experience

• Assurance that the mentor/sponsor will be responsible for the clinical trial

SLIDE | 44

Peer Review of Human Subjects Section

• Each reviewer will assess human subjects involvement & protections

• Actual or potential unacceptable risks, or inadequate protections, or

insufficient information

• Peer review group will determine overall rating of “acceptable” or

“unacceptable”

• Summary Statement:

• PROTECTION OF HUMAN SUBJECTS: UNACCEPTABLE (Code 48)

• Code 48 is a restricted to award

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Just-in-Time Requirements

After peer review, during just-in-time period:

• Provide Institution’s OHRP Federal-wide Assurance Number

(FWA)

• Certify:

• IRB approval (or exemption)

• Human subjects education for key personnel

46SLIDE | 46

Just-in-Time Requirements

• Work with Institute/Center staff to resolve unacceptable inclusion concerns

• Provide inclusion enrollment report(s) if missing or needs updated as a

result of peer review and/or programmatic adjustments

47SLIDE | 47

After the Award…Now What?

• Provide actual inclusion enrollment data in progress reports

• Provide required information for delayed onset studies

• For NIH-defined Phase III Clinical Trials – report

status/results of analyses by sex/gender, race, and ethnicity

• For applicable NIH-defined Phase III Clinical Trials, report

results by sex/gender and/or race/ethnicity in

Clinicaltrials.gov within 1 year of primary completion date

• Keep in mind you are expected to follow NIH single IRB policy

if site is addedSLIDE | 48

Useful Resources: Human Subjects Protections and Inclusion

• NIH OER Human Subjects Website https://grants.nih.gov/policy/humansubjects.htm

• Certificates of Confidentiality https://grants.nih.gov/policy/humansubjects/coc.htm

• Single IRB Policy https://grants.nih.gov/policy/humansubjects/single-irb-

policy-multi-site-research.htm

• Inclusion of Women and Minorities https://grants.nih.gov/grants/funding/women_min/women_min.htm

• Inclusion Across the Lifespanhttps://grants.nih.gov/grants/funding/lifespan/lifespan.htm

SLIDE |49

Useful Resources: Clinical Trials

• Clinical Trials Requirements website: https://grants.nih.gov/policy/clinical-trials.htm

• Clinical Trial FAQs: https://grants.nih.gov/policy/clinical-trials/faq-list.htm

• Video overview of Human Subjects and Clinical Trials form: https://www.youtube.com/watch?v=nz9NWFhYOG8&list=PLOEUwSnjvqBJeHcb4yai7_fDnFZFPEmQK&index=1

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Questions

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CONTACT US

Dawn Corbett dcorbett@mail.nih.gov