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Research Involving Human Subjects

NIH Regional Seminar

Yvonne Lau, MBBS, MBHL, PhDDirector, Division of Education and Development (DED)

Office for Human Research Protections (OHRP)Department of Health and Human Services (HHS)

Ann Hardy, DrPHNIH Human Research Protections Officer

Office of Extramural Research, NIH

Meredith Temple O’Connor, PhDNIH Inclusion Policy Officer

Office of Extramural Research, NIH

Session Overview

• Human Subjects Regulations and application of the Common Rule

• NIH policies for grant applications proposing human subjects research

• NIH policies on inclusion of women, minorities and children in NIH-funded research

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Learning Objectives• Describe the ethical rationale for the federal regulations on human

research protections

• Apply the basics of the Common Rule

• Recognize the requirements for human subjects in NIH grant applications

• Provide post-award requirements for research involving human subjects

• Explain the requirements for addressing inclusion of women, minorities, and children in NIH grant applications

• Provide an understanding of what studies inclusion policy applies to

• List post-award requirements for monitoring inclusion in clinical research

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OHRP - WHO ARE WE?

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Office for Human Research Protections (OHRP)

Mission

Provides leadership in the protection of the

rights, welfare and wellbeing of subjects

involved in research conducted or supported

by the U.S. Department of Health and Human

Services (HHS).

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Division of Education & Development (DED)

• Conducts educational programs, quality improvement activities & develop training tools & informational materials

• Provides ethical guidance & regulatory interpretation of the HHS-regulations for human research protections

• Conducts public outreach to enhance awareness of human research protections

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ETHICS & REGULATIONS ON HUMAN RESEARCH PROTECTIONS

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What is Research?

Research refers to a systematic investigation … designed to develop or contribute to generalizable knowledge

45 CFR 46.102(d)

• Research serves the Common Good• Research subjects are the ‘means’ to achieve

this goal• Primary interest of research is not about

benefiting subjects 8

Research Ethics – “In the name of the Common Good”: A discipline built out of tragedies

Nazi docs at Nuremberg Trial

Henry Beecher NEJM 1966

Tuskegee Syphilis Experiment

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Tuskegee Syphilis Study (1933-72)• Subjects were not told that they were

participating in a research study• Subjects were not offered penicillin

when this became established as the standard of treatment

• Subjects were even prevented access to it

1974: National Research Act1979: Belmont Report1981: Protection of Human Subjects Laws

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The Belmont Report (1979)

Three Basic Ethical Principles

1. Respect for PersonsPromoting autonomy

2. BeneficenceMaximize benefits; minimize harms

3. JusticeEquitable distribution of burden &

benefits

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“The Common Rule” 45 CFR Part 46 Subpart A

Adopted by 18 federal departments & agencies

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“The Common Rule” Basic Protections

1. Institutional Assurances (Federalwide assurance - FWA)

2. Institution Review Boards (IRB)

3. Informed Consent

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Additional HHS Protections

• Subpart B - Pregnant Women, Human

Fetuses, and Neonates

• Subpart C - Prisoners

• Subpart D - Children

• Subpart E - IRB Registration

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HHS vs. FDA Regulations

• Differences in Scope

– HHS regulations applied to HHS-funded research

– FDA regulations applied to clinical investigations

involving FDA regulated products: drugs,

devices, or biologics

• Basic requirements for IRBs and informed

consent are congruent

Detailed differences at FDA Website

IRB Review & Oversight

• 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.

• Why do we need IRB review?

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To Approve Research – IRB Must Find

• Risks minimized • Risk/benefit ratio reasonable• Subject selection equitable• Informed consent – obtained & documented• Data monitored, as appropriate• Privacy and confidentiality, as appropriate• Additional protections for subjects vulnerable to

coercion or undue influence§46.111(a) & (b)

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Informed Consent

Purpose: Subjects can make an informed decision about participation

What are the key elements?

• Information

• Comprehension

• Voluntariness18

APPLYING THE HHS REGULATIONS

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When do the Regulations Apply?

• Research involving human subjects conducted or supported by HHS that is not otherwise exempt

-OR-

• Non-exempt human subject research

covered by Assurance of Compliance

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How to Apply the Regulations?

1. Does activity involve Research?

2. Does research involve Human Subjects?

3. Is human subjects research Exempt?

ASK QUESTIONS IN THIS ORDER!

See Human Subject Regulations Decision Charts

Is it ‘Research’?

• A team of physicians see a patient with an unusual constellation of symptoms.

• They run a variety of diagnostic tests and procedures.

• Results of the test do not yield a known diagnosis.

• They write up a case summary of their observations and submits it to a medical journal for publication.

Is this Research?

Research refers to a systematic investigation … designed to develop or contribute to generalizable knowledge

45 CFR 46.102(d

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Does it involve ‘Human Subjects’?

• Human subject – a living individual about

whom an investigator conducting research

obtains

– data through intervention or interaction

with the individual, or

– identifiable private information*

* Identity of the subject is or may readily be ascertained by the investigator or associated with the information

Quiz Question

A study protocol describes the following proposed research activities:• Investigator will receive biological

specimens from an outside source

• Investigator cannot identify the individuals to whom the specimens pertain

• Specimens were not obtained for purposes of the current research

Is this Human Subjects Research?

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Is the Human Subject Research Exempt? Categories of Exempt Research*

1. Normal educational

practices in established

educational settings

2. Educational tests, surveys,

interviews, or observation of

public behavior -unless

identified & sensitive**

3. Research on elected or

appointed public officials or

candidates for public office

* Exception for prisoners ** Exception for children

4. Research using existing

data, if publicly available

or recorded without

identifiers

5. Evaluation of public

benefit service programs

6. Taste and food quality

evaluation and consumer

acceptance studies

46.101(b)(1-

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Quiz Question

A study protocol describes the following proposed research activities:

• the study involves prisoners as subjects

• The subjects will be asked to complete surveys about food preferences

• The information is neither identifiable nor sensitive

Is this Human Subjects Research Exempt?

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Contact OHRP

• Visit OHRP website

• OHRP email box ohrp@hhs.gov

• Phone inquiries240-453-6900

• Join OHRP ListServ athttp://www.hhs.gov/ohrp/newsroom/index.html

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NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS FOR HUMAN SUBJECTS

RESEARCH

Ann Hardy, Dr.P.H. (hardyan@od.nih.gov)NIH Extramural Human Research Protection OfficerNIH Office of Extramural Research (OER)

• Describe the ethical rationale for the federal regulations on human

research protections

• Apply the basics of the Common Rule

• Recognize the requirements for human subjects in NIH grant

applications

• Provide post-award requirements for research involving human

subjects

• Explain the requirements for addressing inclusion of women,

minorities, and children in NIH grant applications

• Provide an understanding of what studies inclusion policy applies to

• List post-award requirements for monitoring inclusion in clinical

research

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Learning Objectives

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Regulatory Requirements for Sponsoring Agency (NIH)

• Agencies evaluate applications/proposals involving human subjects for risks, adequacy of protections, benefits and importance of knowledge to be gained

▫ NIH delegates to Peer Review

• Do not make an award unless regulatory requirements are met

▫ Administrative procedures to ensure compliance

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Human Subjects Section In NIH Application (Non-exempt HSR)

•Risks▫Human subjects involvement and characteristics;

vulnerable populations

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

▫Potential Risks – physical, psychological, social

•Adequacy of Protection Against Risks▫Recruitment; consent

▫Procedures to minimize risks▫Additional protections for vulnerable subjects

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Human Subjects Section In NIH Application (Non-exempt HSR) -2

•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

• Importance of Knowledge to be Gained▫Discuss in relation to risks

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Additional NIH Requirements •For Clinical Trials:▫Data and Safety Monitoring Plan or Board ▫Registration in ClinicalTrials.gov

•For NIH-Defined Clinical Research▫Inclusion of Women, Minorities, and

Children

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Preparing the Human Subjects Section

•Use Instructions for Preparing HS section•Select one of 6 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

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Scenario A: No Human Subjects

Are Human Subjects Involved? Yes X No

Human subjects section NOT required BUT must provide justification if using human specimens/ data

- samples provided from research repository without identifiers

- samples are purchased from commercial vendor

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Research Involving Coded Data or Specimens

• If research involves only secondary analysis of coded data/specimens it is NOT human subjects research if:▫Collected for other reason▫None of investigators can

readily ascertain the identity of subjects (Provider has no other role in research)

http://www.hhs.gov/ohrp/policy/cdebiol.html

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Scenario B: Non-Exempt Research

Are Human Subjects Involved? X_ Yes ___ No

Research Exempt? ___ Yes _X_ No

Clinical Trial? ___ Yes _X_ No

NIH-Defined Phase III CT? ___ Yes _X_ No

• Human Subjects Section- no page limitations▫ Address 4 required points (risk, protections, benefits, knowledge)

• Inclusion of Women, Minorities, and

Children

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Scenario C: Exempt ResearchAre Human Subjects Involved? X Yes No

Research Exempt X Yes No

Exemption Number _X_1 __2 __3 __4 __5 __6

Clinical Trial? ___Yes _X_ No

NIH-Defined Phase III CT? ___Yes _X_ No

• Human Subjects Section

▫ Justify selection of exemption(s)

▫Sources of research materials

• Inclusion of Women, Minorities, and Children *

*Not required for Exemption 4

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Scenario D: Delayed Onset HS Research

Are Human Subjects Involved? _X_ 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 can’t be described in the application

• Human Subjects Section – explain why delayed onset

• If funded, awardee must provide FWA, IRB approval, human subjects and inclusion sections to NIH before involving human subjects

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Scenarios E & F: Clinical Trial

• Recently revised Definition of Clinical Trial: a research study in which 1 or more subjects are prospectively assigned to 1 or more interventions (including placebo) to evaluate effects on health-related biomedical or behavioral outcomes.

• 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)

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Scenario E: Clinical Trial (not Phase III)

Are Human Subjects Involved? _X_ Yes ___ No

Research Exempt? ___ Yes _X_ No

Clinical Trial? _X_ Yes ___ No

NIH-Defined Phase III CT? ___ Yes _X_ No

• Provide information required for Scenario B (Non-Exempt Human Subjects Research)

• Must have a Data and Safety Monitoring Plan• ClinicalTrials.gov

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Data and Safety Monitoring Plan

• Data and Safety Monitoring Plan includes:

▫Overall framework for data and safety monitoring

▫Responsible party for monitoring

▫ Procedures for reporting Adverse Events/Unanticipated

Problems

• Data and Safety Monitoring Board (DSMB) required for:

▫Multi-site trials > minimum risk and generally for Phase III

trials

• Funding IC approval before enrollment begins

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Scenario F: NIH-Defined Phase IIIClinical Trial

Are Human Subjects Involved? _X_ Yes ___ No

Research Exempt? ___ Yes _X_ No

Clinical Trial? _X_ Yes ___ No

NIH-Defined Phase III CT? _X_ Yes ___ No

• Provide information required for Scenario E• Generally requires DSMB• Additional inclusion policy requirements to be

addressed related to study design

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Peer Review of Human Subjects Section

•Each reviewer will assess human subjects 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 44)

Code 44 is a bar to award

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Common HS Concerns Identified in Peer Review

•Human Subjects Section inadequate•Missing/inadequate DSMP/B•Source of specimens/data inadequately

described •Physical/psychological risks not adequately

addressed • Informed consent issues•Confidentiality of data• Incidental findings not addressed

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Just-in-Time Requirements

•After peer review, for grants likely to be funded, provide:▫OHRP Assurance Number (FWA)▫Certification of IRB approval▫Certification that Key Personnel have completed

appropriate human subjects research education https://phrp.nihtraining.com/users/login.php

▫Resolution of unacceptable Human Subjects Section Written response to IC NIH OER concurrence

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After the Award…Now What?

•Human Research Protections :

▫Annual IRB approval

▫UP/AE Reports – within 3 days or as required

▫Prior NIH Approval for changes in human subjects research that increase risk Add HS activities to non-HS award or add Clinical trial

New enrollment of preg. women, children or prisoners

Addition that is greater than minimal risk or new info that study procedure/intervention is higher risk

Discuss plans with PO before starting!!

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Certificates of Confidentiality (CoC)

• Purpose:▫ Protects investigators/institutions from forced disclosure of

identifiable research info (subpoena)

▫ Encourage participation

• For IRB approved studies that collect personal identifiers

and sensitive info

• DHHS Agencies that issue: CDC, IHS, SAMHSA, HRSA,

FDA, and NIH

• Federal funding not required but research must be health

related (NIH and FDA issue bulk of CoCs for non-funded

research)

http://grants.nih.gov/grants/policy/coc/index.htm

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Resources for NIH HS Policies

•SF 424 & Electronic Submission Page

http://grants.nih.gov/grants/funding/424/index.htm

•NIH OER Human Subjects Website:http://grants.nih.gov/grants/policy/hs/

•NIH Revised Definition of Clinical Trial:

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html

•NIH Data and Safety Monitoringhttp://grants.nih.gov/grants/policy/hs/data_safety.htm

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NIH POLICIES AND GRANT APPLICATION INSTRUCTIONS FOR INCLUSION OF WOMEN,

MINORITIES, AND CHILDREN IN CLINICAL RESEARCH

Meredith D. Temple-O’Connor, Ph.D. NIH Inclusion Policy OfficerOffice of Extramural Research (OER)National Institutes of Healthinclusion@od.nih.gov

• Describe the ethical rationale for the federal regulations on human

research protections

• Apply the basics of the Common Rule

• Recognize the requirements for human subjects in NIH grant

applications

• Provide post-award requirements for research involving human

subjects

• Explain the requirements for addressing inclusion of women,

minorities, and children in NIH grant applications

• Provide an understanding of what studies inclusion policy applies to

• List post-award requirements for monitoring inclusion in clinical

research

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Learning Objectives

NIH Inclusion Policies

• Inclusion of Women and Minorities ▫Must be included in NIH-defined clinical

research unless exclusion is justified for scientific reasons

▫Justify the proposed sample in the context of who is at risk for the disease/condition and the scientific goals of the specific study

▫Plans for outreach and recruitment▫Provide Inclusion Enrollment Report form(s)

with proposed sex/gender, race, and ethnicity of the sample

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NIH Inclusion Policies (con’t)

• Inclusion of Children▫Children must be included in clinical

research unless there are scientific or ethical reasons not to do so

▫“Children” are defined by the NIH as individuals <21 years

▫Applicants should justify the proposed age range of the participants, with specific attention to justifying the inclusion/exclusion of individuals under 21

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Defining the Universe

• Inclusion of women and minorities in all NIH funded or supported clinical research is mandated by

law

• What is subject to the statute/policies?

▫ All studies (intramural, extramural, contracts) that meet the NIH definition of clinical research

NIH definition of clinical research: (1) Patient-Oriented Research: Research conducted with

human subjects (or on material of human origin such as tissues, specimens, and cognitive

phenomena) for which an investigator (or colleague) directly interacts with human subjects.

Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked

to a living individual (e.g., IRB Exemption 4). Patient-oriented research includes (a)

mechanisms of human disease, (b) therapeutic interventions, (c) clinical studies, or (d)

development of new technologies; (2) Epidemiologic and Behavioral Studies; and (3) Outcomes

Research and Health Services Research

▫ Additional requirements for NIH-defined Phase III clinical trials related to unbiased design and

assessment of potential differences

• Bottom line:

▫ If you answer yes to human subjects and not E4, you should address inclusion because there

are very few studies that will not be considered NIH-defined clinical research.54

But what does it mean to include?

• Purpose Statement: NIH supported clinical

research should address/include the population(s)

at risk for the disease or condition under study.

The purpose of NIH Inclusion Policies is to ensure

that the distribution of study participants by

sex/gender, race, ethnicity, and age reflects the

population needed to accomplish the scientific

goals of the study, rather than enumeration of

research participants.  All NIH-funded studies that

meet the NIH definition for clinical research are

subject to NIH Inclusion Policies, regardless of

funding mechanism*. (*Funding mechanism includes any activity code

associated with extramural grants, R&D contracts, and cooperative agreements as well as intramural

projects and R&D contracts)

• Bottom line: Does the study have the right people

for the science?55

What’s required for inclusion in a competing application?

• Remember the “universe” to determine whether inclusion applies to your application

• Plans for inclusion of women and minorities

▫ Includes addressing plans for valid analysis if conducting an NIH-defined Phase III clinical trial

• Plans for the inclusion of children

• Inclusion enrollment report

▫ Planned or Cumulative (actual) depending on the study design

• NOTE: Follow the scenarios described in Human Subjects’ protection section to further understand what’s expected for different scenarios

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Inclusion Enrollment Report Forms

• Inclusion Enrollment Report Forms▫Now a structured data form in Forms C▫Need to consider race and ethnicity separately▫Which form to use?

Planned or Cumulative?

•Separate report forms for US and International participants (even if part of the same study)

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Peer Review of Inclusion

•Each reviewer will assess the inclusion plans▫Plans for inclusion ▫Justification in the context of the science

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

•Summary Statement: INCLUSION OF WOMEN, MINORITIES, AND/OR

CHILDREN: UNACCEPTABLE (U CODE) Unacceptable (U) code is a bar to award

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Common Inclusion Concerns Identified in Peer Review

• Inadequate information describing the sex/gender, race, ethnicity, and/or age(s) of the sample

• Inadequate justification for proposed sample▫ Sex/gender, race, ethnicity, and/or age(s) breakdown not

appropriate for the scientific goals of the study or not adequately justified

•Unrealistic sampling

▫Appropriate from scientific perspective but not realistic Collaborations and outreach plans may help

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Just-in-Time Requirements

•After peer review, for grants likely to be funded:▫Work with Institute/Center staff to resolve

unacceptable inclusion concerns Written response to IC

▫Provide inclusion enrollment report(s) if missing or need update as a result of peer review and/or programmatic adjustments This now happens directly in the Inclusion

Management System through Commons

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• Provide cumulative inclusion enrollment (e.g., actual enrollment)

information at least annually or as frequently as specified by the funding

Institute/Center

▫ Provided in Inclusion Management System through RPPR or through

Commons Status

• For NIH-defined Phase III Clinical Trial– report any analysis or findings related

to outcomes by sex/gender, race, and ethnicity if available

• Note progress (or challenges) in recruitment as needed in RPPR

• 2012 Policy – Prior NIH Approval for changes in human subjects research that

increase risk

▫ Changes the project from no to yes for human subjects involvement or from

no to yes for clinical trial

▫ Discuss plans with NIH PO before starting

▫ Ensure that inclusion plans and/or inclusion enrollment are provided (prior

to start or at RPPR—check with funding Institute/Center for specific

procedures)61

After the Award…Now What?

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Inclusion Resources for Investigators

• Training and Guidance

▫FAQs

▫How To Videos and User Guides for

working in the Inclusion Management

System

▫Podcasts

▫Narrated slide decks

•Guide notices and other policy related

documents

•Public website▫ http://grants.nih.gov/grants/funding/women_min/women_min.htm

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