The HHS Office for Human Research Protections Presents:
Quality Assessment Workshop 2.0: Focus on Informed Consent
7:30 8:00
Registration
8:00 8:15
Welcome and Introductions
8:15 10:30
History and Overview of the Regulations
This presentation will provide a review of the ethical foundation and applicability of
the regulations and discuss the three basic protections described in the Department of
Health and Human Services (HHS) regulations at 45 CFR part 46.
10:30 10:45
Break
10:45 12:00
Informed Consent
This presentation will review informed consent under the HHS regulations, including
discussion of the substantive elements and documentation of informed consent,
waivers of informed consent and documentation of informed consent, informed
consent in special circumstances, and case studies illustrating some of the
complexities inherent in the process.
12:00 1:00
1:00 2:30
Lunch (on your own)
Guest Speaker
Our special guest will share thoughts and cutting edge ideas in the analysis and
implementation of strategies designed to foster appropriate informed consent.
2:30 2:45
Break
2:45 4:30
Informed Consent Exercises
Groups of participants will explore different critical issues regarding informed
consent.
4:30 5:00
Wrap up: Q & A
OHRP Quality Assessment Workshop 2.0:
Focus on Informed Consent
Objectives
This OHRP training workshop is designed for an institution’s key personnel involved
with ensuring the protection of human subjects in research. The workshop will cover
the basic regulatory requirements for your human subject protections program, and
then delve into complex issues surrounding informed consent.
At the conclusion of this workshop, the participant should be able to:
•
Understand the history and basic requirements of the U.S. Department of Health
& Human Services (HHS) human subject protections regulations codified at Title 45
CFR Part 46.
•
Understand in detail the regulatory requirements for obtaining and documenting
informed consent.
•
Identify points to consider and new tools for implementing regulatorily compliant and
subject-appropriate practices in informed consent.
OHRP Quality Assessment Workshop 2.0:
Focus on Informed Consent
Department of Health and Human Services (HHS)
Office for Human Research Protections (OHRP)
Division of Education and Development (DED)
1
Welcome


Introductions
Mission of the Division of Education and
Development (DED)

Primary workshop goal

Secondary workshop goals

Housekeeping Issues

Certificate of Attendance/Participants Lists: Get
them online!
2
Workshop Content

History & Overview of the Regulations

Informed Consent -- Basics and “Applied”

Guest Speaker: Informed Consent “Hot Topic”

Informed Consent Challenges

Wrap-up/Q&As
3
1
History and Overview of Regulations
4
Outline

Ethical Principles

Regulated Human Subject Research

Applicability of HHS Regulations

Institutional Responsibilities/SOPs

Regulatory Protections for Research Subjects
5
Ethical Principles
6
2
Ethical Principles

Nuremberg Code

Declaration of Helsinki

The Belmont Report
7
Regulated Human Subject Research
8
Oversight of
Human Subject Research

Federal departments & agencies that are signatories
to “The Common Rule” (including HHS)

FDA

Informed Consent- 21 CFR 50

IRB- 21 CFR 56

State and local

Institutions
9
3
Federal Regulation and Policy
HHS regulations: Title 45 CFR part 46

Subpart A – basic HHS Policy
 Basic IRB & informed consent requirements
 “The Common Rule” - Federal Policy
 Other Federal Departments & Agencies have
adopted
Departments of Agriculture, Energy, Commerce, HUD, Justice,
Defense, Education, Veterans Affairs, Transportation, HHS &
Homeland Security. NSF, NASA, EPA, AID, CIA, and the
Consumer Product Safety Commission
10
Additional HHS Protections

Subpart B - Pregnant Women, Human Fetuses,
and Neonates



Subpart C - Prisoners
Subpart D – Children
Subpart E – IRB Registration
11
HHS vs. FDA Regulations

Basic requirements for IRBs and for informed
consent are congruent

Differences in applicability

HHS regulations based on HHS funding of research

FDA regulations based on use of FDA regulated
product: drugs, devices, or biologics
12
4
Applicability of HHS Regulations
13
Determining Applicability of Regulations
Prerequisite:

Research involving human subjects conducted or
supported by HHS (or other Federal Departments or
Agencies) that is not otherwise exempt
OR

Non-exempt human subject research covered by
Assurance of Compliance
14
Determining Applicability, cont’d

Does activity involve research?

Does research involve human subjects?

Is the human subject research exempt?

Is your institution engaged?
Human Subject Regulations Decision Chart:
http://www.hhs.gov/ohrp/policy/decisioncharttext.html
15
5
Does the Activity Involve Research?

Research – a systematic investigation designed to
develop or contribute to generalizable knowledge

includes research development, testing, evaluation,
pilot studies
16
Does the Research 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 b
y the
investigator or associated with the information
17
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;
or confidentiality protection,
without exception
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)(1-6)
* Exception for prisoners
** Exception for children
18
6
Is your Institution Engaged?
Institution is generally engaged in human
subject research:

when employees or agents obtain, for research
purposes:

data about the subjects of the research through
intervention or interaction with them;

identifiable private information about them; or

informed consent
Guidance at: http://www.hhs.gov/ohrp/policy/engage08.html
19
Regulatory Protections for
Research Subjects
20
Basic Protections
The regulations contain basic protections
for human subjects:

Institutional (Assurances, SOPs)

IRB Membership, Review & Approval

IRB Recordkeeping

Informed Consent
21
7
Institutional Assurance
22
Institutional Assurance


Required when engaged in non-exempt human
subject research
Documentation of institution’s commitment to
comply with applicable regulations - §46.103(b) & (f)

A method of compliance oversight

Federalwide Assurance (FWA) - only option

Designate only registered IRB(s)

Five year approval period
23
Assurance Applications –
Extending FWA


Individual Investigator Agreement

Independent investigators

Investigators at another institution
Assured institution responsible for oversight of
research
Sample agreement and guidance available at OHRP website:
http://www.hhs.gov/ohrp/assurances/forms/unaflsup.rtf
http://www.hhs.gov/ohrp/policy/guidanceonalternativetofwa.html
24
8
Assurance Applications –
Relying on External IRB
Institution responsibility

Written agreement

IRB authorization agreement
http://www.hhs.gov/ohrp/assurances/forms/irbauthorizpdf.pdf

Ensure research conducted per IRB approved plan

Procedures for reporting to OHRP
25
10 minute Break
26
Written Policies and Procedures

“Magnificent 7” required elements & operational
procedures

Procedures necessary to meet other HHS
requirements

Additional considerations
27
9
Required Elements of
Written IRB Procedures
§46.103(b)(4-5)
28
Required Elements 1 & 2
Procedures IRB will follow for conducting:

initial review of research [1] and

continuing review of research [2]
§46.103(b)(4)(i)
29
Initial & Continuing Review
Description of

Method of review

Reviewer system

Documents received and distributed for review

IRB review, findings, & determinations

Range of possible actions by IRB
30
10
IRB Review, Findings, & Determinations
Description of process:
 Criteria for approval under §46.111 & applicable
subparts
 Informed consent considerations
 Note for Continuing Review – New guidance with
“presumptions” that may streamline process
Institution may conduct further review:
 Institutional policies relevant to review
 Actions that may be taken by institution

institution may not override IRB disapproval
31
Required Element 3
Procedures the IRB will follow for reporting
its findings and actions to the investigator
and the institution
§46.103(b)(4)(i)
32
Required Elements 4 & 5
Procedures the IRB will follow for determining
which projects:

require review more often than annually [4] and

need verification from sources other than the
investigator that no material changes have occurred
since previous IRB review [5]
§46.103(b)(4)(ii)
33
11
Considerations for Elements 4 & 5
 Both go to questions of “what is the nature of the
research” and “who is conducting the research”?
 Specific criteria used to make these determinations
 Random selection of projects
 Complexity of project
 History or concerns re: investigator compliance
34
Required Element 6
Procedures for ensuring prompt reporting to the
IRB of proposed changes in a research activity
and ensuring that such changes in approved
research may not be initiated without IRB review
and approval except when necessary to eliminate
apparent immediate hazards to the subject
§46.103(b)(4)(iii)
35
Required Element 7
Procedures for ensuring prompt reporting to the
IRB, appropriate institutional officials, the
Department or Agency head, and OHRP of any

unanticipated problems involving risks to
subjects or others

any serious or continuing noncompliance

any suspension or termination of IRB approval
§46.103(a) and §46.103(b)(5)
36
12
Unanticipated Problems

Unexpected

Related or possibly related

Suggests greater risk of harm
Reviewing and Reporting Unanticipated Problems
And Adverse Events:
http://www.hhs.gov/ohrp/policy/advevntguid.html
37
Most Adverse Events are not
Unanticipated Problems
Do Not Report AE that are not UP
to OHRP
Report all UP
38
Reporting Considerations

Who is responsible for prompt reporting
 to whom/which office(s) or official(s)

Time frames for accomplishing reporting
requirement

Range of possible actions taken by the IRB in
response to reports
Reporting Incidents to OHRP:
http://www.hhs.gov/ohrp/policy/incidreport_ohrp.html
39
13
Other HHS Requirements
and Additional Considerations
40
Other Issues for Possible Inclusion

Important definitions

Preparing for review/meeting

IRB member selection & retention

IRB meeting attendance

IRB member responsibilities

Research with vulnerable populations
41
Other Issues for Possible Inclusion (cont’d)

Relying on an external IRB

Serving as IRB for other institutions

Managing allegations of non-compliance

Minimizing coercion and undue influence

Other relevant authorities
42
14
Key Points -Required Elements of
Written IRB Procedures

Institutions must have written procedures
comprised of the seven required elements

Include step-by-step operational details that are
user friendly and effective

Implement throughout the organization

OHRP guidance is available
43
IRB Membership, Review, and Approval
44
Membership Requirements

Number of Members






minimum of 5 members - §46.107(a)
Experience and Expertise - §46.107(a)
Diversity of Members - §46.107(a) & (b)
At least one:
 scientist - §46.107(c)
 nonscientist - §46.107(c)
nonaffiliated - §46.107(d)
Prisoner Research - §46.304(a) & (b)
45
15
Flexibility & Efficiency


Expert Consultant -
§46.107(f)

provides supplement review

does not vote
Alternate members

appropriate expertise

substitute for entire meeting or any portion of meeting
46
IRB Member Conflict of Interest
- §46.107(e)

May provide information requested by the IRB

Recusal from IRB’s deliberations and voting;
suggest leave room

Conflicted members do not contribute to the
quorum
47
IRB Review
48
16
IRB Review & Approval

Initial – prior to enrolling subjects

Continuing review – at least annually

Prior to initiating changes to approved research
49
Types of IRB Review

Convened meeting of IRB –

Expedited review –
§46.108
§46.110

minor changes to approved research

no greater than minimal risk and on “list” at:
http://www.hhs.gov/ohrp/policy/expedited98.html
50
Criteria for IRB Approval


Make findings required by §46.111
Additional findings under applicable subparts B, C,
and D

Categories of permissible research

Informed consent, assent, permission

Other considerations
-- e.g., IRB composition, Secretarial panel
process, expert consultants
Note: IRB must have sufficient information to make
required findings at §46.111 and any relevant
subpart(s)
51
17
Range of Possible IRB Actions
Description of action:

Approve research

Require modifications in order to secure approval

Disapprove research (convened IRB only)

Suspend or terminate previously approved research
52
IRB Recordkeeping
53
Outline

IRB records


IRB meeting minutes
Retention of IRB records
54
18
IRB Records

Copies of

research proposals reviewed

scientific evaluations, if any

approved sample consent documents

progress reports submitted by investigator

reports of injuries to subjects
§46.115(a)(1)
55
IRB Records (cont’d)

IRB meeting minutes

Records of continuing review activities

Correspondence between IRB and
investigators
§46.115(a)(2-4)
56
IRB Records (cont’d)

List of IRB members

Written IRB procedures

Statement of significant new findings provided
to subjects
§46.115(a)(5-7)
57
19
IRB Meeting Minutes

Regulatory requirements - §46.115(a)(2)

Objective

Too much or too little: It’s always a balancing act!
58
IRB Meeting Minutes to Describe
Regulatory requirements

Attendance

IRB actions

IRB vote

Basis for requiring changes in or disapproving
research

Controverted issues
59
Attendance at Meeting

Document attendance

members

others

Entry/Exit/Recusals

Document quorum

Loss of quorum = no further IRB action
60
20
IRB Actions and Votes

Minutes to reflect actions taken by convened
IRB


regulatory

institutional
Vote on IRB actions

for

opposed

abstain
61
Examples of IRB Vote *



Total Voting = 15;

Vote: For-13, Opposed-1, Abstain-1;

APPROVED
Total Voting = 14 (1 Recusal due to COI);

Vote: For-8, Opposed-3, Abstain-3;

APPROVED
Total Voting = 14 (1 Recusal due to COI);

Vote: For-7, Opposed-1, Abstain-6;

NOT APPROVED
* assumes quorum is met
62
Basis for Requiring Changes
in or Disapproving Research

Why IRB required changes to specific proposed
research

Why IRB disapproved research
63
21
Controverted Issues


Written summary

discussion and

resolution
Dictionary definition of controverted:
- to dispute or oppose by reasoning
- to engage in controversy
64
Remember: Waiver of Informed Consent
Alteration or waiver of informed consent must be
documented under §46.116(c) & (d)
65
Sample Working Outline


Date/Time
Attendance - nonscientist present






is attendance current with roster on file with OHRP?
Approval of prior meeting minutes
Convened IRB review and votes
initial review, continuing review, amendments and/or
protocol changes
consider protocol-specific justifications where
appropriate
Adverse events/unanticipated problems/safety
reports/DSMB reports
66
22
Sample Working Outline (cont’d)

Expedited review report – e.g., new studies,
continuing review, amendments, protocol
changes, required documented findings

Suspensions/terminations

Other


discussion of educational topic
Adjournment time
67
Retention of IRB Records

Minimum three years

Accessible for inspection and copying
§46.115(b)

Check state and local laws
68
Key Points IRB Recordkeeping

Maintain records in compliance with regulations

Minutes should reflect activities, discussions, and
considerations of determinations

All records shall be accessible for inspection
69
23
Informed Consent
70
Outline

General Considerations

Elements of Informed Consent

Research with Children

Waiver or Alteration of Informed Consent

Documentation of informed consent

Compliance Oversight – Findings and Actions
71
General Considerations
72
24
Informed Consent
Key principles of the informed consent process:
Full disclosure of the nature of the research and the

subject's participation
Facilitate comprehension on the part of the potential

subjects or legally authorized representative (LAR)
The subject's voluntary choice to participate or not

73
Legally Effective Informed Consent

Obtain and document (unless waived)

Follow HHS regulations & local laws

Opportunity to consider participation

Language must be understandable to
subject/LAR
74
Legally Effective Informed Consent (cont’d)

LAR for adults with impaired capacity to consent
Parental (or guardian) permission and child assent
Local laws dictate age of consent; who is a
guardian; and who is LAR
Minimize coercion or undue influence

No exculpatory language (see draft guidance):



http://www.hhs.gov/ohrp/newsroom/rfc/exculpatorydraft2011.html
75
25
Informed Consent is a PROCESS

Educational process

Includes recruitment materials and verbal
instructions

Usually, on-going—continuing after study starts,
and in some instances, ends

NOT:

single event, in most cases

a form
76
Elements of Informed Consent
77
Basic Elements of Informed Consent
 Research
 Alternatives

purpose
 Confidentiality

duration
 Compensation for injury

procedures
 Whom to contact
 Risks, discomforts
 Benefits
 Right to refuse,
withdraw without
penalty
§46.116(a)
Note: Additional elements, when appropriate
§46.116(b)
78
26
Elements of Informed Consent, cont’d

Description of research

Purposes of research

Expected duration of subject’s participation

All procedures to be followed, including any
experimental
79
Elements of Informed Consent, cont’d



Descriptions of any:

reasonably foreseeable risks or discomforts

reasonably expected benefits to subjects or others

appropriate alternatives
Extent to which, if any, confidentiality will be
maintained
compensation for injury, or lack thereof, if greater
than minimal risk
80
Elements of Informed Consent, cont’d


Whom to contact re: questions

about the research

about subject’s rights

in event of research-related injury
Participation voluntary; refusal or withdrawal
without penalty or loss of benefits
81
27
Pay heed: “if any”
The regs require that the informed consent include
“any”

experimental procedures,

reasonably foreseeable risks or discomforts, benefits, 
appropriate alternatives, and

a description of the extent to which records that
identify subjects will be confidential
82
Pay heed: “if any”

If no expected benefits, OHRP recommends stating
directly

If lack of confidentiality could pose risk, must disclose

If lack of confidentiality poses no risk, then not
required to disclosure (but OHRP recommends you do)
83
Additional Elements of Informed Consent - as appropriate

Procedure may involve unforeseeable risks to
subject (or fetus)

Potential reasons for termination of participation

Costs to subject

Consequences of withdrawal

Significant new findings will be provided to subject
84
28
Research with Children
85
Research Involving Children-Parental
Permission

Must be adequate provisions to seek
parent/guardian permission, as required by
§46.116

Minimal risk research or with prospect of direct
benefit---IRB may allow permission from one
parent

Greater than minimal risk without direct benefit--need permission from both parents
§46.408(b)
86
Research Involving Children- Assent

“Assent”---child’s affirmative agreement to
participate

Failure to object is not assent

Assent required when IRB judges the children
capable of assenting

If direct benefits to the health or well-being of the
child that is only available through the research,
assent not necessary
87
29
Research Involving Children- Assent,
cont’d

Determination of capability of assent should take
into account:


children’s age, maturity, psychological state
Judgment can be made for all children or for
each child
88
What happens when there is disagreement
between a parent and his/her child about
research participation?
89
Disagreement between a parent and
his/her child…

If child is capable and says NO
NO GO!
UNLESS:

IRB waives assent requirement under §46.116 or
waives assent because intervention or procedure
holds out prospect of direct benefit important to
the health or well-being of the child AND is
available only in the context of research
90
30
Disagreement between a parent and
his/her child, cont’d

Conversely, if a child is capable and says YES
BUT

Parental permission has not been waived by the
IRB and parent says NO
= NO GO!
91
Assent---Missing Pieces
Regulations DO NOT

Specify specific age, developmental level, etc.

Specify specific method to obtain or document
assent

Specify what information about the research
must be given to the child
92
Waiver or Alteration of Informed
Consent
93
31
Waiver or Alteration of Informed Consent

Consistent with §46.116(c) or (d)

Waiver of child assent & parental permission §46.408 (subpart D)
Secretarial waiver §46.101(i) – e.g., research

conducted in emergency setting
94
Waiver or Alteration of Informed Consent - §46.116(d)
To omit or alter some or all of the required
elements of informed consent, IRB must find and
document that:




Research no more than minimal risk
Waiver or alteration will not adversely affect the
rights and welfare of subjects
Research could not practicably be carried out
without the waiver AND
Whenever appropriate, the subjects will be
debriefed
95
Research Involving Children- Waiver of Parental Permission


In accordance with §46.116(d)
If parental permission is not reasonable to protect
the children (e.g., neglected or abused children)
permission can be waived, if:

appropriate mechanism for protecting children is
substituted, and

waiver is not inconsistent with Federal, state or local
law
§46.408(c)
96
32
Research Involving ChildrenWaiver of Assent

If IRB determines that children are capable of
assenting, may still waive assent requirements in
accordance with §46.116
§46.408(a)
97
Secretarial Waiver of Informed Consent for
Certain Emergency Research

Waiver can be obtained when subject (due to
condition and lack of LAR) cannot provide consent
and needs emergency therapy, if certain conditions
are met

Both FDA and OHRP have provisions for a waiver

OHRP guidance on emergency research waiver:
http://www.hhs.gov/ohrp/policy/hsdc97-01.html
98
Documentation of Informed Consent
99
33
Documentation of Consent
Informed Consent will be Appropriately
Documented, in Accordance with,
and to the Extent Required by §46.117
§46.111(a)(5)
100
Two Types of Consent Forms are
Permissible:
 Written consent document that includes:
 basic elements of informed consent
 any applicable additional elements
OR
 Short form which states:
 that the elements of informed consent have been
presented orally to the subject
101
Documentation of Informed Consent –
Long form
Embodies all consent elements

Adequate opportunity to read document

Signed by subject/legally authorized
representative

Copy given to subject or representative
§46.117(b)
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Documentation of Informed Consent–
Short form
Oral presentation of all consent elements

IRB approved written summary of oral
presentation

Signed by subject or representative

Witness signs short form & summary

Person seeking consent signs summary

Copy of summary and short form given to
subject or legally authorized representative
§46.117(b)
Oral Explanation
(in language
understandable to
subject)
Short Form
Documentation
of Informed
Consent:
§46.117 (b)(2)
Short Formstatement that all
elements
presented orally (in
a language
understandable to
subject)
Signed by
Subject/LAR
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Written
Summary- What
was presented
orally
(can be in
English)
Signed by
Witness (who is
fluent in English
& subject’s
language)
Signed by
Witness
Signed by
Person
Obtaining IC
Give Copy to
Subject/LAR
Give Copy to
Subject/LAR
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Signatures

Recommend dating (req’d for FDA)

Electronic


Check state & local laws & FDA requirements
Faxed okay
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Signatures, cont’d

Who must sign?

Long Form: Subject / legally authorized rep

Short Form: Subject / LAR, witness, person obtaining consent

Permission: One or both parents (or guardian)
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Do the regulations under subpart D
require that assent be documented?
NO

“Adequate provisions”

Can be verbal

Can be written

Should be tailored to the research and
age/maturity of the subject
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Waiver of Documentation of Informed
Consent
IRB may waive requirement for signed
consent for some or all subjects if it finds:

the research is no more than minimal risk; and 
the procedures do not require written consent
when performed outside of a research setting.
§46.117(c)(2)
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Waiver of Documentation of Informed
Consent, cont’d
IRB may waive requirement for signed consent for
some or all subjects if it finds:

breach of confidentiality is principal risk; and

consent form is the only record linking the subject
with the research
§46.117(c)(1)
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Points to Remember

IRB findings and documentation

Consent alteration or waiver generally required
for deception research

"Passive consent" or "implied consent" is not
consent (requires waiver)

IRBs—exercise waiver authority if research
meets criteria; remember to document
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Compliance Oversight -Findings and Corrective Actions
111
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Citations of Noncompliance &
Deficiencies- Overall
112
113
Compliance Oversight Findings

Failure to obtain legally-effective informed
consent

Failure to adequately address required elements
of informed consent

Failure to document informed consent

Coercion/undue influence
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Corrective Actions

Notified subjects, if necessary

Procedures to ensuring IRB only approves informed
consent that includes adequate information to
inform subjects about research
- if failure on part of IRB
Ensuring IRB receives sufficient information to

review and approve research under §46.111
- if failure on part of investigator
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What to do With Data Collected without
Consent?



Regulations don’t address
Determined by IRB, appropriate institutional officials
and study sponsor (and FDA, if appropriate)
Possibilities:

Not allow data use

Inform subjects and solicit permission to publish data

Require PI to inform journals
116
OHRP Contact Information

Phone: 866-447-4777
240-453-6900

Fax:
240-453-6909

E-mail: ohrp@hhs.gov

Web Site: http://www.hhs.gov/ohrp

ListServ: http://www.hhs.gov/ohrp/newsroom/index.html
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for protecting
Human Subjects !
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