Quorum Review presents a special webinar with J. Claire Carbary, JD, CIP to discuss IRB expectations when research involves minors or adults with limited capacity to consent. The presenter will outline guidance in recruiting these populations and clarify who might serve as the appropriate legal representatives based on federal regulations and state law.

1. fully accredited since 2006
September 10 & 12, 2013
Research Involving
Subjects with Limited Capacity:
IRB Expectations for Recruitment and Consent

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4. • Questions & Answers
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• We will address a select number of questions
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Responses will be sent by the presenters
following the presentation for the remainder.

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WEBINAR HOUSEKEEPING

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ABOUT QUORUM REVIEW IRB
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THE QUORUM ADVANTAGE

9. Quorum Review Regulatory Attorney
J. Claire Carbary, JD, CIP
IRB Experience
 Joined Quorum Review IRB in September 2009
 WIRB prior to Quorum
 CIP certification since 2010
 Member of the Northwest Association for
Biomedical Research (NWABR) and Public
Responsibility in Medicine and Research (PRIM&R)
Legal Background
 Juris Doctor from Seattle University
 Member of the Washington State Bar Association (WSBA)
 Member of the Health and Corporate Law Sections of the WSBA
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ABOUT THE PRESENTER

10. Research Involving Subjects with Limited Capacity:
IRB Expectations for Recruitment and Consent
Research Involving Children 11
 Allowable Research with Children 12
 Defining “Child” 16
 Recruitment for Research Involving Children 20
 Assent 21
 Permission 27
 Wards 32
 Neonates 35
Research Involving Adults Requiring a Legally
Authorized Representative (LAR) 37
 Allowable Research with Adults Requiring an LAR 38
 Determining whether an LAR is Needed 40
 Identifying an Appropriate LAR 43
 Recruitment for Research with Adults Requiring an LAR 46
 Assent 47
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WEBINAR OVERVIEW

11. 11
Research
Involving
Children
“The inclusion of children in research
advances the commitment to justice in
research by improving our knowledge of,
and ability to respond to, the unique needs
of children throughout their development”
- Canadian Tri-Council Policy Statement
(TCPS 2), Ethical Conduct for Research
Involving Humans

12. Category 1:
Research not involving greater than “minimal risk”
• “Minimal Risk” means that the probability and magnitude of
harm or discomfort anticipated in the research are not greater in
and of themselves than those ordinarily encountered in daily life
or during the performance of routine physical examinations or
tests.
• Must have adequate provision for soliciting assent of children
and permission of parent/guardian
Citation: 21 CFR 50.51, 50.53; 45 CFR 46.404, 46.102(i)
Allowable Research with Children
12

13. Category 2:
Research involving greater than minimal risk but
presenting the prospect of direct benefit to the
individual subjects
• Risks must be justified by anticipated benefits
• Risk-benefit ratio must be at least as favorable as
that presented by alternative approaches
• Must have adequate provision for soliciting assent of
children and permission of parent/guardian
Citation: 21 CFR 50.52; 45 CFR 46.405
Allowable Research with Children
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14. Category 3:
Research involving greater than minimal risk and no
prospect of direct benefit to individual subjects, but likely to
yield generalizable knowledge about the subject’s disorder
or condition
• Risk must represent a “minor” increase over minimal risk
• The intervention or procedures must present experiences
on par with those inherent in their actual or expected
“situations”
• Must have adequate provision for soliciting assent of
children and permission of both parents/guardian
Citation: 21 CFR 50.53; 45 CFR 46.406
Allowable Research with Children
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15. Allowable Research with Children
Category 4:
Research not otherwise approvable which presents an opportunity to
understand, prevent, or alleviate a serious problem affecting the health
or welfare of children
• Must be disapproved by the IRB and sent to the Commissioner of Food and Drugs or
Secretary of HHS
• IRB must find that research presents a reasonable opportunity to further understanding,
prevention, or alleviation of a serious problem affecting the
health or welfare of children
• The Commissioner or Secretary (as applicable) must determine the
research actually meets one of the previous categories OR must agree
with IRB determination about the research and find:
o that the research will be conducted in an ethically sound manner, and
o Must have adequate provision for soliciting assent of children and
permission of parent/guardian
Citation: 21 CFR 50.54; 45 CFR 46.407
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16. 16
“Quote involving children in research…”
Defining
“Child”
“A person’s a person,
no matter how small.”
- Dr. Suess, Horton Hears A Who!

17. Defining “Child”
Children means persons who have not attained the legal age for consent to
treatments or procedures involved in clinical investigations, under the
applicable law of the jurisdiction in which the clinical investigation will be
conducted.
Citation: 21 CFR 50.3; 45 CFR 46.402
17

18. • Most states set the age of majority at 18 or over, with some exceptions:
o Alabama- Age 19 (Ala. Code § 26-1-1)
o Nebraska- Age 19 (Nebraska Revised Statues 43-2101)
o Puerto Rico- Age 21 (21 P.R. Laws Ann. Tit. 31 § 971)
State Law & Age of Majority
Nebraska
Alabama
Puerto Rico
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If the protocol inclusion
criterion regarding age
indicates “18 and older”, and
the research will be in these
jurisdictions, then, the research
involves “children.”

19. • Generally- minors aged 14-15 can consent to medical “treatment”
• There may be notification requirements:
o Connecticut: Minors 14 and older may consent to mental health
treatment, provided that the parents are notified within five days.
See Connecticut Gen. Stat. §21a-110.
Citation: Boonstra, Heather and Elizabeth Nash; Minors and the Right to Consent to Health Care, Guttmacher Institute,
Guttmacher Report on Public Policy, August 2000, Volume 3, Number 4
Available at: http://www.guttmacher.org/pubs/tgr/03/4/gr030404.html, accessed 08.26.2013.
State Law &
Consent to Medical Care vs. Research
19
If the research involves
procedures or
interventions that are not
treatment, it is likely
parental permission is
needed.
Connecticut

20. • Payments
o Who is paid?
o Type of payment?
• Advertisements
o Where are you advertising?
o Directed to children or parents?
Recruitment for
Research Involving Children
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• Understandability
o Is advertisement or recruitment
aimed at children written at an
appropriate grade
level?
• Therapeutic misconception
ENROLL
YOUR CHILD
TODAY!

21. 21
Obtaining Assent
Childrenfrom

22. Assent means a child's affirmative
agreement to participate in a clinical
investigation. Mere failure to object
should not, absent affirmative
agreement, be construed as assent.
Citation: 21 CFR 50.3; 45 CFR 46.402
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What is Assent?

23. The IRB must determine whether “adequate
provisions are made for soliciting the assent
of children WHEN…the children are capable
of providing assent”
If the IRB determines the capability of some
or all of the children is so limited that they
cannot reasonably be consulted or that the
intervention or procedure involved in the
research holds out the prospect of direct
benefit that is important to the health or well-
being of the children and is available only in
the context of the research, the assent of
the children is not a necessary condition for
proceeding with the research.
Citation: (21 CFR 50.55(a); 45 CFR 46.408(a)
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When is Assent of Children Required?

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State Laws
Regarding Assent for Research
• Illinois: Minors must consent when considered “capable.”
(405 ILCS 5/2-110 774 Ad. Code 260.1900 (2010)).
• Maine: Subjects between the age of
12-18 must provide consent unless they
are unable to do so in addition to
parent/guardian consent.
(CMR 14-472001 (XI)(H)(3)(c)(2010)).
• Massachusetts: Informed consent cannot be
given on behalf of a minor who has refused consent.
(105 CMR 700.009(E)(4)).
• California: If subject is older than 7 years or older - must provide consent themselves.
(California Health and Saf. Code § 111530 (2012).
California
Illinois
Maine
Massachusetts

25. The IRB should take into account:
• Ages of the participants
• Maturity level
• Psychological state
Citation: 21 CFR 50.55(a); 45 CFR 46.408(a)
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Factors to Consider when determining
whether Assent is required

26. • Written assent forms for ages that
would typically be reading
• Reading level should match age-
range of participants (might need
multiple assent forms)
• Consider including images to explain
concepts
• Consider an electronic-based
approach to assent
• Signature or not?
Obtaining Assent

27. 27
Parental
Permission

28. • The IRB must determine that the
permission of each child’s parents
or guardian is granted
• For categories 1 and 2 of research
involving children - the IRB may
determine that the permission of
one parent is sufficient, otherwise
permission of both parents is
required
• The signature of the second parent
is not required if that parent
is deceased, unknown,
incompetent, or not reasonably
available
Citation: 21 CFR 50.55 (e); 45 CFR 46.408(b)
Parental Permission

29. Permission means the agreement of
parent(s) or guardian to the participation of
their child or ward in a clinical investigation.
Parent means a child's biological or adoptive
parent.
Guardian means an individual who is
authorized under applicable State or local law
to consent on behalf of a child to general
medical care.
Citation: 21 CFR 50.3; 45 CFR 46.402
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Permission for Children to
Participate in Research

30. • Legally effective consent
of children is required if
the research is ongoing
(including data collection)
• Remote consent may be
needed
• If this is anticipated,
develop a consent form to
be signed by adolescents
that will reach the age of
majority during the
research
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When Children Become Adults

31. 31
Minor Parents
• Minor parents are still parents
• May not be able to consent for themselves
but can consent for their children.
o Delaware: a minor parent may
consent for medical treatment for
his/her child
(13 Del. C. §707 (2010).
o Maryland: minors who are parents
may consent to healthcare treatment.
Md. Health Code 20-102-20-104 (2010).
o Minnesota: Minor parents may
consent to health care.
(Minn. R 952S.3050.)
• This can complicate consent for some
studies (example: pregnancy exposure
registry that would follow mother and child)
Minnesota
Maryland
Delaware

32. 32
Research Involving “Wards”
Ward means a child who is placed in the legal custody of the State or other
agency, institution, or entity, consistent with applicable Federal, State, or local law.
Citation: Citation: 21 CFR 50.3; 45 CFR 46.402

33. 33
Additional Federal Requirements
for Research Involving “Wards”
Research that would not provide direct benefit (Categories 3 and 4) is not
allowable unless the research meets one of the following requirements:
1. Relates to their status as wards; or
2. Is conducted in schools, camps, hospitals, institutions, or similar settings in which the
majority of children involved as subjects are not wards.
Citation: 21 CFR 50.56(a); 45 CFR 46.409(a).

34. 34
Research Involving Wards
and State Law
State laws may provide additional protections for children-further restricting
research involving wards of the state.
• Alabama: Juveniles in residential facilities are not permitted to be subjects in medical
or pharmaceutical experiments (Alabama- Ala Admin. Code r. 950-1-6-.03 (6)(d))
• New Hampshire: Guardian of a minor cannot consent to experimental treatment of any
kind unless approved by order of a court
(New Hampshire Revised Statutes Annotated 463:12).
.
New Hampshire
Alabama

35. 35
Research Involving Neonates
• Research involving viable neonates- is subject to the requirements for the standard Subpart D
requirements for research involving children
• Research involving neonates of uncertain viability and nonviable neonates is subject to a
number of additional requirements:
o Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data
for assessing potential risks to neonates.
o Individuals providing consent must be fully informed regarding the reasonably foreseeable impact of the
research on the neonate.
o Individuals engaged in the research can have no part in determining the viability of a neonate.
Neonates of uncertain viability.
 Research must potentially enhance the
probability of survival of the neonate to
the point of viability, and any risk is the
least possible for achieving that
objective, OR
 The purpose of the research is the
development of important biomedical
knowledge which cannot be obtained by
other means and there will be no added
risk to the neonate resulting from the
research; and
 Consent of one parent
Nonviable neonates.
 Vital functions of the neonate will not be
artificially maintained for research;
 Research will not terminate the
heartbeat or respiration of the neonate;
 There will be no added risk to the
neonate resulting from the research;
 The purpose of the research is the
development of important biomedical
knowledge that cannot be obtained by
other means; and
 Consent of both parents (unless one is
not available) - consent by LAR is not
acceptable

36. Ramifications of storing tissue/specimens
– Data privacy concerns due to limited ability to “de-identify” data
– Genetic markers discovered in the future could identify risk for developing
diseases or conditions
– Growing concerns may lead to laws impacting genetic testing-
• Example: Genetic testing on minors can only be performed with the consent of the
parent/legal guardian and written informed consent of the minor
(Arizona A.R.S. § 12-2803)
36
Specimens & Genetic Testing –
Research Involving Children

37. 37
Research
Involving
Incapacitated
“In keeping with the principle of Justice,
those who lack the capacity to consent on
their own behalf must neither be unfairly excluded
from the potential benefits of research participation,
nor may their lack of capacity to consent be used
to inappropriately include them in research.”
- Canadian Tri-Council Policy Statement (TCPS 2),
Ethical Conduct for Research Involving Humans
Adults

38. • Earliest version of the Nuremberg Code only allowed
subjects to consent for themselves
• No federal regulatory restrictions on the research in the
U.S. Proposed additional regulations in 1978 for
research involving the “institutionalized mentally infirm”
were never finalized
• The International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use, Guideline for Good
Clinical Practice (ICH-GCP) (E6) provides guidance on
research involving incapacitated adults
38
Allowable Research Involving Adults
Requiring an LAR
Citation: National Bioethics Advisory Commission. Research involving persons with
mental disorders that may affect decision-making capacity: report and recommendations,
December 1998.

39. Non-therapeutic trials may be conducted in subjects with consent of a legally
acceptable representative provided the following conditions are fulfilled:
(a) The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent
personally.
(b) The foreseeable risks to the subjects are low.
(c) The negative impact on the subject’s well-being is minimized and low.
(d) The trial is not prohibited by law.
(e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects,
and the written approval/ favorable opinion covers this aspect.
Such trials unless an exception is justified, should be conducted in subjects having a
disease or condition for which the investigational product is intended. Participants in
these trials should be particularly closely monitored and should be withdrawn if they
appear to be unduly distressed.
Citation: ICH GCP E6
39
Allowable Research Involving Adults
Requiring an LAR

40. “It is generally agreed that a prospective
subject’s capacity to decide whether to
participate in a particular research project
cannot be determined through a general mental
status assessment. Instead, investigators must
develop and present the specific material
relevant to that project and evaluate the
prospective subject’s understanding and
appreciation of that information.”
40
Standards for Assessing Capacity
Citation: National Citation: National Bioethics Advisory Commission. Research involving persons
with mental disorders that may affect decision-making capacity: report and recommendations,
December 1998.

41. • Protocol may dictate the tools or process that should be used to
assess capacity- for example specific scores on the MMSE
• Should be conducted by the person obtaining consent
• Depending on risk/benefit ratio and other factors- an independent
capacity assessment might be warranted
• Evaluate for:
– Ability to evidence a choice (express their preference)
– Ability to understand relevant information
– Ability to appreciate the situation and its likely consequences
– Ability to manipulate information rationally
Citation: Bankert, Elizabeth A. and Robert J. Amdur, Institutional Review Board Management and Function, 2nd Edition,
Research Involving Adults with Decisional Impairments, 2006. Leo, Raphael J., Competency and the Capacity to Make
Treatment Decisions: A Primer for Primary Care Physicians, Prim Care Companion J Clin Psychiatry. 1999 October; 1(5):
131-141.
41
Capacity Assessment

42. • Idaho: “Any person with sufficient intelligence and awareness to
understand the necessity of, nature of, and significant risks involved in
any medical treatment is competent to consent to the treatment.”
(Idaho Code § 39-4502 (2010).
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State Law Definitions of Capacity
Idaho

43. 43
Identifying an appropriate LAR
Legally authorized representative
means an individual or judicial or other
body authorized under applicable law
to consent on behalf of a prospective
subject to the subject's participation in
the procedure(s) involved in the
research.
Family member means any one of the
following legally competent persons:
Spouse; parents; children (including
adopted children); brothers, sisters,
and spouses of brothers and sisters;
and any individual related by blood or
affinity whose close association with
the subject is the equivalent of a
family relationship.
Citation: 21 CFR 50.3; 45 CFR 46.102

44. 44
State Law and LARs
for Incapacitated Adults
• General order of authority for consent
o Agent/guardian with authority to make health care decision on person’s
behalf
o Spouse /Domestic Partner
o Adult children
o Custodial parent
o Adult sibling
o Adult grandchild
o Available adult relative with closest degree of kinship
• If there are multiple people at the same level- they generally
must all agree (for example- siblings or children) unless one
is the designated agent under an advance health care
directive
• U.S. jurisdictions with civil unions or same-sex marriage:
o Civil Unions: Colorado, Hawaii, Illinois, and New Jersey
o Same-sex marriage: California, Connecticut, Delaware, Iowa, Maine,
Maryland, Massachusetts, Minnesota, New Hampshire, New York,
Rhode Island, Vermont, Washington and the District of Columbia
o Domestic Partnerships: Nevada, Wisconsin, Oregon, and the District
of Columbia (for both same-sex and opposite-sex couples)
Same-Sex Marriage
Civil Unions
Domestic Partnerships

45. Colorado: If a patient is not competent to provide consent the
physician must make efforts to locate as many interested persons
(spouse, parent, adult child, sibling, grandchild or close friend) as
possible and inform them of the patient’s lack of decision-making
authority so the interested persons may select a proxy. (Colorado-
C.R.S. 15-18.5-103(3)).
Colorado: Experimental research involving developmentally disabled
individuals is prohibited without consent and a non-affiliated
interdisciplinary team is consulted
(Colorado—C.R.S. § 27-10.5-114 (7)).
Delaware: Restrictions on research involving residents in a state-
operated mental health institution include: objective psychiatrist to
monitor capacity to provide consent, witness of consent process and
documentation with signature on the consent form—special state-run
IRB review. (16 Del. C. §5171-5175).
Minnesota: The guardian of a patient at a mental health institution
cannot provide consent to research participation unless a court initially
grants approval. (Minn. R §952S.3060).
New Jersey: A public guardian for an elderly individual cannot consent
to medical experimentation without the permission of the court. (N.J.St.
52:27G-26).
45
State Law and Permission for
Incapacitated Adults
Minnesota
Colorado
New Jersey
Delaware

46. • Advertising
– Care providers or LARs
– Support groups
• Consider Logistics
– Payment or services
– Ease of access to
sites/parking, etc.
• Therapeutic Misconception
46
Recruitment for Research Involving
Incapacitated Adults

47. “When a trial (therapeutic or non-
therapeutic) includes subjects who can
only be enrolled in the trial with the
consent of the subject’s legally
acceptable representative (e.g. minors
or patients with severe dementia), the
subject should be informed about the
trial to the extent compatible with the
subject’s understanding and, if capable,
the subject should sign and personally
date the written informed consent.”
Citation: ICH GCP E6, Section 4.8.12
47
Assent for Adults Requiring an LAR

48. • Missouri: Consent cannot be provided if the
incompetent adult expressly declines to participate
in the research. (R.S.Mo. § 431.064).
• Indiana: Mental Health patients must be informed
of the investigator’s credentials, the risks and
benefits of participating in the clinical study, and
their ability to revoke consent. (Burns Ind. Code
Ann. § 16-36-1.5-10).
• New Mexico: Involuntary commitment to a mental
institution does not necessarily mean the patient is
incapable of providing consent to research. (New
Mexico-N.M. Stat. Ann. §43-1-15).
48
State Law & Assent from Adults
Requiring an LAR
New Mexico
Missouri
Indiana

49. • There are several additional
considerations when utilizing proxy
consent for research involving children and
incapacitated adults in research.
• It is important to be aware of the legal
requirements and ethical guidelines when:
– Designing research
– Developing recruitment, and
– Approaching the consent process
SUMMARY
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50. • You may submit questions during our webinar
survey, or…
• You may email your questions to:
clientrelations@quorumreview.com
• We will do our best to follow-up individually or
answer your questions in the Q&A we post on
our website
50
ADDITIONAL QUESTIONS

51. • The webinar Recording, Slide Deck,
and Q&A will be posted on our
website
• We will email you a link to view
these items as they become
available
• We value your opinion – please take
our SURVEY and provide us with
feedback
51
WEBINAR FOLLOW-UP

52. Connect with Quorum Review
52
Thank you for your time!

53. THANK YOU FOR ATTENDING!
53

54. fully accredited since 2006
September 10 & 12, 2013
Research Involving
Subjects with Limited Capacity:
IRB Expectations for Recruitment and Consent