The CEO's letter discusses a recent controversy surrounding a study on care for premature infants that raised issues for IRBs. 23 IRBs had approved similar consent forms for the study, but the OHRP later issued a letter critical of the consent forms. The letter sparks debate around how much risk/benefit information should be included in consent forms. Two enclosed articles provide more information on consent for legally incapacitated adults and FDA changes regarding placebo-controlled pediatric trials.

1. May 8, 2013 | Volume 3, Issue 2
Institution Bulletin
Letter from the CEO
A recent controversy in the news raises difficult issues for IRBs. In 2004 and
2005, 22 institutions initiated a study (the SUPPORT trial) of the optimum
care of premature infants. A template consent form was developed and
similar versions approved by 23 IRBs. The study yielded clinical
information hailed as critically important.
But earlier this year, the Office for Human Research Protection issued a determination letter critical of the study’s
informed consent forms. OHRP concluded that for one arm of the study, the consent forms identified a possible
benefit without identifying possible risks; for the other arm, OHRP concluded that the consent forms did not
identify either risks or benefits.
The OHRP letter has sparked controversy and criticism. Aside from the specifics of the SUPPORT trial, the
letter raises the perennial question: how much information is enough? Regulators, researchers and IRBs are
concerned that consent forms are too long and technical. But the OHRP letter reminds us of the importance of
fully informing patients and their families of the possible risks and benefits of the proposed research.
In this increasingly complex world of research, we all struggle to make the right decisions. To help you with your
human research protection program, enclosed are two articles regarding vulnerable populations. One article
describes the use of legally authorized representatives and witnesses in the consenting process. The other
summarizes recent FDA developments regarding pediatric research.
Quorum Review is honored to have the privilege of working with you and your research teams. Please let us
know if we can be of further assistance.
Sincerely,
Cami Gearhart, CEO
Quorum Review IRB

2. April 25, 2013 | Volume 3, Issue 2
Q&A with Quorum: Consent for Legally Incapacitated Adults and
Subjects Physically Unable to Sign
Our practice sees many elderly patients
that occasionally require someone to
consent on behalf of the patients for their regular
medical treatment. How is consenting different for
these patients in a research context?
Before a site can obtain a person’s consent for
research, the investigator must ensure that an
individual has the decisional capacity to consent to
the research. The investigator may make this
assessment by using a capacity assessment tool, such
as the Mini Mental State Examination (MMSE) or
other appropriate tests or evaluations. The FDA and
Department of Health and Human Services (HHS)
define a legally authorized representative (LAR) as,
“…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.”1
Local law determines
whether a person
can serve as an LAR
and what powers
this person has. It is
the investigator’s
responsibility to
ensure compliance
with his or her local laws and to have a system in
place to ensure that only properly qualified LARs
consent to research on behalf of a participant who
does not have capacity to provide consent for
themselves.
1
21 CFR 50.3; 45 CFR 46.102.
An IRB has the authority to restrict the use of LARs
in a study if it determines that it would not be
appropriate to enroll individuals who cannot
consent for themselves. For trials that do not present
a therapeutic value to subjects, ICH GCP advises
that individuals who cannot consent for themselves
should only be enrolled with the consent of a legal
representative when the following conditions are
fulfilled:
 The objectives of the trial cannot be met by
means of a trial in subjects who can give
informed consent personally
 The foreseeable risks to the subjects are low
 The negative impact on the subject’s well-
being is minimized and low
 The trial is not prohibited by law
 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
aspect2
When an LAR is needed and allowed by the IRB,
study staff must conduct the consent discussion with
the LAR, and the consent form must be signed by
the LAR to document their consent. While the FDA
and HHS regulations and guidance only require a
copy of the consent form be given to the LAR, ICH
GCP requires a signed copy of the consent be
2
ICH E6, Good Clinical Practice: Consolidated Guidance, 4.8.14;
available at:
http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf
(accessed 04/10/2013)

3. April 25, 2013 | Volume 3, Issue 2
While the FDA and HHS regulations
and guidance only require a copy of the
consent form be given to the LAR, ICH
GCP requires a signed copy of the
consent be provided to the LAR once
consent has been obtained.”
“
provided to the LAR once consent has been
obtained.1
Assent from adult participants who lack the
decisional capacity to consent to research should be
obtained where possible. Individuals who can
provide assent can sign and date the consent as well,
though their signature is not the legally valid
documentation of consent.2
Dissent should be
respected, and individuals should not be enrolled
against their wishes. Even if an LAR has authorized
an individual’s participation, an investigator has an
obligation to discontinue that individual’s
participation should the individual express fear,
discomfort or any disagreement with study
procedures.
Quorum Review takes several steps to evaluate the
enrollment of subjects requiring an LAR in research.
First, Quorum requests information from the
sponsor and the investigator as to whether they
would allow the enrollment of subjects requiring an
LAR in the research. Second, during review of the
research, Quorum’s Board determines whether the
enrollment of such subjects is appropriate for the
research. If the Board allows the enrollment of
subjects requiring an LAR, Quorum’s approval
documents will indicate this determination. The
investigator will also be provided with information
summarizing local laws that address surrogate
1
Id. 4.8.11.
2
Id. 4.8.12.
consent for research. In addition, the consent form
provided to the investigator will include an
attestation and signature line for the LAR to indicate
their consent for the subject to enroll in the
research.
Our research site has a patient who
understands English, but is illiterate and
not able to sign the consent form. If the patient
qualifies and agrees to be in a trial, how can they
indicate their consent to be in the trial?
If a participant can understand and
comprehend English, but is unable to sign a
consent form, two steps must be taken to capture the
person’s consent on the consent form:
First, a participant must “make their mark”
where a participant would normally sign in
accordance with state law. An individual making
their mark should be able to make the mark for
themselves without an individual assisting them.
If the individual is physically unable to sign, the
method with which they indicate consent needs
to be documented on the consent form.
Second, an impartial witness must witness the
consent process and attest that they have
witnessed the consent process.3
This should be
documented on the consent form with a witness
signature line. An impartial witness is someone
who is independent of the trial, who cannot be
unfairly influenced by people involved with the
trial, and who attends the informed consent
process if the subject or legal representative
cannot read.4
3
FDA Information Sheet, A Guide to Informed Consent, Last updated:
08/09/2011, available at:
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.
htm (accessed 04/10/2013).
4
ICH E6, Good Clinical Practice: Consolidated Guidance, 1.26.

4. April 25, 2013 | Volume 3, Issue 2
FDA Subpart D Changes:
Implications for Placebo-Controlled Pediatric Trials
The Food and Drug
Administration
(FDA) published a
final rule on
February 26, 2013,
amending Subpart D
of its regulations,
which apply to
clinical
investigations
involving children.
This rule finalizes
the interim rule
published in 2001 to bring FDA regulations into
compliance with provisions of the Children's Health
Act of 2000 (the Children's Health Act). The
effective date for the rule was March 28, 2013.
The rule updated several definitions, making them
consistent with the parallel HHS Subpart D
regulations. The rule comments and changes to the
regulations also clarified the application of the
emergency research provisions to children. Though
the regulatory changes are minimal, there is an
updated interpretation in the rule comments that
has an impact on the IRB evaluation of placebo-
controlled studies in children.
In research involving children, IRBs must find that
the research meets one of three categories under
Subpart D before it can be approved. A fourth,
seldom used category requires referral of the research
to the FDA.1
The three categories are summarized
below.
1. 21 CFR 50.51: Clinical investigations that
present no greater than minimal risk to
children
2. 21 CFR 50.52: Clinical investigations
involving greater than minimal risk but
presenting the prospect of direct benefit to
individual subjects (either due to
intervention procedure or monitoring
procedure likely to contribute to the subject’s
well-being)
3. 21 CFR 50.53: Clinical investigations in
which more than minimal risk to children is
presented by an intervention or procedure
that does not hold out the prospect of direct
benefit, if the risk is only a minor increase
over minimal risk, the intervention and
procedures present experiences
commensurate with those in their expected
medical, dental, psychological, social, or
educational situations; and the intervention
or procedure is likely to provide generalizable
knowledge about the subject’s disorder or
condition
In the comments to this final rule FDA concludes,
the placebo arm of a study does not meet the
requirements under §50.52. This section allows
research that poses risks that are more than minimal
1
Clinical investigations not otherwise appropriate that present an
opportunity to understand, prevent, or alleviate a serious problem
affecting the health or welfare of children, defined at 21 CFR 50.54

5. April 25, 2013 | Volume 3, Issue 2
if the research offers the possibility of direct benefit
to subjects.1 The FDA further explains that arms
receiving investigational products, however, could be
considered to have direct benefit. Describing the
Subpart D analysis this way suggests IRBs should
conduct a separate analysis of each arm of placebo-
controlled studies, as opposed to a single evaluation
of the possible benefits and risk for the entire trial.
As the FDA notes, it has been recommended by
various groups, and this approach may be taken by
some IRBs prior to the rule change. However, the
comments indicate this approach would be FDA’s
expectation going forward.
Required Parent Permission
In addition to the IRB analysis of the approvability
of the research, this interpretation has implications
for the IRB determination related to parent
permission. When research poses only a minimal
risk (§50.51) or offers possibility of benefit (§50.52),
the IRB can decide whether one or both parents
should provide permission.2 If the research does not
offer a direct benefit and presents risks that are more
than minimal, Subpart D (§50.53) requires both
parents to provide permission (with some exceptions
if the second parent is unavailable).3
Under the FDA’s updated interpretation, IRBs are
more likely to consider a study with a placebo-only
arm to meet the requirements under §50.53. This
will require permission of both parents and two
1
This is a change from FDA’s previous statement in the interim rule
issued in 2001, which stated: “FDA believes clinical investigations
involving placebos in children may be conducted in accord with
§50.52. There is evidence of direct benefit to subjects from
participating in placebo-controlled trials, including increased
monitoring and care of subjects, even though a subject may not
actually receive the test product. FDA invites comment on the issue of
conducting placebo-controlled trials in children.”
2
21 CFR 50.55(e)(1).
signature lines on
the consent forms.
When both parent
signatures are
required, and the
second parent is
not “reasonably
available”—the
standard used in
the regulation—the lack of availability should be
documented as part of the consent process.
3
21 CFR 50.55(e)(2). Note that the regulations include an exception if
“one parent is deceased, unknown, incompetent, or not reasonably
available, or when only one parent has legal responsibility for the care
and custody of the child if consistent with State law.”
Contact Quorum Review
Interested in learning more about Quorum
Review?
Our Institutional Team is ready to answer your
inquiries regarding your organization’s specific
institutional IRB needs.
Nancy Jane Earnhardt
Institutional Specialist
nearnhardt@quorumreview.com
T | 919-930-5198
The Institution Bulletin is a special publication of the
Quorum Forum, and brought to you by the Institution
Team at Quorum Review IRB.