1 July, 2003
Bernard Schwetz, D.V.M., Ph.D.
Acting Director,
Office for Human Research Protections
The Tower Building
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Doctor Schwetz:
I appreciate the opportunity to review the protocol for
the study “HIV Replication and Thymopoiesis in Adolescents.”
In addition to attending the panel review of 17 June,
2003, I have carefully reviewed the investigator’s application to involve human
subjects in research, protocol, informed consent documents and considered the scientific
discussion. I conclude that the
research described therein is not approvable within the guidelines established
in 45 CFR 46.404, 46.405, or 46.406.
My comments address why I perceive this protocol
generates more than minimal risk to the participant without adequate corresponding
prospect of benefit, which excludes the protocol from approval under 45 CFR 46.404,
46.405 and 46.406.
I believe the research is approvable within the
guidelines established in 45 CFR 46.407,
with modifications to the informed consent and assent forms.
I. Research not approvable under 45 CFR 46.404, 46.405
or 46.406:
Because this protocol involves more than minimal
risk with no direct benefit to healthy volunteer children (one-third
of the study participants), and will not yield knowledge about their
condition or disorder (because they don’t have one), I do not find that it
meets the provisions for approval under the federal rules except under 45 CFR
46.407. I believe the probability and/or
magnitude of harm or discomfort, though relatively minor, are nonetheless
greater risks than those encountered in a healthy child’s daily life or during
the performance of routine physical or psychological examinations or tests. I
understand that the radiation exposure of the CT scan represents approximately
16 months of background radiation which is greater than a non-participant would
receive and some subjects may have as many as three CTs within about 30 months.
It is reasonable to expect that the I.V. placement
with duration of up to 24 hours and/or drinking of water solution will cause
discomfort as well. I find that the age of the adolescent participants to be
recruited for this study, however, mitigates the risk because they are able to
understand, assent, cooperate and tolerate these “risks” in a manner that an
infant or young child might not be able to do.
II. Research approvable under 45 CFR 46.407, with
protocol/informed consent modifications:
In my opinion, the research presents a reasonable opportunity
to further understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of children. The study appears to be very
promising and scientifically sound. My comments and recommendations are chiefly
administrative.
III.
Comments:
PREGNANCY
(Risk not addressed):
Since pregnancy will not exclude women from the study,
this information should be included in the guardian consent and the youth
assent forms. A statement such as,
“Pregnancy does not warrant exclusion or withdrawal from this study,” would also
be helpful in the Withdrawal of Participation by the Investigator
section of the forms. A confidentiality plan should be in place and described to
protect the adolescent’s privacy regarding discussion and dissemination of this
information. The risks to an adolescent who is/becomes pregnant and to the baby
should be addressed, even if there are no risks. Female adolescents in this study
may be/become pregnant during the course of this potential 30 month study. The risks
(physicals, blood tests, CT exposure, I.V. infusion of labeled glucose or drinking
the special water solution) to pregnant females and/or their child should be
included. The very nature of this protocol is likely to draw recruits who could
be involved in high-risk adult behaviors which may result in pregnancy.
CT scan:
The statement included in the consent forms’ POTENTIAL
RISKS AND DISCOMFORTS section which reads, “The amount of radiation to
which you will be exposed for each CT scan is the same as a chest x-ray”
is vague and should be omitted. Both the consent and assent forms should
describe, specifically, the amount of radiation to which the subject will be
exposed. I understand the organ dose estimate as follows: thymus (20 mGy), esophagus
(20mGy), breasts (7 mGy), and thyroid (4.5 mGy), as well as the estimated
radiation dose equivalent of 1.3 years
of background radiation for youths of this age group participating in this
study. I believe this clear statement should be included in the consent/assent forms
along with the existing statement that healthcare workers are permitted to
receive twelve times more than this during a year of work which is a helpful
reference to the layman.
PROCEDURES:
The consent forms do not include information about the
infusion of sugar solution or drinking of water solution in the PROCEDURES
section. This should be added to the consent form for both HIV+ and control
subjects to prevent confusion and include this important data.
The assent forms do not include information about the CT
scan(s) in the PROCEDURES section. This should be added to the
assent form for both HIV+ and control subjects to prevent confusion and include
this important data.
The timelines in the HIV+ consent and assent forms PROCEDURES
section are displayed very differently. The manner in which they are drafted
could lead the guardian and/or subject to misunderstand what is expected of the
subject on certain dates, as the following roadmaps differ in content as well
as the timeline construction:
HIV+ Group:
Consent
Form Procedure Timeline: Month 0, Month 6, Months 12 and 18, Months 24 and 30
Assent
Form Procedure Timeline: Month 6
Control
Group:
Consent
Form Procedure Timeline: Month 0, Month 6, Months 12 and 18
Assent
Form Procedure Timeline: Month 6
The descriptions contained in the consent and assent
forms for each group should be combined. Identical descriptions and timelines
should be listed in both consent and assent forms. The language of the youth
assent forms is no more challenging to comprehend than the consent forms, so
there seems no value to having different descriptions.
Potential Risks and Discomforts:
The assent forms do not have CT scan listed in
the POTENTIAL RISKS AND DISCOMFORTS section although it is listed in the
corresponding consent form. This information should be added to the assent
forms for both HIV+ and control subjects to prevent confusion and include this
important data.
The consent forms do not have Infusion of sugar
solution or Drinking of water solution listed in the POTENTIAL
RISKS AND DISCOMFORTS section, although these risks are listed in the corresponding
assent forms. This information should be added to the consent forms for both
HIV+ and control subjects to prevent confusion and include this important data.
PAYMENT FOR
PARTICIPATION:
Adding a statement similar to the following underlined
sentence would add clarity and prevent subject misunderstanding by explaining the
purpose of the compensation:
If
you choose to participate in this study, you will be paid $XX for each visit during this study, or a total of $XX if you complete the visits. These
payments are to compensate you for accepting the risks and/or inconveniences
described herein and participating in this research protocol.
SAMPLE
REMAINING AT THE END OF THE STUDY:
The details regarding what will happen with the sample
remaining at the end of the study described in the consent and assent forms should
be more informative. The statement, “The researcher is not required to store
your sample(s) indefinitely,” does not describe how long the sample will be stored or the purpose(s) for
which it may be used. This section should also include information about the
sample/patient confidentiality plan. The purposes for which “other researchers”
may pursue specific studies with the sample should be more descriptive, (i.e.
who may use the sample, how long the sample will be stored/available to “other
researchers” and how the sample may be used), so that the subject may make a truly
informed consent in donating their sample.
The participant may be willing to allow the sample to
be used for some types of research, but not others. As the consent/assent forms
are currently drafted, subjects/guardians must choose either an implicit waiver
of all authority over purposes for which the sample may be used or a total
declination to share their sample. They should have the right to limit the
extent of their sample(s) use. There may be research with which they are ethically
opposed, for example, such as controversial use fetal tissue or in support of
human cloning, and for which they should be permitted to decline participation.
It is reasonable to assume that many, if not most, of
the subjects/guardians in the study will be motivated to contribute toward
improved understanding of HIV for personal reasons since two-thirds of them
will be HIV+. They should not be made to feel obligated to share their sample
with other researchers for reasons that are not described, may not be related
to HIV or with which they may be morally opposed. Physically and/or emotionally
vulnerable subjects often feel burdened to contribute to the benefit of
research, especially if they believe it will further the knowledge about their
child’s disease or their own. To avoid the potential injustice of coercing this
population, adding a third option such as the following to the SHARING OF
SAMPLES section of the consent/assent form would be beneficial:
“________ I agree to have my
tissue/fluid sample shared with other researches, except under the following conditions or for the following
purposes ___________________________________ .”
INFORMATION
ABOUT YOUR SAMPLE:
The section of the assent form which asks the
participant if they want to receive “specific information about what the study
found about me” is vague. This could lead a participant to believe they might
learn more about their individual health status or benefit more from
participation than is reasonable. The form would be less ambiguous if it stated
specific examples of what they could expect to receive, such as copies of labs,
etc..
In order to receive either “general information about
what the study found” or “specific information about what the study found about
me,” the process for maintaining confidentiality should be described. The
participant should be specifically told if they will receive a copy of this study
when it is published if they so desire. If confidentiality causes this to be a
burdensome challenge, providing the participants with an internet website where
the study will be posted and the anticipated release date could be a simple
solution.
PRIVACY AND
CONFIDENTIALITY:
Should the subject permit their samples to be shared
with other researchers, the confidentiality associated with this process should
be stated. The obligation and plan to provide confidentiality to female
subjects who are/become pregnant and the confidential manner in which general
or specific information drawn from the study will be provided to subjects who
have requested it should be described.
PARTICIPATION
AND WITHDRAWAL:
Again, since pregnancy will not exclude women from the
study, a statement such as, “Pregnancy does not warrant exclusion or withdrawal
from this study,” would be helpful in the Withdrawal of Participation by the
Investigator section of the forms.
IDENTIFICATION
OF INVESTIGATORS:
This section lists five investigators with their current
contact information for the purpose of research related injury, adverse
reaction or emergency related to this study. It should not serve a dual use as
contact information for subjects who desire “general information about what the
study found” or “specific information about what the study found out about me”
per the Information about My Sample section of the consent and assent forms.
The consent/assent forms state the participant is
responsible for contacting “the investigator” to provide address and/or telephone
number changes if they desire to receive information about their sample. Subjects
are directed to the Identification of Investigators section of their
consent/assent form for contact information. It is not evident that either a confidential
process is in place that will permit any of the five investigators to field a
phone message from an (unknown) adolescent providing their phone or address
change, or those investigators are administratively prepared to follow-up with
the record update. The process whereby subjects/guardians may provide update
contact information in order to receive requested general or specific information
and the confidentiality associated with this should be more clearly described.
I appreciate the opportunity to review and comment on
this most interesting research protocol and hope that my comments and
recommendations are helpful. Thank you for the invitation to participate in the
public discussion of this study.
Respectfully,
Colleen M. O’Brien