|
Return
to APS/SPR Homepage
|
STATEMENT BEFORE THE
INSTITUTE OF MEDICINE
COMMITTEE ON CLINICAL RESEARCH INVOLVING CHILDREN
PARTICIPATION AND PROTECTION OF CHILDREN IN CLINICAL RESEARCH
PRESENTED
BY:
CHRISTINE GLEASON, MD, FAAP
on
behalf of the
Society for Pediatric Research
American Pediatric Society
Endorsed
by the
Ambulatory Pediatric Association
July
9, 2003
National Academy of Sciences
Good Morning,
Dr.
Behrman and distinguished members of this Committee, I am Christine
Gleason, M.D., Professor of Pediatrics and Head of the Division of
Neonatology at the University of Washington School of Medicine. I have
been active in both clinical and basic research relevant to newborn health
and my work has been funded by the National Institutes of Health for the
past 15 years. I am a member of the Society for Pediatric Research (SPR),
the American Pediatric Society (APS) and the American Academy of
Pediatrics (AAP). I recently served as a member of the Children's
Workgroup which had been established by the National Human Research
Protection Advisory Committee (NHRPAC). Today, I am providing testimony to
the Institute of Medicine's Committee on Clinical Research Involving
Children on behalf of the Society for Pediatric Research and the American
Pediatric Society. These societies have approximately 10,000 members and
are devoted to fostering outstanding pediatric research and education and
development of young pediatric investigators. The Ambulatory Pediatric
Association, an organization of over 2000 members who are academic general
pediatricians and child health professionals, also supports and endorses
this statement.
OVERVIEW:
Along
with the AAP, we recognize that these are extraordinary times for
advancing the health and well-being of all members of society, but
especially children. As pediatricians, we are pleased that significant
strides have been made over the last several years to include infants,
children and adolescents in clinical research. Just like adults, children
should benefit from the explosion of scientific research relevant to both
health and disease. However, as pediatric researchers we recognize that
along with the awareness and commitment to include children in research
comes a serious responsibility to recognize that children as research
subjects comprise an especially vulnerable population and must be provided
adequate protection. Overall, the pediatric research societies support
efforts to balance increasing the inclusion of children in clinical
research while improving the local research review process designed to
provide adequate protection for children participating in this research.
As providers of care to sick children we are often in the position of
using therapies that were evaluated only in adults. Children are a
vulnerable population, they also deserve to have therapies that have been
carefully and rigorous evaluated.
An
accurate view of pediatric clinical research must also be presented to the
public. A well-informed public can balance concern over the tragic
"bad cases" with the overwhelming good that has come from
increased support for research involving children. In my own field of
neonatology, most of us have come to accept that the majority of drugs,
equipment, and clinical care plans that we use in the incredibly
vulnerable population of premature infants are untested, and in most
instances, are based on extrapolation from studies or anecdotal reports in
adults or much older children. That is slowly changing now, thanks to
support for our neonatal clinical research network and to a general
awareness that fragile infants are not just little adults needing
proportionately lower drug doses and smaller machines. On the other end of
childhood are adolescents with varying developmental stages at similar
ages and the ethical issues of assent and consent that these developmental
differences imply.
I
would now like to address the topics put forward by your Committee. The
Societies I represent concur fundamentally with the statement presented by
the American Academy of Pediatrics. My comments address some additional
points that our societies have considered.
-
The
written and oral process of obtaining and defining "assent",
"permission" and "informed consent" with respect
to child clinical research participants and their parents/guardians.
The SPR and APS support the AAP's statement that whenever possible
the wishes of both parents and guardians, as well as the child, should
be taken into account when decisions are made about participation in
research. In addition, serious consideration should be given to each
patient's developmental capabilities for participating in decision
making. Our Societies believe that the original intent of the informed
consent process is in some danger of being lost in a sea of additional
rules and regulations which are being tacked on to the consent
process. Inclusion of information regarding such issues as privacy and
legal remuneration in the event of an adverse event have added
potential confusion to both parents and children, allowing them and
their investigators to lose track of important information regarding
the purpose of the study and the potential risks and benefits
occurring to the participants. Another important point endorsed by the
Societies is the role the child's physician can play in the consent
process. The patient's or the family's physician could be instrumental
in helping the family/child to understand both the research study in
question and the process of informed consent.
While acknowledging that the review of consent and the process should
be local and specific to the community, by and large, the community is
national in scope. The SPR and APS believe that some degree of
standardization of the consent process, both written and oral and
specific to children, be developed for use by pediatric investigators
and by institutional review boards (IRBs). Development of consistent
forms, procedures and definitions would be beneficial for all those
involved in pediatric research. Overall, we endorse efforts to make
the entire consent process more "user friendly." Parents and
children would benefit from increased attention to information and
communication. IRBs would benefit from the infusion of needed
expertise and consistency an IRB often struggles to provide.
Increasing numbers of young pediatric investigators are discouraged by
the complexity of ensuring full compliance with an ever increasing
list of regulatory requirements that add little to the real
protections provided to potential research participants and may
unwittingly undermine their safety. It is also worth emphasizing that
families may be deterred from participating in meritorious research
because of encountering sometimes overly long or confusing consent
forms.
-
The
expectations and comprehension of child research participants and
parents ... for the direct benefits and risks of the child's research
involvement, particularly in terms of research vs. therapeutic
treatment.
Again, the SPR and APS are concerned that the entire process of
informed consent has become excessively complex, trying to include so
many different pieces that parents and children can be overwhelmed. We
support the AAP's recommendations regarding developing some type of
consistent study participant feedback regarding their comprehension of
the benefits and risks of their child's research involvement. For
example, "exit interviews" for research participants/parents
could be included in the study protocols, specifically relating to the
initial informed consent and the actual participation in the research
project. We believe that true "informed consent" is rarely
possible. The amount of information and education necessary to be
truly informed cannot be transmitted as part of the consent process,
nor are all risks completely understood by the research investigators.
Therefore, in the process of developing consent and assent forms, it
should be determined a priori what the expectations and comprehension
of the research participants should be for specific issues. For
example, whether a child will directly benefit from the research study
or whether the child will be receiving no benefit but "helping
other children." Worthy of note is that recently the General
Clinical Research Centers have put in place a research subject
advocate who among other things monitors the consent process and
provides an on-sight neutral party. This program may be particularly
relevant for children in these settings.
-
Definition
of "minimal risk" with respect to a healthy child or child
with an illness.
The Societies support the AAP's statement that the distinction between
the "healthy" child and the child with an illness or
condition is somewhat artificial and certainly that the increment from
"minimal risk" to a minor increase above minimal risk is
vague. While these definitions are not precise, the Societies strongly
oppose any effort to manipulate the risk assessment simply to get a
specific study through an IRB. In addition, the Societies believe that
these issues are very complex and unique to pediatrics. The former
Children's Workgroup of NHRPAC, on which I served, developed draft
guidelines on minimal and more than minimal risk. To our knowledge,
these guidelines have not been disseminated. We endorse the
development of a comparable independent pediatric workgroup within the
Office of Human Research Protection (OHRP), which could develop
additional guidelines to inform and advise both pediatric
investigators and IRBs regarding issues such as but not limited to
definitions of minimal risk with respect to all different groups of
both healthy children and children with illnesses. The SPR and APS
believe that improved guidance from the federal government through
such workgroups could be very helpful in decreasing the current level
of variability in the interpretation of "minimal risk" and
other regulations under Subpart D of Part 46 of Title 45 (Code of
Federal Regulations).
-
The
appropriateness of the regulations applicable to children of differing
ages and maturity levels, including regulations relating to legal
status.
The SPR and APS support the AAP's statement that the FDA's decision
not to adopt 46.408(c) of Subpart D (pertaining to waivers of informed
consent) failed to appreciate the unique circumstances involved in
children's and adolescents' participation in research. We agree with
the Academy that the IRB should be given a limited ability to acquire
a child's assent rather than guardian's consent if the rights of the
participant would be better protected. This is, after all, the primary
role of the IRB. In addition, the Societies believe that age does not
always accurately reflect maturity level. There are special
circumstances in which emancipated minors may be invited to have their
newborns participate in research studies, and their level of maturity
must be considered similarly to other adolescents giving assent to
their own participation in research studies.
-
Whether
payment (financial or otherwise) may be provided to a child or his/her
parent for the participation in research and, if so, the amount and
type of payment that may be made.
The Societies endorse the AAP's position that it is in fact in accord
with traditions and ethics of society to pay people to participate and
cooperate in activities that benefit others. However, there are
various and unique ethical considerations that occur when payment is
offered to adults acting on behalf of minors in return for allowing
them to participate as research subjects. Parents should not receive
compensation more than they require to cover their expenses for
allowing their children to participate in research studies. Children
should receive no more than a "thank you gift" that is
clearly understood to be because they are helping others. In addition,
the APS and SPR believe that physicians should not be remunerated or
rewarded in any way for getting their own patients into studies. Since
payment or reward can be coercive, and therefore could jeopardize the
safety of a prospective research participant, it is within the purview
of IRBs to carefully review any proposed remuneration in order to be
assured that the possibilities for coercion have been avoided.
Important considerations are those settings in which both research
participants and non-participants are being cared for in the same
setting. In this case, it is very important that even subtle rewards,
such as increased attention, not be showered on the participants, thus
engendering feelings of potential guilt or remorse among, or
perception that less attention is being paid to, non-participants. The
Societies believe that it is unethical for researchers to foster the
notion that participation in clinical research studies is the only way
to get the very best treatments available. Participation in a research
study should be understood by parents to be primarily to further the
common goal of improving treatment and outcomes and not a better
treatment for their child.
-
Compliance
with the regulations referred to in Subsection (a)(1)(A) the
monitoring of such compliance (including the role of IRBs) in the
enforcement actions taken for violations of such regulations.
The SPR and APS agree with the Academy that training and competence in
the ethical conduct of research by investigators is ultimately the
most important safeguard for the protection of children in research.
Furthermore, in our opinion, training of young investigators in these
areas must be enhanced. We believe that IRBs do play an important role
in monitoring compliance with federal regulations, but that most IRBs
are limited in their expertise regarding both interpretation of the
regulations and their ability to determine whether or not a specific
protocol or investigator is complying with them.
Consistent with our statement above regarding the development of more
specific guidelines regarding minimal risk, we believe that specific
compliance forms governing children's participation in research could
be developed, which IRBs could then review in a fairly straightforward
manner. Violations of the regulations would be more clearly identified
and specific enforcement actions could then be taken.
By the same token, IRBs cannot be overburdened with regulatory
requirements that are not critical to protection of human research
subjects such as additional Health Insurance Portability and
Accountability Act of 1996 (HIPAA) documentation forms. Additional
regulatory activity may impose an excessive burden detrimental to the
historic IRB mission. For example, IRBs are being asked to review
requests for personal confidential information, and when the volume
becomes excessive, formation of a separate privacy board should be
considered.
Again, our societies believe that it is important for us to work
together to achieve an appropriate balance between fostering research
inquiry (particularly regarding therapeutics) in pediatrics and
protection of this most vulnerable patient population.
In addition, a unique IRB process could be explored that includes
other vulnerable patient populations such as the mentally disabled and
aged along with pediatrics, thus consolidating resources.
-
The
unique roles and responsibilities of institutional review boards in
reviewing research involving children, including composition of
membership.
Along with the AAP, the SPR and APS believe that local IRBs are indeed
capable of protecting the rights of children, but that it is
imperative that these IRBs have proper pediatric expertise and
adequate institutional support in order to fulfill this role. We
further believe that education of IRB members is essential. There is
considerable regional variation as to how IRBs function with regard to
pediatric clinical research. For example, we know of one institution
that has a separate pediatric protocol review committee as well as a
pediatric advisory committee for all research protocols pertaining to
children. These committees perform scientific as well as federal
regulatory compliance review prior to an application reaching an IRB.
In some large institutions, there is enough expertise to be
concentrated in such groups that additional training or expertise may
not be required. However, in other institutions, there is a
significant paucity of pediatric expertise relating to research and
thus the SPR and APS recommend developing mechanisms for pooling
resources at multiple institutions or perhaps the development of
formal regional pediatric research review committees or advisory
committees that can advise hospital IRBs.
While we do not think that it is the primary responsibility of the
IRBs to provide scientific review, it is certainly within their
purview to determine scientific merit. A breakdown in the system,
though, comes when minimum credentials required to ensure the validity
and worth of IRB comments are not met. Indeed, the practice of
unqualified IRB members taking on a role of primary scientific review
has enormously increased the workload of these IRBs, and, in some
instances, has led to a collapse in academic medical research.
Furthermore, IRBs cannot be spending all or a significant percent of
their effort focused on regulatory requirements or legal points that
are relatively minor with regard to protection of human research
subjects (such as new privacy regulations).
Investigational modules and training programs have been developed at
NIH and Public Responsibility in Medicine and Research (PRIM&R),
but to our knowledge these are not specific to pediatrics, which has
other very different concerns. We believe that training programs
specific to pediatrics for IRB members should also be developed at the
national level and then be made available for all IRB members,
including training on issues related to research in children. Our
pediatric academic societies would be pleased to play a role in their
dissemination. This could ultimately result in some national
uniformity and consistency in the ethical conduct of research in
children as well as other vulnerable populations. Additionally, to
facilitate patient protection and expedite clinical research for large
multi-center protocols, a regional or national pediatric IRB should be
considered.
CONCLUSION:
We
must strive for a balance between supporting meaningful pediatric research
and protection of the rights of children and other vulnerable populations.
There is a wide variability in the interpretation of the existing
regulations regarding clinical research involving children. The Societies
support a national workgroup devoted to developing consistent guidelines
as well as examples of various categories enumerated on the common rule
for use by investigators and IRBs. This could also extend to the variable
approaches to conflict of interest among institutions with regard to
pediatric and other types of research. Pediatric expertise is clearly
needed in all phases of the development and review process for clinical
research protocols involving children. We recommend a development of
specific guidelines for the review process pertaining to pediatric
clinical research and the creation of either regional or institutional
advisory committees to provide that specific expertise to IRBs as they
review protocols involving children.
The
Society for Pediatric Research and the American Pediatric Society
appreciate the opportunity to both submit a written statement as well as
participate in this important public dialogue on such a critical issue -
clinical research involving children. We welcome the opportunity to
discuss this further with you as develop this important IOM report.
|
