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4
Ethical Issues in Pediatric Drug Studies
O
ne broad principle for the conduct of pediatric drug studies is that
children should not be subjected to research that is not necessary
to advance knowledge relevant to child health. Another is that
children should not participate in studies that are designed or conducted
in ways that predictably undermine their potential to yield such advances.
In either situation, children may be exposed to more than minimal risk in
research without the expectation of an advance in generalizable knowledge.
Thus, shortcomings in the design or conduct of pediatric drug studies that
are described elsewhere in this report have ethical implications. Moreover,
it is important that the exclusivity incentive and associated profit potential
provided by the Best Pharmaceuticals for Children Act (BPCA) be accom-
panied by clear expectations that pediatric studies undertaken under the
act are needed, soundly designed and executed, and public in their results.
One element of the task for the Institute of Medicine (IOM) was to as-
sess ethical issues presented by studies requested under BPCA or required
under the Pediatric Research Equity Act (PREA). To put this task in con-
text, this chapter briefly reviews the federal regulatory protections provided
to child participants in research and describes the resources available in the
Food and Drug Administration (FDA) to provide guidance on ethical ques-
tions related to pediatric studies. It then considers several specific ethical
issues, including the public availability of information from clinical trials,
the enrollment of healthy children in pharmacokinetic studies, and the use
of placebo controls in pediatric trials.
89
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90 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
REGULATORY REQUIREMENTS FOR PROTECTION
OF HUMAN RESEARCH PARTICIPANTS
As described in Chapter 1, deaths and other harms resulting from the
use of drugs not studied in children have underscored the need for policies
that encourage or require the testing of drugs for safety and efficacy with
pediatric use. Such testing comes with its own risks and associated debates
about what constitutes an acceptable risk. For example, following a study
of chloramphenicol and two other antibiotics in the late 1950s (see discus-
sion in Chapter 2), trial investigators were criticized for failing to stop fur-
ther administration of the drug after early evidence of excess fatality rates
was collected in the chloramphenicol arms of the trial. The argument at the
time was that continuation of the trial was necessary to provide convincing
evidence that the drug was unsafe (Murphy, 2000). Such debates, as well
as examples of ethical lapses in clinical and other research involving both
adults and children, have contributed to the adoption of general protec-
tions for all participants in clinical research and to the creation of special
protections for children.
General Protections
The special protections for children in research function in the context
of broader protections for all human research participants. Today, all clini-
cal research regulated by FDA, regardless of source of funding and auspices,
must meet certain ethical standards (21 CFR 50 and 56). FDA’s rules are
similar but not identical to the regulations of the U.S. Department of Health
and Human Services (HHS) that cover research conducted or funded by the
department (45 CFR 46).
FDA regulations require several determinations about possible research
harms and benefits (Box 4-1). Although sponsors, investigators, and regu-
lators also have responsibilities for weighing and minimizing risks, insti-
tutional review boards (IRBs) are panels created under regulations for the
explicit purpose of reviewing human research conducted or funded by HHS
or regulated by FDA. The primary responsibility of IRBs is to protect the
rights and welfare of human research participants.
The responsibilities of sponsors under FDA regulations include select-
ing qualified investigators and monitoring research conduct, for example,
to confirm that investigators have secured approval of trials from the ap-
propriate IRBs. As described in Chapter 3, sponsors must submit an Inves-
tigational New Drug (IND) application before they can ship investigational
drugs or biologics across state lines and begin human research. The IND
process requires conformance with FDA regulations, and applications in-
clude a signed statement (Form 1572) from investigators confirming that
they will comply with these regulations (FDA, 2010b).
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
BOX 4-1
Determinations of Research Risks and Potential
Benefits Required by FDA Regulations
Are risks to research participants minimized by using procedures that are consis-
tent with sound research design and that do not unnecessarily expose participants
to risk and, whenever appropriate, by using procedures already being performed
for diagnostic or treatment purposes? 21 CFR 56.111(a)(1)
Are risks to participants reasonable in relation to anticipated benefits to partici-
pants and to the importance of the knowledge reasonably anticipated from the
research? 21 CFR 56.5111(a)(2)
Is the selection of research participants equitable, taking into account the pur-
poses of the research, its setting, and the special problems of research involving
vulnerable populations, such as children? 21 CFR 56.111(a)(3)
Are appropriate provisions for monitoring participant safety made? 21 CFR
56.111(a)(6)
Are appropriate provisions for protecting participant privacy and confidentiality
made? 21 CFR 56.111(a)(7)
Does the research meet the regulatory criteria for studies involving children,
including those requiring parental permission and, as appropriate, child assent?
21 CFR 50.51-50.54
SOURCE: Adapted from IOM (2004).
In addition to the rules for the protection of research participants, FDA
is concerned about the scientific and ethical integrity of data from clinical
trials. For example, as described later in this chapter, the agency conducts
routine audits of data integrity in clinical trials.
FDA also has conflict-of-interest policies that are intended to protect
the integrity of research from bias arising from the financial relationships
of investigators. The policies require sponsors either to certify that investi-
gators for studies submitted in support of FDA approval had no financial
interest in the studied product or the sponsor (e.g., by holding company
stock) or to report the financial interests disclosed by the investigators.
FDA reviews any disclosures to assess whether the interests had the poten-
tial to bias the findings of the research. A thorough discussion of conflict
of interest in pediatric drug studies is beyond the scope of this report, but
the financial significance of such studies not only to sponsors but also to
many academic programs and investigators and to some community-based
physicians does raise concerns about the potential for bias in the design,
evaluation, and reporting of research.
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92 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
Studies Conducted Outside the United States
The IND application process is mandatory for studies conducted within
the United States. For studies conducted outside the United States, sponsors
may chose to conduct the study under an IND application.
Alternatively, under regulations issued in 2008 (73 FR 22800), FDA
may accept results from foreign studies not conducted under an IND ap-
plication if the studies conform to the terms of good clinical practice
specified by the International Committee on Harmonization (ICH, 1996).
The regulations define good clinical practice as “a standard for the design,
conduct, performance, monitoring, auditing, recording, analysis, and re-
porting of clinical trials in a way that provides assurance that the data and
reported results are credible and accurate and that the rights, safety, and
well-being of trial subjects are protected, including review and approval by
an independent ethics committee (IEC), and provided that FDA is able to
validate the study data through an onsite inspection, if necessary” (21 CFR
312.120(a)(i)). The 2008 regulations replace earlier rules that specified that
international trials conform to the standards of the Declaration of Helsinki.
The amount of clinical research conducted outside the United States
has grown substantially in the past several decades. An analysis of trials
registered at ClinicalTrials.gov (a clinical trials registration database that
is described further in Chapter 8) found that as of November 2007, one-
third of Phase III trials sponsored by the 20 largest U.S. pharmaceutical
companies were conducted entirely at foreign sites and the majority of ac-
tual study sites were outside the United States (Glickman et al., 2009). An
analysis of published reports of studies conducted for pediatric exclusivity
from 1998 to 2007 found that 65 percent of the studies that reported study
locations had at least one site outside the United States, 38 percent had at
least one site in a developing/transition country, and 11 percent had no
U.S. sites (Pasquali et al., 2010; see also Dunne et al., 2011a; Maldonado
et al., 2011).
The globalization of research has raised questions about the adequacy
of FDA and sponsor oversight of foreign studies and the adequacy of
protections for research participants in certain countries (see, e.g., NBAC,
2001, and OIG/HHS, 2001).1 These questions involve, among other is-
sues, possible inadequate review for conflicts of interest and possible inap-
propriate inducements for parents to permit their children’s participation
in research. Another concern involves the ability of sponsors and lead
1 In one clinical review for the drug lamotrigen (Lamictal), the reviewer noted that many
studies were in countries in which the FDA had little experience (Katz, 2009a). Concerns
about data integrity led to extensive discussions with the sponsor about its site inspections
and to requests that the sponsor conduct further data analyses, which FDA staff reviewed
before concluding that reasonable explanations for discrepancies in data among sites existed.
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
investigators to monitor studies that involve very large numbers of widely
dispersed trial sites.
Drug studies conducted in other countries may also raise questions of
fairness or justice. This may happen when research in developing countries
exposes the research participants to risk but the primary future benefits of
the knowledge gained will accrue to patients in wealthier countries because
the new drugs will not be affordable in the countries where they were
studied (NBAC, 2001; Glickman et al., 2009). Moreover, pharmaceutical
research taken as a whole may neglect diseases that are common in poor
countries and rare in wealthier countries, a reality that has prompted a
variety of international initiatives to increase research on specific neglected
diseases, such as malaria, leishmaniasis, and schistosomiasis (see, e.g.,
Hotez et al., 2007; USAID, 2009; and WHO, 2011b).
In the studies assessed by the IOM committee, one specific ethical issue
in a pediatric trial appeared to be related to shortcomings in the conduct of
a trial at an international site. In that case, the clinical reviewer stated that
efficacy data on the prevention of maternal transmission of HIV infection
were not evaluated, in part because the trial protocol did not incorporate
the accepted standard of care for these study participants (Ayalew, 2002).
FDA did, however, approve the addition of pharmacokinetic and safety in-
formation to the labeling of the products generated by the trial component
that investigated treatment of HIV-exposed or infected neonates. This com-
ponent had been the subject of a written request from FDA (Kweder, 1999).
Equity in international research is an important and complicated ethical
issue that could not be effectively considered in the context of this study
or on the basis of the documents that the committee reviewed. Because
children are a vulnerable population, particular vigilance is important to
ensure the ethical conduct of international pediatric research.
Special Protections for Children in Research
Beyond the general protections described above, both HHS and FDA
regulations establish special protections for child research participants that
extend beyond those applicable to adults. (For HHS, the regulations are
found at Subpart D of 45 CFR 46; for FDA, they are found at 21 CFR 50.)
Although HHS first issued its regulations in 1983, FDA did not explicitly
adopt the special protections until April 2001, as required by the Children’s
Health Act of 2000 (PL 106-310). As summarized in Box 4-2, the FDA
(and HHS) regulations define four categories of research involving children
that IRBs can approve. As an example of how the regulations may limit
studies that are permitted for adults, these definitions would preclude the
participation of healthy children in pharmacokinetic studies that involve
more than minimal risk.
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94 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
BOX 4-2
Categories of Clinical Research Involving Children
That Are Approvable Under 21 CFR 50
• linical investigations that involve not greater than minimal risk (50.51)
C
• linical investigations that involve greater than minimal risk but present the
C
prospect of direct benefit to individual subjects such that (a) the risk is justified
by the anticipated benefit to the subjects and (b) the relation of the anticipated
benefit to the risk is at least as favorable to the subjects as that presented by
available alternative approaches (50.52)
• linical investigations involving greater than minimal risk and no prospect of
C
direct benefit to individual subjects, but likely to yield generalizable knowledge
about the subjects’ disorder or condition and (a) the risk represents a minor
increase over minimal risk; (b) the intervention or procedure presents experi-
ences to subjects that are reasonably commensurate with those inherent in
their actual or expected medical, dental, psychological, social, or educational
situations; and (c) the generalizable knowledge is of vital importance for the
understanding or amelioration of the subjects’ disorder or condition (50.53)
• linical investigations not otherwise approvable that present an opportunity
C
to understand, prevent, or alleviate a serious problem affecting the health or
welfare of children as agreed to by the Institutional Review Board and the
Commissioner of the FDA after consultation with a panel of experts (50.54)
SOURCE: IOM (2004).
Approvals of research involving children are also contingent on ad-
equate provisions for parental permission for a child’s participation in
research and, when appropriate, for the assent of that child to such par-
ticipation. Under the regulations, “children” are individuals who are not
of legal age to consent to research as defined in the laws of the jurisdiction
in which the research is to be conducted. Despite some uncertainty and
disagreement about the concept of assent and its meaningfulness in actual
research settings when a child’s parents favor participation, a 2004 IOM
report argued that it is desirable to involve children in research discussions
and decisions—consistent with their maturity and psychological state. Do-
ing so “respects their emerging maturity, helps them prepare for participa-
tion in research, gives them an opportunity to express their concerns and
objections, and, possibly, allows them to influence what happens to them”
(IOM, 2004, p. 7). Research is limited but suggests that practices concern-
ing assent vary in actual pediatric trials (see, e.g., Olechnowicz et al., 2002;
Ungar et al., 2006).
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
Making decisions about the four categories of approvable pediatric
research defined in the HHS and FDA regulations necessarily involves sub-
jective judgments about the risks and potential benefits to children of clini-
cal studies. What is minimal risk? What is a minor increase over minimal
risk? Can data help inform judgments about risk? (See, e.g., Wendler et al.,
2005; Nelson, 2010; Roth-Cline et al., 2011.) These and other questions
have been the subjects of ongoing debate both generally and with respect to
specific research protocols. The 2004 IOM report cited above made several
recommendations about the interpretation of key concepts in the HHS and
FDA regulations. In brief, it recommended that investigators and reviewers
of research protocols should
• interpret minimal risk in relation to the normal experiences of average,
“
healthy, normal children” and “focus on the equivalence of potential
harms or discomfort anticipated in research with the harms or discom-
fort that average, healthy, normal children may encounter in their daily
lives or experience in routine physical or psychological examinations or
tests;
• interpret minor increase over minimal risk to mean a slight increase in
“
the potential for harms or discomfort beyond minimal risk” and “assess
whether the research procedures or interventions present experiences
that are commensurate with, that is, reasonably comparable to, experi-
ences already familiar to the children being studied”;
• consider the risk of harms or discomfort in relation to the ages of the
“
children to be studied and assess the duration as well as the probability
and magnitude of potential harms or discomfort in determining the
level of risk”; and
• nterpret condition to mean “a specific (or a set of specific) physical,
i
psychological, neurodevelopmental, or social characteristic(s) that an
established body of scientific evidence or clinical knowledge has shown
to negatively affect children’s health and well-being or to increase their
risk of developing a health problem in the future.” (IOM, 2004, p. 17)
In addition, in evaluating whether to approve research that involves a
minor increase over minimal risk and no direct benefit to a child with a con-
dition or disorder, IRBs should find that “the research is likely to generate
vital knowledge about the children’s disorder or condition” (IOM, 2004,
p. 18). The research should not “unjustly single out or burden any group of
children for increased exposure to research risk on the basis of their social
circumstances” (p. 17). In situations in which some research procedures
have the prospect of direct benefit and others do not, then “the potential
benefits from one component of the research should not be held to offset
or justify the risks presented by another” (p. 17).
The issue of excessive risk has arisen in the context of the one written
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96 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
request for the pediatric study of an off-patent drug that was accepted by
the sponsor (NICHD, 2008). Although the drug, lindane, was also on the
BPCA priority list for the National Institutes of Health (NIH) (see Chapter
3), an NIH advisory group described it to be too toxic—on the basis of
existing evidence—to be ethically studied in children (NICHD, 2003). The
rationale for the request was that despite label warnings about its toxicity,
the drug did have considerable pediatric use for scabies; thus, dosing and
safety studies might yield information to guide this use. As far as the com-
mittee is aware, the requested studies have not been undertaken. (One study
registered at ClinicalTrials.gov describes a completed study of an alternative
product that also included an assessment of the incidence of use of lindane
[ClinicalTrials.gov identifier: NCT00604084].)
FDA ORGANIZATIONAL RESOURCES TO SUPPORT
ETHICAL STANDARDS IN PEDIATRIC RESEARCH
FDA has developed generally available resources to promote ethical
standards for studies undertaken to support approvals of medical products.
It has also created resources specific to pediatric studies. The discussion in
this section starts with the latter.
Expertise in Pediatrics, Pediatric Research, and Research Ethics
In 1999, FDA created a pediatric advisory subcommittee to its Anti-
Infectives Advisory Committee. Among other issues, the subcommittee
advised on ethical questions in pediatric studies. In 2004, as provided for
by BPCA of 2002 and PREA of 2004, FDA created the publicly deliberat-
ing Pediatric Advisory Committee (69 FR 46098). This committee, in turn,
created a subcommittee on ethics that continues. Among other issues, the
Pediatric Advisory Committee and its subcommittee may be asked to con-
sider whether studies not otherwise approvable under 21 CFR 50 should
be recommended for approval by the FDA Commissioner under Section
50.54 (FDA, 2006c).2 In addition to specific study proposals, the ethics
subcommittee has also considered broader topics. One recent example is the
status of clinical studies that might, in the future, involve the exploratory
administration of subtherapeutic doses, or “microdoses” of investigational
products to children (Nelson, 2011b).
2 The process is rarely used. One example that came before the FDA Commissioner in 2004
involved a proposed study that would have used magnetic resonance imaging to examine the
effects of a single dose of dextroamphetamine versus placebo for attention deficit hyperactiv-
ity disorder. It was recommended for approval by the Pediatric Advisory Committee but was
withdrawn before final action (SACHRP, 2005).
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
In 2002, when Congress directed the creation of the Office of Pediatric
Therapeutics at FDA, it specified that the office would have at least one
person with “expertise concerning ethical issues presented by the conduct
of clinical research in the pediatric population” (21 USC 393a). The Office
of Pediatric Therapeutics currently includes two pediatric ethicists as well
as other members with expertise in pediatrics. These resources are available
to staff of the Center for Drug Evaluation and Research (CDER) and the
Center for Biologics Evaluation and Research (CBER) as well as staff of the
Center for Devices and Radiological Health (CDRH).
In addition, the Pediatric and Maternal Health Staff within the Of-
fice of New Drugs at CDER provides pediatric expertise to assist that
center’s review divisions. At both CBER and CDER, approximately 15 to
20 percent of medical officers are pediatricians (personal communication,
Catherine Lee, Office of Pediatric Therapeutics, FDA, November 21, 2011).
Such expertise is relevant not only to the valid and reliable assessment of
scientific questions but also to the assessment of age- and condition-specific
risks required by the special protections for child research participants.
As described in Chapter 3, in 2007 Congress provided for an internal
FDA committee to review written requests and pediatric studies conducted
under BPCA and to review pediatric plans, assessments, deferrals, and
waivers under PREA (21 USC 355d). This review committee was to include
expertise in pediatric ethics specifically as well as expertise in pediatrics,
biopharmacology, statistics, chemistry, and legal issues. FDA created the Pe-
diatric Review Committee (PeRC) to undertake the required reviews, which
cover both scientific and ethical issues. These reviews frequently result in
recommendations for significant changes in study plans, including recom-
mendations for changes in inclusion criteria, additional adult or animal
studies, or modifications in trial design to achieve an acceptable balance of
risk and potential benefit (personal communication, Robert Nelson, Office
of Pediatric Therapeutics, FDA, August 10, 2011). The agency can impose
a clinical hold that delays or suspends work on studies that violate the
regulations governing the protection of children in research.
In addition to topics considered during committee or subcommittee
meetings, issues may be brought to the FDA pediatric ethics staff for
consultation. Such consultations have covered the ethical implications of
many elements of pediatric drug studies, including the definition of the
pediatric population to be studied, the choice of control group, the use of
invasive placebos, the requirements for parental permission and child as-
sent, the assessment of risk and benefit, the appropriate standard of care
in international studies, and the planning of first-in-children studies (i.e.,
when a drug or an indication has not been previously studied in adults)
(personal communication, Robert Nelson, Office of Pediatric Therapeutics,
FDA, August 10, 2011). The consultations have involved a wide array of
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98 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
specific product classes and clinical conditions, for example, long-acting
beta-agonists; proton pump inhibitors in infants; antiretroviral products;
growth hormones; monoclonal antibodies for respiratory syncytial virus
and asthma; psychotropic medications; cognitive enhancers in Down syn-
drome; and stem cell therapies for diabetes mellitus, cancer, autism, cerebral
palsy, and spinal muscular atrophy.
Some of the IOM committee’s assessments covered studies that were
requested, required, and undertaken before the resources just described
were in place. Although the committee could not reasonably assess the
sufficiency of past or current pediatric expertise across CDER and CBER
review divisions and in the Office of the Commissioner, this report empha-
sizes that such expertise is critical to the design, conduct, and evaluation of
scientifically and ethically sound pediatric drug studies.
Other Resources Relevant to Research Integrity
Among other resources, FDA has developed a number of guidance or
draft guidance documents on ethics and integrity in FDA-regulated trials,
including guidance for IRBs and investigators about FDA policies and ex-
pectations (FDA, 2010b). The infrastructure to support the ethical conduct
of research also includes the Office of Good Clinical Practices in the Office
of the FDA Commissioner. This unit, among other responsibilities, admin-
isters FDA’s Human Subject Protection/Bioresearch Monitoring Council.
Within CDER, the Division of Scientific Investigations (DSI) is respon-
sible for verifying the “integrity of efficacy and safety data submitted to
the FDA in support of new drug applications [NDAs] and to assure that
the rights and welfare of human research subjects are protected” (FDA
Regulatory Procedure Manual at 1-4-5; see also FDA, 2009a). (For CBER,
the equivalent office is the Division of Inspections and Surveillance.) The
division engages both in routine audits of data integrity in clinical trials
as part of the review of NDAs and in investigations of specific complaints
about the conduct of trials, including complaints about the protection of
research participants. Among other tasks, a routine inspection might verify
that investigators secured IRB approval(s) and parental permission. It might
compare sites at which investigators have financial interests in the outcome
of the trial (e.g., because they hold stock in the sponsor company) with
other sites for indications that financial interests have influenced reported
results. When an audit cites violations of protocols or good clinical practice,
an FDA reviewer may assess these violations to determine whether they
could affect study findings. The reviewer may then disallow acceptance of
certain data in support of applications.
If a DSI or other investigation casts doubt on the efficacy or safety find-
ings of a sponsor’s trial of a product with adults, then the use of data from
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
that trial as a basis for starting pediatric trials may also be cast into doubt.
An example involves the drug telithromycin (Ketek), which was approved
in 2004 for treatment of certain forms of acute bacterial exacerbations
of chronic bronchitis, acute bacterial sinusitis, and community-acquired
pneumonia; the approval specified required pediatric studies of the last
two indications (Goldberger, 2004). After public disclosure of significant
irregularities in a key clinical trial and questions about FDA management
procedures, FDA withdrew approval for the first two indications in 2007
(Ball, 2007; Ross, 2007; see also Soreth et al., 2007). Subsequently, after
public questions about the safety of pediatric studies involving the drug
but also after several studies were completed, the company halted pediatric
studies (Ault, 2006; Harris, 2006).
ETHICAL ISSUES IN STUDIES CONDUCTED
UNDER BPCA AND PREA
An overarching ethical question for pediatric studies is whether the ex-
pected benefit of the knowledge to be gained from the research is reasonable
in relation to the potential risk to child participants. This can sometimes be
difficult to assess, particularly many years after the studies were conducted
when the uncertainties of an earlier time may have diminished as knowledge
about benefits and harms has accumulated from different sources.
During its assessments of ethical issues in studies requested and required
under BPCA and PREA, the committee primarily relied on the information
in clinical, clinical pharmacology, and statistical reviews prepared by FDA
staff. Staff reviewers have access to the voluminous submissions of spon-
sor data, the record of communications between sponsors and FDA about
the design and conduct of the pediatric studies, and the reports from DSI.
Except for egregious problems, the reviews and the information on
which they are based are unlikely to allow assessments of certain aspects
of the ethical conduct of research. These aspects include the soundness of
processes for obtaining parental permission and child assent to research
participation, the nature and risks of incentives offered for clinician par-
ticipation (e.g., payments per child enrollee in office-based studies), and the
extent and appropriateness of incentives offered to parents and children
(e.g., payments for time and inconvenience and provision of gifts). The
IOM committee did not search the literature to determine whether others
had raised questions about the ethical status of particular studies requested
under BPCA or required under PREA, although committee members were
sometimes aware of such questions. In addition to examples drawn from
the committee’s assessments, this discussion also cites other cases that il-
lustrate ethical questions or concerns with studies conducted under BPCA
and PREA.
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100 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
The first issue that the committee identified involves transparency in
the form of public access to information from requested or required pedi-
atric studies. The following discussion also describes issues of integrity or
ethics that clinical reviewers have identified and notes concerns about the
participation of healthy children in pharmacokinetic studies and the use of
placebo-controlled trials.
Transparency, Labeling, and Dissemination
Transparency in the form of public access to information generated by
studies requested under BPCA or required under PREA has ethical as well
as scientific implications. Provisions for such access recognize and respect
the contributions that children (and parents) make by participating in re-
search, acknowledge these research results as a public benefit, and support
the accountability of sponsors and FDA for their actions and decisions.
As described in Chapter 3, in the reauthorization of BPCA and PREA
in 2007, Congress required that the results of studies requested under BPCA
or required under PREA be reflected in labeling changes in most cases. It
also required FDA to make public the staff clinical, clinical pharmacol-
ogy, and statistical reviews associated with requested or required studies
in a timely way and to make written requests public following exclusivity
determinations. Before these changes, BPCA of 2002 required posting of
brief summaries of product reviews for studies requested under BPCA, but
the requirement did not apply to studies required under PREA. FDA does
make available some information about adult studies through Drugs@FDA.
Such information, especially for studies submitted in supplemental NDAs or
Biologics License Applications (BLAs) following a drug’s initial approval,
is not as extensive as that required for pediatric studies, and it can be more
difficult to find (O’Connor, 2009).
The public information requirements of the 2007 legislation did not
apply retroactively. Thus, information about studies requested under BPCA
and, even more so, studies required under PREA is still restricted for prod-
ucts with study assessments or exclusivity determinations made before the
2007 reauthorizations. Information can be requested under the Freedom of
Information Act (FOIA), but that process is typically time-consuming and
burdensome. Whether they are related to FOIA requests or not, many of the
FDA documents consulted during the preparation of this report had signifi-
cant redactions in ethically sensitive sections of clinical reviews, including
overall risk-benefit assessments (see discussion in Chapter 5).
Although FDA agreed to provide the committee with redacted requests
and reviews for up to 50 products with labeling changes prior to September
27, 2007, the release of such documents for some products with exclusivity
but no labeling changes could occur only with the permission of the spon-
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
sor. As discussed in Chapter 6, both of the sponsors of neonatal studies of
bacterial conjunctivitis for which no information was added to the label
but for which exclusivity was granted in 2003 refused to provide permis-
sion. Substantial numbers of babies were studied in these trials, but that
exposure has contributed only brief FDA summaries of study results to the
public record at FDA.
In addition, FDA is still limited in what it can disclose about studies
that have not had results submitted in connection with an NDA or BLA,
for example, when sponsors have abandoned clinical development of a
drug. One serious documented instance of this involves the drug cisapride
(Propulsid), which was withdrawn from the market in 2000 (Willman,
2000; Harris and Koli, 2005). This withdrawal came some years after FDA
first became concerned about the drug’s risks, including its risks to children.
It likewise came some years after the agency knew of sponsor trials (which
had not been submitted) that showed a lack of efficacy in children. At the
time that the drug was withdrawn, a spokesman for a children’s hospital
at which a child had died during a clinical trial of the drug said the drug
“has been widely prescribed by pediatricians and pediatric specialists for
the treatment of gastroesophageal reflux in children and infants due to its
efficacy and presumed safety based on the adult data” (Neergaard, 2000).
Citing ethical obligations, some have called for the creation of a publicly
accessible database of results of abandoned trials (Rogawski and Federoff,
2011).
In addition to these issues of transparency, another concern involves
the appearance in the published literature of information that appears to
be inconsistent with the assessments of FDA reviewers and information in
a product’s label. A study by Benjamin and colleagues reported an analysis
of 129 of 137 BPCA-related labeling changes that occurred by September
2007 (Benjamin et al., 2009). As summarized by the authors,
Thirty-three products (26%) had pediatric safety information added to the
labeling. Of these, 12 products had neuropsychiatric safety findings, and
21 had other important safety findings. Only 16/33 (48%) of these trials
were reported in the peer reviewed literature; however, 7/16 of these pub-
lications focused on findings substantively different from those highlighted
in the FDA reviews and labeling changes. (p. 180)
For studies leading to pediatric exclusivity, the authors suggest the
need for a mechanism to increase the dissemination of unbiased informa-
tion based on these studies (see also Benjamin et al., 2006). Given concerns
that physicians do not generally read the study details or other information
in drug labels and more general concerns about selective publication by
sponsors, such unbiased dissemination could increase clinician awareness
of important safety and efficacy findings (see Appendix B).
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102 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
In this context, it should be noted that FDA reviews of pediatric
and adult studies—even those that are public—are not integrated into
resources such as PubMed and ClinicalTrials.gov. Thus, these evaluations
may not be identified and incorporated into evidence-based reviews of clini-
cal therapeutics.
FDA Reviewer Comments on Study Integrity and Ethics
Particularly in recent years, FDA clinical reviews of sponsor applica-
tions have included sections that variously comment on study integrity,
ethics and good clinical practices, and financial disclosures or conflicts of
interest. In these sections, reviewers may discuss protocol violations, spon-
sor affirmations about compliance with ethical principles or good clinical
practices (which should subsume compliance with regulatory protections
for children), and sponsor certifications about investigator financial rela-
tionships or conflicts of interest.
In general, in the clinical reviews that included sections on data integ-
rity, financial disclosures, or ethics (with minimal redactions), the commit-
tee identified no major ethical issues based on the reviewers’ assessments.
Particularly for more recent reviews, these sections of the reviews did docu-
ment FDA attention to the issues, which potentially reinforces adherence to
standards for scientifically and ethically sound investigations. Early reviews
examined by the committee omitted mention of these issues more often than
recent reviews. In some cases, the committee found that review sections
related to issues of study integrity had been redacted (see, e.g., Bastings,
2002). In addition, most specific information about investigator financial
relationships or conflicts of interest was redacted.
A clinical review may make clear that the reviewer was relying pri-
marily on the statements and certifications of the sponsor. For example,
“[t]he applicant states that the quality of study data was assured through
monitoring of investigational sites, appropriate training of study personnel,
independent audits, investigational site visits, and periodic data source veri-
fication” (Roman, 2007, p. 14). Similarly, “the [sponsor’s] clinical overview
states that the studies were conducted in compliance with ethical principles
that have their origin in the Declarations of Helsinki and in accordance
with the International Conference on Harmonization (ICH) E6 Guideline
for Good Clinical Practice (GCP)” (Xiao, 2009, p. 14).
If sponsor disclosures or onsite audits identify issues, reviews may as-
sess whether the situation (e.g., a protocol violation or a financial relation-
ship with the sponsor) could be expected to influence study findings. For
example, in connection with an application submitting requested studies
of valganciclovir hydrochloride (Valcyte), DSI’s routine, onsite investiga-
tions found a number of protocol violations. In the clinical pharmacology
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
review, the reviewers discussed each type of violation and determined that
some information submitted by the sponsor could not be accepted but
that other protocol violations would not be expected to affect conclusions
(Krudys and Arya, 2008). After additional information was submitted,
FDA approved the drug for prevention of cytomegalovirus (CMV) disease
in children age 4 months or over who received kidney or heart transplants
and were at high risk for developing the disease.3
Pharmacokinetic Studies with Healthy Children
As described in Chapter 2, pharmacokinetic studies undertaken with
children typically differ from those undertaken with adults. For adults,
Phase I studies often start with a small number of healthy volunteers. The
studies seek to investigate a drug’s pharmacokinetics in individuals not af-
fected by a disease under study; therefore, they offer no prospect of medical
benefit to these volunteers. For children, if either the drug or the research
procedures (e.g., extensive blood draws), or both, are deemed to involve
more than minimal risk without the prospect of direct benefit to the child,
then the regulatory framework outlined earlier precludes the enrollment of
healthy children in such studies. Alternatives to such studies might involve
pharmacokinetic studies of children with the condition under investigation
or pharmacokinetic studies undertaken as part of an efficacy and safety
trial.
Although most pediatric pharmacokinetic studies do not include
healthy children, exceptions exist. For example, for a pharmacokinetic
study of almotriptan (Axert), investigators recruited what were described
to be healthy adolescent and adult subjects, with or without a history of
migraine; of the adolescents recruited, only 2 of the 18 had a history of the
condition (Harris, 2009). The original written request for a study of this
drug specified a study of adolescents with a history of migraine (Behrman,
2001a); the clinical and clinical pharmacology reviews did not comment
on the inclusion of adolescents without a history of migraine. The clinical
review noted that the triptan drugs are generally considered to be safe but
also noted concerns about cardiac and other risks. As presented for IRB
review, the study protocol should have been clear that healthy children
could be recruited for the pharmacokinetic study and the review should
3 As amended, the written request (which derived from a sponsor proposal) sought pharma-
cokinetic and safety studies but not efficacy studies for three categories of transplant patients
and a pharmacokinetic and safety study for neonates with congenital CMV disease (Pikis,
2009). Because the latter condition does not occur in adults, the clinical review explained
that efficacy could not be extrapolated and, thus, that FDA could not approve use of the drug
for that indication.
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104 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
have considered whether such a study presented no more than minimal risk
to healthy children.4
Use of Placebo-Controlled Pediatric Trials
The use (and nonuse) of placebo controls may present ethical ques-
tions in both pediatric and adult clinical trials, and ethicists, governments,
investigators, and others have sought to provide principles to guide the use
of such controls. For example, the Declaration of Helsinki, as amended,
states:
The benefits, risks, burdens and effectiveness of a new intervention must
be tested against those of the best current proven intervention, except in
the following circumstances:
• he use of placebo, or no treatment, is acceptable in studies where no
T
current proven intervention exists; or
• here for compelling and scientifically sound methodological reasons
W
the use of placebo is necessary to determine the efficacy or safety of an
intervention and the patients who receive placebo or no treatment will
not be subject to any risk of serious or irreversible harm. Extreme care
must be taken to avoid abuse of this option. (WMA, 2008, p. 5)
What constitutes compelling and scientifically sound reasons for the
use of placebos in adult trials is a subject of debate (see, e.g., Temple and
Ellenberg, 2000; Miller and Shorr, 2002; and Temple and Meyer, 2003).
FDA no longer specifies adherence to the declaration as a standard for in-
ternational clinical trials (73 FR 22800). Rather, studies are to be conducted
consistent with the good clinical practice standards cited earlier.
Because children are a vulnerable population and because many chal-
lenges surround parental permission and child assent for a child’s participa-
tion in research, particular caution is needed when placebos are employed
in pediatric trials. When the use of a placebo control in a pediatric clinical
trial is proposed or contemplated, several questions warrant consideration.
4 Other historical examples of pharmacokinetic studies with healthy children can be cited.
FDA has accepted pharmacokinetic studies of cold medicine combination products (ibuprofen
and pseudoephedrine hydrochloride) that enrolled healthy children (ages 4 to 11 years in one
study [Adebowale, 1999] and ages 6 to 11 years in the other [Adebowale, 2002]). One justifi-
cation for such studies is that it is healthy children who get colds and whose parents may then
treat them with these products. To cite another example of healthy children in pharmacoki-
netic studies, at the time that it was approved in 1998, the antibiotic rifapentine (Priftin) had
labeling that described the results of a pharmacokinetic study with healthy volunteers ages 12
to 15 years that yielded results similar to those found for adults (Sanofi-Aventis, 2009). See
also Marshall et al. (1999) (abstract).
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
• Is the condition to be studied one for which one or more therapies
have been demonstrated to be safe and effective in the pediatric
age group to be studied? In these cases, comparative effectiveness,
superiority, or inferiority trials may be more appropriate than
placebo-controlled studies.
• What would be the expected harm of forgoing the use of such an
existing therapy and using a placebo instead, taking into account
what is known about the safety and efficacy of that therapy? Omis-
sion of a proven treatment may harm a child, so investigators and
IRBs must ask whether that harm involves no more than a minor
increase over minimal risk.
• Does the study design require that children who are currently re-
ceiving an effective therapy have that therapy withdrawn, or is the
placebo to be used concurrently with such a therapy in one arm
of the trial?
In the written requests and studies that were reviewed for this report,
placebo-controlled trials of efficacy were fairly common. For example,
among the sample of 45 labeling changes that the committee assessed,5 tri-
als with both an active comparator and a placebo control were undertaken
for 3 products, at least one placebo (only)–controlled trial was performed
for 22 products, and active comparators (only) were used for 7 products.
For the remaining labeling changes, situations varied, involving, for ex-
ample, FDA acceptance of extrapolation of efficacy from adult studies with
no requirement for a controlled trial of efficacy.
The conditions investigated in active comparator-controlled trials in-
cluded, in some cases, conditions that were also studied in placebo-con-
trolled trials, for example, asthma and osteogenesis imperfecta. Other
conditions studied with active comparators included certain bacterial infec-
tions and Kawasaki disease. FDA has not necessarily approved the com-
parator drugs for pediatric use. Examples, discussed in Chapter 6, include
requested studies of bacterial conjunctivitis in neonates.
The conditions studied in placebo-controlled pediatric trials included
asthma, anxiety, hypertension, schizophrenia, mania associated with bipolar
disorder, migraine, osteogenesis imperfecta, attention deficit hyperactivity
disorder, and juvenile rheumatoid arthritis. At the time of some of the
placebo-controlled trials, no treatments had been approved by FDA (for
the pediatric age group studied) for the condition under study (e.g., irrita-
bility associated with autism). The use of placebo controls in these studies
does not create the potential for harm by depriving a child of a therapy
5 See Appendix A for a description of how the committee selected its sample.
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demonstrated (or widely thought) to be effective and thus does not raise
ethical concerns.
In other cases, effective treatments were approved and children were
taken off effective treatments. For example, effective treatments for asthma
were available at the time that some of the pediatric placebo-controlled
trials were undertaken.6 A review published in 2004 examined rates of
exacerbation and related participant withdrawal from trials in 45 placebo-
controlled trials that did not specify the use of anti-inflammatory drugs
in all those participating (Coffey et al., 2004). The review concluded that
withdrawals and exacerbations were more frequent in the placebo groups.
Of the 45 trials, 14 enrolled only children; the other 31 included both adults
and children. The child-only trials showed the same pattern of higher num-
bers of withdrawals and exacerbations in the placebo groups. Subgroup
analyses were not reported for the children in trials that combined adults
and children. This omission of subgroup analyses by age—and, thus, the
omission of child-specific data—also raises ethical concerns. As the authors
of the review observe, children in these studies were “being exposed to the
risks and harms of research, but there is no advance in pediatric medicine
from their participation” (Coffey et al., 2004, p. 91).
In pediatric hypertension, another condition for which effective treat-
ments (e.g., diuretics) were available at the time of placebo-controlled pe-
diatric studies, investigators examined adverse events and serious adverse
events in 10 placebo-controlled efficacy trials of drugs for hypertension
(Benjamin et al., 2008). In this case, they found no difference in the rates
of occurrence of such events between the children receiving the placebo and
those receiving the study drug.
Some alternatives to the placebo-controlled trial raise their own ques-
tions. For example, in a noninferiority trial comparing the test drug and
an active comparator, one question is, what can be appropriately assumed
about the effect of the comparator drug? Randomized withdrawal designs
also have disadvantages. The committee discussed issues with these and
other trial designs but concluded that a systematic ethical review was not
feasible given the complexity of (and disputes about) the issues and the
scope of the committee’s other tasks.
6 In 1991, the National Heart, Lung, and Blood Institute issued guidelines that advised
that anti-inflammatory medications be used for both children and adults who had more than
mild asthma (NHLBI, 1991); updates followed in 1997 and 2004 and most recently in 2007
(NHLBI, 2007).
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Ethical Aspects of Pediatric Exclusivity
The committee was not asked to examine the ethical implications of
the incentives for pediatric studies provided by BPCA, but these implica-
tions, including questions of intergenerational justice, do need attention. It
may be argued, on the one hand, that studies conducted in response to the
exclusivity incentive for pediatric studies, first, offer justice to the youngest
members of society and, second, provide some balance both to usual market
forces that favor studies with adults and to federal programs such as Social
Security and Medicare. (For a discussion of generational fairness issues and
federal policies, see, for example, Newacheck and Benjamin, 2004.) On the
other hand, some have cited costs to older members of society associated
with the delayed entrance of generic competitors associated with the extra
6 months of marketing protection offered by pediatric exclusivity. For
example, Dor and colleagues (2007) noted that although “evidence sug-
gests value in reauthorizing BPCA, significant concerns have been raised
over the cost to both the federal government and consumers regarding the
length of time (currently 6 months) of the market exclusivity extension”
(p. 7). Medicare, Medicaid, and private health insurance plans (and, thus,
taxpayers or premium payers) pay some of the costs of higher drug prices,
and some are paid by patients.
Some analyses have attempted to estimate the economic benefit to
sponsors of pediatric exclusivity. In an analysis involving nine drugs for
hypertension, Baker-Smith and colleagues (2008) reported that the median
cost to complete pharmacokinetic studies was $862,000 and that the me-
dian cost to complete safety and efficacy trials was $4.3 million. Taking
the after-tax sales into account for the 6 months of additional marketing
protection, they reported that the ratio of net economic return to study cost
was strongly positive but also quite variable (average return of 17 to 1 with
a range from 4 to nearly 65).
In another study that examined nine representative products for which
sponsors received exclusivity, Li and colleagues (2007) estimated that
the median net benefit from the existing exclusivity period of 6 months
was $134,265,456, with a range of a negative $8,946,033 to a positive
$507,899,374. (The authors noted limitations of information about the
cost to sponsors of conducting trials.) Although generally favorable about
the benefits of BPCA, the authors concluded that the pediatric exclusivity
incentive of BPCA “overcompensates blockbuster products for performing
clinical trials in children while other products have more modest returns on
investment under this program” (p. 487).
Both the studies cited above relied on detailed data from sponsor sub-
missions to FDA that are not public (e.g., data on specific lab tests, study
site visits, screening of potential participants, and regulatory audits among
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108 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
other variables). For these analyses, FDA allowed investigators who were
special government employees to have access to data that were stripped of
personal identifiers such as investigator names but otherwise not redacted.
Before the 2007 reauthorization of BPCA, some requested studies led
to the granting of pediatric exclusivity without labeling changes and with-
out public access to the clinical and other reviews of the studies. Sponsors
obtained the reward of exclusivity with little or no information benefit to
clinicians, child patients, or the public. In 2007, Congress sought to correct
this situation by requiring that information from studies conducted under
BPCA be included in the label and that clinical and other reviews be posted
(see Chapter 3). Nonetheless, instances still occur in which sponsors are
granted exclusivity without a labeling change (see the discussion of bival-
rudin and gatifloxacin in Chapter 7).
Another issue with studies requested under BPCA is the extent to which
value can be obtained from a fifth or sixth request for pediatric studies of
drugs in the same class and with the same mechanism of action as previ-
ously investigated drugs. Because most written requests are not public7 and
because FDA cannot make information about INDs public, it is not possible
to identify comprehensively requests that involve the same class of drug, the
same indication, all or some of the same types of studies, and all or some
of the same age groups.
Multiple studies are a particular concern when they consistently show
a lack of efficacy. Chapter 6 describes several such situations with studies
with newborns. One question is whether there was a point at which suf-
ficient information showing a lack of efficacy had been submitted that the
benefit anticipated from continuing the studies (e.g., data on pharmaco-
kinetics to guide persisting off-label use) no longer justified the risks and
economic costs.
CONCLUSIONS
A number of national and international standards are in place to pre-
vent unethical clinical studies in general and with children specifically. They
include the FDA and HHS regulations, the system of research review and
monitoring that these regulations have helped create, and various programs
of ethics education for regulators, investigators, sponsors, and IRBs. The
provisions made by Congress for FDA to add expertise in pediatrics and
pediatric research ethics offer additional protections to children.
Still, an ethical tension may exist in pediatric drug studies and, indeed,
7 As of February 1, 2012, and as required by FDAAA, FDA had posted 47 written requests
(with amendments) at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Development
Resources/ucm049997.htm.
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ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
clinical research generally. That is, depending on the specifics of a research
situation, investigators in pediatric studies may face a conflict between the
best interest of an individual child as a potential research participant and
the interests of future children who might benefit from the research. Spe-
cial safeguards help protect child participants in research, but they do not
eliminate the tension. Likewise, although regulations and research ethics
programs are valuable, they do not substitute for sponsors, investigators,
and FDA staff who—beginning with the earliest stages of study planning
through its completion, evaluation, and dissemination—understand and
follow ethical and scientific standards for pediatric research.
The committee was not asked to assess the benefits of BPCA and PREA
in relation to their costs. Such a policy evaluation would be complicated
and require many assumptions in the absence of evidence to support state-
ments about causation. To help provide information for a narrower assess-
ment of the costs incurred and benefits accrued by sponsors of pediatric
studies requested under BPCA, Congress or FDA could support additional
analyses similar to those cited earlier in this chapter.
Relying primarily on FDA clinical reviews, the committee identified
some concerns about pediatric studies conducted under BPCA and PREA.
One concern involves placebo-controlled trials. Such trials do not necessar-
ily present problems, but it is important that protocols for such studies be
consistent with ethical and scientific standards. The committee suggests that
FDA document the scientific and ethical rationales for the use of placebo-
controlled pediatric trials, first, in written requests that include such studies
and, second, in clinical reviews prepared by FDA staff. Such documenta-
tion, particularly in cases in which effective alternative treatments exist,
could help clarify whether the research will meet or has met the ethical
standards described earlier in this chapter. Justification should also be con-
sidered in some other situations, for example, when FDA accepts the use
of an unapproved drug as the active comparator in a controlled trial or to
the inclusion of healthy children in pharmacokinetic studies.
Another concern that the committee identified is some continuing limi-
tations on public access to information from studies conducted under BPCA
and PREA. Despite substantial improvements for recently submitted stud-
ies, access issues continue for clinical and other reviews for older NDA and
BLA submissions. Redactions of significant sections of clinical reviews also
present concerns.
Congress and FDA have several options to further expand access to
information from pediatric studies. One is for Congress to direct that FDA
make public the clinical and other reviews of drugs and biologics approved
before September 27, 2007. An additional option is for Congress to direct
the Government Accountability Office or other entity independent of FDA
to analyze the use of redactions for reviews of pediatric studies. The task
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110 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
would be to assess whether redactions exceed what is necessary to protect
confidential commercial information and trade secrets and critical aspects
of FDA’s internal deliberations. A further step would be for FDA to explore
with the National Library of Medicine how clinical and other reviews might
be made accessible through PubMed and through links to trials registered
at ClinicalTrials.gov. Such integration could provide an independent as-
sessment to supplement sponsor summaries and publications. To obtain a
better understanding of the dissemination of information, FDA could seek
an assessment of private sector dissemination of findings from pediatric
studies and labeling changes conducted under BPCA and PREA, including
both the speed of dissemination and the accuracy and completeness of the
information as disseminated.
The committee recognizes FDA’s limited resources. At the same time, it
is concerned that rationales for ethically sensitive decisions be clear and also
that the public have access to information in which sponsors, investigators,
research participants, taxpayers and premium payers, and FDA staff have
already invested—in different ways—considerable expense or effort.
