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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
Pregnancy and for Treatment of Infants and Children.” In 1977, the FDA
issued a Pediatric Guidance called “General Considerations for the Clinical
Evaluation of Drugs in Infants and Children.” In the same year, the American
Academy of Pediatrics, reacting to the paucity of information for children on
drug labels, asserted that it was unethical to adhere to a system that forced
physicians to use drugs in what was basically an uncontrolled experiment
whenever they wrote prescriptions for children. The Academy stated that it
was imperative for new drugs that were to be used in children to be studied
in children under controlled circumstances so that the benefits of therapeutic
advances would become available to all who would need them. This was a
powerful, yet simple statement: Children deserve the same standard as
adults. If adequate and well-controlled studies were required to determine
the efficacy of the products used in adults, then the same should be true for
products used to treat children. It was now considered unethical not to study
children. Following this unprecedented statement, in 1979, the FDA
confirmed the need to have information on how best to use a product in the
pediatric population and issued a Regulation on the Pediatric Use
Subsection of Product Package Insert Precautions Section (21 CFR 201.57
(f)).
Thereafter, a number of milestones in Pediatric Drug Development in the
United States and in Europe occurred (see Table FM 1.1). The FDA issued a
regulation in 1994 that required that statements on pediatric use of a drug for
an indication approved for adults must be based on substantial evidence
derived from adequate and well-controlled studies conducted in children,
unless the requirement was waived.
The intent of the initial regulation (1994 rule) was to encourage
manufacturers to conduct the necessary trials so that adequate prescribing
information would be available to physicians. Unfortunately, it did not
generate the response intended. Few clinical trials were initiated in the
pediatric population. Manufacturers cited financial, medicolegal, and
methodologic disincentives, especially for products already approved for
adults. These products were available to physicians for prescription use
outside of labeled indications through the practice of medicine. The FDA
could encourage but not require that a sponsor conduct the appropriate trials
to support pediatric labeling.
At the time this rule was issued, approximately 80% of drugs listed in the
Physicians’ Desk Reference did not have directions for use in the pediatric
population based on clinical trials. This disturbing situation was heightened
by the AIDS epidemic, which served to contrast the disparity between the
pace of drug development between adults and children. In 1994, the FDA
issued a final, slightly modified rule requiring drug manufacturers to survey
the existing data and determine whether those data were sufficient to support
additional pediatric use information in a drug’s labeling. In addition, the rule
explicitly stated that controlled clinical studies need not be carried out in
pediatric patients when the course of the disease and the response to
treatment were similar in adults and children. Extrapolation from adult
efficacy data to pediatric patients was permitted. Therefore, controlled
clinical studies in adults, together with other information, such as
pharmacokinetic and adverse reaction data in pediatric patients, could be
found to be sufficient to establish pediatric safety and efficacy. Under the
1994 rule, the manufacturer could determine that existing data permitted
modification of the label’s pediatric use. The manufacturer, however, had to
submit a supplemental new drug application to the FDA, seeking approval of
the labeling change.
It is important to recognize that the 1994 rule did not require that
manufacturers conduct pediatric studies if existing information was not
adequate to support a labeling change. Instead, where there was insufficient
information to support a pediatric indication or pediatric use statement, the
1994 rule allowed the manufacturer to include in the drug’s labeling the
statement, “safety and effectiveness in pediatric patients have not been
established.”
The FDA was hopeful and enthusiastic about this regulation.
Unfortunately, well over half of the responses to the rule concluded that there
were insufficient data, and the resulting labeling change consisted of
inclusion of the statement just given. Only 23% of the responses resulted in
improved labeling for pediatrics.
Clearly, if the goal of ensuring the safe and effective use of therapeutic
agents in children was to be met, additional steps had to be taken. Two
pieces of legislation underscored the commitment of the FDA to the safe and
effective use of therapeutic agents in children. The first of these was Section
111 of the FDA Modernization Act (FDAMA). Congress passed this act in
November 1997 (see Table FM 1.1). Section 111 of this act created a
financial incentive (called “pediatric exclusivity”) consisting of an
additional 6 months of marketing exclusivity for conducting pediatric studies
on new drugs and drugs already on the market and under patent. The second
advance was the 1998 Final Pediatric Rule, which was to become effective
in 1999. This regulation required that pediatric studies be conducted for
certain new as well as marketed drugs and biologic products. Requiring
studies in the pediatric population represented a significant departure from
the previous regulations, which were voluntary. Both the final rule and the
pediatric exclusivity provision were critical to ensuring that necessary and
timely pediatric drug development occurred and that improved pediatric
labeling would be the result. The financial incentive of an additional 6
months of marketing exclusivity could apply to both new drugs and marketed
drugs as defined by the FDAMA. If the 6 months of additional marketing
exclusivity was granted, all the sponsor’s products that contain the drug
(“active moiety” formulations of the drug) might receive this extension.
Because of this wide application, this was seen as a significant “carrot” in
getting manufacturers to conduct pediatric studies. To qualify for pediatric
exclusivity, the drug manufacturer had to receive a written request for
pediatric studies from the FDA. This written request outlines the studies that
the drug manufacturer must conduct and complete, and which complete study
reports must be submitted by an agreed-on date. New and approved drugs
that this law applied to were those that had been determined as likely to
produce health benefits in the pediatric population. For any given drug, the
FDA evaluated every indication under development or that had been
previously approved and requested that the appropriate studies were
performed. Conducting pediatric studies in response to a written request was
voluntary. To obtain pediatric exclusivity, final reports of the submitted
studies had to meet the terms of the written request and the drug needed to
have existing patent protection or exclusivity.
Because voluntary efforts such as the 1994 Pediatric Rule did not
substantially increase the number of products entering the market with
adequate pediatric labeling, the FDA concluded that additional steps were
necessary to ensure the safety and effectiveness of drugs and biologic
products for pediatric patients. In addition, even though the pediatric
exclusivity offered by the FDAMA was expected to provide a substantial
incentive for sponsors to conduct pediatric studies, that provision did not
apply to drugs that no longer had existing patent protection or exclusivity or
to biologics or “old” antibiotics. It was a voluntary program, making it likely
that manufacturers might elect not to conduct studies in products with smaller
markets, even though there might be a great medical need for the product in
pediatric patients. Therefore, it was felt that there were still many situations
where there was a need to require the collection of data in children.
The 1998 Pediatric Rule required the manufacturers of new and marketed
drugs and biologic products to evaluate the safety and effectiveness of their
products in pediatric patients. It was designed to ensure that new drugs and
biologic products contained adequate pediatric labeling for the claimed
indication at the time of, or soon after, approval. This rule established a
presumption that all new drugs and biologics would be studied in pediatric
patients, but allowed manufacturers to obtain a waiver of the requirement in
some circumstances (e.g., if the indication was not applicable to the pediatric
population). This rule applied to new chemical entities, new indications,
new dosage forms, new dosing regimens, and new routes of administration.
This rule also authorized the FDA to require pediatric studies of
marketed drugs and biologic products where there was a compelling need for
studies (defined as situations in which the product is used in a substantial
number of pediatric patients) and the absence of adequate labeling could
pose significant risks for pediatric patients, or the product would provide a
meaningful therapeutic benefit over existing treatments. Thus, this rule was
mandatory and gave the FDA additional power to require studies in children.
Although this rule was being implemented, the rule was considered by the
Federal courts to be illegal and not within the FDA’s authority.
FDAMA was authorized for 5 years. At its termination in 2002, because
of its unprecedented success, it was reauthorized for 5 to 7 additional years.
In doing so, Congress incorporated the pediatric exclusivity provisions of
FDAMA into the Best Pharmaceuticals for Children Act (BPCA). This
legislation had important provisions for infants and children. The BPCA
identified the NIH as a major player together with the FDA in supporting
drug studies in infants and children. The act made provisions to address new
(on-patent) drugs, but also asked the NIH and FDA to identify off-patent
drugs that need to be evaluated in the pediatric population.
TABLE FM 1.1
In 2003, the Pediatric Research Equity Act (PREA) was passed into US
law as an enactment of the Pediatric Rule of 1998. The provisions of PREA
mandated the conduct of pediatric clinical trials for drugs under development
that had the indications which also occurred in pediatric patients. Under the
2007 Food and Drug Administration Amendments Act (FDAAA), provisions
in BPCA and PREA were renewed in addition to a section pertaining to the
study of pediatric devices, a requirement for FDA to actively monitor safety
for all drugs studied under the provisions of this legislation, and the
formation of an FDA Pediatric Review Committee to standardize pediatric
drug development programs. After another 5 years, BPCA and PREA were
finally made permanent under the 2012 FDA Safety and Innovation Act
(FDASIA). FDASIA also focused on one of the neglected pediatric groups in
drug development, the neonates.
In 2017, the FDA Reauthorization Act (FDARA) focused on another
neglected pediatric patient group in drug development, namely pediatric
oncology patients. Because cancer indications in adults frequently do not
pertain to pediatric patients, studies cannot be required under PREA, which
is indication based. Therefore, the Research to Accelerate Cures and Equity
(RACE) for Children Act was passed as part of FDARA and changed the
basis for PREA inclusion to be molecular targets for pediatric oncology
instead of indication. The RACE Act for Children also removes the PREA
exemption for orphan drug products, which is critical in small oncology
patient groups. This change to PREA-based pediatric drug development
study requirements will take place in August 2020.
Mile s tones in Pediatric Drug Deve lopment
1977—AAP Statement concerning the need to conduct clinical trials in children
1979—The US Food and Drug Administration (FDA) establishes a section for drug labels and
requires trials in children parallel to adult process
1994—FDA requirement for sponsors or drug manufacturers to update drug labels, to evaluate
existing data, and to determine whether these data are sufficient to support information for pediatric
drug labeling. The FDA also implements a voluntary collection of data on pediatric use before and
after a drug is approved. FDA introduces the “extrapolation concept”
1997—US Congress passes FDAMA (FDA Modernization Act) and prolongs patent exclusivity for
6 months to pharmaceuticals that voluntarily perform studies on the drug in children
1998—The FDA publishes the Pediatric Rule, which requires manufacturers to assess the safety
and efficacy of drugs and biologic products in children in specified circumstances
2002—The Best Pharmaceuticals for Children Act (BPCA) was signed into law by President G. W.
Bush. BPCA renewed exclusivity or patent protection for an additional 6 months. Provides additional
mechanisms, such as studies funded by the National Institutes of Health to obtain drug data from
“off-patent” or patented drugs (which manufacturers decline to study in children). BPCA provides
process for “off-patent” drug development, public posting of results, and reporting of all AEs for 1
year after exclusivity is granted
2003—Pediatric Research Equity Act (PREA) is passed, which requires the study of drugs and
biologics for pediatric population except in defined situations and also creates a Pediatric Advisory
Committee
2006—European Parliament passes the Best Medicines for Children Act on December 12, 2006,
which became law in January 2007. The law requires studies of drug in newborns and children and a
pediatric investigation plan (PIP) for all drugs being developed. It creates a pediatric committee to
decide priority drugs to study and to review protocol proposals and study plans for drug development
in children. It also provides procedures to study drugs for newborns and children and funding
mechanisms. EMEA (European Medication Evaluation Agency) reviews data for approval and
marketing licensure
2007—US Congress reauthorized BPCA. Thereafter, the number of clinical pharmacology studies in
newborns and children increased followed by several labeling changes
2012—US Congress made BPCA and PREA permanent under the 2012 FDA Safety and
Innovation Act (FDASIA). FDASIA also focused on one of the neglected pediatric groups in drug
development, the neonates
2017—US Congress approved the FDA Reauthorization Act (FDARA) and the Research to
Accelerate Cures and Equity (RACE) for Children Act. FDARA also focused on another neglected
pediatric patient group in drug development, namely, pediatric oncology patients
AAP, American Academy of Pediatrics; AEs, adverse events.
In Europe, parallel regulatory developments were also occurring. On
December 12, 2006, the European Parliament passed the Best Medicines for
Children Act, which became law in January 2007. The law requires studies
of drug in newborns and children and a pediatric investigation plan (PIP) for
all drugs being developed. It provides for the creation of a pediatric
committee to decide priority drugs to study. The pediatric committee also
reviews protocol proposals and study plans for drug development in
children. It also provides procedures and funding mechanisms to foster
studies of drugs for newborns and children. Thus, there is an increasingly
concerted effort in Europe and North America to ensure that requisite data
for the safe and effective drug use in children are obtained.
All of this work can only be done through collaborative efforts. One
model for this is the development of public–private partnerships or consortia
that bring together stakeholders from academia, industry, patient/parent
advocacy groups, regulators, and other government entities. In October 2014,
a workshop sponsored by the Critical Path Institute, Burroughs-Wellcome
Fund, and the FDA was held at the FDA to discuss the logistics to support a
neonatal consortium. Based on this initial meeting, the International Neonatal
Consortium (INC) was launched in May 2015 at a workshop in London. In its
first year, the INC focused on four key areas: clinical pharmacology,
seizures, bronchopulmonary dysplasia, and databases.
Another consortium working on neonatal issues is the International Life
Sciences Institute (ILSI)—Health and Environmental Sciences Institute
(HESI) Developmental and Reproductive Toxicology (DART) Committee.
ILSI-HESI DART is a multisector collaborative research effort to identify
and explore nonclinical models to inform the efficacy and long-term safety of
drugs as they apply to neonatal disease. The working groups are surveying
established nonclinical neonatal disease models, identifying nonclinical
models to inform efficacy and safety of neonatal drug therapy in neonatalspecific conditions and physiology as it pertains to neonatal absorption,
distribution, metabolism, and excretion (ADME), and reviewing case studies
to highlight the uses of nonclinical data to inform the selection of safe starting
doses for neonatal studies.
These consortia provide opportunities for the scientific community to
work together to develop innovative trial designs, new biomarkers, new
outcome assessment tools, and clinically meaningful short- and long-term
endpoints.
Collaborative efforts are needed to support the infrastructure for the
actual trials in neonates. A successful example of these collaborative efforts
is the Pediatric Trials Network (PTN), an alliance of clinical research sites
sponsored by the NICHD and managed through the Duke Clinical Research
Institute that has focused on conducting clinical trials to support studies of
off-patent drugs prioritized by the NICHD under BPCA, leading to several
labeling changes of drugs used in newborns and children.
Since the publication of the previous editions of this book, neonatal and
pediatric pharmacology has grown and flourished. Indeed, the future appears
bright, and we welcome the day when therapeutic orphans will no longer be
applicable to drug use in infants and children.
Johannes N. van den Anker
Jacob V. Aranda
S E C T I O N
I
General Principles
Steven Hirschfeld
Susan McCune
Lynne Yao
Donna L. Snyder
Gerri R. Baer
Bridgette L. Jones
Anne Zajicek
C H A P T E R
1
Clinical Trials Involving Children: History, Rationale, Regulatory Framework, and Technical Considerations
INTRODUCTION
The premise for this chapter is that clinical trials are a justifiable activity to
guide decision-making. Clinical trials are formal mechanisms to evaluate
interventions by capturing observations and measurements about exposure to
the intervention in a structured manner from individuals with a particular
phenotype that are selected to represent the larger population of all people,
current and future, with the phenotype of interest. A phenotype may be
characterized as individuals with or at risk for a particular condition, whether
it is chronic or temporary, whether it is life threatening or a mild annoyance.
The data that represent the signals from the individual observations and
measurements are subsequently pooled and analyzed to infer a generalization
about the effects of the intervention under evaluation.
The decision types that are supported by the analysis of clinical trials
include whether a patient might receive benefit with acceptable risk if
exposed to an intervention or whether a body of data about an intervention
support marketing authorization or whether cumulative data warrant further
development of an intervention. In all cases, the amount, type, and quality of
collected data generated from a clinical trial will be important components of
the credibility, validity, and confidence in any analysis and the inferences and
decisions that are influenced by that analysis.
The general paradigm is illustrated in Figure 1.1.
Figure 1.1 General paradigm for individual data capture in a clinical trial showing a person with a
defined phenotype with or without a defined genotype exposed to an intervention followed by a structured
measurement. The signal from the structured measurement is captured and the collection of the data
from all individuals is pooled and analyzed.
The concept of exposure includes the concepts of amplitude or intensity,
duration, and frequency. All are variables and must be described. The concept
of structured measurements includes the concepts of methodology, precision,
sensitivity, specificity, receiver-operator characteristics, and other factors to
be discussed in further detail subsequently. These must also be described to
properly interpret the signals and perform informative analyses.
A historical asymmetry characterizes the role of children in exposure to
interventions that are either untried or have a history but no formal body of
evidence establishing the benefit and potential risks to children. Just as the