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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
brain dead patient. The following paragraphs have brief comments for each
population.
The child with handicaps (mentally, physically, or emotionally) must be
stringently protected from disproportionate representation in research studies
through either exclusion or inclusion. Institutionalized children should rarely
be considered for participation in research studies because of the possibility
of not having sufficient safeguards.
The International Conference on Harmonization (ICH) document on
pediatric studies, discussed later, is consistent with the AAP guidelines,
noting that information that can be obtained in a less vulnerable, consenting
population should not be obtained in a more vulnerable population or one in
which the patients are unable to provide individual consent. Studies in
populations with handicaps or institutionalized pediatric populations should
be limited to diseases or conditions found principally or exclusively in these
populations, or to situations in which the disease or condition in these
pediatric patients would be expected to alter the disposition or
pharmacodynamic effects of a medicinal product.
Patients requiring emergency care may participate in research and have
the usual procedures for informed consent or permission or assent altered or
waived if
the clinical condition is potentially life threatening or permanently
disabling
AND
permission cannot be obtained in a timely way
AND
the only available therapy is investigational or not validated
AND
no accepted therapy is known to be superior to the proposed
experimental therapy
The Code of Federal Regulations in Title 21 Part 50.24 provides the
authority to proceed, and compliance with Subpart D of the Common Rule
Title 45 Part 46 is still required.
In addition, the relevant IRB should receive assurance that the risk is not
more than a minimal added risk, equipoise exists among therapeutic
alternatives, participants and parents or guardians will be provided with
pertinent information regarding the study as soon as feasible, and the waiver
will not affect the rights and welfare of participants.
The dying patient may be enrolled in a study if the question being
addressed is extremely important, the therapy being proposed is well founded
in animal and clinical research, or there is good expectation that the therapy
may be beneficial and the potential benefits exceed the potential risks. In
addition, physicians not involved in the research must document that death
appears inevitable and that standard therapy has not improved the patient’s
prognosis.
Patients with chronically progressive or potentially fatal disease and their
parents or guardians are potentially prone to feel an obligation to participate
in research proposed by physicians that care for these patients due to the
dependent relationship that can develop. Investigators who are not involved in
the care of the patient should obtain approval for participation.
The brain dead patient is legally dead in most jurisdictions. The
circumstance of considering research would involve some measurements on
remaining body functions. The AAP document stipulates that research may
proceed if the death certificate has been signed by a physician independent of
the planned research, the medical question addressed by the research is of
utmost importance, permission is received from the parents, the research
procedure is brief, the drugs are intended for human use, and the research will
not compromise either organ donation or an autopsy, if either is planned.
DESIGNING CLINICAL TRIALS: GENERAL
CONSIDERATIONS
To be ethical, a clinical trial must be informative. To be informative, a trial
must measure an outcome in an unbiased, valid, and interpretable manner. The
sequence of steps can vary, but an effective approach to designing a clinical
trial is to
first decide what the potential benefit may be as it relates to mitigating or
solving a problem for a population with a phenotype (condition or
disease) of interest
select an intervention to evaluate
determine whether there is an outcome measure or small collection of
measures that could inform the nature, magnitude, and duration of the
benefit
assess the reproducibility and applicability of the outcome measure to
the phenotype (disease or condition) of interest
decide what type of study design would be most resource effective,
minimize bias, and maximize certainty
select the appropriate elements to write a study protocol
ADDITIONAL PEDIATRIC-SPECIFIC
CONSIDERATIONS FOR TRIAL DESIGN
Studies in pediatric populations require additional considerations on ethical,
technical, and scientific grounds. For these reasons, pediatric research should
be led by investigators trained and experienced in studying children and
performed at facilities that have the staffing and infrastructure to support and
comfort children. In such a facility, children can feel positive about
participation in clinical research.
94
The ideal circumstance in clinical research is that consent, risk, and
benefit are vested in the same individual. This is the case with adult
volunteers. In pediatric research, formal consent does not apply, but
permission is provided by a third party—usually parents or legal guardians,
the risk is always borne by the child, and the benefit may or may not accrue to
the child. The consequence of permission process is always imperfect,
especially in multiarm studies, because if neither the subject nor the
researcher knows which therapy is being consented to or what the possible
risks may be, the process of being “informed” cannot be considered complete.
A need to educate parents and patients about clinical trials should be a
component of the process.
95,96
The institutional approval of pediatric studies is also a challenge and
would require pediatric expertise on IRBs and ethics committees. The
question of whether children who are not affected by a disease or condition
under study should be enrolled was formally addressed by an FDA Advisory
Subcommittee on November 15, 1999.
The Pediatric Subcommittee of the Anti-Infectives Drugs Advisory
Committee, supplemented by ethicists, was charged with providing guidance
on the ethical consideration for the conduct of pediatric clinical trials, namely
the role of pediatric volunteers who do not have the disease under study.97 The
consensus areas of the discussion were as follows:
1. In general, pediatric studies should be conducted in subjects who may
benefit from participation in the trial. Usually this implies the participant
has or is susceptible to the disease under study. The Pediatric
Subcommittee utilized a broad definition of potential benefit. For
example, almost any child has the potential to benefit from a treatment
for otitis media due to the likely risk of developing the condition.
2. In general, children who can give assent should be enrolled in a study in
preference to, or prior to, children who cannot give assent. Careful
consideration must be given to the importance of the potential benefit of
the study. In certain circumstances, the potential benefit that may be
derived from studying children who cannot give assent may override the
preference for first enrolling assenting children.
As a result of the subcommittee discussions, it is considered appropriate
and preferable to refer to children enrolled in clinical research as patients
rather than subjects or participants to emphasize the expectation of potential
benefit. The subcommittee also recommended that the federal regulations that
apply to protecting children enrolled in research studies that receive federal
funding, 45CFR46, be adapted and extended to studies that receive other
sources of funding.
In April 2001, the FDA published in the Federal Register an adaptation of
45CFR46 Subpart D that applies to all children enrolled in studies that are
FDA regulated.98 The regulation was finalized in 2013.
99
Placebo-controlled studies have been formally addressed by the AAP
1995 guidelines, which state that placebo or untreated observational control
groups can be used in pediatric studies if their use does not place children at
increased risk.
The International Conference on Harmonisation Efficacy Document 11 (E-
11), which the FDA contributed to and accepts as guidance, also comments on
placebo-controlled studies. Acceptable conditions include when there is no
commonly accepted therapy for the condition, or when the commonly used
therapy is of questionable efficacy, or when the commonly used therapy has a
high frequency of undesirable side effects and the risk may be greater than the
benefits. A placebo is also considered acceptable in a comparative add-on
study design where a new treatment or placebo is added to an established
regimen.
100
As a consequence of the prior discussions and recommendations, current
thinking is that comparison with a placebo may be acceptable if there are no
approved or adequately studied therapies for children with the condition
under study. For serious or life-threatening illness, a data monitoring
committee with planned interim analysis and study-topping rules should be
used.
In all studies, each patient should have escape criteria to minimize
exposure to ineffective treatment. For serious and life-threatening illnesses or
when other risks to study conduct or completion exist, such as a major
efficacy study that is intended to define policy or be submitted for FDA
labeling or enrolls a population that requires additional protections or
addresses a condition about which controversy or social sensitivity may be
present or a multinational study, a data monitoring committee may be
advisable. For minor illness or discomfort symptoms, a randomized
withdrawal study may minimize exposure to placebo. Individual patient
escape rules should be defined. A data monitoring committee would generally
not be needed unless there was a specific safety concern.
Criteria for enrolling children in Phase 1 or initial exposure studies were
commented upon by the Pediatric Subcommittee of the FDA Oncologic Drugs
Advisory Committee in 2002 as it pertains to children with cancer who have
relapsed or who are refractory to available anticancer therapy and would be
candidates for investigational drugs. The consensus was that the evidence for
initiating clinical studies in children with cancer should include biologic
plausibility of the product having activity against a pediatric tumor (which
could be obtained from preclinical data), some expectation of potential
benefit, a reasonable expectation of safety, and sufficient information to
choose an appropriate starting dose.
If a scientific rationale and a population of pediatric cancer patients with
no available anticancer therapy exists, then pediatric oncology clinical studies
should be initiated, in most cases, immediately following adult Phase 1
studies.
101
Although the committee only commented on children with cancer,
the same principles may be applicable to children with diseases other than
cancer that may also be life threatening and have limited therapeutic options.
The ICH began work on a guideline for pediatric research in 1998. These
guidelines were adopted as a recommendation by all participating regions in
the year 2000 and subsequently updated in 2017.
100
The document is identified
as E11, which is the eleventh document in a series of recommendations
related to the conduct of clinical studies. The letter E stands for efficacy.
Major provisions of the document, due to its global importance, are
summarized in the following paragraphs.
The general principles are that pediatric patients should be given
medicines that have been properly evaluated for their use in the intended
population. The product development programs should include pediatric
studies when pediatric use is anticipated, that pediatric development should
not delay adult studies or adult availability, and that pediatric therapeutic
development is a shared responsibility among companies, regulatory
authorities, health professionals, and society as a whole.
The default state is that data on the appropriate use of medicinal products
in the pediatric population should be generated unless the use of a specific
medicinal product in pediatric patients is clearly inappropriate. Factors to
consider when deciding to begin a pediatric development program are the
prevalence and seriousness of the condition to be treated in the pediatric
population, whether there are unique pediatric indications, age ranges of
probable patients, availability and suitability of alternatives (including
adverse events and pediatric-specific safety concerns), pediatric knowledge
about the class of compounds, potential need for a pediatric formulation, and
the need to develop pediatric-specific endpoints for study.
The timing of initiation of pediatric studies will depend on the prevalence,
seriousness, availability, and suitability of alternatives. E11 states that the
most important factor is the presence of a serious or life-threatening disease
for which the medicinal product represents a potentially important advance in
therapy and should initiate an urgent and early introduction of pediatric
studies in the development program. For products that are predominantly or
exclusively intended for pediatric use, all phases of development may occur
in children.
Products intended for serious or life-threatening conditions occurring in
adults and children for which there are no or limited therapies should begin
pediatric studies following initial adult safety and preliminary evidence of
potential benefit (early Phase 2). This recommendation differs from the FDA
Advisory Committee recommendation of October 2002 that those pediatric
studies begin immediately after adult Phase 1.
For all other conditions, pediatric studies should begin when safety and
efficacy have sufficient data to justify exposing children to a product.
Exposure of children to a product that will be of no benefit should be
avoided. In all studies, accurate dosing and patient compliance must be
assured: thus, a pediatric formulation may be required. In developing a
formulation, the variability of susceptibility of patients of different ages and
developmental stages to the toxicity of excipients must be addressed.
Four types of studies are discussed: pharmacokinetics,
pharmacokinetics/pharmacodynamics, efficacy, and safety. A pharmacokinetic
study in pediatric patients with additional safety data may be adequate to
establish pediatric use when the disease process is similar in adults and
children and the outcome of therapy is likely to be comparable. In such a case,
extrapolation from adult efficacy data may be appropriate. An approach based
only on pharmacokinetics is likely to be insufficient when product blood
levels are known or expected not to correspond with efficacy or when there is
concern those concentration–response relationships vary with age.
If the comparability of the disease and outcome of therapy are similar, a
combined pharmacokinetic/pharmacodynamic approach may be possible.
Although relative bioavailability comparisons of formulations should be done
in adults, definitive pharmacokinetic studies for dose selection for pediatric
patients should be done in the intended population.
In general, dosing should be based on a per-kilogram basis (body weight)
because errors in measuring height or length are common and lead to errors in
the calculation of body surface area. However, some medications with a
narrow therapeutic index may require dosing based on body surface area. In
all studies, principles of good clinical practice, design and statistical
considerations, and principles of safety monitoring and adverse event
reporting in ICH apply.
Clinical endpoints must be age and developmentally appropriate and
validated. Endpoints that rely on patient self-assessment may be unreliable.
Age-appropriate laboratory and clinical values should be used. Some efficacy
studies may be simplified by extrapolation of efficacy findings from older to
younger patients. The pediatric adverse event profile of a product may differ
from the adult profile in types of events and magnitude of severity or duration
due to different surface-to-volume ratio in children of varying ages and
different levels of maturation of organ function and metabolism.
Unintended exposure such as accidental ingestion may provide additional
opportunity for dose and safety information. Long-term or surveillance studies
should be considered, particularly for chronic therapies, to observe effects on
growth and development. Dimensions to consider are skeletal growth,
cognitive function, and maturation. Postmarketing surveillance and/or longterm follow-up studies may provide safety and/or efficacy information for
subgroups within the pediatric population or additional information for the
entire pediatric population.
ICH E11 discusses age classification and the ICH E11 addendum (R1)
pays particular attention to the neonate.
Neonatal period for term newborn infants—0 to 27 days of age
Neonatal period for preterm newborn infants—day of birth through
expected date of delivery plus 27 days
Infants and toddlers—28 days to 23 months
Children—2 to 11 years
Adolescents—12 years to 16 or 18 years, depending on region
Any age classification is arbitrary, and therefore decisions on how to
stratify studies and data by age should take into consideration developmental
biology and pharmacology. The category of preterm newborn infants is not a
homogeneous group of patients, and protocol development should incorporate
expert input from neonatologists and neonatal pharmacologists. A child of 25
weeks gestational age and weighing 500 g is very different in terms of
metabolism and response to therapy than a newborn of 30 weeks gestational
age weighing 1,500 g.
A distinction should also be made for low-birth-weight newborns (<2,500
g) as to whether they are immature or were growth restricted in utero.
Extrapolation of study findings from other populations is generally not
feasible. This is due to the immaturity of renal and hepatic clearance
mechanisms, protein binding and displacement issues (particularly bilirubin),
the integrity of the blood–brain barrier, subsequent penetration of medicinal
products into the central nervous system, transdermal absorption, and rapid
and variable maturation of all physiologic and pharmacologic processes
leading to different dosing regimens with chronic exposure. Neonatal disease
states and morbidities such as respiratory distress syndrome of the newborn,
patent ductus arteriosus, primary pulmonary hypertension, necrotizing
enterocolitis, intraventricular hemorrhage, and retinopathy of prematurity add
further complexity. Adolescence has a variable upper age limit that depends
on the context.
CONSIDERATIONS RELATED TO AGE
The ICH Guidance E-11 notes that pediatrics extends up to age 16 to 18 years
depending upon the region. The World Health Organization notes that the age
may be up to 20 years.
102
The Food and Drug Administration Amendments Act of 2007 in Section
303 includes people till 21 years as a target population for pediatric device
product development. The intent is not to recast the 16- or 18-year-old to 21year-old population as a pediatric population that would be responsive to
regulatory expectations, but rather allow extension of the upper age limit in
pediatric studies, particularly for chronic diseases or those with growth delay,
to gain additional follow-up information.
Figure 1.4 shows a comparison of different classification systems for
pediatric age groups.
Figure 1.4 Variability of boundaries of ages and stages schema for human development during
childhood. Ages and stages are generally guided by cognitive and behavioral criteria. (From Hirschfeld S,
Zajicek A. What could the future of safety monitoring look like? Ther Innov Regul Sci 2019;53(5):590–
600.)
For all age groups, risk, discomfort, and distress can be minimized if
studies are designed and conducted by investigators trained and experienced
in the treatment of pediatric patients. Specific suggestions on minimizing
distress include the use of trained personnel, the use of topical anesthetics,
minimization of sample collection volume and frequency, comforting physical
settings, and the availability and cooperation of parents.
Age has limitations in that children of the same chronologic age can be at
different physiologic and developmental stages. In many cases, using a size
parameter such as weight or surface area with or without a developmental
stage indicator may be more precise and preferable than simply an age range.
CHARACTERIZATION OF STUDY GOALS