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Guidance for Industry
Nonclinical Safety Evaluation of Pediatric Drug Products
(PDF version of this document)
U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
February 2006
Pharmacology and Toxicology
Guidance for Industry
Nonclinical Safety Evaluation of Pediatric Drug Products
Additional copies are available
from:
Office of Training and Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
February 2006
Pharmacology and Toxicology
Guidance for Industry
Nonclinical Safety Evaluation of Pediatric Drug Products
This
guidance represents the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this guidance.
If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
This document provides guidance on the role and
timing of animal studies in the nonclinical safety evaluation of
therapeutics intended for the treatment of pediatric patients. The
guidance discusses some conditions under which juvenile animals can
be meaningful predictors of toxicity in pediatric patients and makes
recommendations on nonclinical testing.
The scope
of this guidance is limited to safety effects that cannot be
adequately, ethically, and safely assessed in pediatric clinical
trials. Serious adverse effects that are irreversible are of
particular concern. The guidance also makes recommendations on the
timing and utility of juvenile animal studies in relation to phases
of clinical development. Sponsors are encouraged to
communicate with the appropriate review division to determine
whether a juvenile animal study is needed for a particular drug
product and to discuss protocol designs before study initiation.
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the
word should in Agency guidances means that something is
suggested or recommended, but not required.
Many therapeutics marketed in the United States
and used in pediatric patients lack adequate information in the
labeling for use in that population. A survey conducted by the
American Academy of Pediatrics shows that the majority of the drugs
listed in the Physician’s Desk Reference lack information on
safety and/or efficacy for pediatric use (Committee on Drugs,
American Academy of Pediatrics 1995). However, recent
pediatric legislation, including the Best Pharmaceuticals for
Children Act (BPCA 2002) and the Pediatric Research Equity Act (PREA
2003), have provided a mechanism to obtain the needed pediatric
safety and efficacy information in drug product labels.
Drug development programs have
used safety data from clinical studies in adults, supported by
nonclinical studies in adult animals, to support the use of a drug
in pediatric patients. This assumes that pediatric patients will
exhibit similar disease progression, and respond similarly to the
intended therapeutic intervention. It is clear, however, that
these studies may not always assess possible drug effects on
developmental processes specific to pediatric age groups.
Developmental processes in pediatric patients may differentially
affect drug pharmacokinetics and pharmacodynamics compared to adult
therapeutic use. Some
adverse
effects may be very
difficult to detect in clinical trials or during routine
postmarketing surveillance. Data obtained from clinical
pediatric initiatives have identified ineffective dosing and
overdosing of effective drugs as well as unnecessary exposure to
ineffective therapies and identification of novel pediatric adverse
events. Juvenile animal studies may assist in identifying
postnatal developmental toxicities that are not adequately assessed
in reproductive toxicity assessments and that may not be adequately
and safely tested in pediatric clinical trials.
Considerations such as postnatal development
and the utility of studies conducted using juvenile animals are
discussed in this section.
Some therapeutics
have shown different safety profiles in pediatric and adult
patients. Inherent differences between mature and immature
systems introduce the possibility of drug toxicity, or resistance to
toxicity in immature systems that are not observed in mature
systems. Several factors contribute to these potential differences.
Postnatal growth and development can affect drug disposition and
action. Examples include developmental changes in metabolism
(including the maturation rate of Phase I and II enzyme activities),
body composition (i.e., water and lipid partitions), receptor
expression and function, growth rate, and organ functional capacity.
These developmental processes are susceptible to modification or
disruption by drugs.
Although some age-dependent
effects can be largely predicted by knowledge of the changes in drug
metabolic pathways during development, others cannot.
There are several examples of drugs that exhibit differences in
toxicity between adult and pediatric patients. These include
the following:
·
Acetaminophen — Acute acetaminophen toxicity is
a classic example of how maturation can affect the toxicity profile
of a drug. Young children are far less susceptible to acute
acetaminophen toxicity than adults because children possess a
higher rate of glutathione
turnover and more active sulfation. Thus, they have a greater
capacity to metabolize and detoxify an overdose of acetaminophen
when compared to adults (Insel 1996).
·
Valproic acid
— In contrast to acetaminophen, young children treated with valproic
acid appear disproportionately vulnerable to fatal hepatotoxicity (Dreifuss
et al. 1987).
·
Chloramphenicol
— Chloramphenicol is associated with mortality in newborns because
exposure is increased due to a longer half-life (t½ = 26
h) compared to adults (t½ = 4 h) (Kapusink-Uner et al.
1996).
·
Inhaled
corticosteroids —
Inhaled corticosteroids have been found to decrease growth velocity
in children, an irrelevant endpoint in adults (FDA Talk Paper,
Class Labeling for Intranasal and Orally Inhaled
Corticosteroid Containing Drug Products Regarding the Potential for
Growth Suppression in Children,
1998).
·
Aspirin
— Aspirin should not be used to treat children with influenza or
varicella infections because of their increased risk of developing
Reye’s syndrome, a complication not seen in adults (Belay et al.
1999).
·
Lamotrigine
— Children are at greater risk for developing hypersensitivity-type
reactions, including Stevens-Johnson syndrome, when treated with
lamotrigine (Guberman et al. 1999).
Adult clinical data can provide
useful information regarding study design and dose selection for
further study in children in some circumstances. Nonclinical
developmental toxicity studies have traditionally focused on
prenatal development, with only limited assessment of postnatal
developmental effects. Animals used in multiple-dose
toxicity studies are usually peripubertal. In some
circumstances, data generated from these studies may provide
sufficient information to support pediatric clinical trials without
additional animal studies, particularly if the intended use includes
adolescents but not younger children or infants. Since young
animals in general exhibit developmental characteristics similar to
pediatric patients, they are considered appropriate models for
assessing drug effects in this population.
The Agency believes that data from juvenile animal studies can contribute
to the assessment of potential drug toxicity in the pediatric
population, and can provide information that
might not
be derived from standard toxicology studies using adult animals, or safety
information from adult humans.
It is
thought that
organ
systems
at highest risk for drug
toxicity are those that undergo significant postnatal development.
Thus, evaluation of postnatal developmental toxicity is a primary
concern. The structural and functional characteristics
of many organ systems differ significantly between children and
adults as a result of the growth and development that takes place
during postnatal maturation. Examples include the following:
·
Brain, where neural development continues through
adolescence (Rice and Barone 2000)
·
Kidneys, where adult levels of function are first
reached at approximately 1 year of age (Radde 1985)
·
Lungs, where most alveolar maturation occurs in the
first 2 years of life (Burri 1997)
·
Immune system, where adult levels of IgG and IgA
antibody responses are not achieved until about 5 and 12 years of
age, respectively (Miyawaki et al. 1981)
·
Reproductive system, where maturation is not completed
until adolescence (Zoetis and Walls 2003)
·
Skeletal system, where maturation continues well into
adulthood for 25-30 years (Zoetis and Walls 2003)
·
Gastrointestinal systems, which may have direct
consequences on bioavailability, clearance, and biotransformation of
drugs are functionally mature by about 1 year of age (Walthall
2005).
Studies
in juvenile animals
may
be useful in the
prediction of age-related toxicity in children, as shown in the
following examples:
·
The effects of phenobarbital on cognitive performance
in children were predicted by experimental studies examining the
effects of this drug on the developing rodent nervous system
(Farwell et al. 1990; Fonseca et al. 1976; Diaz et al. 1977)
·
The vulnerability of human neonates to hexachlorophene
neurotoxicity was modeled in developing rats and monkeys (Towfighi
1980)
·
The increased susceptibility of infants to verapamil-induced
cardiovascular complications would be expected based on animal
studies demonstrating a greater sensitivity of the immature heart to
calcium channel blockade (Skovranek et al. 1986; Boucek et al. 1984)
·
An increased risk of convulsions in young children
treated with theophylline was
predicted by studies of the preconvulsant effects of this agent in
developing rodents (Mares et al. 1994; Yokoyama et al. 1997)
Examples of drug-induced
postnatal developmental toxicity
demonstrated
in animals include the
following:
·
Neurobehavioral
impairment in adult rats following early postnatal exposure to
methamphetamine (Vorhees et al. 1994)
·
The effects of
methylphenidate on growth and endocrine function in young rats
(Greeley and Kizer 1980; Pizzi et al. 1987)
·
Apoptotic
neurodegeneration in neonatal rats treated with NMDA receptor
antagonists (Ikonomidou et al. 1999)
·
Decreased
myelination and axonal damage induced in preweanling rats by
vigabatrin (Sidhu et al. 1997)
·
Long-term changes
in serotonergic innervation in rats exposed to fluoxetine during
early juvenile life (Wegerer et al. 1999)
·
Chondrotoxicity in
immature animals treated with fluoroquinolones (Stahlmann et al.
1997)
Although the significance of
these findings for humans is uncertain, there is evidence that some
of these effects can be relevant to growing children, notably those
of methylphenidate (Mattes and Gittelman 1983; Croche et al. 1979)
and fluoroquinolones (Chang et al. 1996; Le Loet et al.
1991).
The nonclinical
safety evaluation of pediatric therapeutics should primarily focus
on their potential effects on growth and development that have not
been studied or identified in previous nonclinical and clinical
studies. Juvenile animal
testing may be useful in assessing potential developmental
age-specific toxicities and differences in sensitivity between adult
and immature animals. Although the toxicological
assessment should focus primarily on the active moiety, testing the
inactive ingredients in the clinical formulation can also be
important, particularly when a drug’s pharmacodynamics or
distribution are altered by the inactive ingredients or when
uncharacterized excipients are present. Additional
recommendations on testing excipients can be found in the guidance
for industry Nonclinical Studies for the Safety Evaluation of
Pharmaceutical Excipients.
The toxicological assessment should include local and systemic
analyses of effects on postnatal growth and development in the
anticipated pediatric population. The known pharmacological and
toxicological properties of the drug relative to the proposed
patient population should be considered. Any concerns for
postnatal developmental toxicity can be addressed either in juvenile
animal studies or by modified study designs (e.g., modification of
segment III reproductive toxicity studies to include animals of
similar developmental status as the pediatric population of
concern). Juvenile animal studies are especially relevant when
a known target organ toxicity occurs in adults in tissues that
undergo significant postnatal development. The extent and
timing of nonclinical safety studies will depend on the available
safety information for a particular product. For example, the
information needed to support a new pediatric indication for an
approved product used in adults may be quite different from the
information needed to support pediatric use of a new molecular
entity because of the postnatal developmental safety concerns in the
later population. These concerns will be considered for their
particular clinical indications on a case-by-case basis within the
drug review divisions.
Specific recommendations regarding the timing
of nonclinical toxicology studies are available in the ICH guidance
for industry M3 Nonclinical Safety Studies for the Conduct of
Human Clinical Trials for Pharmaceuticals (ICH M3 safety studies
guidance). The recommendations presented here for juvenile animal
studies may assist in identifying postnatal developmental toxicities
that are not adequately assessed in general toxicity studies with
mature animals and that may not be adequately and safely tested in
pediatric clinical trials.
Most clinical studies in pediatric subjects do
not involve long-term exposure to a therapy because they are
generally of short-term duration (less than 6 months). This is
especially true when the trials are intended to determine
pharmacokinetics rather than efficacy. As a result, long-term
exposure during postnatal developmental periods is not usually
addressed in pediatric clinical trials. If the drug is
indicated for chronic use then some assessment of the long-term
developmental effects of the drug in animals should be made before
marketing. However, in those cases when pediatric clinical
studies do involve long-term exposure, we recommend conducting
juvenile animal studies before initiation of the long-term
clinical studies. When designing juvenile animal studies, the
age of the pediatric population for which the drug is intended is
important. Neonates, infants, and older children are at very
different developmental stages, and appropriate nonclinical data
should support the drug’s use in the intended pediatric population.
Depending on the
indication and use of the drug, safety concerns, and the number of
subjects exposed, there may be a need for juvenile animal studies in
conjunction with clinical studies even if the trials are designed
for short-term exposure. Because juvenile animal studies may
identify potential hazards and these hazards may have relevance to
human safety, it may be more useful to complete juvenile animal
studies before conducting clinical studies so that appropriate
monitoring can be incorporated into the clinical trial design to
limit human risk.
Typically, pediatric subjects are included in
clinical trials after there has been considerable experience in the
adult population. When there is insufficient clinical data or
experience because of minimal prior adult and pediatric experience,
completed juvenile animal studies are needed before initiation of
pediatric clinical trials regardless of whether the clinical trials
involve long-term exposures. Similarly, when there have been
reports of adverse effects with off-label use in pediatric patients
and there are inadequate data to evaluate the relationship between
the drug and the adverse effects, completed juvenile animal studies
are needed before initiation of pediatric clinical studies.
The timing of juvenile animal studies relative to clinical testing
of therapeutics indicated for serious or life-threatening pediatric
conditions will be considered on a case-by-case basis by the review
division.
C.
Issues to Consider Regarding Juvenile Animal Studies
These considerations are important in
determining the appropriateness and design of juvenile animal
studies: (1) the intended or likely use of the drug in children;
(2) the timing of dosing in relation to phases of growth and
development in pediatric populations and juvenile animals; (3) the
potential differences in pharmacological and toxicological profiles
between mature and immature systems; and (4) any established
temporal developmental differences in animals relative to pediatric
populations. We also recommend that endpoints relevant to
identifying target organ toxicity across species be included in the
juvenile animal study design. Juveniles generally undergo more
dynamic development than is seen in the relatively stable adult.
Although the greatest concern is with chronic, long-term therapy,
the duration of anticipated treatment of the pediatric population
should be considered in relation to the duration of developmentally
sensitive phases. For instance, a relatively short exposure
time for neonates may cover a period of more substantial development
than would a longer exposure in prepubescent children where
development occurs over a much longer time frame. It is
important for juvenile animal toxicology studies to be designed
efficiently, using the least number of animals to identify potential
pediatric safety concerns. Whenever feasible, we recommend
designing an initial study to address endpoints of concern for
multiple potential pediatric populations. In all cases,
studies using juvenile animals are appropriate when adequate
information cannot be generated using standard nonclinical studies
or from clinical trials. The following issues are specific to
studies in juvenile animals for assessing toxicity.
Consideration should be given to the age of the
intended population and thus the stage of postnatal development.
The condition to be treated may also influence the type, extent, and
timing of testing considered appropriate. Selection of
appropriate endpoints in the nonclinical studies to address concerns
for the specific pediatric populations
is
important. Recommendations regarding specific age
ranges of pediatric subpopulations are discussed in the ICH guidance
for industry E11 Clinical Investigation of Medicinal
Products in the Pediatric Population.
Evaluation of the available data is important
when considering the need for studies in juvenile animals. Toxicity
studies in juvenile animals may be appropriate when available
nonclinical or clinical data are insufficient to support reasonable
safety of a therapeutic for pediatric patients. Gaps in the age
ranges of rodent and nonrodent species used in standard toxicity
testing are widely acknowledged. These age gaps can affect
assessment of nervous system toxicity endpoints in particular
because of the extended process of maturation. Standard
toxicity studies with adult animals cannot assess all of the
relevant endpoints, especially growth present in the immature
animal. In other circumstances, however, juvenile animal
studies would be neither informative nor necessary. For
example, juvenile animal studies might not be necessary when:
(1) data from similar therapeutics in a class have identified a
particular hazard and additional data are unlikely to change this
perspective; (2) there are adequate clinical data and adverse events
of concern have not been observed during clinical use; (3) target
organ toxicity would not be expected to differ in sensitivity
between adult and pediatric patients because the target organ of
toxicity is functionally mature in the intended pediatric population
and younger children with the functionally immature tissue are not
expected to receive the drug.
Most drugs that are intended for use in
pediatric patients have established efficacy and safety profiles in
adult humans. Some data may also be available from pediatric
patients aged 12 years or older. For some drugs a
preponderance of clinical data will be obtained from children, as in
the case of inhaled corticosteroids (FDA Talk Paper, Class
Labeling for Intranasal and Orally Inhaled Corticosteroid Containing
Drug Products Regarding the Potential for Growth Suppression in
Children, 1998). For approved drugs that have already
undergone extensive clinical testing, substantial nonclinical
pharmacology and toxicology data will have already been performed.
The toxicology assessment generally includes studies of general
toxicity, reproductive toxicity, genetic toxicity, carcinogenicity,
and special toxicities, as well as studies in juvenile animals, if
available. Target organs of toxicity of the drug both in
humans and animals should have been identified in these studies.
A thorough evaluation of these data should enable scientists to:
(1) judge the adequacy of the nonclinical information; (2) identify
some of the potential safety concerns for the intended population;
and (3) identify any gaps in the data that might be addressed by
testing in juvenile animals.
Based on the observation that embryo-fetal
development is especially sensitive to perturbation during
organogenesis, tissues that undergo significant postnatal
development in pediatric patients and juvenile animals may also have
greater sensitivity to certain drug-induced toxicities than mature
tissues. Organ systems identified as undergoing considerable
postnatal growth and development include the nervous, reproductive,
pulmonary, renal, skeletal, gastrointestinal, hepatobiliary, and
immune systems. Given the variable rate of postnatal development
during different periods of childhood, the definition of long-term
treatment can vary by pediatric population. Intended treatment
of several weeks may not be considered long term in early
adolescence, but might involve considerable development for the
neonate given the duration of some developmental windows.
The timing of the intended use of the drug as
it relates to periods of rapid postnatal growth and development is
important. If the drug is intended for use in children undergoing
phases of rapid overall growth and development, it is important to
evaluate an animal model undergoing a corresponding growth phase.
Organ systems mature at specific times in specific species.
Human-to-animal comparisons of developmental periods for the
nervous, reproductive, skeletal, pulmonary, immune, renal, cardiac,
and metabolic systems are presented in Section VII at the end of
this guidance. These can be used as general guides to appropriate
periods of treatment to assess the development of specific systems
in various animal models. Immature animals have accelerated
chronological development compared to humans, which can facilitate
evaluation of long-term effects following acute or chronic exposure
using well-defined endpoints (e.g., assessment of reproductive or
nervous function).
In addition to consideration of models and
endpoint assessments based on the intended pediatric human use,
target organs for toxicological and pharmacological activity
identified in adults need special consideration. It is
important that organ systems identified as specific targets of drug
toxicity in adults and that undergo significant postnatal
development be studied in juvenile animals for those specific
effects, even when the primary postnatal developmental period in
humans does not coincide with the intended treatment phase.
This is based on the observation that development is generally a
continuous event. Additionally, a therapeutic target tissue
may be developmentally regulated by other tissues or organ systems.
In such cases, it may be advisable to examine the effects of the
drug during the stages of development relevant to all of those
tissues/organs in a test species.
Testing
approaches can use generalized screening tests to provide hazard
identification or can be designed to specifically address identified
concerns. We recommend the selection of an appropriate,
scientifically justified study design. The effects of dosing
and handling on immature animals can be systematically assessed.
Studies conducted in juvenile animals to support the safety of
pediatric therapeutics may
either be protocols designed to address a specific safety concern,
or modified peri- and postnatal developmental study protocols.
Dedicated juvenile animal protocols can be designed to address
specific concerns based on known properties of the drug, product
class, or other information. Modified repeat-dose toxicity studies
can provide a more general screen for potential hazards in some
instances. However, we recommend that such studies modify the
animal age at study initiation, duration of treatment, and endpoints
assessed to address the specific concerns. Modification of
standard ICH studies designed to address developmental stages C-F
would include ensuring adequate exposure in juvenile animals during
the postnatal period and assessment of developmental endpoints
appropriate for the intended pediatric population. Assessment
of developmental endpoints not usually included in standard
repeat-dose toxicity studies also may be appropriate. In
addition to ensuring adequate exposure to the drug, histopathologic
examinations and effects on specific growth parameters and
functionally immature tissues in the juvenile animal would be
important. In these modified designs dosing can be initiated
with animals younger than usual and extended until the developmental
period for the intended pediatric population has been completed in
the animal species in accordance with the age of the pediatric
patients who would use the drug. Information from such studies
can be compared with the findings from treated adults of the same
species to evaluate whether the effects are specific to juvenile
animals.
The species of the juvenile animal tested
should be appropriate for evaluating toxicity endpoints important
for the intended pediatric population. Traditionally, rats and
dogs have been the rodent and nonrodent species of choice. In
some circumstances, however, other species may be more appropriate.
For example, when drug metabolism in a particular species differs
significantly from humans, an alternative species (e.g., minipigs,
pigs, monkeys) may be more appropriate for testing. When
determining an appropriate species, sponsors are encouraged to
consider certain factors, such as the following:
·
Pharmacology, pharmacokinetics, and toxicology of the
therapeutic agent
·
Comparative developmental status of the major organs
of concern between juvenile animals and pediatric patients
·
Sensitivity of the selected species to a particular
toxicity
A study in juveniles from one animal species
may be sufficient to evaluate toxicity endpoints for therapeutics
that are well characterized in both adult humans and animals.
It is anticipated that this evaluation often can be accomplished in
the rodent using modified perinatal and postnatal developmental
studies, although other approaches can be used.
The age of the animals at initiation of dosing
should be determined by the postnatal development parameters of
interest. It is important that the stage of development in the
animals being studied be comparable to that in the intended
pediatric population.
We recommend including both male and female
animals in these studies. It is important that adequate
numbers of animals are used to demonstrate the presence or absence
of effects of the test substance. When determining the sample
size, consideration of the magnitude of the biologic effect that is
of concern is also important. The particular study design used
(e.g., a screening study or one designed to address an identified
concern, modification of a standard design, composite or split
litter design) will influence the number of animals it takes for an
adequate evaluation.
When performing nonclinical studies, the
intended clinical route of administration and dosage formulation
should be used unless an alternate route of administration and
dosage formulation provides greater exposure or is less invasive
with adequate exposure. Assessment of toxic effects by more
than one route of administration can be appropriate if the drug is
intended for clinical use by more than one route of administration.
When different routes are expected to result in differences in
systemic and local exposure of such magnitude that occurrence of
postnatal toxicity would be expected, sponsors should consider
testing by multiple routes. When the intended clinical
administration is intravenous, this route should be sufficient.
Since the primary purpose of these studies is to identify potential
hazards, small changes in exposure/distribution by route generally
would not be considered important.
Since adverse effects can sometimes be related
to metabolic differences between adult and juvenile animals,
toxicokinetic studies can provide useful information for assisting
in study interpretation. Assessment of developmental
differences in parent drug disposition and profiles of significant
metabolites in juvenile animals should be made according to
established guidelines (see the ICH guideline for industry S3A
Toxicokinetics: Assessment of Systemic Exposure in Toxicity
Studies).
The frequency of
administration should be relevant to the intended clinical use of
the drug. In some cases, however, the use of dosing frequencies
similar to those anticipated for clinical administration are not
feasible because of technical considerations for the animal models
used. Changes in frequency can be made when variables such as
metabolic and kinetic differences are considered.
The duration of treatment in animals should
include at least the significant periods of relevant postnatal
development for the selected species. When the aim of the
study is to evaluate potential long-term effects, dosing duration
should be increased relative to the intended therapeutic use. One
approach to consider is establishing exposure and initial
tolerability in a dose-range finding study followed by a definitive
study powered to assess specific concerns. Treatment-free
periods designed to assess reversibility of possible adverse effects
should also be considered. Inclusion of recovery periods in
studies can be valuable in distinguishing acute to intermediate
pharmacodynamic effects from frank developmental toxicity, and this
information could influence the evaluation of potential human risk.
Depending on the concern being addressed, it may be sufficient to
assess delayed toxicity through organ maturity or it may be
necessary to continue until the juvenile animal reaches adulthood.
It is important to establish a clear
dose-response relationship for adverse effects in juvenile animals,
when possible. The high dose should produce identifiable toxicity
(either developmental or general). The intermediate dose
should produce some toxicity so that a dose-response relationship
can be demonstrated if one exists. The low dose should produce
little or no toxicity, and a NOAEL should be identified, if
possible. We recommend evaluating and potentially modifying
intermediate and low doses in relation to those that produce the
desired pharmacodynamic effect in the test species.
The selection of
toxicological endpoints to be monitored in a juvenile animal study
is critical for assessing the effects of a drug on development and
growth. Designing studies to determine drug effects on overall
postnatal growth as well as postnatal development of specific organ
systems (e.g., skeletal, renal, lung, nervous, immunologic,
cardiovascular, and reproductive) is appropriate. It is
important that studies include measurement of overall growth (e.g.,
body weight, growth velocity per unit time, tibial length), clinical
observations, measurement of organ weights, gross and microscopic
examinations, assessment
of
sexual maturation (mating,
fertility), and neurobehavioral testing. More specific
measurements can be reserved for case-specific evaluations based on
the knowledge of the pharmacologic or toxicologic target.
Clinical pathology determinations can also be useful but
can
be limited by the technical
feasibility of obtaining adequate samples for analysis, particularly
in the case of rodents. For developmental neurotoxicity
assessments, well-established methods should be used to monitor key
central nervous system (CNS)
functions, including
assessments of reflex ontogeny, sensorimotor function, locomotor
activity, reactivity, learning,
and memory. Modifications of existing toxicity designs or
de novo juvenile studies should be used depending on the
concerns to be addressed.
It can be helpful to
determine the relationship between toxicologic endpoints and drug
exposure (e.g., predosing, immediately postdosing, time of peak
plasma concentration). To differentiate long-term effects on
development from acute effects, it might be appropriate to measure
certain endpoints immediately before daily administration of the
drug. Also, adding recovery group animals is helpful in
determining whether the drug-induced effects are reversible.
The more specific the concern, the more directed the study design
approach can be. A more generalized screening approach may be
useful if little information is available.
It is important that nonclinical toxicology
studies designed to support the safety of clinical trials in
pediatric subjects identify hazards specific to the treated
population. These studies can provide information useful in
limiting the risk of experiencing adverse events and identify
appropriate clinical monitoring. When adverse effects are
observed in nonclinical toxicology studies, there are a number of
possible uses of these findings. Biomarkers of adverse effects
could be identified in nonclinical studies that would be useful in
monitoring subjects in clinical trials. In cases where biomarkers
cannot be identified or safely used in clinical studies, nonclinical
pharmacokinetic data could be useful because a given adverse effect
would be associated with a particular level of systemic exposure
which might be extrapolated to clinical use. Blood level monitoring
could then be used in clinical trials to minimize the probability of
such an adverse effect occurring. If toxicities identified in
juvenile animal studies are likely to occur in pediatric patients,
cannot be monitored clinically, and would not be considered an
acceptable potential consequence of exposure, it may not be possible
to safely conduct pediatric clinical trials. Consideration of
the risk-benefit analysis of a given drug therapy is important.
Nonclinical toxicology studies in juvenile
animal models could demonstrate adverse effects that should be
considered in seeking postmarketing commitments by the sponsor, in
labeling a product for pediatric use, or in determining the
approvability of a drug for pediatric use. Delayed or
irreversible adverse effects might be identified in animal studies
but not in clinical trials because the pediatric clinical trial
might have been of insufficient duration to demonstrate the adverse
effect. It is possible that biomarkers of adverse effects
could be identified in nonclinical studies that were not seen in
clinical trials, but might nevertheless be important to include in
the product label. Depending on the nature and severity of
these adverse effects and the risk-benefit relationship of the
intended use, the sponsor might conduct long-term follow-up human
safety studies as a postmarketing commitment. The sponsor
might conduct long-term follow-up studies even following acute drug
exposure if these effects were found to be delayed or irreversible.
Use of the drug could be restricted to serious indications based on
nonclinical findings even if the adverse effects were not
demonstrated in clinical trials. In this case, the product
label would include information on the relevant adverse effects
observed in nonclinical studies. Adverse effects associated
with chronic drug exposure in nonclinical studies might not have
been observed in clinical trials of comparable length. In such
a case, the label might be written to reflect these findings.
Juvenile animal studies might also be useful in identifying specific
age groups in which the drug should not be used or in determining
unsafe parameters of exposure. Finally, it is possible that
nonclinical findings could result in a product label that
specifically warns against use in pediatric patients based on a
risk-benefit analysis.
VII.
Human-to-animal comparisons of developmental periods
The information on comparative developmental
timing, shown in Tables 1 – 8, was considered current at the time
this guidance was developed. These comparisons should be
considered with new information as it becomes available in deciding
how best to design appropriate juvenile animal studies to address
risks to the pediatric population. Neither the human nor the
animal data represent a precise determination of the timelines of
development due to the inherent variability and different endpoints
examined. Because of the nature of science, these tables should
only serve as a general starting point.
Table 1:
Nervous System
Developmental Event |
Postnatal Developmental Period |
|
Human
(Years) |
Primate
(Weeks) |
Dog
(Weeks) |
Rat
(Days) |
Glutamate receptors1
(Maximal binding) |
1-2 Cortex Decline to adult 2-16 |
|
|
28
Decline to adult >28 |
Monoamine system2 |
2-4 Maximum receptor density |
|
|
21-30 Adult levels |
Ocular dominance3 |
0-3 |
|
|
21-35 |
Cerebellum persistent external germinal
layer3 |
0.6-2 |
|
|
0-21 |
Rapid phase of myelination ends4 |
2 |
|
|
25-30 |
Cognitive development
Delayed response learning5 |
1-2 |
9-36 |
12-16 |
10-35 |
Ikonomidou et al. 1999
2
Rice and Barone 2000
3
Sidhu et al. 1997; Kimmel and Buelke-Sam 1994
4
Radde 1985
5
Wood et al. 2004
Table 2: Reproductive System
Developmental Event |
Postnatal Developmental Period |
Human
(Years) |
Rhesus Monkey
(Years) |
Dog
(Days) |
Mouse
(Days) |
Rat
(Days) |
Puberty1 |
11-12 |
2.5-3 |
180-240 |
35-45 |
40-60 |
1
DeSesso and Harris 1995; Marty et al.
2003; Beckman and Feuston 2003; Lewis et al. 2002
Table 3: Skeletal System
Developmental Event |
Postnatal Developmental Period |
Fusion of 2o Ossification Centers1 |
Human
(Years) |
Monkey
(Years) |
Dog
(Years) |
Rabbit
(Weeks) |
Rat
(Weeks) |
Mouse
(Weeks) |
Femur Distal Epiphysis |
14-19 |
3-6 |
0.7-0.9 |
32 |
15-162 |
12-13 |
1Zoetis 2003
Table 4:
Pulmonary System1
Developmental Event |
Postnatal Developmental Period
(Days) |
Alveoli Formation2,3,4 |
Human |
Rat |
Mouse |
Onset |
Prenatal |
1-4 |
1-2 |
Completion |
730 |
28 |
28 |
1
The stages of lung development (glandular, canalicular, saccular,
alveolar) at birth varies with the species. Human lungs have
few alveoli and are considered in the alveolar stage at birth.
Rodent lungs are less developed and considered in the saccular stage
without alveoli at birth (Zoetis and Hurtt 2003).
2
Burri 1997
3
Merkus et al. 1996
4
Tschanz and Burri 1997
Table 5: Immune System
Developmental Event |
Postnatal Developmental Period
(Days) |
|
Human |
Mice |
B-cell
Development1 |
Prenatal |
Prenatal |
T-cell
Development1 |
Prenatal |
Prenatal |
NK-cell
Development1 |
Prenatal |
21 |
T-dependent Antibody response1 |
0 |
14
41-56 Adult level |
T-independent Antibody response1 |
45-90 |
0
14-21 Adult level |
Adult
level IgG1 |
1825 |
42-56 |
Table 6a:
Renal — Functional
Developmental Event |
Postnatal Developmental Period
(Days) |
|
Human |
Rat |
Glomerulo-/Nephrogenesis1,2 |
Prenatal |
8-14 |
Adult GFR and tubular secretion1,2 |
45-180 |
15-21 |
1
Snodgrass 1992
2
Travis 1991
Table 6b:
Renal — Anatomical
Developmental Event |
Postnatal Developmental Period
(Weeks) |
|
Human |
Dog |
Rabbit
|
Rat
|
Mouse
|
Pig
|
Completion of Nephrogenesis1 |
Prenatal
Week 35 |
2 |
2-3 |
4-6 |
Prenatal |
3 |
1
Zoetis 2003
Table 7: Metabolism
Developmental Modulation of Phase I/II Metabolism |
|
Maturation of Enzyme Activity |
Enzyme |
Human
(Years) |
Rat
(Days) |
Rabbit
(Days) |
CYP2D61,2 |
0-3 |
NA* |
NA* |
CYP2E12,3,4 |
0-1 |
4-17
¯ Post weaning male>female |
14-35
2X adult @35 |
CYP1A21,5,6,7 |
0.5
1(> adult) |
7-100 Low levels |
21-60 |
CYP2C81,2 |
<1 |
NA* |
NA* |
CYP2C91,2 |
<0.5
0.5 (> adult) |
NA* |
NA* |
CYP3A42 |
0-2 |
NA* |
NA* |
Acetylation1,2 |
1
(35% adult) |
NA* |
NA* |
Methylation1,2 |
<1
(50% adult) |
NA* |
NA* |
Glucuronidation1,2 |
0 (>adult)
12 |
|
NA* |
Sulfation1,2 |
0 |
NA* |
NA* |
* NA = not available
1
Kearns and Reed 1989
2
Leeder and Kerns 1997
3
Waxman, Morrissey, Le Balnc 1989
4
Peng, Porter, Ding, Coon 1991
5
Ding, Peng, Coon 1992
6
Imaoka, Fujita, Funai 1991
7
Pineau, Daujat, Pichard, Girard, Angevain 1991
Table 8: Cardiac1
Cardiac Parameter |
Postnatal Developmental Period
(Maturation Level Similar to Adult) |
Human
(Years) |
Dog
|
Rat
(Weeks) |
Electrophysiology (ECG) |
5-7 years |
NA* |
3-8 |
Cardiac
Output (CO) and Hemodynamics |
Birth 138 bpm; Adults 85 bpm.
<2 yrs: Smaller ventricular vol., stroke index, ejection fraction
vs. adult
Birth BP 62/40; 2 months 85/47; 0.5-8 yrs. Diastolic 58-62 |
Increase in BP and decrease in HR from 1 week to 0.5 years |
Early increase in HR then constant into adulthood
High CO and low PVR
Neonate-puberty systolic BP doubles reaches maturity by 10 weeks |
Myocytes |
Diploid at birth compared to 60% in adults (40% polyploidy) |
NA* |
Primarily diploid in infant and adult |
Coronary
Vasculature |
Diameter of arteries doubled at 1 yr. max at 30 yrs. Capillary
angiogenesis occurs postnatally and density decreases with age |
Capillary angiogenesis occurs postnatally and density decreases with
age |
Capillary angiogenesis occurs postnatally arterial maturation by 1
month |
Cardiac
innervation |
Neuron number increase and reach adult pattern/density in childhood |
Continued development during 2-4 months |
Adrenergic pattern mature by 3 weeks and nerve density mature by 5
weeks. Cholinergic matures postnatally |
* NA = not available
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