Guidance for Industry
`
`E11 Clinical Investigation of
`Medicinal Products
`
`in the Pediatric Population
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
` ICH
`ICH
`December 2000
`
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`Guidance for Industry
`
`E11 Clinical Investigation of
`Medicinal Products
`
`in the Pediatric Population
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`
`Rockville, MD 20857
`(Tel) 301-827-4573
`(Internet) http://www.fda.gov/cder/guidance/index.htm
`
`Of"
`
`Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
`Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
`Internet: http://www.fda.gov/cber/guidelines.htm.
`Fax: 1-888-CBERFAX or 301-827-3844
`
`Mail: the Voice Information System at 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`Center for Biologics Evaluation and Research (CBER)
`
` ICH
`ICH
`
`December 2000
`
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`EDIATRIC
`EVELOPMENT
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`EDIATRIC ATIENTS
`...........................................................................................................12
`EDIATRIC
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`EDIATRIC
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`Guidance for Industry1
`
`E11 Clinical Investigation of Medicinal Products
`in the Pediatric Population
`
`It does
`This guidance represents the Food and Drug Administration's current thinking on this topic.
`not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`
`statutes and regulations.
`
`An alternative approach may be used if such approach satisfies the requirements of the applicable
`
`I.
`
`INTRODUCTION (1.)
`
`A.
`A.
`
`Objectives of the Guidance (1.1)
`
`The number of medicinal products currently labeled for pediatric use is limited. This
`guidance is intended to encourage and facilitate timely pediatric medicinal product
`development internationally. The guidance provides an outline of critical issues in pediatric
`drug development and approaches to the safe, efficient, and ethical study of medicinal
`products in the pediatric population.
`
`B.
`
`Background (1.2)
`
`Other ICH documents with relevant information affecting pediatric studies include:
`
`E2:
`
`E3:
`
`E4:
`
`E5:
`
`E6:
`
`E8:
`
`E9:
`
`Clinical Safety Data Management
`Structure and Content of Clinical Study Reports
`Dose-Response Information to Support Drug Registration
`Ethnic Factors in the Acceptability of Foreign Clinical
`Data
`
`Good Clinical Practice: Consolidated Guideline
`
`General Considerations for Clinical Trials
`
`Statistical Principles for Clinical Trials
`
`1 This guidance was prepared under the auspices of the International Conference on Harmonisation of the
`Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
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`E10: Choice of Control Group in Clinical Trials
`M3:
`Nonclinical Safety Studies for the Conduct of Human Clinical Trials for
`Pharmaceuticals
`
`Q1 :
`02:
`Q3:
`
`C.
`C.
`
`Stability Testing
`Validation of Analytical Procedures
`Impurity Testing
`
`Scope of the Guidance (1.3.)
`
`Specific clinical study issues addressed in this guidance include:
`
`1. Considerations when initiating a pediatric program for a medicinal product;
`2. Timing of initiation of pediatric studies during medicinal product development;
`3. Types of studies (pharmacokinetic, pharmacokinetic/pharmacodynamic (PK/PD),
`efficacy, safety);
`4. Age categories; and
`5. Ethics of pediatric clinical investigation.
`
`This guidance is not intended to be comprehensive; other ICH guidances, as well as
`documents from regional regulatory authorities and pediatric societies, provide additional
`detail.
`
`D.
`D.
`
`General Principles (1.4)
`
`Pediatric patients should be given medicines that have been appropriately evaluated for
`their use in those populations. Safe and effective pharmacotherapy in pediatric patients
`requires the timely development of information on the proper use of medicinal products in
`pediatric patients of various ages and, often, the development of pediatric formulations of
`those products. Advances in formulation chemistry and in pediatric study design will help
`facilitate the development of medicinal products for pediatric use.
`
`Drug development programs should usually include the pediatric patient population when a
`product is being developed for a disease or condition in adults and it is anticipated the
`product will be used in the pediatric population. Obtaining knowledge of the effects of
`medicinal products in pediatric patients is an important goal. However, this should be done
`without compromising the well-being of pediatric patients participating in clinical studies.
`This responsibility is shared by companies, regulatory authorities, health professionals,
`and society as a whole.
`
`ll.
`
`GUIDANCE (2)
`
`A.
`A.
`
`Issues When Initiating a Pediatric Medicinal Product Development
`
`Program (2.1)
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`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. The timing of initiation of clinical studies in relation to studies conducted in
`adults, which may be influenced by regional public health and medical needs, is discussed
`in section ”.0. Justification for the timing and the approach to the clinical program needs to
`be clearly addressed with regulatory authorities at an early stage and then periodically
`during the medicinal product development process. The pediatric development program
`should not delay completion of adult studies and availability of a medicinal product for
`adults.
`
`The decision to proceed with a pediatric development program for a medicinal product,
`and the nature of that program, involve consideration of many factors, including:
`
`- The prevalence of the condition to be treated in the pediatric population
`- The seriousness of the condition to be treated
`
`••• ••••••
`
`- The availability and suitability of alternative treatments for the condition in the
`pediatric population, including the efficacy and the adverse event profile (including
`any unique pediatric safety issues) of those treatments
`- Whether the medicinal product is novel or one of a class of compounds with known
`properties
`- Whether there are unique pediatric indications for the medicinal product
`- The need for the development of pediatric-specific endpoints
`- The age ranges of pediatric patients likely to be treated with the medicinal product
`- Unique pediatric (developmental) safety concerns with the medicinal product,
`including any nonclinical safety issues
`Potential need for pediatric formulation development
`
`-
`
`Of these factors, the most important is the presence of a serious or life-threatening disease
`for which the medicinal product represents a potentially important advance in therapy. This
`situation suggests relatively urgent and early initiation of pediatric studies.
`
`Information from nonclinical safety studies to support a pediatric clinical program is
`discussed in ICH M3.
`It should be noted that the most relevant safety data for pediatric
`studies ordinarily come from adult human exposure. Repeated dose toxicity studies,
`reproduction toxicity studies, and genotoxicity tests would generally be available. The need
`forjuvenile animal studies should be considered on a case-by-case basis and be based
`on developmental toxicology concerns.
`
`B.
`B.
`
`Pediatric Formulations (2.2)
`
`There is a need for pediatric formulations that permit accurate dosing and enhance patient
`compliance. For oral administration, different types of formulations, flavors, and colors may
`be more acceptable in one region than another. Several formulations, such as liquids,
`suspensions, and chewable tablets, may be needed or desirable for pediatric patients of
`different ages. Different drug concentrations in these various formulations may also be
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`needed. Consideration should also be given to the development of alternative delivery
`systems.
`
`For injectable formulations, appropriate drug concentrations should be developed to allow
`accurate and safe administration of the dose. For medicinal products supplied as single-
`use vials, consideration should be given to dose-appropriate single-dose packaging.
`
`The toxicity of some excipients may vary across pediatric age groups and between
`pediatric and adult populations (e.g., benzyl alcohol is toxic in the preterm newborn).
`Depending on the active substance and excipients, appropriate use of the medicinal
`product in the newborn may require a new formulation or appropriate information about
`dilution of an existing formulation. International harmonization on the acceptability of
`formulation excipients and of validation procedures would help ensure that appropriate
`formulations are available for the pediatric population everywhere.
`
`C.
`C.
`
`Timing of Studies (2.3)
`
`During clinical development, the timing of pediatric studies will depend on the medicinal
`product, the type of disease being treated, safety considerations, and the efficacy and
`safety of alternative treatments. Since development of pediatric formulations can be
`difficult and time consuming, it is important to consider the development of these
`formulations early in medicinal product development.
`
`1.
`
`Medicinal Products for Diseases Predominantly or Exclusively
`Affecting Pediatric Patients (2.3.1)
`
`In such cases, the entire development program will be conducted in the pediatric
`population except for initial safety and tolerability data, which will usually be obtained in
`adults. Some products may reasonably be studied only in the pediatric population even in
`the initial phases (e.g., when studies in adults would yield little useful information or expose
`them to inappropriate risk). Examples include surfactant for respiratory distress syndrome
`in preterm infants and therapies targeted at metabolic or genetic diseases unique to the
`pediatric population.
`
`2.
`
`Medicinal Products Intended to Treat Serious or Life-Threatening
`
`Diseases, Occurring in Both Adults and Pediatric Patients, for
`Which There Are Currently No or Limited Therapeutic Options
`
`(2.3.2)
`
`The presence of a serious or life-threatening disease for which the product represents a
`potentially important advance in therapy suggests the need for relatively urgent and early
`initiation of pediatric studies.
`In such cases, medicinal product development should begin
`early in the pediatric population, following assessment of initial safety data and reasonable
`evidence of potential benefit. Pediatric study results should be part of the marketing
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`In circumstances where this has not been possible, lack of data
`application database.
`should be justified in detail.
`
`3.
`
`Medicinal Products Intended to Treat Other Diseases and
`
`Conditions (2.3.3)
`
`In such cases, although the medicinal product will be used in pediatric patients, there is
`less urgency than in previous cases, and studies would usually begin at later phases of
`clinical development or, if a safety concern exists, even after substantial postmarketing
`experience in adults. Companies should have a clear plan for pediatric studies and
`reasons for their timing. Testing of these medicinal products in the pediatric population
`would usually not begin until phase 2 or 3.
`In most cases, therefore, only limited pediatric
`data would be available at the time of submission of the application, but more would be
`expected after marketing. The development of many new chemical entities is discontinued
`during or following phase 1 and 2 studies in adults for lack of efficacy or an unacceptable
`side effect profile. Therefore, very early initiation of testing in pediatric patients might
`needlessly expose these patients to a compound that will be of no benefit.
`
`In cases of a nonserious disease where the medicinal product represents a major
`therapeutic advance for the pediatric population, studies should begin early in
`development, and pediatric data should be submitted in the application. Lack of data
`should bejustified in detail. Thus, it is important to carefully weigh benefit/risk and
`therapeutic need in deciding when to start pediatric studies.
`
`D.
`D.
`
`Types of Studies (2.4)
`
`The principles outlined in ICH E4, E5, E6, and E10 apply to pediatric studies. Several
`pediatric-specific issues are worth noting. When a medicinal product is studied in
`pediatric patients in one region, the intrinsic (e.g., pharmacogenetic) and extrinsic (e.g.,
`diet) factors2 that could affect the extrapolation of data to other regions should be
`considered.
`
`When a medicinal product is to be used in the pediatric population for the same
`indication(s) as those studied and approved in adults, the disease process is similar in
`adults and pediatric patients, and the outcome of therapy is likely to be comparable,
`extrapolation from adult efficacy data may be appropriate.
`In such cases, pharmacokinetic
`studies in all the age ranges of pediatric patients likely to receive the medicinal product,
`together with safety studies, may provide adequate information for use by allowing
`selection of pediatric doses that will produce blood levels similar to those observed in
`
`2 In the ICH E5 guideline on Ethnic Factors in the Acceptance of Foreign Data, factors that may result in
`different drug responses to a drug in different populations are categorized as intrinsic ethnic factors or
`extrinsic ethnic factors.
`In this document, these categories are referred to as intrinsic factors and extrinsic
`factors, respectively.
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`If this approach is taken, adult pharmacokinetic data should be available to plan the
`adults.
`pediatric studies.
`
`When a medicinal product is to be used in younger pediatric patients for the same
`indication(s) as those studied in older pediatric patients, the disease process is similar,
`and the outcome of therapy is likely to be comparable, extrapolation of efficacy from older
`to younger pediatric patients may be possible.
`In such cases, pharmacokinetic studies in
`the relevant age groups of pediatric patients likely to receive the medicinal product,
`together with safety studies, may be sufficient to provide adequate information for pediatric
`use.
`
`An approach based on pharmacokinetics is likely to be insufficient for medicinal products
`where blood levels are known or expected not to correspond with efficacy or where there is
`concern that the concentration-response relationship may differ between the adult and
`pediatric populations.
`In such cases, studies of the clinical or the pharmacological effect of
`the medicinal product would usually be expected.
`
`Where the comparability of the disease course or outcome of therapy in pediatric patients
`is expected to be similar to adults, but the appropriate blood levels are not clear, it may be
`possible to use measurements of a pharmacodynamic effect related to clinical
`effectiveness to confirm the expectations of effectiveness and to define the dose and
`concentration needed to attain that pharmacodynamic effect. Such studies could provide
`increased confidence that achieving a given exposure to the medicinal product in pediatric
`patients would result in the desired therapeutic outcomes. Thus, a PK/PD approach
`combined with safety and other relevant studies could avoid the need for clinical efficacy
`studies.
`
`In other situations where a pharmacokinetic approach is not applicable, such as for
`topically active products, extrapolation of efficacy from one patient population to another
`can be based on studies that include pharmacodynamic endpoints and/or appropriate
`alternative assessments. Local tolerability studies may be appropriate.
`It may be
`important to determine blood levels and systemic effects to assess safety.
`
`When novel indications are being sought for the medicinal product in pediatric patients or
`when the disease course and outcome of therapy are likely to be different in adults and
`pediatric patients, clinical efficacy studies in the pediatric population are recommended.
`
`1.
`
`Pharmacokinetics (2.4. 1)
`
`Pharmacokinetic studies generally should be performed to support formulation
`development and determine pharmacokinetic parameters in different age groups to
`support dosing recommendations. Relative bioavailability comparisons of pediatric
`formulations with the adult oral formulation typically should be done in adults. Definitive
`pharmacokinetic studies for dose selection across the age ranges of pediatric patients in
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`whom the medicinal product is likely to be used should be conducted in the pediatric
`population.
`
`Pharmacokinetic studies in the pediatric population should generally be conducted in
`patients with the disease. This may lead to higher intersubject variability than studies in
`normal volunteers, but the data will better reflect clinical use.
`
`For medicinal products that exhibit linear pharmacokinetics in adults, single-dose
`pharmacokinetic studies in the pediatric population may provide sufficient information for
`dosage selection. This can be corroborated, if indicated, by sparse sampling in multidose
`clinical studies. Any nonlinearity in absorption, distribution, and elimination in adults and
`any difference in duration of effect between single and repeated dosing in adults would
`suggest the need for steady state studies in the pediatric population. All these approaches
`can be facilitated by knowledge of adult pharmacokinetic parameters. Knowing the
`pathways of clearance (renal and metabolic) of the medicinal product and understanding
`the age-related changes of those processes can often be helpful in planning pediatric
`studies.
`
`Dosing recommendations for most medicinal products used in the pediatric population are
`usually based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose.
`While dosing based on mg/square meter body surface area might be preferred, clinical
`experience indicates that errors in measuring height or length (particularly in smaller
`children and infants) and calculation errors of body surface area from weight and height are
`common. For some medications (e.g., medications with a narrow therapeutic index, such
`as those used in oncology), surface-area-guided dosing may be necessary, but extra care
`should be taken to ensure proper dose calculation.
`
`Practical considerations to facilitate pharmacokinetic studies
`
`The volume of blood withdrawn should be minimized in pediatric studies. Blood volumes
`should be justified in protocols. Institutional review boards/independent ethics committees
`(lRBs/lECs) review and may define the maximum amount of blood (usually on a milliliters
`(mL)/kg or percentage of total blood volume basis) that may be taken for investigational
`purposes. Several approaches can be used to minimize the amount of blood drawn and/or
`the number of venipunctures.
`
`-
`
`Sensitive assays for parent drugs and metabolites to decrease the volume of blood
`required per sample
`
`• • •
`
`- Laboratories experienced in handling small volumes of blood for pharmacokinetic
`analyses and for laboratory safety studies (blood counts, clinical chemistry)
`
`- Collection of routine, clinical blood samples wherever possible at the same time as
`samples are obtained for pharmacokinetic analysis
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`••-
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`The use of indwelling catheters, to minimize distress as discussed in section II.E.5.
`
`- Use of population pharmacokinetics and sparse sampling based on optimal sampling
`theory to minimize the number of samples obtained from each patient. Techniques
`include (1) sparse sampling approaches where each patient contributes as few as 2 to
`
`4 observations at predetermined times to an overall population area-under—the—curve
`and (2) population pharmacokinetic analysis using the most useful sampling time points
`derived from modeling of adult data.
`
`2.
`
`Efficacy (2.4.2)
`
`The principles in study design, statistical considerations, and choice of control groups
`detailed in ICH E6, E9, and E10 generally apply to pediatric efficacy studies. There are,
`however, certain features unique to pediatric studies. The potential for extrapolation of
`efficacy from studies in adults to pediatric patients or from older to younger pediatric
`patients is discussed in section II.D. Where efficacy studies are going to be conducted,
`companies may want to develop, validate, and employ different endpoints for specific age
`and developmental subgroups. Measurement of subjective symptoms, such as pain, calls
`for different assessment instruments for patients of different ages. In pediatric patients with
`chronic diseases, the response to a medicinal product may vary among patients not only
`because of the duration of the disease and its chronic effects but also because of the
`
`developmental stage of the patient. Many diseases in the preterm and term newborn infant
`are unique or have unique manifestations precluding extrapolation of efficacy from older
`pediatric patients and call for novel methods of outcome assessment.
`
`3.
`
`Safety (2.4.3)
`
`ICH guidances on E2 topics and ICH E6, which describe adverse event reporting, apply to
`pediatric studies. Age-appropriate, normal laboratory values and clinical measurements
`should be used in adverse event reporting. Unintended exposures to medicinal products
`(accidental ingestions) may provide the opportunity to obtain safety and pharmacokinetic
`information and to maximize understanding of dose-related side effects.
`
`Medicinal products may affect physical and cognitive growth and development, and the
`adverse event profile may differ in pediatric patients. Because developing systems may
`respond differently from matured adult organs, some adverse events and drug interactions
`that occur in pediatric patients may not be identified in adult studies.
`In addition, the
`dynamic processes of growth and development may not manifest an adverse event acutely,
`but at a later stage of growth and maturation. Long-term studies or surveillance data, either
`while patients are on chronic therapy or during the posttherapy period, may be needed to
`determine possible effects on skeletal, behavioral, cognitive, sexual, and immune
`maturation and development.
`
`4.
`
`Postmarketing Information (2.4.4)
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`Normally the pediatric database is limited at the time of approval. Therefore,
`postmarketing surveillance is particularly important.
`In some cases, long-term follow-up
`studies may be important to determine effects of certain medications on growth and
`development of pediatric patients. Postmarketing surveillance and/or long-term follow-up
`studies may provide safety and/or efficacy information for subgroups within the pediatric
`population or additional information for the entire pediatric population.
`
`E.
`
`Age Classification of Pediatric Patients (2.5)
`
`Any classification of the pediatric population into age categories is to some extent
`arbitrary, but a classification such as the one below provides a basis for thinking about
`study design in pediatric patients. Decisions on how to stratify studies and data by age
`should take into consideration developmental biology and pharmacology. Thus, a flexible
`approach is necessary to ensure that studies reflect current knowledge of pediatric
`pharmacology. The identification of which ages to study should be medicinal product-
`specific and justified.
`
`If the clearance pathways of a medicinal product are well established and the ontogeny of
`the pathways is understood, age categories for pharmacokinetic evaluation might be
`chosen based on any break pointwhere clearance is likely to change significantly.
`Sometimes, it may be more appropriate to collect data over broad age ranges and
`examine the effect of age as a continuous covariant. For efficacy, different endpoints may
`be established for pediatric patients of different ages, and the age groups might not
`correspond to the categories presented below. Dividing the pediatric population into many
`age groups might needlessly increase the number of patients required.
`In longer term
`studies, pediatric patients may move from one age category to another; the study design
`and statistical plans should prospectively take into account changing numbers of patients
`within a given age category.
`
`The following is one possible categorization. There is, however, considerable overlap in
`developmental (e.g., physical, cognitive, and psychosocial) issues across the age
`categories. Ages are defined in completed days, months, or years.
`
`Preterm newborn infants
`
`•••••
`
`-
`
`- Term newborn infants (0 to 27 days)
`-
`Infants and toddlers (28 days to 23 months)
`- Children (2 to 11 years)
`- Adolescents (12 to 16-18 years (dependent on region))
`
`1.
`
`Preterm Newborn Infants (2.5.1)
`
`The study of medicinal products in preterm newborn infants presents special challenges
`because of the unique pathophysiology and responses to therapy in this population. The
`complexity of and ethical considerations involved in studying preterm newborn infants
`suggest the need for careful protocol development with expert input from neonatologists
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`and neonatal pharmacologists. Only rarely will it be possible to extrapolate efficacy from
`studies in adults or even in older pediatric patients to the preterm newborn infant.
`
`The category of preterm newborn infants is not a homogeneous group of patients. A 25-
`week gestation, 500-gram (g) newborn is very different from a 30-week gestation newborn
`weighing 1,500 g. A distinction should also be made for low-birth-weight babies as to
`whether they are immature or growth retarded. Important features that should be
`considered for these patients include:
`
`S-"PP’NT‘
`
`9’
`
`7.
`
`8.
`
`gestational age at birth and age after birth (adjusted age);
`immaturity of renal and hepatic clearance mechanisms;
`protein binding and displacement issues (particularly bilirubin);
`penetration of medicinal products into the central nervous system (CNS);
`unique neonatal disease states (e.g., respiratory distress syndrome of the newborn,
`patent ductus arteriosus, primary pulmonary hypertension);
`unique susceptibilities of the preterm newborn (e.g., necrotizing enterocolitis,
`intraventricular hemorrhage, retinopathy of prematurity);
`rapid and variable maturation of all physiologic and pharmacologic processes
`leading to different dosing regimens with chronic exposure; and
`transdermal absorption of medicinal products and other chemicals.
`
`Study design issues that should be considered include:
`
`1. weight and age (gestational and postnatal) stratification;
`2. small blood volumes (a 500-g infant has 40 mL of blood);
`3. small numbers of patients at a given center and differences in care among centers;
`and
`
`4. difficulties in assessing outcomes.
`
`2.
`
`Term Newborn Infants (0 to 27 days) (2.5.2)
`
`Although term newborn infants are developmentally more mature than preterm newborn
`infants, many of the physiologic and pharmacologic principles discussed above also apply
`to term infants. Volumes of distribution of medicinal products may be different from those
`in older pediatric patients because of different body water and fat content and high body-
`surface—area-to-weight ratio. The blood-brain barrier is still not fully mature and medicinal
`products and endogenous substances (e.g., bilirubin) may gain access to the CNS with
`resultant toxicity. Oral absorption of medicinal products may be less predictable than in
`older pediatric patients. Hepatic and renal clearance mechanisms are immature and
`rapidly changing; doses may need to be adjusted over the first weeks of life. Many
`examples of increased susceptibility to toxic effects of medicinal products result from
`limited clearance in these patients (e.g., chloramphenicol grey baby syndrome). On the
`other hand, term newborn infants may be less susceptible to some types of adverse effects
`(e.g., aminoglycoside nephrotoxicity) than are patients in older age groups.
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`3.
`
`Infants and Toddlers (28 days to 23 months) (2.5.3)
`
`This is a period of rapid CNS maturation, immune system development, and total body
`growth. Oral absorption becomes more reliable. Hepatic and renal clearance pathways
`continue to mature rapidly. By 1 to 2 years of age, clearance of many drugs on a mg/kg
`basis may exceed adult values. The developmental pattern of maturation is dependent on
`specific pathways of clearance. There is often considerable inter-individual variability in
`maturation.
`
`4.
`
`Children (2 to 11 years) (2.5.4)
`
`Most pathways of drug clearance (hepatic and renal) are mature, with clearance often
`exceeding adult values. Changes in clearance of a drug may be dependent on maturation
`of specific metabolic pathways.
`
`Specific strategies should be addressed in protocols to ascertain any effects of the
`medicinal product on growth and development. Children achieve several important
`milestones of psychomotor development that could be adversely affected by CNS-active
`drugs. Entry into school and increased cognitive and motor skills may affect a child’s
`ability to participate in some types of efficacy studies. Factors useful in measuring the
`effects of a medicinal product on children include skeletal growth, weight gain, school
`attendance, and school performance. Recruitment of patients should ensure adequate
`representation across the age range in this category, as it is important to ensure a
`sufficient number of younger patients for evaluation. Stratification by age within this
`category is often unnecessary, but it may be appropriate to stratify patients based on
`pharmacokinetic and/or efficacy endpoint considerations.
`
`The onset of puberty is highly variable and occurs earlier in girls, in whom normal onset of
`puberty may occur as early as 9 years of age. Puberty can affect the apparent activity of
`enzymes that metabolize drugs, and dose requirements for some medicinal products on a
`mg/kg basis may decrease dramatically (e.g., theophylline).
`In some cases, it may be
`appropriate to specifically assess the effect of puberty on a medicinal product by studying
`pre— and postpubertal pediatric patients.
`In other cases, it may be appropriate to record
`Tanner stages of pubertal development or obtain biological markers of puberty and
`examine data for any potential influence of pubertal changes.
`
`5.
`
`Adolescents (12 to 16-18 years (dependent on region)) (2.5.5)
`
`This is a period of sexual maturation; medicinal products may interfere with the actions of
`sex hormones and impede development. In certain studies, pregnancy testing and review
`of sexual activity and contraceptive use may be appropriate.
`
`This is also a period of rapid growth and continued neurocognitive development.
`Medicinal products and illnesses that delay or accelerate the onset of puberty can have a
`profound effec