Clinical Trials in Pediatric Population E11 (R1)

Question 1

Parental (legal guardian) Consent/Permission

Answer 1

Expression of understanding and agreement by fully informed parent(s) or legal guardian to permit the investigator/sponsor of a clinical study to enroll a child in a clinical investigation.
The choice of the terms parental consent or parental permission in different regions may reflect local legal/regulatory and ethical considerations.

Question 2

Child Assent

Answer 2

The affirmative agreement of a child to participate in research or to undergo a medical intervention.
Lack or absence of expression of agreement or disagreement must not be interpreted as assent.

Question 3

Modelling and Simulation (M&S)

Answer 3

A range of quantitative approaches, including pharmacometrics/systems pharmacology and other mathematical/statistical approaches based on physiology, pathology and pharmacology to quantitatively characterize the interactions between a drug and an organ system which could predict quantitative outcomes of the drug and/or system’s behavior in future experiments. In modelling and simulation, existing knowledge is often referred to as “prior” knowledge.

Question 4

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:

Answer 4

• 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

Question 5

What is the most important factor when considering a pediatric development program for a medicinal product?

Answer 5

The presence of a serious or life-threatening disease for which the medicinal product represents a potentially important advance in therapy.

Question 6

It should be noted that the most relevant safety data for pediatric studies
ordinarily come from:

Answer 6

Adult human exposure

Question 7

There is a need for pediatric formulations that permit:

Answer 7

Accurate dosing and enhance patient compliance

Question 8

During clinical development, the timing of pediatric studies will depend on:

Answer 8

• The medicinal product
• The type of disease being treated
• Safety considerations
• 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.

Question 9

In the case of medicinal products for disease predominately or exclusively affecting pediatric patients, the entire development program will be conducted in the pediatric population except for:

Answer 9

Initial safety and tolerability data, which will be obtained in adults.

Question 10

In what case would medicinal product development begin early in the pediatric
population, following assessment of initial safety data and reasonable evidence of potential benefit?

Answer 10

When the medicinal product is intended to treat serious or life-threatening disease, occurring in both adults and pediatric patient, for which there are currently no or limited therapeutic options.
In this case, pediatric study results should be part of the marketing application database.

Question 11

If a medicinal product does not represent a major therapeutic advance for the pediatric population, there is less urgency and studies would begin:

Answer 11

At later phases of clinical development or, if a safety concern exists, even after substantial post-marketing experience in adults.

Question 12

When a medicinal product is studied in pediatric patients in one
region, what should be considered?

Answer 12

The intrinsic (e.g., pharmacogenetic) and extrinsic (e.g., diet) factors that could impact on the extrapolation of data to other regions

Question 13

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, is extrapolation from adult efficacy data appropriate?

Answer 13

Yes, it may be.

Question 14

In cases where the 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, what may provide adequate information for use?

Answer 14

Pharmacokinetic studies in all the age ranges of pediatric patients likely to receive the medicinal product, together with safety studies, that will produce blood levels similar
to those observed in adults.

Question 15

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, is extrapolation of efficacy from older to younger pediatric patients possible?

Answer 15

Yes, it may be.

Question 16

In cases where the 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, what may provide adequate information for use?

Answer 16

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.

Question 17

In pediatric studies, when is an approach based on pharmacokinetics likely to be insufficient?

Answer 17

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.

Question 18

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.
Thus, a PK/PD approach combined with safety and other relevant studies could avoid
the need for what?

Answer 18

Clinical efficacy studies

Question 19

When are clinical efficacy studies in the pediatric population needed?

Answer 19

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.

Question 20

Relative bioavailability comparisons of pediatric formulations with the adult oral formulation typically should be done in:

Answer 20

Adults

Question 21

Definitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the medicinal product is likely to be used should be conducted in:

Answer 21

The pediatric population

Question 22

Are pharmacokinetic studies in the pediatric population generally conducted in patients with the disease or in healthy patients?

Answer 22

Patients with the disease

Question 23

Since pharmacokinetic studies in the pediatric population are generally conducted in patients with the disease, this may lead to higher inter-subject variability than studies in normal volunteers, but the data better reflects:

Answer 23

Clinical use

Question 24

Any nonlinearity in pharmacokinetics - 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:

Answer 24

Steady state studies in the pediatric population

Question 25

Dosing recommendations for most medicinal products used in the pediatric population are usually based on:

Answer 25

Milligram (mg)/kilogram (kg) body weight up to a maximum adult dose

Question 26

Even though dosing based on mg/square body surface might be preferred in pediatrics, what common issue does clinical experience indicate?

Answer 26

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.

Question 27

The volume of blood withdrawn should be minimized in pediatric studies. Several approaches can be used to minimize the amount of blood drawn and/or the number of venipunctures:

Answer 27

- Use of sensitive assays for parent drugs and metabolites to decrease the volume of blood required per sample - Use of 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 - The use of indwelling catheters, etc., to minimize distress - Use of population pharmacokinetics and sparse sampling based on optimal sampling theory to minimize the number of samples obtained from each patient

Question 28

The use of population pharmacokinetics and sparse sampling based on optimal sampling theory can minimize the number of samples obtained from each pediatric patient. Techniques include:

Answer 28

- 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” - Population pharmacokinetic analysis using the most useful sampling time points derived from modeling of adult data

Question 29

In pediatric, where efficacy studies are needed, it may be necessary to develop, validate, and employ different endpoints for:

Answer 29

Specific age and developmental subgroups

Question 30

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:

Answer 30

Developmental stage of the patient

Question 31

Why do many disease in the preterm or term newborn infants call for novel methods of outcome assessment?

Answer 31

Because many disease in the preterm and term newborn infant are unique or have unique manifestations precluding extrapolation of efficacy from older pediatric patients.

Question 32

Medicinal products may affect physical and cognitive growth and development, so what may be different in pediatric patients than in adult patients?

Answer 32

The adverse even 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.

Question 33

The dynamic processes of growth and development may not manifest an adverse event acutely, but at a later stage of growth and maturation. Therefore, 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:

Answer 33

- Skeletal development - Behavioral development - Cognitive development - Sexual development - Immune maturation and development

Question 34

What is particularly important since the pediatric database is limited at the time of approval?

Answer 34

Post-marketing surveillance

Question 35

Decisions on how to stratify studies and data by age need to take into consideration:

Answer 35

Developmental biology and pharmacology

Question 36

What is a "break point" in pharmacokinetics?

Answer 36

The point at which clearance is likely to change significantly (specific age, weight, developmental stage, etc.)

Question 37

Because in longer term studies, pediatric patients may move from one age category to another, what needs to prospectively take into account the changing numbers of patients with a given age category?

Answer 37

The study design and statistical plans

Question 38

Possible, general categorization for pediatric studies (age groups):

Answer 38

- 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))

Question 39

Why does the study of medicinal products in preterm newborn infants present special challenges?

Answer 39

Because of the unique pathophysiology and responses to therapy in this population.

Question 40

The complexity of and ethical considerations involved in studying preterm newborn infants suggest the need for careful protocol development with expert input from:

Answer 40

Neonatologists and neonatal pharmacologists

Question 41

Only rarely will it be possible to extrapolate efficacy from studies in adults or even in older pediatric patients to what pediatric population?

Answer 41

The preterm newborn infant

Question 42

Important features that should be considered for preterm newborn infant patients include:

Answer 42

(1) Gestational age at birth and age after birth (adjusted age) (2) Immaturity of renal and hepatic clearance mechanisms (3) Protein binding and displacement issues (particularly bilirubin) (4) Penetration of medicinal products into the central nervous system (CNS) (5) Unique neonatal disease states (e.g., respiratory distress syndrome of the newborn, patent ductus arteriosus, primary pulmonary hypertension) (6) Unique susceptibilities of the preterm newborn (e.g., necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity) (7) Rapid and variable maturation of all physiologic and pharmacologic processes leading to different dosing regimens with chronic exposure (8) Transdermal absorption of medicinal products and other chemicals

Question 43

Study design issues that should be considered in the preterm newborn infant population include:

Answer 43

(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 (4) Difficulties in assessing outcomes

Question 44

Why would the volumes of distribution of medicinal products be different in term newborn infants from those in older pediatric patients?

Answer 44

Because of the different body water and fat content and high body-surface-are-to-weight ratio

Question 45

Why might medicinal products and endogenous substances gain access to the CNS with resultant toxicity in term newborn infants?

Answer 45

The blood-brain barrier is still not fully mature in this population.

Question 46

Newborn infants may be less susceptible to some types of adverse effects (e.g., aminoglycoside nephrotoxicity) than are patients in:

Answer 46

Older age groups

Question 47

What is he period of rapid CNS maturation, immune system development and total body growth?

Answer 47

Infants and toddlers (28 days to 23 months)

Question 48

What form of absorption becomes more reliable in the infants and toddlers population?

Answer 48

Oral absorption

Question 49

By 1 to 2 years of age, clearance of many drugs on a mg/kg basis may exceed:

Answer 49

Adult values

Question 50

In what age group is there often considerable inter-individual variability in maturation?

Answer 50

Infants and toddlers

Question 51

In what age group are most pathways of drug clearance (hepatic and renal) mature, with clearance often exceeding adult values?

Answer 51

Children (2 to 11 years)

Question 52

Children (2 to 11 year) achieve several important milestones of psychomotor development that could be adversely affected by:

Answer 52

CNS-active drugs

Question 53

What may affect a child's ability to participate in some types of efficacy studies?

Answer 53

Entry into school and increased cognitive and motor skills

Question 54

Factors useful in measuring the effects of a medicinal product on children include:

Answer 54

- Skeletal growth - Weight gain - School attendance - School performance

Question 55

Why is it important that recruitment of patients should ensure adequate representation across the age range in the child category?

Answer 55

To ensure a sufficient number of younger patients for evaluation

Question 56

Stratification by age within the child category is often unnecessary, but it may be appropriate to stratify patients based on:

Answer 56

Pharmacokinetic and/or efficacy endpoint considerations

Question 57

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:

Answer 57

Decrease dramatically

Question 58

In what age group may medicinal products interfere with the actions of sex hormones and impede development, since it is a period of sexual maturation?

Answer 58

Adolescents (12 to 16-18 years)

Question 59

Medicinal products and illnesses that delay or accelerate the onset of puberty can have a profound effect on:

Answer 59

The pubertal growth spurt and, by changing the pattern of growth, which may affect final height

Question 60

Many disease are influenced by the hormonal changes around puberty. Hormonal changes may thus influence:

Answer 60

The results of clinical studies

Question 61

Within this group, adolescents are assuming responsibility for their own health and medication, because of this what is a special problem?

Answer 61

Noncompliance, particularly when medicinal products (for example, steroids) affect appearance.

Question 62

When protocols involving the pediatric population are reviewed, there should be IRB/IEC members or experts consulted by the IRB/IEC who are knowledgeable in:

Answer 62

Pediatric ethical, clinical, and psychosocial issues

Question 63

For pediatric studies, participants of appropriate intellectual maturity should personally sign and date either:

Answer 63

A separately designed, written assent form or the written informed consent

Question 64

Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the opinion of the investigator and parent(s)/legal guardian, the welfare of a pediatric patient would be jeopardized by his or her failing to participate in the study. In this situation, is continued parental (legal guardian) consent sufficient to allow participation in the study?

Answer 64

Yes

Question 65

Studies in handicapped or institutionalized pediatric populations should be limited to:

Answer 65

Diseases or conditions found principally or exclusively in these populations, or 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.

Question 66

Practical considerations to ensure that pediatric participants’ experiences in clinical studies are positive and to minimize discomfort and distress include the following:

Answer 66

- Personnel knowledgeable and skilled in dealing with the pediatric population and its age-appropriate needs, including skill in performing pediatric procedures - A physical setting with furniture, play equipment, activities, and food appropriate for age - The conduct of studies in a familiar environment such as the hospital or clinic where participants normally receive their care - Approaches to minimize discomfort of procedures, such as: * Topical anesthesia to place IV catheters * Indwelling catheters rather than repeated venipunctures for blood sampling * Collection of some protocol-specified blood samples when routine clinical samples are obtained

Question 67

A fundamental principle in pediatric drug development requires that children should not be enrolled in a clinical study unless necessary to achieve:

Answer 67

An important pediatric public health need

Question 68

Without a prospect of direct clinical benefit from an experimental intervention or procedure, the foreseeable risks and burdens to which pediatric participants would be exposed must be:

Answer 68

Low, i.e., comparable to those risks and burdens encountered in their routine clinical care.

Question 69

Experimental interventions or procedures that present greater than low risk to pediatric participants must offer:

Answer 69

A sufficient prospect of clinical benefit to justify or outweigh exposure of a pediatric population to such risk.

Question 70

Over the course of a clinical study, it may be necessary to reassess the assent of a child in recognition of their advancing age, evolving maturity and competency, this is especially important in which studies?

Answer 70

Long-term studies or studies that may require sample retention

Question 71

During clinical studies there is a requirement for obtaining adequate informed consent for continued participation from pediatric participants once a child reaches the age of:

Answer 71

Legal consent

Question 72

The transparency of clinical research in pediatric drug development includes:

Answer 72

The registration of clinical trials on publicly accessible and recognized databases, and the public availability of clinical trial results.

Question 73

To address regional differences, timely and efficient drug development in the pediatric population requires a common scientific approach for which the following questions should be considered:

Answer 73

- What is the medical need in one or more pediatric populations that the drug could address? - Who are the appropriate pediatric populations or subgroups that could be considered? - What are the key issues in the drug development program that need to be addressed based on the intended pediatric use of the drug? - Based on the existing knowledge, including developmental physiology, disease pathophysiology, nonclinical data, data in adult or pediatric populations, or data from related compounds, what are the knowledge gaps that should be addressed to establish the safe and effective use of the drug? What specific nonclinical studies could be considered? - What clinical studies and/or methodological approaches could be considered? - What pediatric-specific clinical study design elements could be considered? - What practical and operational issues should be considered? - Are there different formulations/dosage forms or delivery devices that will be needed for specific pediatric subgroups, both to facilitate an optimal dose-finding strategy, and for treatment of pediatric patients in different subgroups?

Question 74

Chronological age alone may not serve as an adequate categorical determinant to define developmental subgroups in pediatric studies. What are the factors that need to be considered in determining the subgroups in pediatric studies?

Answer 74

- Physiological development and maturity of organs, - Pathophysiology and natural history of the disease or condition - Available treatment options - The pharmacology of the investigational product

Question 75

Depending on factors such as the condition, the treatment, and the study design, could it be justifiable to include pediatric subpopulations in adult studies or adult subpopulations in pediatric studies?

Answer 75

Yes

Question 76

Should planning for pediatric studies wait until adult development has concluded?

Answer 76

No, waiting to begin planning until adult development has concluded can limit the opportunity to generate meaningful data for pediatric drug development

Question 77

The concept of “extrapolation” is used in different ways in drug development. “Pediatric extrapolation” is defined as:

Answer 77

An approach to providing evidence in support of effective and safe use of drugs in the pediatric population when it can be assumed that the course of the disease and the expected response to a medicinal product would be sufficiently similar in the pediatric and reference (adult or other pediatric) population.

Question 78

The process of pediatric extrapolation examines several factors that support the assumptions of similarity of disease and similarity of response to therapy between the pediatric and the reference populations, including:

Answer 78

- Disease pathogenesis - Criteria for disease diagnosis and classification - Measures of disease progression - Pathophysiological, histopathological, and pathobiological characteristics

Question 79

Support for the assumptions of similarity of disease and response to therapy, including exposure-response relationship and prediction of an effective dose and regimen for the intended population, may be derived from:

Answer 79

- Existing data about the use of the drug - Published literature - Expert panels and consensus documents - Previous experience with other products in the same therapeutic class

Question 80

When pediatric extrapolation is considered in a pediatric drug development strategy, the following framework of questions should be assessed to identify what additional supportive data are needed:

Answer 80

1. What evidence supports a common pathophysiology of disease, natural history, and similarity of the disease course between the reference and pediatric population(s)? 2. What is the strength of the evidence of efficacy in the reference populations? 3. Is there a biomarker or surrogate endpoint in the reference populations that is relevant in the pediatric population? 4. What evidence supports a similar exposure-response between the reference and intended populations? 5. What uncertainties and/or limitations do the existing data (e.g., clinical or historical data and published literature) have, and what uncertainties about the pediatric population remain? 6. If uncertainties remain, what additional information should be generated (e.g., information from M&S, animal, adult, pediatric subgroup studies) in order to inform the acceptability of the extrapolation approach?

Question 81

What can help quantify available information and assist in defining the design of pediatric clinical studies and/or the dosing strategy?

Answer 81

Modelling and Simulation

Question 82

The usefulness of M&S in pediatric drug development includes, but is not limited to:

Answer 82

- Clinical trial simulation - Dose selection - Choice and optimization of study design - Endpoint selection - Pediatric extrapolation

Question 83

When building a model, it is important to consider several elements, including the context of use of the model, the quality and the extent of the existing data, and the assumptions made. Assumptions are usually structured around five main areas:

Answer 83

- Pharmacology - Physiology - Disease considerations - Existing data - The mathematical and statistical assumptions underpinning the model

Question 84

A series of what kind of cycles should be used for model building and simulation/prediction, and be confirmed as soon as new information is generated?

Answer 84

"Learn and confirm"

Question 85

Before deciding which types of methodological approaches are to be used in clinical trial design and execution, one should consider several practical factors that influence the design and execution of pediatric clinical trials. Three key practical factors to consider are:

Answer 85

- Feasibility - Outcome assessments - Long-term clinical aspects, including safety

Question 86

Pediatric drug development faces unique feasibility issues, including:

Answer 86

- A small number of eligible children for clinical research - Limited pediatric specific resources at research centers - The scarcity of dedicated pediatric trial networks

Question 87

For pediatric studies, consideration should be given to the available centers that:

Answer 87

- Are willing to participate - Have access to eligible pediatric participants - Are appropriately staffed in research and clinical care of pediatric patients

Question 88

When studying pediatric conditions, it may be necessary to consider implementing clinical trial operational strategies, including, but not limited to:

Answer 88

- The use of pediatric research coordinating centers; the development of master protocols for pediatric clinical trials or registries - Planned and conducted in a collaborative manner to evaluate multiple therapies for the same disease or condition with a common control arm - The enhancement of pediatric clinical research networks

Question 89

Additional considerations for pediatric formulations to optimize efficacy and reduce the risk for medication and dosing errors should include:

Answer 89

- Age-appropriate dosage forms - Ease of preparations and instructions for use for caregivers - Acceptability (e.g., palatability, tablet size) - Choice and amount of excipients - Use of alternative delivery systems - Appropriate packaging

Question 90

Excipients may lead to adverse reactions in children that are not observed (or not to the same extent) in adults. Thus, the use of excipients in pediatric medicines should take into account factors such as:

Answer 90

- Age - Weight - Maturity (e.g., term and preterm newborns related to their physiologic development) - Frequency of dosing - Intended duration of treatment - Potential for additional excipient exposure from commonly co-administered medicines.