ICH E11 -CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE PEDIATRIC POPULATION

Question 1

True or False

Drug development programs should usually include the pediatric patient population when a product is being developed for a disease or condition in adults and population.

Answer 1

True

Question 2

Who’s responsibility is it to protect the well-being of pediatric patients participating in clinical studies?

Regulatory Authorities
Health Professionals
Society as a whole

Answer 2

ALL OF THEM

Question 3

Justification for the timing and the approach to the
clinical program needs to be clearly addressed with ___________ _________ at an early stage and then periodically during the medicinal product development process

Answer 3

regulatory authorities

Question 4

True or False?

The pediatric development program should not delay completion of adult studies and availability of a medicinal product for adults

Answer 4

True

Question 5

What are the factors that guide the decision to proceed with trial with pediatric patients?

Answer 5

–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 6

What is the most important factor in determining to do a pediatric study?

Answer 6

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.

Question 7

It should be noted that the most relevant safety

data for pediatric studies ordinarily come from __ ____ _____

Answer 7

adult human exposure.

Question 8

Medicinal Products for Diseases Predominantly or Exclusively Affecting Pediatric Patients the entire development plan with bee conducted in the population except ___ and ___ __, which will usually be obtained in adults

Answer 8

safety and tolerability data

Question 9

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, medicinal product development should begin early in the pediatric population, following assessment of ______ and reasonable evidence of ___________.

Answer 9

initial safety data and reasonable evidence of potential benefit.

Question 10

True or False?

Pediatric study results should be part of the marketing application database.

Answer 10

True

Question 11

Medicinal Products Intended to Treat Other Diseases and Conditions-True or False? although the medicinal product will be used in pediatric patients, there is
less urgency than in the 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.

Answer 11

True

Question 12

Testing of Medicinal Products Intended to Treat Other Diseases and Conditions in pediatric patients usually begins in what phases?

Answer 12

2 or 3

Question 13

True or False? When a medicinal product is studied in pediatric patients in one region, the intrinsic (e.g., pharmacogenetic) and extrinsic (e.g., diet) factors that could impact on the extrapolation of data to other regions should not be considered.

Answer 13

False-Should be considered

Question 14

Is this statement true? 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.

Answer 14

Yes-True

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, 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. True or False?

Answer 15

True

Question 16

Why should Pharmacokinetics studies be performed in pediatric populations?

Answer 16

Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations.

Question 17

Are Pharmacokinetic studies in the pediatric population are generally conducted in patients with the disease?

Answer 17

Yes

Question 18

In Pharmacokinetic studies in the pediatric population, when studying patients with the disease, what can it lead to result wise?

Answer 18

This may lead to higher intersubject variability than

studies in normal volunteers, but the data better reflect clinical use.

Question 19

What is the most common dosing recommendation for pediatric patients?

Answer 19

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.

Question 20

Why is mg/square meter body surface not used for dosing recommendations?

Answer 20

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

Question 21

What other type of dosing may be necessary in pediatric populations? E.g medications with a narrow therapeutic index

Answer 21

surface-area-guided dosing may be necessary, but extra care should be taken to ensure proper dose
calculation

Question 22

True or False?

The volume of blood withdrawn should be minimized in pediatric studies.

Answer 22

True

Question 23

Do blood volume withdrawls have to be in the protocol?

Answer 23

Yes

Question 24

Can Institutional Review Boards/Independent
Ethics Committees (IRB’s/IEC’s) review and may define the maximum amount of blood?

Answer 24

Yes- (usually on a milliliters (mL)/kg or percentage of total blood volume basis) that may be taken for investigational purposes.

Question 25

List of approaches used to minimize amount of blood withdrawn and/or number of venipunctures?

Answer 25

• 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 as discussed in section 2.6.5.
• Use of population pharmacokinetics and sparse sampling based on optimal sampling theory to minimize the number of samples obtained from each patient.

Techniques include:
-Sparse sampling approaches where each patient contributes as few as 2 to 4 observations at predetermined times to an overall “population area under-thecurve”

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

Question 26

Which of the following apply to pediatric patients?

A. 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

B. ICH guidances on E2 topics and ICH E6, which describe adverse event reporting,
apply to pediatric studies

Answer 26

Both

Question 27

True or False?

Medicinal products may affect physical and cognitive growth and development, and the adverse event profile may differ in pediatric patients.

Answer 27

True

Question 28

Describe the age range categories given in this ICH

5 of them

Answer 28

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 29

What important features should be considered in Preterm Newborn Infants?

Answer 29

(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 30

What study design issues should be considered in Preterm Newborn Infants?

Answer 30

(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.

Question 31

True or False?

Oral absorption of medicinal products may
be less predictable in Term Newborn infants than in older pediatric patients

Answer 31

trueeeeeeee

Question 32

Does oral asorption become more reliable in infants and toddlers then newborns and preterms?

Answer 32

Yes

Question 33

In children, what can puberty affect?

Answer 33

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)

Question 34

In what age group is non-compliance a problem?

Answer 34

LOL adolescents

Question 35

True or False?

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 pediatric ethical, clinical, and psychosocial issues

Answer 35

True

Question 36

Is this true? As a rule, a pediatric subject is legally unable to provide informed consent. Therefore
pediatric study participants are dependent on their parent(s)/legal guardian to assume responsibility for their participation in clinical studies.

Answer 36

True

Question 37

Fully informed consent should be obtained from the __ _____ in accordance with regional laws or regulations

Answer 37

Legal Guardian

Question 38

Where appropriate, participants should ________ to enroll in a study (age of assent to be determined by
IRB’s/IEC’s or be consistent with local legal requirements).

Answer 38

assent

Question 39

True or False?
Participants of appropriate intellectual maturity should personally sign and date either a separately
designed, written assent form or the written informed consent.

Answer 39

True

Question 40

Emancipated or mature minors (defined by local

laws) are not capable of giving autonomous consent.

Answer 40

False-they are

Question 41

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

Answer 41

• 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 42

__________should consider how many venipunctures are acceptable in an attempt to obtain blood samples for a protocol and ensure a clear understanding of procedures if an indwelling catheter fails to function over time.

Answer 42

IRB’s/IEC

Question 43

Of all the factors to determine to proceed with a pediatric study, what is the most important?

Answer 43

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.

Question 44

What phase study would you begin pediatric studies for medicinal products intended to treat other diseases and conditions?

Answer 44

Phase 2 and 3

Question 45

T/F-Pharmacokinetic studies generally should be performed to support formulation
development and determine pharmacokinetic parameters in different age groups to
support dosing recommendations

Answer 45

True

Question 46

T/F-Pharmacokinetic studies in the pediatric population are generally conducted in
patients with the disease.

Answer 46

True

Question 47

How is amount of blood drawn usually justified ?

Answer 47

usually on a milliliters (mL)/kg or percentage of total blood volume basis