BATCH 1

MONISHA MOHANANUPAM

PGD ACR - V

� The Pediatric Rule requires drug makers of

selected new and existing drugs to conduct

studies on drug safety and effectiveness in

children.s The Best Pharmaceuticals for Children Act,

in exchange for studying the drug in children, the

drug maker gets six months of selling their

product without competition.

3. The Pediatric Research Equity Act

gives FDA the right to ask drug companies

to study the effectiveness of new drugs in

children.

The paediatric studies should include –

(a)Clinical trials,

(b) Relative bioequivalence comparisons of the paediatric formulation with the adult formulation performed in adults, and

(c) Definitive pharmacokinetic studies for dose

selection across the age ranges of paediatric patients in whom the drug is likely to be used. These studies should be conducted in the paediatric patient population with the disease under study.

E 11- Clinical investigation of medicinal products in the pediatric population

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))

Unique pathophysiology and responses

to therapy

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.

Gestational age at birth and age after birth (adjusted age)

Immaturity of renal and hepatic clearance mechanisms

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)

Transdermal absorption of medicinal products and other chemicals.

(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

Term newborn infants are developmentally more mature than preterm newborn infants

Volumes of distribution of medicinal products may be different from those in older pediatric patients because of different body water and fat content.

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.

Hepatic and renal clearance mechanisms are immature and rapidly changing; doses may need to be adjusted over the first weeks of life.

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.

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.

Most pathways of drug clearance (hepatic and renal) are mature, with clearance often exceeding adult values.

- maturation of specific metabolic pathways.

Children achieve several important milestones of psychomotor development that could be adversely affected by CNS-active drugs.

Highly variable and occurs earlier in girls.

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.

Specific strategies should be addressed in protocols to ascertain any effects of the medicinal product on growth and development.

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.

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.

Medicinal products and illnesses that delay or accelerate the onset of puberty can have a profound effect on the pubertal growth spurt and, by changing the pattern of growth, may affect final height.

Evolving cognitive and emotional changes could potentially influence the outcome of clinical studies.

Many diseases are also influenced by the hormonal changes around puberty (e.g., increases in insulin resistance in diabetes mellitus, recurrence of seizures around menarche, changes in the frequency and severity of migraine attacks and asthma exacerbations).

Hormonal changes may thus influence the results of clinical studies.

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.

The volume of blood withdrawn should be

minimized in pediatric studies.

Blood volumes should be justified in protocols.

IRB’s/IEC’s 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.

The number and type of assays and investigations should

take into consideration based on the age and/or

bodyweight (body surface area if appropriate) of the

children to be included in the trial.

Use of sensitive assays for parent drugs and metabolites

to decrease the volume of blood required per sample

For blood and tissue assays, microvolumes and micro-

assays should be used, whenever possible

Use of laboratories- experienced in handling

small volumes of blood for pharmacokinetic

analyses and for laboratory safety studies

(blood counts, clinical chemistry)

Sampling should be performed by trained

staff. The number of attempts for sampling

should be limited.

Collection of routine, clinical blood samples wherever

possible at the same time as samples are obtained for

pharmacokinetic analysis .

Alternative sampling (e.g. urine or salvia sampling) for

pharmacokinetic studies should be preferred when

possible.

- In principle, general and / or local anaesthesia should be used as

appropriate for painful and/or invasive procedures.

Timing of sampling should be co-ordinated as far as

possible to avoid repeated procedures and sampling

during the day in order to minimize pain and distress,

and the risk of iatrogenic complications.

Timing of sampling and number of sampling attempts

should be defined in the protocol. For example, it is

recommended that after one unsuccessful attempt,

another experienced person take over the procedure.

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. 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-the-curve”

i Population pharmacokinetic analysis using the most useful

sampling time points derived from modeling of adult data

Preterm and term neonates have very limited blood

volume, are often anaemic due to age and frequent

sampling related to pathological conditions.

The fact that children, especially in this age group,

receive blood transfusions (or iron or erythropoietin

supplementation) should not be used as a convenience

for increased volume or frequency for blood sampling.

Per individual, the trial-related blood loss (including any losses in

the manoeuvre) should not exceed 3 % of the total blood volume

during a period of four weeks and should not exceed 1% at any

single time.

In the rare case of simultaneous trials, the recommendation of 3%

remains the maximum.

Monitoring of actual blood loss is routinely required in preterm

and term neonates.

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 be considered.

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.

Benefits and discomforts should be described in the level of the child’s understanding

A child >7yrs of age should give consent by signing the assent form

One or both the parents should give consent based on the extent of risk of the trial

Assent and age

Parental consent will probably be invalid if it is given against the child’s interests.

Consent process in emergency

Parental understanding of randomisation

Enrolling patients in multiple trialsEnrolling children in phase I studies

avoidedFactors affecting informed consent -

diff of opinion, personal benefit,

Pharmacokinetic studyEfficacy studiesSafety studiesCohort studyCase–control studies

Open protocol designOpen label trialsHistorical controlBayesian designed trialsCrossover designSurrogate end-pointUnderpowered studies

Children not involved if the study can be done with adults

It should be to obtain knowledgeParent or Legal guardian – Proxy

ConsentAssentsAdequate medical supportRefusal respected

EU Regulation on paediatric medicinesThe EU Regulation on Paediatric Medicines1  was adopted on 12 December 2006 and came into force on 26 January 2007. 

increased availability of medicines specifically adapted and licensed for use in the paediatric population

increased information available to the patient and prescriber about the use of medicines in children, including clinical trial data

increase in high quality research into medicines for children.

BACKGROUND Lamivudine therapy is effective for

chronic hepatitis B infection in adults. We evaluated the efficacy and tolerability of lamivudine as a treatment for chronic infection with hepatitis B virus (HBV) in children.

Children with chronic hepatitis B were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg per kilogram of body weight; maximum, 100 mg) or placebo once daily for 52 weeks. The primary end point was virologic response (defined by the absence of serum hepatitis B e antigen and serum HBV DNA) at week 52 of treatment.

Of the 403 children screened, 191 were randomly assigned to receive lamivudine and 97 to receive placebo. The rate of virologic response at week 52 was higher among children who received lamivudine than among those who received placebo (23 percent vs. 13 percent, P=0.04). Lamivudine therapy was well tolerated and was also associated with higher rates of seroconversion from hepatitis B e antigen to hepatitis B e antibody, normalization of alanine aminotransferase levels, and suppression of HBV DNA.

CONCLUSIONS In children with chronic hepatitis B, 52

weeks of treatment with lamivudine was associated with a significantly higher rate of virologic response than the placebo

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