Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Drug Development

Great Ormond Street Hospital

for Children NHS Trust

The School of

Pharmacy

UCL INSTITUTE OF CHILD HEALTH

Centre for Paediatric Pharmacy Research

Drug Development for Children – Importance of

Clinical Trials

Ian Chi Kei WongProfessor of Paediatric Medicines Research Centre for Paediatric Pharmacy Research

The School of Pharmacy, University of London

“A cheerful heart is good medicine, but a crushed spirit dries up the bones.

(Proverbs 17:22)”.



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Pharmacy



Content• Reasons for lack of paediatric

medications research

• Formulation

• PK study

• Efficacy

• Safety



The School of

Pharmacy





• Formulation

• PK study

• Efficacy

• Safety



The School of

Pharmacy



01020304050

60708090

100

episodes unlicensed off label patients

%

PICUPaedsNICUPaeds EU

Prescribing of unlicensed and off label medicines - hospital

Up to 65% of drugs used for children in hospitals are not licensed for purpose



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Pharmacy



Very small



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Pharmacy



Very bigVery Big



The School of

Pharmacy


Centre for Paediatric Pharmacy Research • “Modern pediatric

pharmacology is a sophisticated clinical discipline capable of carrying out the studies necessary for the safe and ethical evaluation of drugs in children.” (US National Institute of Health 1994)



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Pharmacy



Real problems“Pursuit of such studies, however, is limited by the scarcity of available facilities in which to follow children receiving drugs and to collect data in a systematic way, as well as the insufficient number of qualified clinical investigators interested in this problem.” (NIH 1994)



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Pharmacy



Real problems• Finance

• Research capacity

1. Infrastructure

2. Researchers



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Pharmacy





• Formulation

• PK study

• Efficacy

• Safety



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Pharmacy





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Pharmacy



Poor formulations in clinical trials

• Only 49% used a paediatric formulation

• 25% used tablets/capsules – Only 26% of these gave administration

details

• Reliability and Validity?



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Pharmacy



The majority of medicines are not designed for Children

• Tablets –Solid dosage form –Many children cannot swallow

tablets whole–Crush or cut tablets



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Pharmacy



• Even when using tablet cutters• Splitting tablets causes inaccuracy

Solution or Problem?



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Pharmacy



crushers

Solution or Problem?

0.010.020.030.040.050.060.070.080.090.0

100.0

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

time (min)

% o

f N

ife

dip

ine

re

lea

se

d

crushed tablets

Whole tablets

tablets cut in 2

tablets cut in 4

Adalat Retard10mg Tablets

Tuleu 2005



The School of

Pharmacy


Centre for Paediatric Pharmacy Research • Crushing tablets can affect

bioavailability (Notterman 1986)

Significant?IM injection

Oral syrup

IM solution + apple juice for oral

Crushed tablets + apple sauce for oral

Notterman 1986



The School of

Pharmacy


Centre for Paediatric Pharmacy Research • Crushing tablets can affect

bioavailability (Notterman 1986)

Significant?

Change the PD

Formulation Change the PK



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Pharmacy



• Reasons for lack of paediatric medications research

• Formulation

• PK study

• Efficacy

• Safety



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Pharmacy



General Principles

• The disease process is similar in adults and paediatric patients.

• The outcome of therapy is likely to be comparable.

• Extrapolation from adult efficacy data may be appropriate.

• Pharmacokinetic data showing similarities to those observed in adults will be sufficient.



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Pharmacy



General Principles

• Pharmacokinetic studies support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations.



The School of

Pharmacy



General Principles

• Relative bioavailability comparisons of paediatric formulations with the adult oral formulation typically should be done in adults.

• Definitive pharmacokinetic studies for dose selection across the age ranges of paediatric patients should be conducted in the paediatric population.



The School of

Pharmacy



General Principles

• Linear pharmacokinetics in adults, single-dose pharmacokinetic studies in the paediatric population may be sufficient.

• Any non-linearity 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 paediatric population.



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Pharmacy



Practical points

• The volume of blood withdrawn should be minimized

• Blood volumes should be justified in protocols

• Collection of routine, clinical blood samples• Topical anesthesia to place IV catheters• Indwelling catheters rather than repeated

venepunctures for blood sampling



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Pharmacy



Practical points

• Sensitive assays

• 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”.

• Sampling time points derived from modeling of adult data.



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Example: diclofenac



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Pharmacy





• Formulation

• PK study

• Efficacy

• Safety



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Pharmacy



General Principles

• The principles in study design, statistical considerations and choice of control groups in adults generally apply to paediatric efficacy studies.



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Specific for children

• It may be necessary to develop, validate, and employ different endpoints for specific age and developmental subgroups.

• Measurement of subjective symptoms such as pain requires different assessment instruments for patients of different ages.



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Specific for children

• Duration of the chronic disease and the developmental stage of the patient may affect the response.

• Many diseases in the preterm and term newborn infant are unique or have unique manifestations precluding extrapolation of efficacy from older paediatric patients and call for novel methods of outcome assessment.



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Pharmacy




medications research• Formulation• PK study• Efficacy• Safety



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Pharmacy



General Principle

• Principles of adverse event reporting in adult population is generally applicable to paediatric studies.



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Specific points for children

• Age-appropriate, normal laboratory values and clinical measurements should be used in adverse event reporting

• Accidental ingestions or medication errors etc provide the opportunity to obtain safety and pharmacokinetic information.



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Pharmacy



Specific points for children• Developing physiological systems may

respond to drugs differently from matured adult.– Eg Tetracycline

• Some adverse events occur at a later stage

• Long-term studies or surveillance data may be needed to monitor the effect of developing systems.– Eg ADHD treatment



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Documents

Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Drug Development