great ormond street hospital for children nhs trust the school of pharmacy ucl institute of child...
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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)”.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Content• Reasons for lack of paediatric
medications research
• Formulation
• PK study
• Efficacy
• Safety
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Content• Reasons for lack of paediatric
medications research
• Formulation
• PK study
• Efficacy
• Safety
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Very small
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Very bigVery Big
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
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)
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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)
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Real problems• Finance
• Research capacity
1. Infrastructure
2. Researchers
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Content• Reasons for lack of paediatric
medications research
• Formulation
• PK study
• Efficacy
• Safety
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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?
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
The majority of medicines are not designed for Children
• Tablets –Solid dosage form –Many children cannot swallow
tablets whole–Crush or cut tablets
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
• Even when using tablet cutters• Splitting tablets causes inaccuracy
Solution or Problem?
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
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
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research • Crushing tablets can affect
bioavailability (Notterman 1986)
Significant?
Change the PD
Formulation Change the PK
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
• Reasons for lack of paediatric medications research
• Formulation
• PK study
• Efficacy
• Safety
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
General Principles
• Pharmacokinetic studies support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Example: diclofenac
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Content• Reasons for lack of paediatric
medications research
• Formulation
• PK study
• Efficacy
• Safety
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
General Principles
• The principles in study design, statistical considerations and choice of control groups in adults generally apply to paediatric efficacy studies.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
Content• Reasons for lack of paediatric
medications research• Formulation• PK study• Efficacy• Safety
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
General Principle
• Principles of adverse event reporting in adult population is generally applicable to paediatric studies.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
The School of
Pharmacy
UCL INSTITUTE OF CHILD HEALTH
Centre for Paediatric Pharmacy Research
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