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I am looking for other peoples opinion on the new European 'Better
Medicines for Children regulation'. A client is planning to obtain a
Paediatric Use Marketing Authorisation (PUMA) for a clinically well
established off patent generic grug used in the management of
Childhood Acute Lymphoblastic Leukaemia. The drug is licensed for use
in this condition, but only as a tablet. Problem is young children
often find difficulty taking tablets. The situation currently is not
satisfactory with many pharmacy departments extemporaneously
preparing their own liquid formulations to enable young children to
be treated. The performance of these liquid formulations has never
been tested in vivo.
My client is looking to develop a liquid formulation of the drug in
order to obtain the PUMA. We guess that as a minimum we will need to
do a 'bioequivalence' study, using a licensed tablet as reference, in
leukaemic children. However, the drug is reported to have low
bioavailability (<30%), and significant intra- and inter individual
variability in exposure. This suggests that a study with large
numbers is required. But is such a study really necessary bearing in
mind that clinically the dose of the drug is titrated to absolute
neutrophil counts? Remember that various untested liquid formulations
are already in use, and what the oncologist does is to change the
dose at clinic visits according to the neutrophil counts (this is
also true for the tablets). So my questions are:-
1. Is it necessary to show bioequivalence in this situation? Could we
not argue that for a drug where dose is titrated to a 'biomarker'
what is important is to show that is a robust formulation, that
performs to an acceptable level of variability?
2. Or is it better to do develop a paediatric investigation plan that
involves a 'comparison' with a marketed tablet, but which is not
necessarily looking for 'bioequivalence'. So for example if the
liquid formulation is shown to achieve a mean relative exposure to
the tablet of 0.7, then this is what will go on the label. Remember,
this should not matter a lot since doses are titrated to neutrophil
3. If you think bioequivalence will need to be shown, do you have any
suggestions for the best way to conduct such a study, bearing in mind
the variable nature of the drug, the patients population (oncology,
Any thoughts, words of wisdom is much appreciated
University Hospitals of Leicester
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It's an interesting question, I agree. The obvious thought is that if
did do the bioequivalence study you would not do it in children who
not take the tablets anyway, but in adults since there would be no
problem in adults taking the new liquid formulation. However, the
blood taken will be an issue as they will have a tendency to anaemia
both the leukaemia and the treatment if it has any bone-marrow
effect. Personally, I think that would be the "final nail in the ethical
coffin" when you are considering a trial of a compound that is not
fixed doses so bioequivalence is not a significant clinical issue,
for reasons of efficacy or toxicity.
What is important is ensuring a predictable bioavailability from a given
dose so that a response to the first dose is just as sound a basis for
calculating the next dose as tablets would be. As I see it, that is
dependent on having a stable formulation with consistent absorption.
where your uniform, liquid preparation would have an advantage over
tablets or ad hoc solutions made from tablets.
I cannot immediately think of a way to test consistency of absorption
does not involve an over-demanding trial design in this context, so
left with stability testing only.
I don't know whether the Cmax will affect efficacy for this compound.
is a tendency for liquid formulations to be absorbed faster and so
higher Cmaxs which might alter efficacy or toxicity.... Probably not
significant in this case.
It sounds as though it would be worth talking to the regulatory
and I hope these thoughts help.
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Registered in England & Wales
Registration No. 2934719
Registered Office: 8 Baker Street, London W1U 3LL
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