|
Jane Buckham, Tasneem Khalid, Nigel
Ballantine,
Vicky Holden and Julie Mycroft, of the Paediatric Oncology Pharmacists
Group steering committee
|
The current trend to develop cancer chemotherapy drugs that can be administered
orally at home is commendable in terms of improving patients’ quality
of life. With effective safeguards in place to ensure compliance with
therapeutic regimens and prevent toxicity, as proposed by the British
Oncology Pharmacy Association, this has to be the way forward.
Unfortunately oral cytotoxic preparations rarely provide suitable denominations
of dose, or appropriate formulations such as mixtures, melts or soluble
tablets, for paediatric use. This leaves paediatric oncologists and pharmacists
with the predicament of having to expose children and their carers to
manipulation of adult cytotoxic preparations or have pharmaceutical “specials” manufactured
locally. These “specials” have only limited quality control
validation, because they are supplied at the request of the prescriber
on his or her liability.
“
Special” liquid formulations are often made in a variety of strengths
and although, on the advice of the Paediatric Oncology Pharmacists Group,
standard strengths are recommended for use in current children’s
cancer trials, there is no way of ensuring that hospitals that provide “shared
care” for these children use the standard preparation.
Specials also have not had the benefit of the rigorous testing to satisfy
licensing criteria in a clinical setting.
The alternative of cutting or crushing tablets, or opening capsules and
dispersing the resulting powder in water, exposes both the carers and
the home environment to cytotoxic contamination. In a percentage of families
this may include exposure of the fetus of an unborn sibling to contamination.
Since 90 per cent of children with cancer in the UK are treated at UK
Children’s Cancer Study Group centres, the majority on UKCCSG or
Medical Research Council clinical trials, both options have the potential
to reduce the validity of the trial because variable bioavailability
can affect patient outcomes. This can be accentuated because of the narrow
therapeutic index of cytotoxic agents. It also contravenes the EU clinical
trials directive. The alternative is to develop, with the pharmaceutical
industry, paediatric oral chemotherapy preparations. The proposed EU
directive on patent extension for licensing of preparations with paediatric
studies and exclusivity rights for generic paediatric preparations may
help. However, experience suggests that minority patient groups, such
as children with cancer, do not make such products economically viable
to the pharmaceutical industry.
The Paediatric Oncology Pharmacists group has tried for the past two
years to find a UK manufacturer to take over the production of an unlicensed
small dose tablet of mercaptopurine used in the treatment of paediatric
acute lymphoblastic leuk-aemia. This preparation, available in the UK
for over 30 years, has been with withdrawn because of its unlicensed
status and new regulatory requirements for manufacturing facilities.
The previous manufacturer was not prepared to “sell” the
product to a third party to continue production. Despite the support
of the Department of Health, the combined obstacles of a confined paediatric
market, which is too large for a single “specials” manufacturer
but too small for major commercial gain, plus the necessity for production
in a cytotoxic facility with its additional health and safety requirements,
has meant that we have been unable to source an alternative product in
the UK. Increasing health and safety legislation in the manufacture and
handling of cytotoxic preparations ensures that production costs for
such hazardous substances are high and few pharmaceutical manufacturers
are prepared to enter into this market.
We have therefore been working with a German group to enable it to facilitate
the commercial expansion of a “child friendly” soluble tablet
developed at the University of Münster. Despite the evidence of
a potential Europe-wide market for a drug with an established track record
and potential eligibility for fast-track licensing under “orphan
product” status, the German group has found it difficult to make
the transition into commercial production. As a result, a less “child
friendly” generic non-soluble tablet has been produced, which,
it is hoped, will be licensed in the future. This can then be licensed
in other EU countries by reciprocal agreement, at least improving the
availability of a product to provide suitable dose increments for children
outside the UK.
This, so far, has been a successful co-operation between the trial co-ordinators
for the current children’s leukaemia trials and a pharmaceutical
manufacturer. However, concern was raised again earlier this year at
the suggestion of the withdrawal of the liposomal formulation of daunorubicin.
Although this product is used by both children and adults, it is currently
used predominantly for relapse therapy, so has a small market of vulnerable
patients who have previously had anthracycline therapy and will, therefore,
be unable to tolerate the cardiotoxicity of repeated native anthracycline.
In this case the manufacturer has agreed to continue production.
It is becoming apparent that the UK needs a facility which is able to
take over the production of existing products when commercial or other
considerations would result in them being withdrawn from the market.
This particularly applies to cytotoxic, biological and non-hazardous
low-volume formulations, many of which will be paediatric preparations
by virtue of the restricted paediatric market.
At present only a voluntary DoH code of conduct exists to protect essential
medicines from discontinuation. This area of “discontinuation of
medicines” has been highlighted again in the recent DoH/Medicines
and healthcare Products Regulatory Agency strategy document on medicines
for children as being ineffectively protected by current legislation.
This will continue to happen until legislation is enacted to ensure that
the intellectual rights to a product are made available to a new manufacturer.
We understand that an NHS facility in London has recently been granted
development funds which may enable it to move into the area of cytotoxic
production, but without the original development and production information
development of a replacement product is both more time consuming and
costly and will slow the licensing process of a replacement product further.
These recent EU proposals and investment are to be welcomed but they
need to be taken further to protect existing preparations and ensure
the future development of effective treatment for children with cancer
and other rare diseases. |
The
Pharmaceutical Journal