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The need for innovative approaches to the
accelerated development of new, safe medicines prompted the European
Federation for Pharmaceutical Sciences (EUFEPS) to draw up its “New Safe Medicines Faster (NSMF)” initiative,
Ole Bjerrum from the Danish University of Pharmaceutical Sciences, Copenhagen,
told the audience. The thinking behind the initiative is that new medicines
needed to be affordable and safe and that it is important to keep a significant
amount of pharmaceutical development work in Europe (and not lose it
to the US).
In general, EUFEPS believes that the conditions for research and training
need to be improved and that the drug development process itself has
to be optimised by removing the current bottlenecks. In addition, it
would like Europe to have the best systems and state-of-the-art technology,
and thinks
that the bureaucracy currently associated
with drug development will have to be rethought.
Turning to specifics, Professor Bjerrum said that the NSMF initiative
calls for new techniques and tools for drug selection and screening and
new approaches to drug delivery and targeting to be used. In addition,
it recognises the need for advanced pharmaceutical materials and processes
to be developed. In particular, it believes that the use of “prediction
methodology”, which enables the modelling and simulation of many
processes, will be important. This will require libraries to be created,
and will necessitate wider access to information through readily accessible
databases, Professor Bjerrum pointed out. Moreover, double-blind, randomised
controlled trials might not be the only types of study that should be
used, he added.
Although EUFEPS clearly has a European outlook, the US Food and Drug
Administration (FDA) shares some of its concerns. In its March 2004 document
entitled “Innovation or stagnation?”, the FDA concludes: “Often
researchers are forced to use the last century’s tools to evaluate
this century’s development.”
Reduce costs to survive
The drug industry needs to change radically if it is to survive, was
the stark message from Professor Colin Garner, chief executive officer,
Xceleron, York. The costs of new drug development are now considerable
and the time is right to evaluate new technologies, he added.
Up to 30 per cent of new drugs fail at the phase 1 testing stage. The
main reasons for this are shortcomings in the clinical efficacy, safety
and toxicology profiles. Some of these failures are caused by an inappropriate
dose being used in phase 1 studies, resulting in too much or too little
drug reaching the site of action. To prevent this, it is critical to
understand how drugs are metabolised at an early stage in the research
and development process (ie, “phase 0”), he said.
To this end, two “big physics” techniques are now available
that can be used to obtain pharmacodynamic and pharmacokinetic data.
These are accelerator mass spectrometry (AMS), which can be used to determine
drug kinetics and positron emission tomography (PET), which can be used
to characterise pharmacodynamics. Microdosing using AMS
Professor Garner went on to explain in more detail about AMS. The technique
is based on that developed in the mid 1970s for carbon dating in archaeology.
With carbon dating, however, 9,000 carbon atoms (ie, a sizeable sample)
are needed in order to observe a single decay event. AMS, however,
is much more sensitive — attogram (10–18g) and zeptogram
(10–21g) quantities can be analysed.
This gives rise to the concept of microdosing, in which tiny, subtherapeutic,
subtoxic doses of drugs are given. A typical radioactive tracer dose
would be 80–100 microCuries, but for AMS a nanoCurie amount could
be given. For illustration, Professor Garner pointed out that a typical
adult contains 400 nanoCuries of naturally occurring 14C and a banana
contains about one nanoCurie of naturally occurring 14C.
Samples of blood, urine, faeces and plasma can be analysed, Professor
Garner continued. In each case the sample is processed in the laboratory
to convert biological carbon into inorganic carbon. The sample is then
loaded into the instrument. AMS counts atoms rather than radioactivity,
although the results are still expressed as “disintegrations per
minute”. Providing a 14C atom can be inserted into a molecule,
then its progress in the body can be followed, Professor Garner pointed
out.
Hitherto, drug discovery has involved the synthesis of large amounts
of large numbers of compounds followed by in vitro studies or animal
testing. Microdosing allows the rapid comparison of several molecules
or several dose levels and means that a smaller amount of each compound
needs to be produced for testing. The responses observed in microdosing
are 70–80 per cent predictive of the response that will be elicited
with pharmacological dosing, he said. The technique is also fast — it
only takes a few seconds to “count” a sample.
Currently, preclinical studies can take up to 18 months at a cost of
$3–5m. Microdosing techniques could reduce the time to four to
six months and the costs to $0.35m per new molecule, Professor Garner
explained.
The current disadvantages of AMS are that the equipment is expensive
and large — it takes up space equivalent to two tennis courts.
Smaller and cheaper instrumentation is likely to be developed in the
future though, Professor Garner concluded. |
The
Pharmaceutical Journal