| Parexel’s aborted trial of the monoclonal antibody TGN1412 has
dramatically brought the issue of how medicines are developed and tested
to the public’s attention. However, rather than causing people
to shy away from the risks involved in developing new treatments, the
events at Northwick Park, north London, appear to have led to a surge
in interest in clinical trials.
“The numbers of people expressing interest in trials have, paradoxically,
increased,” Trevor Smart, Schild professor of pharmacology at University
College London, says.
The Medical Research Council says that although its Clinical Trials Unit
usually receives a few queries a month, they received more than a dozen
towards the end of last week. And Hammersmith Medicines Research, a contract
research organisation in London that specialises in phase 1 and 2 studies
(see Panel 1), has also seen a general increase in interest, Malcolm
Boyce, managing director, says.
Panel 1: Pre-clinical testing and clinical
trial phases
Before testing in humans begins, unpromising
compounds are sifted out and candidate compounds selected for
development. Non-clinical
and pre-clinical bench and animal tests are then run before the
drugs are tested in humans. The types of pre-clinical tests that
have to
be conducted on animals vary from medicine to medicine, depending
on the characteristics of the active ingredient, a spokesman for
the Association of the British Pharmaceutical Industry explains. “Typically,
studies will need to be carried out on at least two species. Around
80 per cent of tests are carried out in rats or mice and then on
a larger species,” he says. “The larger species used
will again depend on the medicine being tested but are normally a
larger rodent. Other animals such as dogs, cats or pigs are sometimes
used because of the similarities between some of their organs and
humans’. And any drug for a neurological condition, or involving
the brain, will usually have to be tested in non-human primates
first, before phase 1 trials can begin.”
Clinical trials assessing the safety and efficacy of medicines
in humans are then divided into four phases:
· Phase 1 or healthy volunteers trials are small studies and the
first test of a drug in humans. They are designed to establish
safe or tolerable levels of the drug and the route by which it
should be taken.
The trial at Northwick Park Hospital was a phase I study.
· Phase 2 trials involve groups of 100–200 patients suffering
from the disease which the drug is being developed to treat. They
provide more evidence about activity and safety and are also used
to define the dosage and regimen for the medicine.
· Phase 3 trials are larger scale controlled trials designed to
assess the risks and benefits of the
treatment. Such trials involve 1,000–3,000 patients, sometimes
many more, and compare the
treatment under assessment with either a placebo or acomparator
drug.
· Phase 4 trials are those initiated after a medicine has been
launched and are designed to identify any undocumented adverse
effects. |
He does not believe that this is simply
because people did not know that there was money to be made, but there
were many other more altruistic
reasons that people might want to take part in trials, or they may simply
want more information.
This interest is likely to be a result of an increase in awareness, Professor
Smart believes. “Members of the public probably knew about phase
2 and 3 trials, but they may not have been aware of phase 1 trials, so
this will certainly have highlighted those to them,” he says.
Nirmala Bhogal, science manager at the Fund for the Replacement of Animals
in Medical Experiments, agrees. “This will have brought the issue
of the testing of medicines to people’s attention and they may
have
become much more aware of the testing medicines undergo in other species,” she
says. Such tests in non-human animals must be carried out before the
first tests in humans — phase I trials — can be carried out.
Phase I trials are regulated in the UK by Regulations incorporated the
EU Clinical Trials Directive into UK law in May 2004 (see Panel 2).
Panel 2: Trial regulations
The Medicines for Human Use (Clinical Trials) Regulations 2004,
which implemented the EU Clinical Trials Directive (Directive 2001/20/EC)
into UK law, came into force on 1 May 2004. These Regulations
replaced
the clinical trial provisions of the Medicines Act 1968 and were
designed to provide a statutory basis for the standardisation
of clinical trial procedures.
Robin Harman’s two-part series on international
harmonisation of clinical trials explains the regulatory environment in more
detail (PJ 14 August 2004, p224 and 21 August 2004, p260). |
These Regulations require sponsors of clinical trials to have a clinical
trial authorisation from the MHRA for phase 1 trials — previously
such trials only needed a favourable opinion of an ethics committee.
It was this clinical trial authorisation for the study at Northwick Park
that the MHRA withdrew last week.
Professor Smart believes that this present level of interest may be sustained
in the long term. “I think the numbers will probably remain higher
than before for standard trials of conventional drugs, but for trials
of biologicals there may be a problem, particularly if a trial is for
an agonist monoclonal antibody like the drug used in this trial,” he
says.
However, Dr Bhogal argues that people will now be more demanding about
the data they are given before they take part in trials. “Healthy
people will probably now be unwilling to volunteer unless they are given
more information,” she says. “Perhaps volunteers should be
shown all the available data and allowed to make their own judgements,” she
adds.
The events at Northwick Park are likely to affect not just volunteers
for clinical trials, but also to raise issues of the appropriateness
of conventional clinical trials to assess modern biological therapies,
Dr Bhogal believes. “For a traditional medicine, animal studies
would normally be used to find out the highest tolerable dose, but monoclonal
antibodies may not have an upper tolerable limit so the trial also raises
questions about whether present clinical trials guidelines are suited
to antibody-based therapeutics,” she says. “We may then have
to ask whether we are now trying to fit new therapeutics into an old
testing scheme.”
Saah Shakir, head of the Drug Safety Research Unit in Southampton, agrees
that current testing methods may no longer be appropriate for the new
therapeutics being developed. “I think we need to have a real think
about the trials that are done to test monoclonal antibodies and whether
the types of tests used for conventional medicines are suitable for drugs
like these,” he says. “That certainly raises a lot of questions
and will be an issue for long-term scientific enquiries. There may also
be changes to the regulatory processes, but those will take time to come
through.
“One of the most important things we can learn now, though, is that [as
a result of the six men being given the treatment at almost the same
time] we need to look at dosing patients sequentially rather than simultaneously.
That may involve a change of regulations,” he adds.
However, the impact of the events at Northwick Park will, in the end,
depend on what exactly went wrong, Professor Smart argues. “There
could be implications for how one assesses in future what tests are used
prior to phase 1 to ensure safety of biologics, and how the results are
analysed.” |
The
Pharmaceutical Journal