British Oncology Pharmacy Association
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Participants at a recent meeting on cancer care heard presentations on cancer care improvements, clinical trial developments and advances
in the discovery of new drugs for cancer treatment. Tim Root reports
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A joint meeting of the Royal Pharmaceutical Society’s
Industrial Pharmacists Groups and the British Oncology Pharmacy
Association took place at the Royal Pharmaceutical Society’s
London headquarters on 18 February
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Latest developments in cancer care
Opening the meeting, Jamie Ferguson, consultant in public health, Lambeth
Primary Care Trust, described the development of cancer commissioning
and the concept of managed clinical networks in the South East London
Cancer Research Network over the past three years. PCTs, he explained,
were still finding their feet and this was perhaps a less-than-ideal
environment for the concurrent development of managed clinical networks.
Outlining the funding of the NHS cancer plan over the period 2002 to
2005, he reported that Department of Health figures showed that more
than 90 per cent of the total allocation of £520m had been spent
as intended on cancer services. Of this, approximately 40 per cent had
been spent on drugs although there was a wide variation of between 20
and 70 per cent for individual PCTs.
Dr Ferguson also explained that cancer commissioning and funding developments
had to be viewed in the context of competing priorities and a “funding
hierarchy”. In Lambeth for 2004–05, for example, the top
priority, “must do”, generic cost pressures such as salaries,
implementation of National Institute of Clinical Excellence recommendations,
meeting national targets and forward commitments left only a maximum
of £4m for allocation against all other bids which totalled approximately £25m.
New drugs represent a major cost pressure and will continue to do so.
He said that the massive growth in the number of anti-cancer drugs seen
in the past 10 years was set to continue and estimated that there were
over 400 new anti-cancer drugs in the clinical trial pipeline. Affordability
is therefore a major issue.
Discussing the future and the impact of the new GP contract, he raised
the possibility that the private sector could become involved in commissioning.
Other national initiatives such as the choice and diversity agenda and
payment by results would also have a major impact. Commenting on the
latter, Dr Ferguson referred to the difficulty and complexity of developing
health resource groups for chemotherapy and the fact that the limited
work which had been completed so far was already out of date and was
now being reviewed.
In conclusion he said that improvements in cancer care have greatly increased
the likelihood of cure for many cancers and increased survival even for
some of those which remain incurable. This raised the question of whether
we should target resources preferentially towards potentially curable
treatments. In this connection Dr Ferguson referred to the work of the
London Cancer New Drugs Group (LCNDG) but pointed out that it was inevitably
confined to an advisory and facilitative role and that affordability
must be considered at local level. The work of the LCNDC
Adrian Newland, chairman of the LCNDG and director of the North East
London Cancer Research network, described the work of the group, which
he believed was unique in the NHS. He suggested that it was a successful
model on which a national group might be based and through which a “national
cancer formulary” might be developed. Key objectives would be
to facilitate consistency of interpretation and implementation of NICE
guidance, to produce national guidance on the many drugs which were
never likely to reach the NICE agenda but which nonetheless were believed
to have a significant role to play, and to manage the issue of NICE-blight,
ie, the period between licensing of new drugs and publication of advice
by NICE. He also proposed a role in horizon scanning and informing
the NICE agenda, to ensure consensus about priorities and optimise
dissemination of NICE guidance.
He commented that it would be important for any such group to clarify
and gain acceptance of the status of its advice, for which there must
also be an effective means of dissemination.
There was also a need to define relationships and gain support as well
as to influence the National Cancer Research Nework trials portfolio
and to include supportive care drugs within in the remit. He pointed
out that it had to be accepted that the NICE process could achieve only
so much. The current NICE pipeline included only seven anti-cancer drugs
which represented a tiny proportion of those likely to emerge from the
trials pipeline in the next few years.
Developments in areas of clinical trials and ethics committees
Changes to the law covering clinical trials are imminent, said Elaine
Godfrey, from the clinical trials unit of the Medicines and Healthcare
products Regulatory Agency. She discussed the impact of implementation
from 1 May of the European Clinical Trials Directive. She explained
that the directive’s prime objective was protection of all trial
participants, including healthy volunteers, as well as ensuring the
credibility of trial data. Both of these were politically important.
Trials of medical devices and surgery are excluded.
The deadline for implementation of the directive is 1 May 2004 but
in common with many other EU states, the UK is struggling to achieve
full
implementation by this date. The directive makes few fundamental changes
to existing UK legislation but does, for the first time, impose requirements
for monitoring of all aspects of trial conduct. The current process for
approval of new studies is replaced by a single clinical trial authorisation.
Explanatory letters are going out to all current holders of trial authorisations.
New application under the current system of will be accepted until 13
April and no applications under the EC directive will be determined before
1 May. All queries about the implementation process should be emailed
to clinicaltrialhelpline@mhra.gsi.gov.uk and
supporting information on the MHRA website will be regularly updated.
Ms Godfrey said that the directive
on good clinical practice is causing the most difficulty and is yet to
be published. Other key changes are that the manufacture and import of “investigational
medicinal products” will be licensable and commercial and non-commercial
studies will be subject to the same standards and controls throughout. Future of research ethics committees
Terry Stacey, director of the Central Office for Research Ethics (COREC)
discussed the future of ethics committees. His first point was that
under the new directive, research ethics committees (RECs) will become
legal entities with responsibilities and liabilities in criminal law.
The principal requirements of the directive are that a single ethics
approval only is required for the entire UK, that a committee must deliver
a decision on a valid application within 60 days of receiving it and
is restricted to one written request for clarification or further information
(although the clock stops while the response is awaited). All RECs will
have to be formally recognised for the purpose of reviewing trials for
investigational medicinal products. In the UK, RECs will have to work
to written standard operating procedures (SOPs), will be subject to a
quality assruance mechanism and will be accountable to the UK Ethics
Committee Authority.
There remains the challenge of trying to develop a means of auditing
REC decisions said Dr Stacey. While it may be argued that there are no
right questions which the audit might ask, there are certainly some right
answers which must be sought, he said. Non-recognised committees will
still be permitted to review applications for trials of all other health-related
research not involving medicinal products which form the majority of
the work of most committees.
Further information can be found at www.corec.org.uk
Advances in new drug discovery
The start of the 21st century is an exciting time as an era of structured
drug development, according to Herbie Newell, of the Northern Institute
for Cancer Research in Newcastle. Historically, most drug development
has been derived from serendipity: a molecule, perhaps identified from
random screening programme for potential therapeutic activity but quite
possibly being developed for an entirely non-medical application, was
identified as having potential therapeutic applications and a target
for the drug was then sought. The nitrogen mustards, methotrexate, anthracyclines,
platinum, vinka alkaloids and taxanes were all developed in this way.
New approach
The new approach starts with genomic or proteomic analysis of human tumour
tissue and the identification of specific molecular structures and
process which appear to be linked directly to the process of tumour
growth and development. Chemists can then attempt to design molecules
to interact in a desired way with these targets or receptor molecules
and processes. Molecular pathology targets identified include growth
factor antagonists, receptor kinase inhibitors, second messenger inhibitors
and transcription inhibitors. Drugs recently developed to interact
with these mechanisms include imatinib (Glivec), gefitinib (Iressa)
and trastuzumab (Herceptin).
Cellular pathology had identified as potential targets process such as
local invasion surrounding tissues and distant spread (metastasis) of
tumour cells and angiogenesis, the development of blood supply by a growing
solid tumour. Developments in this field were looking promising.
Professor Newell summarised by saying that said that the aim of modern
anticancer drug development was new agents with greater activity and
far greater selectivity for malignant cell lines than conventional cytotoxic
drugs and that the future for this lay with the new development techniques
and in immunotherapy, gene therapy and chemo-prevention of cancer.
The same themes were continued by Jeff Evans, of the University of Glasgow,
who looked in greater depth at the development pipeline for signal transduction
inhibitors. Professor Evans explained that most neoplasms showed evidence
of aberrant cell signalling pathways and that some mutant signal transduction
proteins appeared to act as oncogenes leading to increased cell proliferation,
sustained angiogenesis, tumour cell metastasis and tissue invasion or
inhibition of apoptosis (programmed natural cell death).
He commented on some of the problems of developing signal transduction
inhibitors (STIs): they may not lead to a rapid and measurable tumour
response, the maximum tolerated dose may not be related to the biologically
effective dose and it was difficult to decide how to define prospectively
the optimum dose schedule and duration of treatment, since this is a
group of drugs whose real potential may lie in the opportunity of chronic
treatment with the objective of controlling or stopping the development
of tumours rather than eliminating or killing them altogether. It was,
therefore, necessary to develop more innovative methods of assessing
efficacy, such as use of metabolic imaging and of biological endpoints.
As an example, he quoted gefitinib (Iressa), which had shown activity
as a single agent in early studies in lung cancer but had shown no benefit
in comparative phase III studies; could this be due to inappropriate
patient selection, use of drug combinations derived empirically rather
than mechanistically or underpowered studies or inappropriate trial design?
The mechanisms the possible development resistance to this group of drugs
had also yet to be fully elucidated.
Anti-angiogenic agents show promise
The potential of anti-angiogenic agents for treatment of cancer was
first identified in 1971, explained Rod Murphey, clinical lecturer, Novartis
Oncology.
Using anti-angiogenic agents to treat cancer requires tumour suppression
of angiogenesis while normal physiological angiogenesis is maintained.
Targets for these agents included processes and molecules involved with
blood vessel formation such as endothelial cell proliferation and metallomatrix
proteins (MMP).
Targeting genetically stable cells may help to avoid development of resistance.
Among drugs of this type currently under development are bevacisumab
(Avastin) and neovastat (derived from shark cartilage). Indirect inhibitors
of angiogenesis include gefitinib (Iressa), cetuximab (Erbitux) and vatalanib.
Dr Murphey also noted that the bisphosphonates, many of which are in
common use for treatment of hypercalcaemia, osteoporosis and bone pain
have also been found to be have potent antiangiogenic activity.
Dr Murphey concluded by saying that after a disappointing start, the
development of anti-angiogenic agents now held great promise for the
treatment of cancer in future and that the current wave of renewed interest
in the field, coupled with improved trial design, innovative methods
of assessing responses to treatment and the support of regulatory authorities
would yield major benefits for patients.
Advantages of radioimmunotherapy
Radioimmunotherapy, the use of isotopes such as yttrium-90 or iodine-131
combined with a targeting mono-clonal antibody molecule, was the subject
of a talk by Richard Begent, Royal Free and University College Medical
School. Key issues were delivery to the tumour, mechanism of action and
therapeutic effect. Delivery to the tumour is primarily a function of
antibody molecular size and receptor whereas its radius determines the
rate of clearance from the tumour site and body. Specificity determines
its tumour selectivity; affinity and dose determines its uptake by tumour
tissue and retention and concentration at the tumour site.
Delivery to the tumour is also dependent on tumour vascularisation. Delivery
of these and other agents to the vasculature to inhibit further tumour
development to poorly vascularised areas of tumour posed a challenge.
Vascular cells present an attractive target, he said. They are present
in most solid tumours, are accessible, drug-sensitive, and represent
a vulnerable, rapidly dividing epithelial cell population.
In conclusion, Professor Begent said that apart from having demonstrated
good efficacy in B-cell lymphomas, radioimmunotherapy looked promising
for treatment of epithelial malignancies.
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