Examination of Witnesses (Questions 240-259)
Professor Tak Lee, Dr Diana Dunstan, Mr Dave Allen
and Professor John Westwick
18 DECEMBER 2006
Q240Lord Taverne: I want to ask you about Sir
David Cooksey's recent review. They recommended that: "greater
priority should be given to supporting medicines and therapies
that tackle unmet health needs in the UK". They recommended
that the Government should set up a new Office for Strategic Co-ordination
of Health Research. Do you think that this approach will overcome
the difficulties which are currently experienced in allergy funding?
They also recommend that the Department of Health should review
the impact of diseases and illnesses to determine the health priorities.
Do you think that will help to establish allergy as one of the
health priorities in the UK?
Dr Dunstan: We welcome the proposals in the
Cooksey report and certainly they will put a major emphasis on
collaboration between the money that is spent through the health
departments on R&D and the MRC. Also they will put a major
emphasis on translation and exactly how that will work out I am
not sure. One of the things they have asked the overarching body
to do is to make sure that unmet needs are met. When UK Clinical
Research Collaboration looked at areas that they have considered
were under-funded in relation to morbidity, respiratory disease,
of which asthma as a part was one and colitis was another, and
I think there is some inflammatory work and allergy related to
that, so they may well fall into the categories of unmet need
that we shall have to direct more attention to.
Professor Lee: Let me add to that. I think it
is absolutely crucial that we do try to estimate the burden of
the disease and unmet need in allergy. I do not underestimate
at all the real difficulty in capturing that information because
at the moment in the Health Service we do not have a structure
that allows us to collect that information. When you look at that
burden and unmet need you have to take into consideration not
only the very few people who find their way to allergy centres
but we also have to take into account the other patients in dermatology
clinics, respiratory clinics and so on. When trying to understand
unmet need you also have to take into considerations estimates
of the holistic patient, not just in that specialty. Whilst I
very, very strongly support the idea that we should do this, I
think collecting the information would be very, very difficult
but necessary. Probably some resource will need to be put into
that to allow that to happen. That is my first point. The second
point is even if you have the resource to do that, methodology
will have to be developed because although we have methodology
for assessing asthma the suite of methodologies for assessing
angio oedema, for example, and other allergic diseases away from
asthma are not very well developed and they may have to be developed
to really understand this problem in the wider context. UKCRC,
that has already been referred to, in respiratory medicine has
been a very big driver in understanding the funding just does
not match the disability, morbidity and mortality of the disease.
We all suspect, and there is evidence, that allergy is in exactly
the same position but allergy is not just respiratory, it is only
the tip of the iceberg when you think about asthma.
Q241 Lord Taverne: You say there
are a lot of difficulties about it but do you agree that a new
strategic framework, as they suggest, the Office for Strategic
Co-ordination of Health Research, would help to face these problems?
Professor Lee: Absolutely. I am very strongly
supportive of that, and I am very strongly supportive of the other
recommendation of the Cooksey review which states that the amount
of productivity and the excellence of the research coming from
the funding of basic fundamental science is of such quality that
that has to be at least sustained, and any new money should go
more towards the translation of clinical aspects. Certainly hearing
from the UKCRC analysis, the vast majority of funding from Government
bodies—MRC; BBSRC Wellcome Trust; Asthma UK and so on—tends
to be more towards the fundamental methodological continuum of
the research spectrum, and we need to do more now to translate
those findings into the patient and into the community.
Q242 Lord Taverne: Should they consider
allergy as a single health issue or would it be more suitable
to consider the health priorities of the various different disorders?
Professor Lee: No, I think we should consider
allergy as a disease grouping because many patients with allergic
problems present with multi-system disease and that, in a sense,
is one of the rationales for establishing a service which allows
a one-stop-shop. I agree with the previous conversation in the
last session where allergists also have to contribute towards
looking after severe asthma in a contributory capacity but allergy
as a specialty has a very major role to play.
Q243 Baroness Platt of Writtle: There
are certain areas of research which may not necessarily have a
precise answer or profitable outcome but, nevertheless, are of
considerable long-term importance. For example, we are still not
able to provide reliable nutritional advice to pregnant women
or young children to prevent allergic disorders. Where should
the funding come from to research areas such as these?
Dr Dunstan: I think the research councils and
the charities have a significant role to play. I guess in some
of the cases you mentioned we are back to long-term studies with
cohorts again. We are doing that, and we are getting partnership
funding for those: ALSPAC, Southampton Women's Survey. For environmental
allergies, I suppose the UK Biobank, which is looking at a more
elderly population, middle aged onwards, will also provide information.
I know, for example, in Professor Lee's centre there are studies
going on about whether children at a high risk of allergies should
be exposed to peanuts or whatever, and we are currently discussing
with the Food Standards Agency whether we can jointly fund a study
on early weaning. I think these kinds of studies should give some
of the answers that your questioner needs.
Professor Lee: I very much support that view.
I think, as I said already, partnership is going to be the answer
in the future, but I also feel there is a role to play in some
of the really big questions which will involve very large cohorts
and will be very expensive to adopt a more iterative approach
to arriving at protocols and arriving at a way forward. I think
for very good reasons much of the funding strategy is a competitive
one and you do obtain very, very good applications of exceptional
quality because of that. We all have to go through that system.
There are major opportunities in the future to work together in
partnership in long-term studies on major questions which will
impact on healthcare where the development of a programme of work
on an iterative basis may be a better way forward. Certainly from
our own perspective, a few years ago we worked very closely with
MRC to develop an iterative programme to look at the safety of
salbutamol in asthma. It took us a long time to arrive at that
programme but we did arrive at that programme and we did the study
which was very informative and was published in a very high impact
journal and is often used as one of the major studies in this
area. I think it can work and we should do more of it.
Q244 Chairman: How much is that iterative
process involving the patient population who have the allergic
manifestation?
Professor Lee: I think the answer is more and
more. Certainly in one of the consultations we have just finished
and published, Basic Asthma Research Strategy, and also the one
on Clinical Asthma Research Strategy, lay people were involved.
In fact, in February there is a conference at the Royal Society
of Medicine which I am chairing for lay people. We will be discussing
our Basic Asthma Research Strategy with them in depth.
Q245 Chairman: Dr Dunstan, can you
tell us how much the MRC will interact with the GA2 LEN centres?
Dr Dunstan: Sorry, with whom?
Q246 Chairman: With the GA2 LEN centres.
Dr Dunstan: I am not sure what the GA2 LEN centres
are.
Professor Lee The European framework.
Dr Dunstan: We interact with European funding
quite a lot, whether we interact specifically with these or not,
I do not know. We are doing quite a lot of work on quality of
life across a variety of diseases on those issues.
Q247 Baroness Platt of Writtle: What
about research into other lifestyle issues, such as the impact
of pollution on allergic disease? Who is carrying out research
into that?
Dr Dunstan: I think pollution may be one of
the issues which comes out of the UK Biobank study and other long-term
cohorts. It is fair to say that the research councils, NERC, ESRC
and MRC, are looking again under a broad heading at what we call
"environmental health" and pollution will form a part
of that. It will be one of the bids which goes forward jointly
from the research councils into the spending review this time.
Mr Allen: Of course environmental triggers are
one of the things which attract a lot of research at a basic scientific
level, things like ozone and particulate matter that will trigger
asthma responses do feature very largely in academic research.
Q248 Baroness Platt of Writtle: Are
your commercial companies involved in that?
Mr Allen: Insofar as we are trying to understand
the response to these allergic triggers, then certainly we are,
yes.
Q249 Viscount Simon: As allergic
diseases involve many different genes and exhibit considerable
phenotypic variation, what steps are being taken to develop more
individualised treatments? Secondly, what research is being undertaken
to understand the factors which determine an individual's susceptibility
to allergic disease?
Mr Allen: From a GSK perspective, we have the
objective of taking, with the patient's consent, blood samples
from every single patient who is involved in a GSK research and
development organised clinical trial, with the objective of genotyping
(subject to clinical trial outcomes) that patient so that we can
subsequently look at how that genotype has reacted to the treatment
and the outcome, both from a safety and efficacy point of view.
That is ultimately the goal. We have a very high percentage (60
per cent) of those samples taken now so we can go back and ask
very careful questions about how certain patients have reacted
to the drug that is in the clinical trial in relation to genotype.
The other thing we need to recognise is there is a huge phenotypic
variation within the allergic diseases. We have heard about severe
asthma patients who do not respond well to steroids, who would
have a difference response, and we need to understand the clinical
phenotypes within each of the diseases as well as between the
diseases. We can only do that by good translational medicine work,
by long-term clinical studies, but also by phenotyping these patients
very carefully so that we can start to understand their disease
long before we can start to attempt to cure it or even modify
it.
Professor Westwick: It is very similar studies
that have been going on in Novartis as well. Again, we like to
identify the phenotype and the genotype. Indeed, a number of papers
have been published in the last four years which were thought
to identify the genes responsible for asthma, but on reproduction
elsewhere that does not seem to be the case. To say that we know
the genetic basis of asthma right now is probably wrong but we
may get to it. The second part of your question, can we modify
the environment so that the allergic responses are removed, goes
back to the first thing I was talking about where we and many
others believe that how the specialised dendritic cells within
the airways respond to the environment in the presence of a specific
antigen and various T-cells is the key to regulating that. For
that reason, we and others have developed agents which modify
particular receptors on these dentritic cells to deviate the response
away from our allergic mechanism.
Q250 Lord Colwyn: Are there any populations
of individuals anywhere in this country or elsewhere who are particularly
susceptible to allergic disorder through inbreeding and inter-marriage?
Professor Westwick: Indeed, that is where the
genetic basis of asthma came from, from these inbred populations.
The problem is when you move to wider populations it does not
seem to hold true in terms of the identity of the gene which was
found in those studies.
Professor Lee: This is an incredibly important
area and it is also an area where I think collaborations between
the universities, academia and industry should flourish because
industry does so many pharmaceutical trials. They have a readout
in a very detailed and well designed way of the responsiveness
of individuals to certain drugs. We know that the distribution
and response to drugs follow a certain pattern and some respond
very well, others do not. To be able to have all the blood samples
genotyped and be able to link that to treatment responsiveness
is very, very powerful. That has been used, especially in the
United States, to look at a number of different questions, including
the efficiency and safety of beta-agonists, for example. I
think the pharmacogenetics effort, which is what this is, at the
NIH is probably very strong as a result of this sort of collaboration
and probably more advanced than what we have in this country.
This is not just an academic question because the regulatory authorities
in the future will demand to have this sort of information when
you are registering your drugs and that is a very powerful driver
to do this sort of work.
Professor Westwick: I would agree with what
Professor Tak Lee was saying, but one has to keep in mind that
most of the studies in asthma and allergy have shown that these
are polygenetic diseases, they are not monogenetic, like cystic
fibrosis. It is a very complicated sector involving a number of
genes as well as an environmental influence.
Q251 Chairman: Who is responsible
for publishing negative results?
Mr Allen: The results of all clinical trials
have to be published.[2]
Whenever possible, public disclosure is via publication
in scientific peer-reviewed publications. In addition, GSK provides
clinical trial results via the GSK Clinical Trial Register [http://ctr.gsk.co.uk/welcome.asp].
Here, GSK provides the results of all trials (phase I-IV) of marketed
prescription medicines and vaccines. GSK will also post trial
results of investigational medicines and vaccines that do not
make it to market when relevant to patient care (eg, when related
to an important safety issue).
Q252Chairman: There may be some analyses though
that can be done which fall outside the main trial protocol. How
much freedom do researchers have to proceed and publish those
when they are in a drug company funded study?
Professor Westwick: I think most academic and
clinical centres worth their salt will not get into an agreement
with a pharmaceutical company unless they can publish the work
they are doing.
Q253 Lord Taverne: What is the panel's
view of what currently are the most important areas of research,
and who is undertaking these?
Mr Allen: How long have you got!
Professor Lee: Let me start because I am going
to give you an answer which will seem a little vague but, nevertheless,
I want to refer you to four documents and that is really my answer
because we have been through this in some detail and they have
been submitted to you in written form. First of all, the most
recently published document on Basic Asthma Research Strategy,
which we lovingly call BARS Version II, was published only a few
months ago. That sets out a number of priority areas with key
questions which we feel we should answer in the asthma area. It
is multi-professional involving many funding bodies in that consultation.
Then about two or three years ago there was a similar consultation
on Clinical Asthma Research Strategy which has already been published.
Some of the issues raised within that consultation are part of
the Health Technology Assessment exercise and have been funded
to some extent by the Department of Health, so, again, that is
already in the public domain. The third is a letter which Professor
Durham wrote to you as part of his written submission on what
the British Society of Allergy and Clinical Immunology believes
the research priorities should be.
Q254 Lord Taverne: This is the one
we have got, is it?
Professor Lee: Yes, that is the one you have.
Q255 Lord Taverne: The recent one,
British Society of Allergy and Clinical Immunology?
Professor Lee: Yes, so you have that information.
The fourth document I will refer you to is a document published
by the Department of Health entitled, "A Review of Services
for Allergy: The Epidemiology, demand for and provision of treatment
and effectiveness of clinical interventions". That review,
apart from many things, covered and highlighted parts of the research
evidence from the health service point of view.
Q256 Lord Taverne: Is that the document
of which Professor Durham and Professor Frew said: "It gives
no grounds for optimism"?
Professor Lee: That is correct, that is it.
They were referring to the development of the health service framework
and health service delivery, but the issues which that document
raised about health services' research required to provide the
information base to develop future strategy I think are very intuitive.
In my answer I will refer you to those four documents, if I may.
Q257 Chairman: Can I go back slightly
to the previous question. If each company has very rich data on
genotype and phenotype, is there a move to produce a pooled Disease
Registry so that all this information can be shared and avoid
duplication and also allow further research projects to be built
on the information which is held?
Mr Allen: I have to be careful because I am
not expert in this sort of area. I do know that a very important
consideration is the consent given by patients when they are involved
in a clinical trial. You have to be very, very explicit about
what the samples would be used for, who would have access to them,
and to what purpose they would be put. Research undertaken is
restricted by the scope of the written consent. It is a very important
part of any governance of clinical trials. The only thing I would
be cautious about is we must therefore only do with these samples
exactly what we have told the patients we will do with them but,
of course, the sharing of information and collaborating with all
of this information is in everybody's interest.
Q258 Chairman: Of course you cannot
do anything with the samples you have got other than what the
consent has permitted, but I was wondering whether there are moves
to establish a pooled Disease Registry with consent in future
studies then ensuring that those patients could be involved and
registered on a central Disease Registry rather than each centre
having its own much smaller cohort of patients?
Professor Westwick: The requirement of published
clinical trials and to register that should provide that information
for everyone to look at, whether it be another pharmaceutical
company or not. I think you are going one stage further where
all basic information that is generated, which may not be generated
from clinical trials but from some sort of analysis of databases
which are either in the public domain or the private domain, that
comes out of that is going to be publicly shared. I do not think
we are there yet.
Q259 Chairman: Professor Lee, have
you got any comments?
Professor Lee: No, except that if that database
was available it would be extremely useful.
2 GSK publicly discloses the results of GSK-sponsored
clinical trials that are relevant for patient care irrespective
of whether the results are positive or negative for GSK prescription
medicines or vaccines. Back
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