Examination of Witnesses (Questions 560-579)|
TUESDAY 11 MARCH 2003
560. The interaction between various vaccines.
A is all right on its own, B is all right on its own but A and
B together . . .
(Dr Miller) We certainly can investigate that with
the record linkage system. If you always have a group of vaccines
given together and there is no disparity where one is given on
its own, you can never sort that out. It is inherently confounded.
For instance, when HIB vaccine was introduced, there were yellow
card reports of convulsions after HIB vaccine. In many cases HIB
vaccine was given together with DTP vaccine but because sufficient
vaccines were given separately, DTP and HIB separately, we were
able to look at the HIB effect independently from the DTP effect.
There are statistical methods if you have enough vaccines which
are not given at the same time. Clearly you have to control for
age and some of the other confounders which may affect the relationship.
561. With respect to safety monitoring, is there
any problem that vaccine developers run into with respect to Animal
Liberation Front people, anti-vivisectionists, especially where
you have to do development work with primates? Is this a problem
or not a problem?
(Mr Kingston) For UVIG, I would say it is a continuing
issue. It is not hampering any development programme at this stage
and, along with all other bodies involved in this field, there
is a commitment to minimise the use of animal experiments. Nonetheless,
it is inevitable that some need to be done to get the medicines
and the vaccines we need. It is an added frustration of the business
we are in, but it is not hampering any development at this stage.
562. No company has gone over to North America
where things are a bit easier in development than here?
(Mr Kingston) I am not aware of any example in the
field of vaccines.
(Dr Chatfield) May I make one other comment on safety?
In terms of talking about monitoring post-licensing, we must not
forget the amount of effort which goes into the monitoring of
safety of vaccines before you get to licensure, as part of getting
the approval for that vaccine. Whenever a vaccine is licensedand
if the vaccine is going to be utilised in a general populationwe
are looking at a substantial safety database, in the tens of thousands,
to be able to get licensure of any particular vaccine. That comes
back to the fact that is an onerous requirement, certainly beyond
the realms of possibility for a company at our stage, but also
difficult for the larger companies in terms of getting those products
563. In the vaccine world we have broadly three
identifiable groups: we have those who do the R&D on vaccines
and the development, we have those who produce them and those
who license them. In some cases those are the same; sometimes
the R&D is done by the companies who do the production, but
how are the relations between those groups? Are they satisfactory
at the moment? Do you think there is scope for revisiting those
and possibly improving them?
(Mr Kingston) UVIG companies would like to emphasise
that they are integrated companies. All the vaccines which are
supplied in the UK currently come from companies which also have
research capabilities. It is not that they are produced by us
but researched by somebody else.
564. But not all research companies have production
(Mr Kingston) Correct. There are more upstream research
companies than production companies. When you are talking about
the companies involved, whether they are the big researchers and
producers or the small researchers, all of us have a common interest
in finding mutually profitable arrangements and collaborations
in R&D and licensing the intellectual property. I should say
at that stage, from my point of view certainly, information flows
well. The third party in the question is the regulatory agencies
who have to approve vaccines for use. In that case the dialogue
is getting better because if there is one thing to encourage vaccine
production and vaccine development, it is to reduce the level
of uncertainty involved at every stage. If we can have better
dialogue with the regulatory agencies so that it is understood
up front what studies need to be done and what questions are deemed
to be particularly sensitive, that is far better than doing your
clinical study on 20,000 or 40,000 subjects and then really struggling
to answer the question because you did not know about it in advance.
565. The UVIG position would be that you do
not have any major problems.
(Mr Kingston) Correct.
566. May I ask Dr Chatfield how he sees it from
the small company point of view?
(Dr Chatfield) I suppose from our perspective, we
are fairly dependent on the larger companies in terms of being
able to partner our vaccines and convince them that there is also
a market for those vaccines in order that development can continue.
We have already talked about the fact that the development costs
are substantial, so there is no way there would be a level of
funding for us to be able to take products as an R&D company
through the later stages of development.
567. Typically, how far does your company take
it? Phase 1 trials?
(Dr Chatfield) No; it is a very interesting area.
Trying to partner in a pre-clinical phase has very little value
with the bigger pharmaceutical companies, so you really do need
to take it to some form of clinical study, if possible efficacy,
if you can do that in the early clinical studies, such as the
phase 1, phase 2 arena. The more important part, to which I alluded
earlier, is that biotech companies have to develop it in a manner
which the bigger companies are then going to be able to take forward
without delay because the last thing the bigger company wants
to do is to have to go back and repeat work and take longer to
get to the market. That places quite an onerous requirement on
the smaller company to get it right at the early stages and vaccine
development is by no means just about clinical. There is a lot
underlying vaccine development in terms of the product development
prior to entering the clinic. There is a need to understand your
product at an early stage, to be able to characterise it, to develop
the appropriate assays, to develop the process and then control
that process and produce a product consistently. The unusual thing
about vaccines in terms of development, unlike small molecules,
is the process is actually considered very much part of the product
profile. If any of that changes, then potentially regulatory authorities
view it as a different product and work then has to be repeated.
Biotechnology companies find it onerous to step up to these types
of challenges. Of course vaccine development involves early interaction
with the regulatory authorities and the MCA is a particularly
good agency that we have in the UK. From a European perspective,
if you want to develop a vaccine, you do not actually get into
a position of involvement of all the individual Member States
as a centralised procedure until much later in the process ie
submission of a marketing authorisation. This raises some difficulties
for UK companies in terms of vaccine R&D because you really
have to be starting to think about introducing the product concept
by going to talk to other European agencies separately from talking
to the MCA because at the end these agencies will be involved
in the review through the CPMP. You have to make sure quite early
on that you are talking to the other agencies so that they understand
the concept. That is quite onerous for a small company to spend
that amount of time going round talking to the individual agencies.
For this reason, we as a company have decided with our first product
that we would go to the USFDA. The advantage there is that you
have a one-stop shop in terms of a single regulatory agency which
is going to deal (in a major market) with the product development
through to licensure. There is the Clinical Trials Directive which
is going to be implemented throughout Europe in the next year
or so, which is going to put more onerous requirements on vaccine
R&D within the UK, particularly more at the research level
in terms of what is expected, on the manufacturing side (GMP requirements)
and also the way that clinical studies are going to be conducted.
One of the most promising areas for vaccine development is new
live attenuated vaccines; the concept being that live vaccines
are very good vaccines. There is a whole new raft of technology
which allows the development of organisms which are genetically
modified to provide new attenuated, safe, immunogenic vaccines.
In Europe, there is now a directive whereby you have to apply
to the local authority, and in the UK it is DEFRA, to get deliberate
release of these genetically modified organisms in order to be
able to do your early clinical studies. Clearly these types of
vaccines shed. Obtaining approval for deliberate release is proving
quite an onerous task for companies such as us, because we not
only have to deal with the MCA, the ethics review, but now another
body which is also to some extent also reviewing the safety of
vaccines. We need to simplify the procedures and get a better
understanding of what each of these respective groups is doing.
568. That is very useful. Certainly I had not
realised that DEFRA was involved in this. I am a little surprised.
(Dr Chatfield) In terms of DEFRA, it is like another
regulatory submission, as large as the one we have submitted to
the MCA or the FDA. In the US this deliberate release application
is not necessary. It is handled by the FDA.
569. A short while ago we were in the USA and
we visited NIH and their section on allergies and infectious diseases.
There we learned that they have a scheme of small business grants
to help develop people almost at the practical level of development.
Is there anything like that in this country from central government,
either the Medical Research Council or a government department?
(Dr Chatfield) From the Medical Research Council and
the BBSRC most of those are aimed at research-based projects.
DTI, if I am correct, do provide much bigger grants, as much as
anything, to try to put in some infrastructure which may be useful
in terms of vaccine development. Certainly not to the same level
as the small business grants you can get in the US which are fairly
easy to get hold of for some of the smaller biotech companies
and our competitors are able to get hold of those sorts of grants
in the US. Because we are not a US based company, we do not have
access to those and that gives them an advantage.
570. You say they are a good thing.
(Dr Chatfield) Yes, they are a good thing. From what
I understand about those small business grants, they do not come
with too many strings attached. There are other forms of funding
in the UK through the EU for instance. There are large framework
grants, the fifth and sixth frameworks. They have been ongoing
for some time. Those are now becoming available in order to be
able to do proof of principle clinical studies, but they do come
with strings in terms of the amount of time and effort it takes
you to be part of a consortium and work with a group on this.
That is not something we as a company have pushed very hard on
Chairman: With NIH, as you hinted, these grants were
meant to obviate the need to put in a massive grant application
and go through the extended process of review and get things moving
for the small businesses, small biotech companies. The reports
we had when we were there were that they were working very well.
571. This question is about what government
should do with its money. One of the things you described is small
business grants, which certainly sound potentially valuable. How
many companies are there like yours in this sort of business in
(Dr Chatfield) In the UK there are probably no more
than five or six.
572. Related to that, another use for government
money is to fund and run a vaccine centre specialising in the
rapid development and so on of vaccines. Should we be pressing
the government to do this?
(Dr Chatfield) My personal view is no. What we really
need to do is to try to provide the appropriate environment which
is going to allow the existing industry expertise and infrastructure
and to be able to use that in developing new vaccines. I would
say that we would be better off trying to fund the existing groups
and infrastructure in the UK rather than setting up something
separate in order to do that.
573. That would mean supporting small businesses
such as yours.
(Dr Chatfield) My personal view is that would be the
better route than trying to set up another organisation. It would
have to be fairly substantial in terms of the onerous requirements
of getting your product not only into clinical development, but
addressing all the things you need to do up front in terms of
the product development.
(Dr Miller) I very much endorse that view. We are
at a stage where we really need innovative research to bring the
next generation of vaccines to licensure. That must be with support
where that innovation is rather than building an institution and
hoping that everything will come together. It has certainly been
tried in other countries and has not really delivered the goods.
These institutes have ended up subcontracting to produce a standard
vaccine like MMR or DTP. They also run into problems where they
have combinations. They cannot produce the whole range of antigens
required to be put into one vaccine. I definitely endorse the
view of needing to promote where the research innovation is. The
difficulty is getting that first batch to go to GMP standard and
going into the first few human subjects. I am not sure whether
or not a facility that could promote that, that could take product
to GMP and could organise the first clinical trials, or at least
advise on it, may be a government funded facility that may assist.
I do not know.
(Mr Kingston) For UVIG again the answer to this question
is no. We would say that we have a gold standard example in the
UK of the meningitis C development campaign, which we have already
referred to, about what all the stakeholders can produce when
the conditions are right. Our perspective would be very much that
if we get the proactive approach from the Department of Health
and its agencies about what is required, a consistent message
and a definitive set of requirements, working with whichever companies
are suitable, we have the stakeholders, we have the expertise
to do a very high quality vaccine campaign from which the public
is already benefiting.
574. The answer is to put the money specifically
into areas which exist but which are underfunded, under-resourced
and could do better and rationalise the regulatory framework so
you do not have to go to a dozen different bodies. Is that the
answer? It is a reasonable answer. I am just wanting to check
that is what you want.
(Mr Kingston) I would add a third strand to that,
which would be that the more consistency and the more definition
about what is actually required and what would be paid for will
create greater confidence and create more private money coming
towards the problem as well.
575. One of the criteria in this particular
question is rapid development of a vaccine. Can your organisation,
UVIG, respond rapidly with several million vaccine doses against
an emergency situation?
(Mr Kingston) If we are talking about actual capacity
to produce and supply significantly more vaccines in an emergency,
the limitations to the industry's ability to deliver are the sheer
capacity of the manufacturing facilities and the absolute minimum
length of time required to make a vaccine. Generally speaking,
we would have difficulty in producing many multiple times the
current demand very quickly, either because the factories are
not big enough, or you are in a situation where, if you take the
annual influenza vaccine, the master seeds, the production process,
starts normally in April, very, very rapid, everything has to
go right to get a supply in August which is then approved and
released into the market in September. That is not atypical. Whatever
you want, if we have not started already, it is very, very hard
to get anything in less than six months.
576. May I ask a very ignorant question? How
generic are our vaccine production facilities? In other words,
imagine that there became a need very quickly for vaccine, one
could say smallpox or something of that kind. Let us say you were
gearing up for an annual production of flu vaccines but it was
agreed nationally that although flu vaccine was a good thing,
it was much more important this other vaccine be developed. How
feasible is it actually to shift with using the same facilities,
from one vaccine to another?
(Mr Kingston) Not easy. In that specific example,
because the actual active ingredient in the flu vaccine is grown
in a completely different way to the way the Listerstrain would
be grown in smallpox, the fact you have a flu capacity is irrelevant.
577. Not much help. But might there be groups
of vaccines which were similar?
(Mr Kingston) Yes.
578. In terms of emergency production, what
other organisations in your opinion should be able to respond?
Would CAMR be one of them, would the Jenner Institute be one of
them or are there others? Even though they may not be able to
do it at present, should they be given the capability of responding
to some of our threats?
(Mr Kingston) Any organisation is going to have to
overcome the time lag barrier to a real swift emergency response.
To some extent you could do that if there were any of the upstream
phases you could do and then deep freeze and then release. Sometimes
you can do that, sometimes you cannot, it depends on the vaccine.
Generally speaking, if we are moving on to a flu pandemic topic,
a very practical way to get closer to what is needed here would
be to find a way of increasing the regular medical demand for
vaccines in a non-pandemic year. That would get the recurring
production capacity closer to what might be required in a pandemic
Baroness Finlay of Llandaff
579. You may feel you have already partly answered
my question but who do you think should take the lead in promoting
the benefits of vaccines?
(Mr Kingston) We do have a view on that one and I
am afraid it is a multipart answer. We live in an age where the
public cynicism is quite high, whatever message is delivered by
whatever party. We should say that an awful lot of people, stakeholders,
in the entire field of public health and in giving vaccines, need
to be encouraged to recognise their potential to disseminate positive
messages. There probably does not need to be a huge amount of
co-ordination and an overly high amount of co-ordination may even
backfire if it is perceived to be a co-ordinated campaign. Whether
it is the primary care groups, the agencies, the Department of
Health, the industry, we think there are gains to be had in realising
what each can do to inform public debate. There are gains to be
had in sharing our positions and we have had some good experience
in the past year with the Department of Health where we have just
said to their press office what our position was, what we were
trying to do and asked whether they could reciprocate. Very simple
things can be very useful. Ultimately, if you ask who should lead
this, we would say that it falls to the people who are setting
the policy and paying for it, which comes back to the Department
of Health, but leadership means co-ordinating a number of diverse
stakeholders who need to be giving roughly co-ordinated but at
the same time independent messages hopefully to boost public confidence.