Select Committee on Science and Technology Minutes of Evidence


Examination of Witnesses (Questions 560-579)

DR STEVE CHATFIELD, MR IAN KINGSTON AND DR LIZ MILLER

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.

Chairman

  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 licensed—and if the vaccine is going to be utilised in a general population—we 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 approved.

Lord Oxburgh

  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 facilities.
  (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.

Chairman

  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 so far.

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.

Lord Turnberg

  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 the UK?
  (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.

Chairman

  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.

Lord Oxburgh

  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.

Chairman

  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 year.

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.


 
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