Science and Technology Committee
Oral evidence: Blood, tissue and organ screening, HC 990
Wednesday 5 March 2014
Ordered by the House of Commons to be published on 5 March 2014.
Written evidence from witnesses:
– DuPont Chemicals and Fluoroproducts
Members present: Andrew Miller (Chair); Jim Dowd; David Heath; Stephen Metcalfe; David Morris; Stephen Mosley; Pamela Nash; Sarah Newton; Graham Stringer; David Tredinnick
Questions 67-144
Witnesses: Professor John Collinge, Director, MRC Prion Unit and Professor of Neurology at the UCL Institute of Neurology, Dr Steven Burton, Chief Executive, ProMetic Biosciences Ltd, Dr Kelly Board, Technical Specialist, DuPont Chemicals and Fluoroproducts, Dr Alex Raeber, Head of Research and Development, Prionics AG, and Nigel Talboys, Global Director of Blood Safety and EMEA Director of Public Policy and Government Affairs, Terumo BCT, gave evidence.
Q67 Chair: Can I welcome the witnesses to this morning’s session? We want to start off by trying to get a better understanding of the level of investment in prion-related technologies and the extent to which this has been taken up by the NHS. Perhaps we can start off by going down the line and inviting you all, first of all, to introduce yourselves and, briefly, set out the prion-related technologies that your organisations have been involved in developing.
Dr Board: Good morning. My name is Dr Kelly Board, and I am a technical specialist for the DuPont Chemicals and Fluoroproducts businesses, specifically for glycolic acid, oxone and chlorine dioxide. Prior to this, I worked as a senior research chemist for the disinfectants business, and from 2008 to 2010 I was involved in the Rely+OnTM Prion Inactivator project, with a technical focus on commercialisation. I joined DuPont in 2005, after having completed my PhD in inorganic chemistry.
The products that we developed were through working with D-Gen Limited, which is a spinout company of the MRC Prion Unit, headed by Professor Collinge. We helped to develop a prion decontamination product for surgical instruments. The background to this is that our former technical director at DuPont approached Professor Collinge’s group after seeing their research demonstrating prion inactivation on surgical instruments using surfactants and a blend of enzymes. Our company has marketed a high-level disinfectant for surgical instruments called Rely+On Perasafe since 1998, and Dr Crout saw an opportunity to incorporate this disinfectant technology with that of the MRC Prion Unit. The product was launched on 1 May 2007 and I was brought into the project in April 2008, preparing the second submission to the RRP. I was the subsequent point of contact for the rapid review panel and worked on commercialisation efforts until the project was put on hold in 2010.
The product itself, Rely+On Prion Inactivator, or RPI, rapidly reduces the potential risk of prion transmission in biosurgical instruments through use of a manual pre-soak product prior to the usual decontamination methods. It is a powder product comprising three packs. Pack one is an oxidising disinfectant, pack two is an anionic surfactant and pack three is a blend of protease enzymes. The product is used by adding each pack sequentially to water at 50º C. The instruments are then fully submerged for a 10-minute contact time, after which time the instruments are then transferred to be sterilised by autoclave or decontaminated by washer disinfectors. The product is at near-neutral pH and contains a blend of corrosion inhibitors to preserve the delicate instrument integrity. RPI has been validated by three prion methodologies and it reduces the risk of infection by greater than 1 million fold.
Q68 Chair: Thank you very much. Let us move along.
Dr Burton: Good morning. My name is Dr Steven Burton. I am the chief executive of a company called ProMetic Biosciences Ltd. This is a UK-based subsidiary of a Canadian corporation called ProMetic Life Sciences. We have been involved in the development of prion capture and removal technology, sometimes referred to as “prion filters” since 2001, when we formed a strategic collaboration—a commercial joint venture—with the American Red Cross. This was at a time before the first identified transmission of vCJD by blood, but there was a significant level of concern at the time that that might happen and that measures to counter this threat should be developed. We undertook a very large programme of work, involving several universities, the Red Cross, ProMetic and a French medical-device manufacturing company called Macopharma.
You asked about the investment costs. Between the American Red Cross and ProMetic, to date, we have invested in excess of $50 million in the development of this technology and the applications of this technology, so it is a very substantial investment. This was made because there was and is an identified threat through transmission of CJD through blood. Prion filtration, unlike testing, does not require any diagnosis. It is a more generic approach to combating the problem, so, essentially, if the vCJD prion is present, on passage through this filter—it is a very specific type of filter that has an active surface that is designed to capture the prion protein—it will capture the prion and remove it.
The first product is a medical device called P-Capt, which is a prion-removal filter for red cells. This gained CE-mark approval in 2006, which means that since 2006 it has been available for use in the processing of blood. It has undergone very extensive testing in several laboratories around the world. It has been shown to be highly effective in capturing and removing prions. It has been shown to be very safe. It has undergone numerous trials whereby the filter blood has been administered to volunteers and patients. In total, four clinical studies have been undertaken and there has been no evidence of any adverse events. It is a very safe device. The blood that is filtered is very well tolerated.
As you might be aware, we have been engaged in discussions with the UK Blood Service for adoption of this device, but at this point in time there has yet to be a decision in relation to the adoption of that product.
Professor Collinge: Good morning. I am professor of neurology at the UCL Institute of Neurology and at the National Hospital for Neurology and Neurosurgery. I direct the Medical Research Council’s Prion Unit, which is a research unit specifically set up to tackle the problems caused by BSE and vCJD in 1998 in response to the BSE crisis. We have about a hundred scientists and support staff working on understanding prion diseases and finding effective solutions to them.
The particular programmes that we have in terms of trying to produce solutions for patients are development of a blood test, which we talked about the last time I was here, of which we published a prototype version in The Lancet three years ago. We developed, at the request of the Department of Health, which funded this work in the unit, means to decontaminate surgical instruments by developing a combination of enzymes and detergents that would effectively destroy prions on metal surfaces, which was work that was subsequently licensed, as you heard, to DuPont to turn into a real practical product. We also had a major activity on developing treatments for prion diseases, such as CJD. We have two programmes that are in an advanced stage. One is to develop classical small-molecule drugs, and that is a collaboration with GlaxoSmithKline, and the second is to develop monoclonal antibodies to treat the disease, which is being taken forward by the MRC unit.
Dr Raeber: Good morning. My name is Alex Raeber. I am heading research and development at the Prionics company, which is a veterinary diagnostic company headquartered in Switzerland, marketing products for animal health worldwide. To give you a little of the background, Prionics was founded in 1997. We are founders of the first commercial product for BSE, which was gaining market access around 2000 and 2001, and this was Prionics-Check Western blot, which was validated by the European Commission in 1999. Subsequently it was approved for use in the BSE surveillance and eradication programme in the European Union, and it was listed in annex 10 of regulation 999/2001.
Subsequently, Prionics has developed further tests for BSE—an ELISA test—which gained approval in 2003, and a lateral flow, a strip test, in 2004. Prionics is currently still one of the major players in the animal diagnostic field for BSE.
In addition to those development programmes, Prionics started back in 2002 with the development of technologies for prion detection in humans, and, in particular, we published a seminal work in Nature in 1997 where we showed that a prion-specific antibody exclusively can capture abnormal forms of the prion protein. This antibody was then developed into the first prototype of a human blood test. In subsequent years, between 2007 and 2011, we evaluated the test, together with NIBSC, and the test was later on found not to be sensitive enough and was not further developed into a commercial product.
Prionics has also developed a further technology in collaboration with the NIH in the US which is known as the eQuIC technology, and which is probably going to be discussed here a little bit later.
Nigel Talboys: Good morning. My name is Nigel Talboys. I am responsible for the blood-safety business for Terumo BCT and I also have responsibility in Europe for our public affairs and public policy. Terumo BCT is a subsidiary of a Japanese medical technology company called Terumo. We are the global leader in blood component and cellular technologies. It is the only company with the unique combination of various collection, processing and blood-safety technologies. We do not manufacture a specific prion reduction or prion-testing technology. We have a broader pathogen-reduction technology. This technology, which is known as Mirasol, was launched in Europe in 2007 and reduces a broad spectrum of pathogens, such as viruses, bacteria and parasites. This technology has had hundreds of millions of dollars invested in it, and it is available and used in approximately 18 countries, primarily in Europe, but also in Russia and north Africa. Approximately 60 different centres are using this technology. We have not only worked in Europe but have a very large programme of development with the Department of Defense in the USA, where we are developing a system for battlefield applications of this technology that can be used in situations where large trauma is involved and safe blood needs to be transfused.
Q69 Chair: In different ways, some of you have partially answered some of my follow-up questions, but I will start with you, Dr Burton, because you were the most complete on what I was going to say next. I am trying to get a handle on approximately how much has been invested in these technologies—you have given us a figure already in your case—and how much financial support you have had from the Government, either directly or through the Research Councils. I am also interested, as an aside, for those of you who have broader international connections, in finding out whether there are any similar arrangements that have benefited your research programmes from other Governments. Further, to what extent have these products generated a financial return, and, of course, the key one in terms of the UK is, have any of these products been used by the NHS or UK Blood Service? As you started that theme, Dr Burton, I will start with you.
Dr Burton: The support that we have had for the development of this product has really come from outside the UK. To my knowledge, we have not had any grant support or other support in kind in relation to the development of this technology. We were fortunate to form this collaboration with the American Red Cross, which, as you know, is a part- governmental, part-voluntary organisation in the US. They were concerned globally about the issue of vCJD transmission by blood and were prepared to invest money in the development of a product to combat that threat. There has not been a similar arrangement in the UK. The UK Government and the Department of Health have relied upon industry to pick up the brunt of the cost of developing a product in the hope that it will, at some point, be used. Of course, everybody, I guess, in a way, hopes that it will not be used and that this disease is a thing of the past. Unfortunately, I do not think we can say that right now, and these measures are required. In our case we had little, if any, support from the UK for the development of this technology.
Q70 Chair: But now that you have CE-mark approval, are you selling the product in the UK?
Dr Burton: We are not. A small number of filters were supplied to the UK blood services as a part of the PRISM clinical trial. Other than that, there is no current supply or sale of this product in the UK for the P-Capt filter. There is another application of the prion technology that we have developed which relates to plasma as opposed to red cells. We have established a collaboration with a Swiss company called Octapharma. They have a virally-inactivated prion-reduced plasma called Octaplas. This is an approved product in the UK, elsewhere in Europe and in the US. There are growing sales of that plasma product. The technology that we developed is being used in relation to the manufacture of that plasma product, but currently it is not being used in the UK in relation to red-cell processing.
Q71 Chair: So in the UK, I guess, it has not produced a financial return yet.
Dr Burton: No.
Q72 Chair: What about elsewhere?
Dr Burton: Elsewhere we have a small return in relation to the investment that we have made from the plasma business. That is growing because it is a safer form of plasma compared with fresh-frozen plasma, for example. We, ultimately, may see a return on our investment, but the focal point for this work has been red-cell filtration. Of course, in the UK that is determined by the Department of Health and the National Blood Service.
Q73 Chair: Who is going to go next? Dr Raeber.
Dr Raeber: Prionics, between 2002 and 2014, when we developed prototype tests for vCJD, spent between €5 million to €10 million for this research programme. This money was, basically, all spent on Prionics’ own behalf so we did not have any government support, neither from the UK Government nor from any other Governments. Basically, it was invested from our revenues which were coming from our BSE tests and other animal diagnostic tests. We had some funding under the EU Seventh Framework Programme, a project called Priority that started in 2009 and will end in September 2014. Under this programme, Prionics is still involved in the development of a blood test for vCJD and has received about €300,000.
With regard to commercial returns out of this programme, Prionics did not have any returns from this research programme. Prionics participated two times in published tenders by the NHSBT. One tender was published in 2007 and the other in 2009. Those were both commercial tenders. Prionics won the 2009 tender for the provision of devices and a testing service to the NHSBT. This led to a framework contract with the NHSBT and, under this framework, Prionics was, basically, commissioned to deliver any products if the NHSBT would ask for such products. This was never the case. Prionics never delivered any products to the NHSBT. I might add that the test was during the time of the tender process on the on-going evaluation, so this was a parallel process, led by the NIBSC, and it turned out that the tests would not be fit for purpose in relation to what the NIBSC was asking for.
Nigel Talboys: The majority of our fundings come from internal sources. In our technology, the Mirasol technology, we have invested in excess of $100 million. There has been some funding from the Department of Defense in the USA, which is approximately $15 million so far. In addition, there is a co-funding programme that we have with the Department of Defense, which is about $50 million additional funding from us and $15 million from the Department of Defense.
From a return standpoint, the product is commercially available and used within the European Union. It is also used in east Europe, north Africa and in Russia today. We have some small evaluations starting in Asia. As far as the UK is concerned, there is a SaBTO working party that is currently looking at pathogen-reduction technologies. We are working with the SaBTO working group on this and providing information to the SaBTO working party. As far as any commercial returns in the UK are concerned, so far they are zero.
Dr Board: We did not receive any financial support in the forms of grants from the UK or from other countries. DuPont made an investment of around £150,000 in terms of out-of-pocket expenses, excluding the staffing costs that were associated with the project. We have not yet had a financial return. There have been no sales of the product at all, so the product was not taken up by the NHS. We did submit the product for review by the Rapid Review Panel on two occasions in 2007 and 2008, in the hope that we would achieve a recommendation 1, because this would have seen the product taken forward for trials in showcase hospitals around the country. However, we obtained a recommendation 3 and then subsequently a recommendation 2. Recommendation 2, essentially, means that the basic R and D has been completed and they recognise that the products may have a potential value, but more in-use evaluations and trials are needed in a health care setting. They had additional comments around the fact that use of a manual soak might not be justifiable, given the uncertainties surrounding the prevalence of CJD in the population. We had some further contact with the NHS through the infection prevention products specialist team. They reviewed the evidence that we had submitted to the Rapid Review Panel, and their further comments were that it would be unlikely that there would be a widespread uptake of novel prion technologies unless they were recommended in authoritative national guidance.
Q74 David Tredinnick: I would like to ask you whether or not you think the main barriers to developing a screening test for vCJD are commercial or scientific. If they are commercial, what are the key obstacles? Dr Raeber, you look as if you are first out of the stalls.
Dr Raeber: There are, of course, a number of commercial barriers. The biggest barrier in order to get a test on to the market is probably the very restricted market. Currently, the main markets are considered to be the UK and France. Those two countries had most of the vCJD cases. Those two countries would be, obviously, the first market to go into. Those markets are relatively restricted in terms of blood donations. If we are talking of 5 million donations, with 2.5 million in France and 2.5 million in the UK, this is a niche market. Any big company would probably not go into that market.
Probably the second biggest challenge is the regulatory framework. Variant CJD blood tests were put under a new regulatory directive under the IVD directive, which is directive 9879. In 2011, they were added to list A of annex 2, which, basically, contains blood tests such as HIV and hepatitis, which are the highest-regulated group of any diagnostic tests. This, of course, poses significant investment costs. It is considered also a significant barrier. In addition, there are scientific barriers, which means that there is still a lot of uncertainty around prions. What is a prion and when is it infectious? Last, but not least, I would say that there are some political barriers—that is why we are all sitting here today—so the market is very much politically influenced. A company developing a test to certain requirements, and those requirements are laid down in the common technical specification of the directive, would expect to get market authorisation for such a test. For this class of test it is different, because there is also a political dimension involved.
Nigel Talboys: I could talk about the broader aspects of blood safety rather than specifically on prion technology, but it has a lot of similarities. The investment on these technologies is rather large and it is a continuing investment in the technologies. We have, for example, currently, clinical studies that are continuing throughout Europe. We have studies going on in the Netherlands, Italy and Norway. We also have studies going on in Canada. This week, our technology is starting a clinical study in Ghana looking at the reduction of the transmission of malaria through blood. Although there has been a significant amount of information in the different directives to suggest that these technologies should be used, such as the Blood Directive of 2002, which said that these type of technologies should be used either for testing for blood safety or for the inactivation of blood products, the uptake has been rather slow. Again, there tends to be a lot of political agenda on the uptake of these technologies throughout Europe and not just in the UK. In September 2008, the mid-term report from the European Environment and Health Action Plan again reiterated that these blood-safety technologies for testing and inactivation of blood products should be taken up if available.
Q75 David Tredinnick: Dr Raeber, you talked about the main market being the UK and France. What about the United States? Are there any other significant markets, or is it really that much of a niche market? In relation to our old ally or foe, would you prefer France?
Dr Raeber: The United States, of course, will be a very interesting market. The question will be that, if the Blood Transfusion Service in the UK starts implementing a vCJD blood test, what impact would this have on the overall blood supply worldwide, and would other countries need to follow in order to adopt the same standard? To me, this is not a question I can answer. It is not my expertise. You could, of course, argue that, if the whole developed world would follow to implement this testing, then the market would be more significant.
Q76 David Tredinnick: You mentioned the politics of health. Is that where politics comes in, do you think?
Dr Raeber: Excuse me?
Q77 David Tredinnick: You mentioned politics earlier on and the political issues around this. Is that partly a political matter—a Government commitment?
Dr Raeber: Coming back to the US, would they really see the same safety issue as in the UK? This, again, would be a political process.
Q78 David Tredinnick: Do you disagree with that, Mr Talboys?
Nigel Talboys: No. I fully agree. Decisions have to be made in health care. Whether it is testing or the inactivation of a particular pathogen within blood, it has a cost associated with that. Therefore, it has a cost to the health care system. Therefore, someone has to pay for this whether it is in Europe or in the US.
Q79 David Tredinnick: So it is more money than politics. In the end, it comes down to hard cash, does it not?
Nigel Talboys: Yes.
Dr Burton: To pick up on that, one needs to look back over quite a lengthy period of time here because the political situation changes depending upon public sentiment and the perceived risk and need to do something. If one looks back to 2001 and 2002, we were recovering from the BSE crisis; we had just seen a relatively large number of cases of vCJD from the oral administration. I said “large number,” but what we are talking about is relative. The numbers may have been 25 deaths per annum at its peak. Then those numbers declined. There was a perception at the time that the problem had gone away, but that doesn’t take into account many other factors such as the whole genotype issue, the length of the incubation period and things of that nature. I would say that political sentiments started to change round about 2004 to 2006 that, maybe, this problem was going away. Then, of course, later on we ran into a global financial crisis that put pressures on budgets. A document was published by the Department of Heath, a five-year strategic plan for the NHSBT, where, clearly, reducing the price of blood is seen as an important objective. It is commented upon in that report that, if additional measures, such as prion infiltration or testing had to be implemented, that would have a negative impact in terms of reducing the cost of blood. There is a political dimension to this.
Q80 David Tredinnick: Thank you very much. Could any of the tests under development be used to detect other pathogens—for example, classical forms of CJD or other currently uncharacterised prion diseases?
Dr Raeber: I am not sure that I understood the question. Do you mean whether this class of tests that we were developing for vCJD could also detect other pathogens?
Q81 David Tredinnick: Yes. Could they detect other pathogens? If all these tests are being developed, is there a wider market out there, to use a commercial term? Are there other opportunities to deploy the knowledge?
Dr Raeber: The knowledge on prion technology, yes, there would be a broader use. When you develop a test for a specific analyte, and in this case the analyte is for vCJD, the test will be specifically developed for vCJD; it could not be used for any other form of CJD.
Q82 David Tredinnick: I understand that, but you have just said that there were other possible uses. Where would they be? Where do you think that these tests could be deployed elsewhere? What other medical issues could these tests help resolve or influence?
Dr Raeber: There are other applications, for example, for classical forms of CJD, such as sporadic forms of CJD. Research programmes are going on, for example, to discriminate between Alzheimer’s disease and Creutzfeldt-Jacob disease.
Q83 David Tredinnick: So Alzheimer’s would be a candidate, would it?
Dr Raeber: Right.
Q84 David Tredinnick: Does anyone else wish to comment?
Professor Collinge: The tests we are developing are specifically oriented to prion detection, the infectious agents that cause CJD and vCJD, so they are highly specific for that indication, although the test that we have developed is beginning to pick up some cases of classical CJD as well as vCJD. It is possible that it could be adapted for that also.
Q85 Chair: You said to us before that your line of research has helped us understand other neurological conditions. Is that a fair assessment?
Professor Collinge: That is right. The fundamental process at a molecular level that is going on in these diseases is about protein aggregation and proteins in the body changing their shape and sticking to each other and forming these seeds which could propagate. Similar processes are happening in Alzheimer’s disease and Parkinson’s disease, for example. The science that we have done at the MRC unit to develop the blood test, which involves capturing these abnormal proteins on a metal powder, could, in principle, be used for some of these other proteins as well. We are thinking about whether the same sort of technology could be used to develop a blood test for Alzheimer’s disease, but that research is in its infancy at the moment.
Q86 David Tredinnick: I have one last question for Professor Collinge, and that is about the scale of the problem. In our last evidence session, Christine Lord suggested that the prevalence of sporadic CJD had increased in recent years from approximately 1 in a million to 1 in 33,000. Does this fit with your understanding, and, if so, what might this increase be attributed to?
Professor Collinge: I think there is some misunderstanding there. The apparent incidence of sporadic CJD is increasing. There are about a hundred new cases a year at the moment, and that has gone up substantially from the start of surveillance. That is thought, principally, to reflect better diagnosis of the disease, although that may not be all the explanation. It is possible, and we can talk about that, that some of that may be BSE-related. However, I think that the specific confusion there is that people talk about sporadic CJD occurring at 1 per million. That is not your individual risk. Your risk is 1 per million every year. Actually, it is nearer 2 per million per year of the population will develop sporadic CJD, but your lifetime risk of developing sporadic CJD is about 1 in 30,000. So that has not really changed. When people talk about 1 per million, often they interpret that as thinking it is incredibly rare. They think they have a 1-in-a-million chance of developing this disease. You haven’t. You’ve got about a 1-in-30,000 chance of developing it.
Q87 Stephen Mosley: I want to concentrate two or three questions on Professor Collinge on the MRC unit’s prion test. Could you tell us what the current status is of the test?
Professor Collinge: The prototype test was published in The Lancet three years ago, showing that we could pick up 71% of definite cases of vCJD. As to that sensitivity of the test, we don’t really know what that means. Obviously, we would like it to be in the 90s. Of course, we don’t know whether everybody who has vCJD has prions in their blood at all. Indeed, we recently published a case history in the Journal of the American Medical Association of a definite vCJD case which had virtually no prions detectable in the periphery system and we could not detect it in the blood, so this would have been a case that would have been missed by the recent prevalence screening that has been done by Public Health England. We achieved 71% sensitivity, but we don’t quite know what that means or how much it is possible to increase that. The test that we developed works on 8 microlitres of blood, which is a tiny amount of blood. A typical blood sample that you would take from a patient’s arm would be more like 8 ml, which is a thousand times more than that. So there is plenty of potential to increase the sensitivity of the test by putting larger volumes of analyte into the test. That is not something that we have done yet.
The important thing in terms of developing a test, either to do what we want to do next, which is to conduct a preliminary prevalent screening in the population, or, ultimately, to produce a test that the National Blood Service could use in a practical sense to screen blood, is the false-positive rate, which needs to be extremely low if you are going to use that population screening. It also needs to be low in terms of doing a prevalence study to make the numbers reasonable. So we screened 5,000 American samples, kindly provided by the American Red Cross, of US donors. The US population has had minimal primary exposure to BSE. Therefore, we wouldn’t have expected to see any true positives in the 5,000 Americans. Indeed, we did not, so the test was 100%-specific. That was very encouraging, and that was our criterion to progress, we hoped, to the next stage of evaluation of this prototype. What we want to do is to screen 20,000 UK individuals and compare that with 20,000 US donors.
The purpose of this is twofold. As you know, the Health Protection Agency, which is now Public Health England, found that approximately 1 in 2,000 appendix samples were positive. So we did power calculations, and worked out that, by comparing 20,000 Americans and 20,000 British samples, we would have an adequate chance of showing a significant difference between those two populations in terms of the number of positives. If we do that, we would expect to find the seven positives in the British population and none in the American population.
If that is what we find, that will conclude two things immediately. One is that our test is capable of detecting carriers, which we don’t formally know yet: we have simply looked at patients. Secondly, we would have confirmed that there is, indeed, a problem in the British donor core. In our view, that piece of research is required to make the case to progress that test further. Our test is a laboratory prototype. It is not something that could be used practically at the moment by the Blood Service, but there is no reason technically why it could not be developed in that way. That we see as the next step. The discussions that we have had with diagnostics companies is very much that they want to see those data first before thinking about whether they would help us to take it any further. As you have heard from other witnesses here, there are other issues about whether the market is really worth while for companies to progress in and to what extent the Department of Health and the others in Government may need to drive that and provide leadership for that to happen to get over these other barriers.
Q88 Stephen Mosley: It sounds as though you have fallen into the Valley of Death at the moment, have you not?
Professor Collinge: That is right.
Q89 Stephen Mosley: The MRC turned down funding for that bigger study last year. Are you moving forward at all now? Are you in abeyance in terms of the project or are you actually continuing without doing that study?
Professor Collinge: Yes. We were rather set back by that. The view of the panel that reviewed that was that we needed to increase the sensitivity of the test further, in the first instance.
Q90 Stephen Mosley: Would you agree with that?
Professor Collinge: No, I don’t agree with that, and that is not the view of our statistical advisers. The sensitivity is perfectly adequate to do the study that we propose to do. Clearly, if you are going to go on and develop it as a blood-screening test, you may want to increase that sensitivity. As I mentioned earlier, we don’t know whether that is possible. It could be that only 70% of people with vCJD have prions in their blood and we are picking up all of them. There is an area of uncertainty here, but there is certainly plenty of capacity, as I have mentioned, not least because the volume of blood that we are putting into tests is tiny. So there is plenty of capacity to increase that.
What we are now talking about is test-development work, which is not what my unit is expert in. We have done the basic science. We have solved the scientific problems, which were formidable, to do this. As we don’t have the expertise, I am reluctant for the unit to get drawn into doing a huge amount of routine test-development work. That is really a matter for others. We have had a lot of discussions in this unit about this since we couldn’t progress with this. We have been doing some further work in the unit to see whether we can partially automate the tests, because the main cost of screening the 20,000 UK and 20,000 US samples is simply the technician time. It is quite a laborious test, so you have to employ, probably, a dozen technicians to do this in a reasonable time. That is where most of the money goes. We have robotic systems in the unit that are used for other purposes, so we are trying to see if we can adapt it to that. The pure purpose for this is to see whether we can reduce the cost so that we can find some way of doing this at a reduced cost. I do feel that this is all rather bizarre, since my unit was set up to do this and that, given the public health considerations, we are trying to fund work-arounds to do what actually is a fairly modest piece of work. As I mentioned last time, the funding required to do that I thought was about £750,000. On the scale of what you have been hearing, it is really trivial.
Q91 Stephen Mosley: I have a bit of a contradiction in my text. Could you just clarify something for me? We have been told that Public Health England suggested that the case for conducting the study would be further increased if it could be shown that the prion deposition in the appendix did not pre-date the BSE crisis, yet elsewhere in my text it says that it would be strengthened if ineffectivity could be shown to pre-date BSE. Could you clarify which it is?
Professor Collinge: I am not quite sure that I understand your question. You are talking now about the appendix prevalent studies that Public Health England have been doing, because they are doing a further study on appendices removed from samples prior to 1980. The purpose of that is to look at appendices from individuals who would not have been exposed to BSE, or who would have less exposure to BSE, to compare that with the positives that they have found so far, although I must say that I am slightly nervous about that because we don’t really know when BSE exposure of the population started. BSE was first recognised in cattle in the UK around 1985. The average incubation period in cattle at the peak of the epidemic was about five years, but the range of incubation periods in cattle, like in other species, is very broad. As you reduce the effective dose that you give to an animal, towards the minimum effective dose in a single infectious unit, the incubation periods increase. The longest incubation period you see in cattle—the former Ministry of Agriculture did this experiment in cattle by infecting them with progressively smaller doses—approached 20 years. So there is likely to have been some exposure of the UK population to BSE well before 1980. So that is a caveat in interpreting that study.
Q92 Stephen Mosley: When we spoke to you in November you said that you had recently spoken to the Public Health Minister, Jane Ellison. Did you get any feedback, any response from that meeting?
Professor Collinge: I have not heard any further from her or her office, no.
Q93 Stephen Mosley: Lastly, just opening the questions up to the rest of the witnesses: Professor Collinge has been advised to go out to industry to get financial support. From your companies’ perspectives, is this the type of technology that you would invest in at this stage of development and, if not, why not? I am not asking you to get out your cheque books here.
Dr Raeber: As Professor Collinge mentioned, it is too premature to make a decision as to whether a company such as ours would invest in this technology because, so far, it is a research-based test. There have been a couple of papers published. One of the main concerns from our side is that there has not been an independent body validating that test, for example, someone like the NIBSC, which has been involved in validating tests in the UK, probably, from more than half-a-dozen companies that were active in test development between 2007 and 2011. This is a very important part for a commercial company to get an independent view on a test development. Currently, it is too early. As Professor Collinge mentioned, it is probably important that further evaluations are being carried out, either on behalf of the NIBSC or the NHSBT. The results of those evaluations will show whether there is an interest from industry.
Q94 Stephen Mosley: Would you agree with that, essentially?
Dr Burton: Yes. Based on our experience, which is not testing, but it is pre-filtration, so it is a different measure in relation to vCJD, if I was asked the question today, “Would we invest another $50 million to develop a technology in this area?”, I think our answer would be no, unless there is a very clear undertaking that, if we developed a product and if that product met the target objectives and specifications, it would be used and there would, indeed, be a market for that product. Companies are not going to invest in the development of products if they are not sure in the knowledge that there is a market for that product.
Q95 Chair: And the others agree.
Nigel Talboys: Yes.
Q96 Pamela Nash: Dr Raeber, I understand that NHS Blood and Transplant had rejected the blood test that you were developing in 2009 saying that it was unsuitable. Could you tell us what explanation was given to Prionics about why that test was unsuitable?
Dr Raeber: Yes. Maybe we have to go a little bit more into what “test development” really means within the framework of the NIBSC process. There are very limited samples of vCJD available for test development. That is probably one of the main restrictions for test developing. That is why, basically, the whole prion community has agreed on using so-called spiked samples. Spiked samples are samples with human plasma where vCJD brain is spiked, in limiting dilutions, into human plasma. Those samples are then being used to mimic a naturally infected vCJD plasma. So we have been using such samples for, basically, most of the development work, and the NIBSC provides, for the first step, spiked examples to test developers. In a second step, animal samples are being used. Basically, the rationale behind it is that an animal with prion disease has similar infectivity in the blood as a human so this is probably the second-best choice of samples because there are no human vCJD samples available. Then in the third stage, negative human-plasma samples are being screened. I am talking about large numbers, such as a couple of thousand. Those three stages were all passed successfully by our work test, which was the Prionics vCJD test.
The last stage was getting access to those very rare vCJD-plasma samples. In our testing evaluation, the NIBSC provided us with two vCJD-plasma samples. We tested those two samples. They were blinded within a panel of negative-plasma samples. It turned out that they were really on the cut-off. Basically, the decision was that the test was not sufficiently fit for purpose.
From a test-developer perspective, of course, you would say that this is really not adequate—to make a decision based on two samples. If you are looking at the test from the MRC, it had a 70% sensitivity on vCJD-plasma samples, which means that there are also vCJD-plasma samples that were missed by that test. So let’s say that if we, maybe, got access to two samples which were really negative, then this final evaluation stage wouldn’t really say anything about the test performance on the real vCJD samples.
Q97 Pamela Nash: So you don’t think that this was a fair decision.
Dr Raeber: Excuse me.
Pamela Nash: You don’t think that this was a fair decision by NHS Blood and Transplant.
Dr Raeber: It was not fair, inasmuch as the whole test was abandoned, based on two samples. The real issues lies in the process of how to get access to such samples. As a foreign company, we had big challenges to get access to such samples.
Q98 Pamela Nash: Is there an alternative process that NHS Blood and Transplant could undertake when examining the tests that are available?
Dr Raeber: I did not understand.
Q99 Pamela Nash: You mentioned that you would do better if more samples were available, but, other than that, would there be an alternative process that NHS Blood and Transplant could undertake in order to examine the success of new tests?
Dr Raeber: I don’t think it is a reason of the process that is not adequate. Maybe the NIBSC was not having access to enough samples and that is why they could only give this very limited amount of samples to the company. I remember that, in 2011, there were just two companies left that were reaching this final stage of development and both companies received two samples. I was wondering if there were not more samples. We knew that there were more samples available but those samples would not be made available to test manufactures.
Q100 Pamela Nash: Since 2009, when this decision was made, has Prionics developed this test any further or has development stalled?
Dr Raeber: No. Prionics continued test development, so we decided to move on to another technology which was getting to a stage which looked really interesting at that time. This is the so-called amplification technology. It is also know as “e-quick” or enhanced quaking-induced conversion assay. It is an amplification technology which allows you to amplify very small quantities of prions in blood. Prionics had collaborated in the last couple of years with the NIH in the US, and we published in 2011 a paper where we showed that this test would detect up to an actogram of prions in blood. So, from a sensitivity point of view, this test looks very promising. Currently, the NHSBT is in the process of evaluating that test and Prionics is still involved in that test, basically from an intellectual property point of view.
Q101 Pamela Nash: Have there been any other conversations with the UK Government following the earlier success of this test to develop it?
Dr Raeber: No.
Q102 Sarah Newton: I would like to carry on exploring the access to CJD samples as an issue of preventing blood tests from developing. With the permission of the Chair, unusually, in our deliberations, do we look at the impact on real people. Our conversation is very much, as it has been this morning, around institutions and processes. We have had very powerful evidence from Christine Lord, the mother of a victim—her son, Andrew Black. She repeatedly criticised this issue of lack of access to samples that she and other victims feel should be made available to help prion tests. It is important that we think there is a human side to everything that we are talking about this morning. Do you agree that there should be limitations on the access to rare samples, and, if you do, how should they be controlled? Perhaps Dr Raeber could answer that question first.
Dr Raeber: In principle, the NIBSC has done an excellent job on setting up the process. I really have to credit the NIBSC for doing that. In my opinion, the NIBSC process should probably have been applicable to all test developers because, as a foreign manufacturer, we had the feeling that we were not treated in the same way as other stakeholders. It is not the process but more, probably, the kind of decisions that were made and at what stage a company would get access to those rare samples.
Q103 Sarah Newton: Would anybody else like to comment?
Professor Collinge: Yes. The background to this, of course, is that vCJD is, thankfully, a rare disease and there are not many blood samples, and many of them are very small. What was happening with respect to the two units in the UK that see most of the patients and have taken samples themselves for research purposes, which is my unit in London and the surveillance unit in Edinburgh, was that there were quite unreasonable requests for large amounts of samples from, often very small companies, with tests that were not very plausible. Had these been agreed to, the whole lot of samples would have disappeared and no one would have been able to work on this disease. That was what led to setting up this CJD resource-centre committee, which has a defined set of samples and a defined process and algorithm in deciding who gets access to these samples. That access is based on test performance on less valuable samples, like the spiked samples that Dr Raeber has described.
My unit and also colleagues in Edinburgh were asked by that centre to provide samples for that collection, which we have done. That process is important because, with all due respect to commercial colleagues here, often claims are made about tests that don’t really have any validity. As academics, we publish our work in peer-review journals for everyone to look at. That is not usually the case with commercial developers and you often don’t know quite what is really going on or how the tests work. It is important that these very valuable samples are only made available if there is a scientific case, if it is plausible that the test is going to work. Otherwise, we just lose all the samples and we would be in serious trouble. That is why that process was introduced, to act as a gatekeeper to access these very valuable samples.
With respect to Christine Lord’s comments, which I read in the transcript, and I know Mrs Lord very well, there is an issue. My unit has had direct requests from companies for samples which has put us in a difficult position because we, as the MRC, are signed up to this national process in terms of access to samples. A Canadian company, for example, that claimed to be very close to having a test asked us for samples. I have been in discussions with patients’ relatives to see whether samples could be obtained. We try to help. In fact, I asked the chair of the committee after discussing it with MRC head office, “Can I provide some samples outside the arrangement?” The committee agreed. We provided some samples directly to that Canadian company, and also we have been providing samples recently to a French group that is working on a blood test. It puts me in a slightly uncomfortable position because you want to help, but there is this national process, which really we should stick to. It is less of a problem now. In the early days there were lots of small companies claiming to have tests and they all wanted bucket loads of samples, which was just impossible. There had to be a control over this. I think the NIBSC is doing as good a job as can be done to try and control access to the samples.
Q104 Sarah Newton: I am sure we would all agree that there has to be some sort of process because there is a limited amount of samples. I would be interested to hear from your commercial colleagues here as to how they respond to the comments you have made. If anybody could think of a way in which the process could be improved, we would like to hear of it. We have received considerable evidence that the process is in fact impeding the development of tests.
Professor Collinge: If I could just say one more thing, we published in The Lancet—again, it is a question of claims and reality, and a lot of the data, of course, are not in the public domain in the way that academics publish data—a benchmark of where you need to be with test sensitivity. Spiked samples are very important to work with first of all, because the real samples are so valuable. The test that we developed was able to detect spiked samples, brain-diluted 10 thousand million times, which is 10 to the order of 10. That shows the ballpark that the tests needed to be in, realistically, to be detecting in human blood. When we published that, that was five orders of magnitude above any other published test. It is important that there is a scientific view that this test is in the right ballpark to begin with, with spiked samples, because if it is not we would simply be wasting the real samples.
Dr Raeber: How could the process be improved? That was your question. I think that the process as it is is fine. There is nothing that is wrong with the process. It is more that the process should be adhered to more strictly. So, basically, all the samples should be made available to the NIBSC and the samples should then be given to those tests that show the biggest promise. That is important because you can only compare tests when they have been evaluated on the same samples. That was, as I have mentioned before, done in a very meticulous way by the NIBSC. When you follow that process, you have a high chance of giving access to those samples to those test developers who have the best test.
Q105 Sarah Newton: Would anybody else like to comment? Dr Board.
Dr Board: Our product has developed in collaboration with D-Gen so we were not involved with the prion-testing part from our side, so that work was completed by Professor Collinge’s group.
Professor Collinge: I would like to make a technical point, which might be relevant here. In our experience, there has been an issue, when we have been asked for access to samples, in that different test developers often mean different analytes. For example, they want the blood sample taken in different ways with different anti-coagulants and so on. It can be quite complicated. That was a complication with respect to one request, which I think you may have heard of, in respect to patients wanting samples sent to the test manufacturers. The samples simply were not suitable for that purpose. The manufacturer could not use them. It is a little more complicated than it might seem, but they are not just samples that can be used for any purpose.
Q106 Sarah Newton: I understand. I have one final question for Professor Collinge. Our Committee has been very concerned, as you say, about commercial developers not making their research findings available, and shares the concerns that you have raised. However, it is our understanding that various protocols are being developed so that private developers, especially those in the pharmaceutical industry, are agreeing to make their research findings available. If such protocols could be agreed with developers who come to you asking for samples, would you be more willing to work with them on the understanding that the results of their research would find their way into the public domain?
Professor Collinge: We are happy to work with anyone who will help produce a blood test for this disease. As I said, it is important that there is a national process here rather than putting individual investigators under pressure to provide samples. There needs to be an officially sanctioned process with criteria and an independent committee looking at it so that you have transparency around this. It would help if the data were publicly available, with some data being made available to these committees, but they are all confidential. It is hard to know the quality of the substance of the claims that are being made.
Q107 Chair: Do you have to go through the NIBSC process yourself when your own researchers want to utilise the samples?
Professor Collinge: No, we don’t. That was agreed up front. We are a Medical Research Council unit that is collecting these samples for an ethically determined research programme, so it would be a bit crazy creating a separate process for ourselves, but we supply all samples to the NIBSC that they have requested.
Q108 Mr Heath: I am afraid I cannot remember whether it was Dr Raeber or Professor Collinge who said that there was a request from a French company. Does France not provide samples? They have the second-highest incidence.
Professor Collinge: It was not a French company. It was a group of independent French academic researchers.
Q109 Mr Heath: The question still arises. Are the French using the same sort of protocols? Is there a common protocol or are they simply not providing samples?
Professor Collinge: The French have vCJD. In fact, in recent years they have had more than the UK. I can’t speak for the French regulations. There are samples in France.
Q110 Mr Heath: Does Dr Raeber know about it, because he operates in France as well?
Dr Raeber: I do not know whether the French really follow the UK process. That was your question, right?
Q111 Mr Heath: Or a similar process, or whether they have a process of their own.
Dr Raeber: I would not know of a process that is similar to the NIBSC process in France. I just know that many companies that were involved in test developing were coming from abroad, so there were Canadian companies. They all followed the NIBSC process. The NIBSC process was very closely linked to the common technical specification in the IVD directive, so it really formed a good basis for test developers. We knew what were the requirements, and later also to get the test approved. I think that the common technical specification laid down in the EU directive and the NIBSC process really matched. Those made it a very good process to follow.
Q112 Graham Stringer: Professor Collinge, the last time you were here you said that you believed that the risk of transmission of vCJD via surgical instruments was a significant problem. If that is the case, why have no cases been reported where vCJD has been transmitted in that particular way?
Professor Collinge: What I was trying to say is that there is clearly a risk there. We have not been able to quantify that risk. It is correct that we don’t know of any cases of secondary vCJD that can be attributed to surgical instruments at this point in time, but it can’t be excluded that some of the cases we have seen so far of vCJD have been related to that. It is a question of how you would tell. That really comes from epidemiological studies. Since a history of prior surgery—particularly a history of prior dental surgery—is so common, and many patients you see will have had prior surgery and certainly virtually all of them will have had dentistry, it is hard to make that link. The link has been made with sporadic CJD where there have been clearly documented instances of transmission of prions by surgical instruments, by neurosurgical instruments. There is also epidemiological evidence from several countries now that patients developing classical CJD are more likely to have had abdominal surgery beforehand, for example. There are sufficient numbers where an epidemiological link has been shown. You are right—we don’t have definite evidence that a surgically transmitted case of vCJD has occurred, but that is, perhaps, not surprising at this point in time.
What we do have is a great deal of scientific evidence that, first of all, the infective agent in vCJD is much more widely distributed in the body than it is in classical CJD, so there is more opportunity for it to contact surgical and medical instruments. Of course, as you heard from the HPA study, there are, potentially, quite a lot of people carrying the infection around. We also know, experimentally, that it is relatively easy to transmit prions by binding them to metal surfaces. In fact, it is something that we use experimentally now. It is a very efficient way of transmitting the disease. Indeed, the blood test that we talked about earlier exploits the affinity of prions on metal surfaces as a way of concentrating the infective agent prior to detection. There is plenty of scientific evidence that this would be an efficient route of transmission. There is plenty of evidence that there are many people in the UK incubating the disease and that the infection would be in tissues that come into contact with surgical instruments. But you are right: so far, there is not a documented example of that happening with vCJD.
Q113 Graham Stringer: I am not quite sure that I understood the first part of your answer. Can we tell from epidemiological studies whether there is an indication that there has been transmission of vCJD? There is no routine testing, but is there any other way that we can have an indication that there has been transmission?
Professor Collinge: No. It would be worth speaking to the epidemiologists at the surveillance unit whose responsibility that is, but, so far, there has been no case that can be readily attributed to prior surgery. As I said, those are difficult studies because surgery, particularly dental surgery, is so common.
Q114 Graham Stringer: NICE introduced guidelines intended to reduce the risk of transmission during surgery in 2006. Do we know if those guidelines have been effective, and are they still relevant at the present time?
Professor Collinge: I’m not sure I can answer for how that is being implemented in the NHS. It is outside my expertise. The awareness of this risk some years ago led to a review of standard hospital decontamination procedures and practice. I was a member of the advisory committee, CEAC, at the time, when this was being discussed. If one can say that one positive thing did come out of the BSE crisis, it is that that did lead to the exposure of a lot of bad practice in terms of surgical instrument decontamination. A lot of places audited were found not to be up to best practice, to put it mildly. A major investment was made of about £500 million at that time by the Department of Health to bring central sterilisation processes up to standard.
Q115 Stephen Metcalfe: Following on from that—perhaps I could ask this question of you, Dr Board—what made DuPont decide to invest in a prion decontamination product in the first place? You gave us a very comprehensive introduction at the beginning, but what was the driver?
Dr Board: We saw a need for the product. The fact is that there are lots of prion decontamination products that are compatible with medical instruments or delicate instruments. Our product is pH neutral and has corrosion inhibitors to help maintain the integrity of the instruments. We felt that we could fill this gap in the market with a product such as this.
Q116 Stephen Metcalfe: So it was a totally commercial decision.
Dr Board: There was a need for the product with the recommendations of single-use instruments or the tracking of instruments. This could be a more cost-effective addition to the process.
Q117 Stephen Metcalfe: So then you, DuPont, as a company, invested in developing a product. Obviously, it has had some challenges getting to market. Could you just run us through what the barriers were to getting it to the point where in 2007 it was launched and then what happened in the interim period up to 2010?
Dr Board: Let me give an overview, because I was not on the project until 2008, of the main barriers that we found overall, the primary one being that there were no regulatory drivers for the product use. We were told very clear by the Rapid Review Panel that, unless there were such recommendations in place, it was unlikely that our product would be taken up widely within the NHS. Also, the fact that it is a pre-soak product adds an additional step to the decontamination process, which means that it can’t be used in the automated-washer disinfectors that are the best practice. In addition, it was very difficult for us to obtain approval to trial the product in health care settings. We made several attempts to have the product trialled but only one materialised, at St Mary’s hospital, and we found this to be a successful trial. There was a lot of resistance to getting the product trialled.
We had some practical commercial aspects as well that were a barrier for us. The product has a six-month shelf life, which is not a problem for the end user, but we have a minimum batch-size production run of over 6,000 packs. Without confirmed orders, this would mean that we would be, essentially, disposing of a large quantity of unused and out-of-date material. A further factor was that one of the ingredients in the disinfectant part of the pack was reclassified in December 2010 so it was given a toxic reproduction classification, which would have meant that the whole product would carry this toxic labelling. So this was removed from the formulation and replaced with a non-toxic equivalent, which was sodium percarbonate. Although this was resolved from a formulation point of view, it would have required further validation in terms of the biocide of the efficacy tests and the prion efficacy validation.
Q118 Stephen Metcalfe: So you were developing a product that there had been an identified need for. You developed that product. Hopefully, it did what it was specified to do and yet, at every stage, challenges were thrown up to almost stop it. Were you not working with the end user during that development period, up until the point that you launched the product so that it would fulfil more of their identified needs and that barriers would not exist?
Dr Board: Yes. We conducted a large number of interviews with the end user. The feedback was that it would be a good product to use. The main barrier was the fact that it was a pre-soak product. Initially, people said that this would not be a problem, but, obviously, further down the line, as we needed a validated automated process, this became more of an issue.
Q119 Stephen Metcalfe: So you thought that the product might develop into something else at some future point.
Dr Board: There was always the intention that a generation 2 product would come out of this, but, unfortunately, it did not materialise.
Q120 Stephen Metcalfe: Is there any market for the product outside of the UK? Did you try that?
Dr Board: We did explore several markets, France in particular, as well as some other European markets, but we found that their lack of demand did not really fulfil further investment in this line.
Q121 Stephen Metcalfe: Have you had any contact with the Department of Health since 2010 when the product was put on hold?
Dr Board: No, we have not.
Q122 Stephen Metcalfe: Do you still have confidence as a company in the product?
Dr Board: We have confidence that the product sets out exactly what it intended to do. However, it is difficult to see with the feedback we have had from the Rapid Review Panel how it would get implemented within the NHS with the current recommendations.
Q123 Stephen Metcalfe: So for you to be able to start redevelopment of the product, perhaps to make it not a pre-soak but something that could be included in a later stage of decontamination, what would kick start that reinvestment? What would get the company looking at this again?
Dr Board: The business case would have to meet a set of criteria for the product-pipeline selection. If it were to be re-engineered to go into automated processes, it would be a complete reformulation. We would be, essentially, starting from scratch so this would take several years, so there would need to be significant justification for a business case. Even if we were to proceed with the manual pre-soak product, there would still be not an insignificant amount of work. It would not just be a case of ordering in the chemicals and putting a product out. We would need to have sufficient commitment to volume to justify this. We would need additional resources from a personnel point of view to support the project. It would be necessary to validate this new carbonate-based formulation product in terms of the bioside or the prion efficacy and end-of-shelf life data as well. There would be a number of factors to consider.
Q124 Stephen Metcalfe: It sounds like it was a tortuous process to get it to where it was. I can understand your reluctance to start re-investing in that. I wanted to come in earlier when we were talking about the politics of all of this. If a product fulfils a specified or an identified need, is then developed and fills that need, I think someone said it should then be adopted but it is not because of, perhaps, political or financial reasons. Has that market changed over the last 10, 15 or 20 years, or has it always been as difficult as it is now to get a product taken up—by the NHS, in this case?
Dr Burton: The climate that existed round about 2000 to 2005 was one of real concern. The UK blood agencies and the Department of Health were very concerned that there was going to be not another epidemic but a growth of cases of vCJD by virtue of blood transfusion. There was, I think, a genuine desire to do something about that. A number of new committees were formed. In the case of pre-infiltration, there was a prion filter working group formed, of which we were part, and various blood agencies—not just in the UK actually, but in other European countries, such as Ireland and France—were also invited on to that panel. I would say that there was a real period of collaboration at that period that we were all working together, industry and the NHS, to try and solve this problem.
That climate changed. We experienced evidence of that in terms of the PRISM study. You might be aware of this. This was the clinical trial that was performed by the UK Blood Service on the prion filter. This was a study on 270 transfused units, which had undergone pre-infiltration, compared with 270 units which had not undergone pre-infiltration. It was a multisite study. Something like six hospitals in the UK were involved. These were major hospitals, not minor local hospitals. That study should have taken, I believe, 18 months to conduct but it took five years. One might ask why that study took so long. In fact, SaBTO commented upon this in 2009. They were concerned that the study was taking too long but it did not complete until the end of 2012. From our perspective that spirit of collaboration that existed in the first half of the last decade disappeared. We were witnessing an environment where, from our perception, road blocks were being placed in the way and things were being stretched and taking longer. As soon as we achieved one hurdle, another one was, all of a sudden, in the way. That was our experience in the latter part of the development of product.
Q125 Stephen Metcalfe: Does anyone want to add anything?
Nigel Talboys: In relation to this, first of all, there was the financial crisis. That has certainly made the introduction of new technologies more difficult, not only in the UK but throughout Europe. However, there are certain cases, such as Switzerland, where, three or four years ago, they had three cases of bacterial contamination of their platelets. They were within a period of one year. Because of the contamination of those platelet products—unfortunately, there was the death of a child associated with one of those platelet products—they implemented a pathogen-inactivation system because of that. What can happen, and where this becomes a political issue, is that, when there is public awareness, there is a high emphasis on testing, or on pathogen inactivation or pathogen reduction of blood products. This is forgotten about after a period of time. If you combine that with a financial crisis, it means that you see, over a period of years, a high emphasis, then people forget about it and the emphasis drops down. That is what we are seeing.
Professor Collinge: Can I add something there? I have spent my whole career as an NHS doctor. It is fair to say that the NHS can be quite resistant to change and it is hard to do new things in it. With respect to the surgical instrument decontamination project, for instance, I was not completely naive about this. I did go and see the then chief medical officer, Sir Liam Donaldson, because we were about to embark, funded by the Department of Health, on a major research programme involving three professors and a great deal of resource in my unit to try and solve this problem of how to decontaminate metal surfaces. I said to Liam, “If we do this, is this actually going to be used? Is the NHS actually going to use this?” He said to me, “John, if this problem is solved, I will instruct all hospitals to use it.” I didn’t think there was a clearer case than that. Of course—this is one of the changes that has been discussed—what has happened is a change in the relationship between the centre and hospital trusts. When we developed this, and I went back to Sir Liam Donaldson again to discuss this, he said, “John, the world’s changed. We don’t tell hospitals what to do any more. This will be a decision taken by individual trusts.” He wrote to me in that regard. Of course, at the level of the individual trust, there is no driver to do this. They’re sat there thinking, “Why should we do this? It involves us changing our procedures. We’ll have to change our working rotas. There’ll be some additional cost,” and it simply doesn’t happen. That change in the relationship between the Department of Health and trusts is also relevant.
Q126 Stephen Metcalfe: Could you tell us when that letter was written or when that discussion was taking place?
Professor Collinge: It is quite a long time ago now. I would have to go back. It is probably seven or eight years. I can certainly find the letter, if Professor Donaldson is happy for me to send it to you.
Stephen Metcalfe: That would be useful. Thank you.
Q127 Mr Heath: Following up on that point first, I would not describe military procurement as being an ideal procurement method, but, nevertheless, when they identify a need, they then ask people to develop it, it is produced and if it works it is implemented. In the NHS, we have a process of nudges and winks, it seems to me, certainly as far as the commercial sector is concerned, as to what might be useful, but nobody takes responsibility for ensuring the testing regimes and the use of potentially valuable technologies within the NHS. Is that a fair characterisation? Professor Collinge, I think you are probably best placed to answer that.
Professor Collinge: Yes. It is unfashionable to have central diktats about things, but when it comes to infectious diseases, which don’t respect any borders, and certainly not the relationship between one trust and another, there needs to be a national position on infectious pathogens. We have this with things like MRSA and C-difficile, which, of course, have been widely aired in the media and led to a number of actions to make sure that all trusts have standards and that they are inspected as to whether they tick the relevant box to ensure that they have taken the appropriate measures to reduce the risk of those pathogens, but there is not that with respect to prions. As far as I am aware, there is no inspection of hospitals, be it the CQC or anybody else, saying, “Have you done a prion-risk assessment in your hospital? Are you doing high-risk procedures? Have you taken appropriate precautions?” So there is no real driver for things to happen.
Q128 Mr Heath: We can’t run infection control on the basis of whether it is on the front page of the Daily Mail, can we?
Professor Collinge: No, absolutely not. There needs to be a clear statement, saying, “Is this worth doing or not? Are we sufficiently concerned about the risks that we are doing anything?” If we are so concerned about the risk, are we blighting people’s lives by informing them that they have been exposed to a contaminated instrument? So presumably we think there is a risk. Then there should be national standards of what we do that all NHS trusts are expected to adhere to.
Q129 Mr Heath: Thank you. Dr Burton, I want to ask you about your filtration process. Are you the only company working in this area or are there other prion filtration processes on the market?
Dr Burton: There have been other products developed by other companies. About the time we started work in this area, a US company called Powell Filtration was also developing their own prion filter. That fell by the wayside a few years ago in terms of issues with performance, I understand, in the case of what is called endogenous infectivity—the blood form of infectivity. With these filters, it is not really possible to undertake the development of them using vCJD blood, partly because there simply isn’t enough available because we are processing whole units of blood here, and partly because we need to have some measure of how much infectivity we combine and, therefore, the brain material tends to be used for that. There is a difference between the brain material and the blood endogenous material. The brain material can be relatively highly aggregated and relatively easy to remove by normal filtration, just removing small particles. Indeed, in the past, people often referred to “prion particles” because it was believed to leave some kind of particulate material. It was later that it became apparent that all blood components were infectious because there is a soluble form of infectivity there. That is the form that we need to address in the case of red cells and plasma. So developing these devices is not straightforward. It does require fairly meticulous studies conducted over quite a large period of time. Yes, other companies have been developing these products but not all of them have proven to be effective with endogenous infectivity, whereas the P-Capt filter that we developed has been proven to be effective.
Q130 Mr Heath: Have any of them been used?
Dr Burton: The company that we license to manufacture the product is Macopharma. They have made sales of this product in various locations. Macau province in China uses this material for their local expatriate population donating blood. Otherwise, in Europe, it has really only been used in relation to clinical studies. In terms of normal use, there has not really been any usage.
Q131 Mr Heath: When you were describing it, you were saying that it was designed specifically for the architecture of vCJD protein. That is what it binds to. Does that mean it does not deal with other prions?
Dr Burton: When we developed our product, we set out to have as broad a selectivity as possible for prions. We screened many millions of different types of compounds over a period of two years. At the end of that process, we had identified five compounds which were able to bind, reasonably selectively, the normal form of prion, sometimes called PrPC, and the infectious form of prion, sometimes called PrPSc. We looked at different sources of infectious prions. We looked at BSE, scrapie, hamster and all these different types of materials, so that, finally, the product that went into the P-Capt filter would have as broad a selectivity as possible for prions. There is a difference in binding. For example, we know that sheep scrapie does not bind as well as human, hamster or monkey prion, but there is some binding. So it gives a broader level of protection.
In the pharmaceutical industry, it is a well-established principle that during manufacture, yes, it is important to test for the presence of viruses, particularly with protein-based drugs—plasma-derived products, for example—but it is also important to have some capacity in the process to bind infectivity, if it is present. One feature of a test is that we can really only test for what we know. We can’t test for what we don’t know, whereas in a process, if there is some capacity to remove other things, if a new form of prion comes along in the future, a different animal source, there is some protection inherent in the processing that has been applied that may or may not be picked up by a test.
Q132 Mr Heath: That is really useful. At the risk of having an instant peer-review session of this, presumably, that would be complementary to any of the other processes which we have had described. If you reduce the potential number of infective agents within your supply, then you have less to deal with either by blocking, testing for them or anything else. Does anyone else want to comment?
Dr Burton: We view testing and filtration as being mutually compatible and desirable steps to take, rather than do you choose one or the other. If one really wanted a robust protection for blood against vCJD, one would implement both of these techniques.
Mr Heath: Yes. Does anyone else wish to comment? No. Thank you.
Q133 Jim Dowd: My question is to Dr Burton and following on from what David said, and also what you said in reply to Stephen earlier. I want to look, briefly, at the P-Capt device and its history. What I understood in your reply to Stephen was that you felt there was an initial encouragement to pursue such research and development but that the rules or the mood changed while you were doing this. When you said that one obstacle after another was put up, I understood that to mean—please correct me if I misunderstood—that that sounded as if there was a degree of artifice involved, that SaBTO did not want to endorse the product and simply looked for reasons for refusing.
Dr Burton: I can’t comment on how SaBTO makes its decisions.
Q134 Jim Dowd: But I’ve just asked you to.
Dr Burton: As I mentioned earlier, we did sense a change of mood. What we experienced at the beginning were comments to the effect of, “If you achieve a C-mark approval for your device, then we could implement it straight away without any additional testing.” When we got to that point, we were told, “Actually, we want to do our own independent testing.” At that point, we had already done safety testing in relation to the impact on red cells—for example, haema-compability studies and that sort of thing. We had undertaken our own safety study in human volunteers for transfusion of blood to show that there were no issues with that. Studies were under way in Ireland to do exactly the same thing, and then the UK Blood Service said, “We want to do our studies as well to demonstrate that the blood that comes out of the filter really is safe.” Initially, SaBTO, in 2009, made a recommendation that P-Capt filter blood should be made available to individuals born after January 1996, subject to the completion of a successful outcome of the PRISM study. As I mentioned, the PRISM study took much longer to complete than was thought.
Q135 Jim Dowd: There were also the efficacy evaluations, weren’t there?
Dr Burton: Yes. Later on, the issue of the repeating of efficacy studies came in. Various groups in the UK were performing these independent studies. There was a study with the HPA. They undertook a study to look at the binding of endogenous infectivity. The results of that study were shared with us in confidence. We had some issues with some aspects of that study, particularly the fact that the flow rate used was substantially in excess of the maximum recommended flow rate for the device, so there was a flaw there in the experimental design. Another study that was undertaken was a sheep study. As I have already mentioned, we know that sheep prions do not bind as well to human or other types of prions, so we don’t think that that is a fair and relevant measure of the performance for human blood. I think that those results have been taken into consideration.
We moved from a position that, as long as we gained the legal approval to have a medical device sold and used, which is a C-mark approval, it would not require any additional testing, yet we found ourselves going through successive rounds of additional testing.
Q136 Jim Dowd: Is it your understanding that either they could not replicate the results that you had obtained before you submitted it or they applied subsequent and different tests which you never did?
Dr Burton: They were, in their ways, different tests. We never performed a study in sheep because we didn’t think it was a relevant model for the device. As to the other study that was done, there were some differences in it. The filter was used outside its stated specification, basically.
Q137 Jim Dowd: Let me be clear. Are you saying that they tested it for things that it was never meant to do?
Dr Burton: They used the product in a way that it was not intended to be used.
Q138 Jim Dowd: From what you have just said, you are still supplying the P-Capts in other parts of the world.
Dr Burton: That is correct.
Q139 Jim Dowd: Have you abandoned any attempt to get it passed in the UK?
Dr Burton: No, we have not abandoned the product. Because of the very long developmental period, there is a limit to the appetite of companies to continue investing at a high level in a product if there does not seem to be a return on that investment. I would say that there has been a decline in activity around this particular product. Work is ongoing with another study. This is work that has been undertaken in France by the CEA laboratory. They have used the P-Capt filter to remove infectious prion from macaque monkey blood. This study is subject to some debate right now because the findings are quite interesting and somewhat unexpected.
On the face of it, what this study in France shows is interesting. The blood taken from monkeys that show symptoms of prion disease is separated in two ways. One undergoes normal leucofiltration, which is a white cell removal filtered step, and then given to healthy monkeys. Blood filtered through normal leucofiltration and the P-Capt prion filtration was given to another group of normal healthy monkeys. This study has been undertaken twice, I understand. The results of this study show that the P-Capt-filtered animals are all alive and well today—this is 66 months after the original transfusion took place—but all the animals in the non-P-Capt filtered group are dead, and they died after 30 months of a prion-like disease. This is the debate right now, as to what is that prion-like disease, because it is atypical in the sense that the lesions are not really centred in the brain, which is typical of CJD. It is one of the measures at autopsy that tissue histologists undertake, and, if there are spongy holes in the brain, that is very indicative of the CJD disease. That was not the case with these animals, where there were lesions in the spinal column. If that was a human case, that individual would not be diagnosed as having any kind of CJD. It would be a different diagnosis that would be made. It would be more akin to a disease called amyotrophic lateral sclerosis than CJD. So it raises some issues, but, in terms of the filter to remove infectivity from a primate model, which is the closest we can do right now to the human situation, it shows very clearly, in black and white terms, that the filter is very effective in removing the infectivity. It provides a very high level of protection in the case of that study.
Q140 Graham Stringer: One always comes out of these inquiries a little bit more scared than when we go into them. What emerging pathogen is the greatest potential threat to the United Kingdom blood supply? Scare us a bit more.
Professor Collinge: That is not my area of expertise. I am talking about prion risk, but I don’t know about other emerging pathogens.
Nigel Talboys: This is an area that we work on. In continental Europe today, through climate change, there are growing concerns over new pathogens that are emerging. In recent years, in Italy, we have seen an outbreak of a disease called chikungunya, which is a tropical disease that was brought into Italy in tyres through a vector called the Aedes albopictus mosquito. This closed down part of the blood service in Italy for a period of months to prevent this disease from spreading. Also, in France, there have been cases of Dengue fever and chukungunya through transmission by the Tiger mosquito, which is Aedes albopictus. In fact, these mosquitoes have been found as north as Antwerp in Belgium and, in 2013, these mosquitoes were found, again in tyres, from the far east, and also in bamboo. It is a fairly short trip across the Channel for these mosquitoes to come to the UK. As far as I am aware, they are not in the UK at the moment, but they do carry a number of different diseases. We have also seen that there has been an increased concern over hepatitis E. In the Netherlands, a study was done of blood donors in 2013 and it looked at donations of blood in 2011 and 2012. Of 45,000 blood donors, they found that about 17% of them had at some time come into contact with hepatitis E. If you are a healthy person, hepatitis E has a small risk, but if you are immunosuppressed, maybe a pregnant woman receiving blood or a patient with haematological malignancies, then hepatitis E can be more of an issue. In France, there was a case in 2013 of a blood transfusion of hepatitis E and now the French regulatory authorities are looking at this at a much higher light.
The technology that we manufacture is effective in reducing not only the known pathogens but also the emerging pathogens or some of these more difficult pathogens such as hepatitis E. Many new pathogens come along. One of the issues is: can you test for every single one? The answer to that is, probably, no. By implementing a pathogen-reduction technology, you are able to inactivate not only the known pathogens to close the window period, when used in conjunction with various testing methods such as nucleic acid testing, but also give a level of protection against those emerging or unknown pathogens.
Dr Raeber: May I just add one comment from a veterinary diagnostic company which has a strong focus on controlling synoptic pathogens entering the food chain, and that was the case with BSE? What we also see, and I confirm what the previous speaker just said with hepatitis E, is a high prevalence of hepatitis E in pigs. We have a test and there are certain prevalence studies being conducted in Europe. What we see there is frightening, especially as dietary habits have changed and people are more into eating not fully-cooked pork meat. This has a high chance of moving over into humans and, potentially, could be a hazard to the blood supply.
Q141 Graham Stringer: Mr Talboys, in your written evidence you say that in relation to these emerging pathogens we don’t assess them for risk.
Nigel Talboys: Yes.
Q142 Graham Stringer: Can you expand on that statement?
Nigel Talboys: In the UK, a very good system is in place today. There is a report called the Serious Hazards of Transfusion report, or the SHOT report, which has shown a very low incidence of transfusion-transmitted infections. However, with climate change, it is an unknown aspect. These new and emerging pathogens appear and can cause issues in the blood supply. Let me take another example, which is West Nile virus. In West Nile virus, there have been a number of tests that have been undertaken in the UK. There has been a potential increase in West Nile virus. We have seen in the US that, in the early 2000s, West Nile virus came into the US and, over a period of years, the incidence dropped down to a low level. In 2012 and 2013, there was a major increase in the number of incidents of West Nile virus. This got into the blood supply and there were increased incidents of receiving this in the blood supply. It is looking at these unknown risks, and it is difficult to risk-assess something that is unknown. We have seen the weather this year, with the flooding in the UK and the fact that there has been a very warm winter again. Can these vectors overwinter and start to bring in some of these tropical diseases that have been unknown in Europe for many, many years? That is what I see as the potential of how you risk-assess something that you don’t really know about.
Q143 Graham Stringer: I have recently re-watched “And the Band Played On.” I don’t know if you have seen the film. It is really about the United States Government’s response to the HIV/AIDS issue in the early and mid-80s. I suppose the film is a polemic against both the Government and the commercial interests in the blood industry where the people who controlled the blood would not do tests because they were worried it would damage them commercially. The point I am getting to is: how does our approach differ from that of other countries? If other countries are not as good at protecting their blood supply from pathogens, does that have any impact on our blood? Do we import blood from other countries?
Nigel Talboys: There is some limited importation of plasma into the UK, but the UK is predominantly self-sufficient in blood, particularly red cells and platelets. As I said earlier, the UK has a very, very good record of having safe blood. We are working with SaBTO on the report to look at pathogen reduction and pathogen inactivation of platelets today. This report is predominantly looking at bacterial infection and also the ability to replace gamma radiation from the use of platelets. We believe there should be a broader look at the safety of the blood supply, not only to look at bacterial infections, which are the largest infections that you see in platelets, but also to extend that to viruses and parasites as well. This is what we see now that other countries are starting to look at because of the emerging pathogens.
If we have a look at technologies across Europe, the technologies for pathogen reduction are used in most countries in western Europe today, not always on every single blood product, but they are starting to be adopted rapidly. As we are seeing in countries like Switzerland, there is a mandated use of pathogen reduction for platelets. We even see in Africa that now, because of the risk to their blood safety, they are starting to look at these types of technologies. As I pointed out earlier, we have a clinical study looking at the prevention of the transmission of malaria through blood transfusion. The clinical study is starting this week in Ghana. If we are successful on that, we expect to see the adoption of our technology in a number of different African countries.
Q144 Graham Stringer: My final question, which you have partially, if not mainly, answered, is this. What do you hope the current SaBTO working group on pathogen-reduction technology will achieve? You have partially answered that. I would be grateful if you would expand on it.
Nigel Talboys: There are a number of steps. We have to look at the adoption of these types of technologies in the UK to add a further level of protection to the blood supply. There are still a number of steps to go through. Each blood service has a different way of implementing these technologies. So the next step after the report has been published is to have a look at the technologies, to have a look at the potential validation of the technologies and to see how it fits into the particular process that we have in the different UK services, whether that is in England, Wales, Northern Ireland or Scotland. Let’s wait until the report is published in the next couple of weeks. Then I would see us moving on to a validation of the different technologies and then potential adoption after the validation of those technologies.
Chair: Can I thank the panel for their very comprehensive responses to questions this morning? If there are any additional pieces of information that you want to send our way, we would be extremely grateful, especially about some of the topics that were discussed earlier. Thank you very much.
Oral evidence: Blood, tissue and organ screening, HC 990 29