Oral evidence: Blood, tissue and organ screening, HC 990Wednesday 5 February 2014

Oral evidence, 5 February 2014.

Witnesses

Professor Marc Turner, Chair, Advisory Committee on the Safety of Blood, Tissues and Organs Prion Group, and Chair, UK Blood Services Prion Working Group, Dr Roland Salmon, Acting Chair, Advisory Committee on Dangerous Pathogens, and Dr Sheila MacLennan, Professional Director, UK Blood Services Joint Professional Advisory Committee, gave evidence.

Chair

Thank you very much for joining us this morning. It would be helpful if you could start off by briefly describing the remit of each of your bodies, explaining how this scientific advisory structure fits together.

Dr Salmon

Shall I start, Chair, as I seem to be back here? I am Dr Roland Salmon. I am a retired medical epidemiologist and I am currently acting as the chair of the Advisory Committee on Dangerous Pathogens. That is a long‑standing committee. It dates from the 1978 Birmingham smallpox outbreak and has a remit to look at really all infectious disease threats that may affect the country. Its initial focus was on laboratory safety and it is responsible for the document by which the safety of organisms worked at in laboratories is categorised, but it now has a broad horizon‑scanning remit. Finally, it has migrated from being a tripartite body with employers, employees and experts under the Health and Safety Executive for a number of years to being an expert committee of the Department of Health.

Dr MacLennan

Good morning, everybody. My name is Dr Sheila MacLennan. I am a consultant with NHS Blood and Transplant, but I am also the chair of the Joint Professional Advisory Committee of the UK transfusion services. Maybe I should explain a little bit as to what JPAC—as it is known—is about. This committee was initially set up in 1987 with the remit to ensure that the UK had a common set of guidelines for blood transfusion services. Since that time, in addition to the guideline role, it also has developed to act as a professional advisory committee to the UK blood services, and in that role it reports to the UK forum, which is comprised of the chief executives and medical directors of the four UK transfusion services. Looking at what guidelines we prepare, we do prepare and regularly update them to have operational guidelines for the blood services contained in what we know as the Red Book, which is now currently in its eighth edition. We also disseminate clinical guidelines for hospitals about transfusion practice in the “Handbook of Transfusion Medicine,” and we also own the donor selection guidelines. There are six donor selection guidelines currently: for whole blood and component donors; deceased and live tissue donors; cord-blood donors; and for stem cell donors. That is the range of guidelines that we manage. The work of JPAC is conducted through seven standing advisory committees, all representing different specialist areas of blood transfusion. Members of those committees are appointed for their specialist professional advice rather than as representatives of certain organisations or blood services. Most of them are actually taken from the UK blood services, but also we have members who are from hospitals and universities as well. The JPAC committee membership is made up of the standing advisory committee chairs, the medical directors of the four UK transfusion services, and we also have the medical director of the Irish transfusion service on JPAC. We have representation from the Medicines and Healthcare Products Regulatory Agency, from the Human Tissue Authority, a representative from SaBTO, and one from the National Institute for Biological Standards and Control. That is just a quick run through JPAC.

Professor Turner

Good morning. My name is Marc Turner. I am here representing the Advisory Committee on the Safety of Blood, Tissues and Organs this morning, of which I was appointed a member from its inception in 2008 and demitted towards the end of last year because I had fulfilled my term. SaBTO, as the name suggests, advises Ministers and the Department of Health, both here at Westminster and at the devolved Administrations, on safety of blood, cells, tissues, organs and gametes for human use. Also, in its terms of reference it has to take cognisance of other aspects, including sufficiency of supply, effectiveness of existing or proposed methods for risk reduction, cost‑effectiveness, and also, of course, give a degree of balance between the duty of care to patients and recipients, and also the duty of care to donors—particularly to live donors. The members are appointed by the Appointments Commission. There are 15 members, including an independent chair, and they have a spectrum of backgrounds. Some are haematologists, transplant surgeons, IVF specialists, patient representatives, and so on and so forth.

Chair

You have heard the evidence session earlier today. Are you confident that the organisations you represent are sufficiently independent, obviously given that most of the funding for respective works comes from Government? Is there sufficient independence in the structure?

Dr Salmon

I think the short answer is yes. These are independent scientific committees. The appointment is done by a public competitive process. The minutes, as far as is possible, are made available to anybody who cares to read them on the internet, and the emphasis is on getting the best scientific opinion available. I suppose I might add that none of the members are paid, so they have no particular immediate interest in protracting the deliberations or anything similar to that.[1]

Dr MacLennan

As far as JPAC is concerned, the members are appointed for their professional expertise, and in fact it is a professional advisory committee. Again, they are not paid. Their day job, as I say, is usually within the UK blood services, so within that remit I think they are as independent as they could be.

Professor Turner

Chair, I would give a similar answer to Dr Salmon for SaBTO. These are independent members appointed through a clear procedure.

Chair

Again, reflecting on the earlier evidence, how do you make sure that your best practice conforms to best practice globally? How do you integrate your scientific effort with that which is happening elsewhere?

Dr MacLennan

As far as JPAC is concerned, one of its main remits is to do external horizon scanning, and we have a lot of collaboration with other blood services throughout the world. I personally sit on a European committee that looks at emerging infectious diseases. That also has representation from Australia and America on that committee. I also sit on European committees. In fact, I currently chair a European committee on blood transfusion. So we do have a lot of collaboration from around the world.

Chair

As I understand it, the Australian link ties into Asia‑Pacific more broadly.

Dr MacLennan

Yes, absolutely.

Dr Salmon

The Advisory Committee on Dangerous Pathogens’ members are broadly chosen for the contribution they can make to introducing science to policy making. Therefore, they have considerable scientific standing in their own right. You can only acquire that by a process of research and publication, which, in a sense, requires you to be up to an international norm because it is an international pursuit. A number of the members, like Dr MacLennan, have membership of other international bodies, and I, for the sake of argument, spent nine years on the Conseil scientifique of the Institut de veille sanitaire, which is France’s health protection agency. My experience is similar to many of the other committee members.

Professor Turner

Again, my answer is going to be similar to Dr Salmon’s. The members of SaBTO are appointed on the breadth of their expertise, but they are all experts in their own fields and have connectivity, therefore, into their own UK and international networks. Where required, SaBTO asks for additional expert help either from other organisations or from other specialists.

David Tredinnick

Good morning. Could you explain why it is that blood donor risk assessment is carried out at a population level rather than on an individual basis, please?

Dr MacLennan

That is probably down to me. I think you are probably referring to the policy.

David Tredinnick

“On the basis of individual risk,” I should perhaps have said.

Dr MacLennan

You are probably referring to the policy on men who have sex with men donation specifically.

David Tredinnick

Yes.

Dr MacLennan

Probably two years ago, SaBTO considered the rules regarding men who have sex with men, and they did consider whether we could move to individual donor risk assessment in that review. The conclusion was that there was insufficient evidence available to be able to determine what the impact of that change would be on the level of risk. They also considered that, if there was an introduction of more extensive donor questioning, the donors may not like that and we may therefore lose some donors on that basis. If you look at policy worldwide, there are probably two countries which currently espouse individual donor risk assessment, but all other countries do it on the basis of evidence from population risk assessment. Some countries, including the UK, have moved to a temporary donor deferral on that basis, but the rest of the countries in fact still keep the lifetime ban. But this is not set in stone, and there is a European group now trying to look at what the risk might be if you did move to such a policy. Also, NHSBT is currently conducting a survey among blood donors looking at what the perception is among donors about the questions that they are asked. So I think, in summary, this is an evidence‑based decision and, if we were to have further evidence to say that we should change it, then we would look at that.

Dr Salmon

I would comment on men who have sex with men, but it is fair to say that the blood service—and indeed many other screening services—aspire to offer an individualised service. But the question is about having the tools that allow you to individualise that risk. If we consider the CJD example, the Advisory Committee on Dangerous Pathogens is very clear that the further development of a blood test so that it could be used would be enormously helpful in that regard; that would allow an individualisation of risk and would certainly reduce the need for approaching the population on a rather crude population basis, with a group of haemophiliacs here, a group of people who have had certain types of surgery there and so on. But you do need the tools to be able to do that.

Professor Turner

I would add that an individualised risk assessment is an ideal. We would require the evidential basis, as my colleagues have said, on which to build those risk assessments. There are also, I think it is fair to say, practical problems and issues. For example, we have around 200 different categories of donor deferral criteria, and we will screen, say, about 7,500 blood donors per day across the United Kingdom. Of course, many of those sessions will be taking place in the community, in village halls or community centres, where sometimes privacy is not as contained as it can be in a custom‑built donor centre. So there are practical problems to an individualised risk assessment for every specific donor.

David Tredinnick

Moving on from that, how many blood donors who are temporarily deferred actually return once the deferral has ended? Of those who do return, how quickly do they do so?

Dr MacLennan

About 30%, the current data suggests, do not return. I am sorry, what was the second part of your question?

David Tredinnick

Of those who do return, how quickly do they do so?

Dr MacLennan

I am sorry I do not have that data, but I could probably find that out for you.

David Tredinnick

You can write to us, okay. Finally, are your advisory bodies currently considering any changes to blood or organ donor selection policy? If they are, what are they, and when are these decisions likely to be made?

Dr MacLennan

Changes to blood and organ—

David Tredinnick

Are your organisations currently considering any changes to blood or organ donor selection policy? Are they proposing any changes? Is there anything out there that you are about to announce? Do you have any plans that we might want to be aware of?

Dr MacLennan

We are constantly looking at changing donor selection criteria. Examples of ones that are currently being implemented are that we have just announced a change to donor deferral for people who visited the French West Indies, because Chikungunya virus has suddenly appeared in the French West Indies and we did not have a deferral in that region. In fact, we constantly monitor where diseases are and the effectiveness of our travel deferrals. As to other ones that we are about to implement, we are removing a donor deferral criteria for patients who are now on Tamoxifen for prophylactic purposes, whereas before they would have been deferred. We are also adding a new medication to the skin disease category for donors—a new medication that can potentially cause problems in recipients. We are also reviewing the entry on mental health problems to allow donors on some medications to donate, which will mean that we get more donors. We are also planning a study to look at the risk around body piercing, particularly acupuncture, to see if we can change and improve the donor selection criteria on that. So we are constantly looking at new donor deferral criteria changes.

David Tredinnick

Finally, on that last point, do you mean more and more people are turning to acupuncture first, very often when they do not want to have drugs that they think might have side‑effects, so they will try that system? What is your experience of it and what do your studies show?

Dr MacLennan

The main potential risk is infectious disease that could be carried by needles. At the moment there is not the evidence base to say that this is definitively safe. That is what we are going to be looking at.

David Tredinnick

But most of the acupuncturists now use throwaway needles; they are not re‑used at all.

Dr MacLennan

Yes, absolutely. That is the sort of risk that we are going to look at, yes.

David Tredinnick

That is almost all of them; there is no risk. Thank you.

Jim Dowd

I want to look briefly at plasma products. Since 2004, we have used foreign‑sourced, overseas‑sourced, fresh frozen plasma as a vCJD risk reduction measure. Can I just ask first off are we sure that the stuff we are now using for those born after 1996, while minimising the risk of vCJD contamination, does not contain other harmful viruses, such as West Nile, for example?

Professor Turner

The United Kingdom started importing plasma for the manufacture of plasma products in 1999, as the speakers earlier this morning said. I believe that we started importing fresh frozen plasma—so clinical plasma products—for those born since 1 January 1996 in 2005. I think that was an MSBTO decision. MSBTO was the predecessor of SaBTO. The plasma is sourced, to my recollection, from other European countries which will have a lesser incidence, certainly, and therefore a presumed prevalence of sub‑clinical variant CJD. They should all comply with the EU Blood Directive and therefore be applying similar standards to ourselves of donor selection and screening. The plasma is also treated with a compound called methylene blue, which will inactivate most, not all, bacteria and viruses. Finally, I do not think, since 2005, that we have seen any instances of transmission of infection by FFP, including that which is imported. [2]

Jim Dowd

Can I go on then? It is only used at the moment to treat those born after 1 January 1996, and UK‑derived plasma is still used for those born before that. Why the difference? Why not just use the fresh frozen imported plasma for everybody?

Professor Turner

SaBTO looked at that issue—I am sorry I can’t remember the date—in around July 2009, I think, but I will clarify that for the Committee, and then again more recently in 2012 and concluded that importation of FFP, clinical plasma, for all patients was not cost‑effective by most yardsticks.[3] Clearly, there is a wide confidence interval on estimates because of the uncertainties around issues such as the prevalence and infectivity of variant CJD, but in the order of magnitude it was between, say, about £250,000 per quality-adjusted life year and several tens of millions per quality-adjusted life year.

Jim Dowd

That is quite a staggering difference. Is that because of the proportions of those being treated who were born after January 1996 compared with those before? Do we have any idea what the proportions might be?

Professor Turner

I cannot give you the precise figures, but obviously people born after 1 January 1996 are still very young, and what we tend to see in terms of overall blood usage is fairly high blood usage in neonates and then it drops very rapidly, and of course in children and young adults it is low. Then it builds as we gracefully age. So, proportionately speaking, a lot more clinical plasma is used in the older population.

Jim Dowd

So it would be pre‑1996.

Professor Turner

Yes.

Jim Dowd

Both the Haemophilia Society and the British Committee for Standards in Haematology have suggested that we discontinue the use of cryoprecipitate and replace it with fibrinogen, which apparently is what everybody else in Europe does. We are the only country that continues with cryoprecipitate. Do you agree with that and, if not, why not?

Professor Turner

SaBTO looked at the issue of cryoprecipitate again in 2009 and was very concerned because, generally speaking, quite a lot of cryoprecipitate is still used in not well‑founded clinical indications. That is a matter of concern. Nevertheless, there are well‑founded clinical indications. SaBTO was certainly, in broad terms, in favour of us using fibrinogen concentrate. Unfortunately, at that stage, at that time, commercial fibrinogen concentrate was not licensed in the United Kingdom. Now, it has subsequently become licensed in the United Kingdom. My understanding is that it is licensed for patients with congenital hypofibrinogenemia, as we call it—an inherited disorder in which you do not produce enough fibrinogen—but not in what we call acquired hypofibrinogenemia. Your fibrinogen can fall very low, for example, if you have a major road traffic accident or you have major liver disease, for example. The vast majority—not all—of cryoprecipitate is used in those acquired circumstances. So, while individual doctors can prescribe fibrinogen concentrate off licence, it becomes then very difficult for an Advisory Committee to advise doctors to do that because that is going against the licensing of the product within this country. So there is a legal and regulatory issue in there.

Jim Dowd

So you are saying that because it is currently available perfectly legally and properly—

Professor Turner

Yes, yes.

Jim Dowd

—you could not advise anybody not to use it. You could not say, “Just use the fibrinogen instead.”

Professor Turner

I personally could as a doctor, but it is very difficult for an advisory committee or, indeed, the Government to say, “Doctors, you should use this product off licence.” You are right that the vast majority of European countries do use fibrinogen concentrate. I think, apart from us, there are one or two other countries like Estonia and Latvia that use cryoprecipitate, but I am afraid I am not familiar enough with their legal and regulatory environments to know what the differences are between their European setting and ours.

Jim Dowd

Thank you.

Stephen Metcalfe

Good morning. I want to talk a bit about viral inactivation and prion filtration reduction. The Haemophilia Society has told us that UK blood products do not currently undergo any viral inactivation. Is that accurate? If so, why?

Professor Turner

The plasma products that are imported do undergo virus inactivation, but they are commercially manufactured products. The vast majority of blood components do not undergo microbiological inactivation, apart from, as I described to your colleague, fresh frozen plasma, which is imported. There are currently no licensed pathogen inactivation systems that are applicable to red cell concentrates, which of course are the majority of the products that are used. There are two, to my knowledge, pathogen inactivation systems—potentially three—which are licensed on a European level for platelets. SaBTO has recently revisited pathogen inactivation for platelet concentrates, balancing that against current methodologies, which include, of course, intensive testing of donors by both serology and nucleic acid testing, and, in terms of bacteria, stringent cleaning of the donor arms and BacT/ALERT testing. That was reviewed in December, and I believe the minute and papers of that meeting will be published very soon.

Stephen Metcalfe

Originally your committee did approve the filtration.

Professor Turner

I am sorry, but I was talking about pathogen inactivation very specifically.

Stephen Metcalfe

Okay, but that process was approved, was it not, in 2009 by your committee, and then the recommendation in December was that it was no longer approved? Is that correct?

Professor Turner

No, that is prion filtration.

Stephen Metcalfe

I am getting confused, I am sorry. Help me out here.

Professor Turner

Pathogen inactivation will deal with microbiological agents—the viruses and bacteria, for example—but it will not deal with prions, which do not have a known nucleic acid component. In terms of prion filtration, if one goes back to 2006, there were two or three companies working on so‑called prion filtration technologies. So that you understand, they are not really filters in the way that you and I might think of them as size filters; they are resin ligands, which have an affinity for the abnormal conformer and bind them. So they are affinity filters, as it were, rather than size filters. One of those two companies withdrew from a CE mark filter, but the other continued to develop its filter. In 2006, SEAC—the Spongiform Encephalopathy Advisory Committee—and MSBTO expressed concern that the CE marking process, while clearly necessary for these kinds of devices, was not sufficient in terms of either demonstrating their efficacy in the real world of removing prions from red cell concentrates or, indeed, their safety, and they asked UK blood services to commission and carry out a number of independent studies. So a series of clinical studies were carried out by UK blood services—the so-called PRISM A study—which broadly showed that the filters were safe and were not causing any adverse impact to patients. There was a complex set of independent effectiveness assessments carried out, both a primary set using crude brain homogenates, and then a secondary set using various kinds of animal models. Those were carried out by the Health Protection Agency and by the Roslin Institute respectively. SaBTO reviewed the outcome of all of that data in December 2012 and on the basis of that data decided not to recommend a prion reduction.

Stephen Metcalfe

I am not sure if it is the report that came to that meeting—it has been redacted anyway—but you talk about the two studies, one being the hamster study and one being the sheep study, presumably.

Professor Turner

Yes.

Stephen Metcalfe

It says on here that the peer‑reviewed journal information will be published in due course.

Professor Turner

Yes.

Stephen Metcalfe

So at that point it had not been published, presumably, when this was being drawn up. Was there a subsequent—

Professor Turner

Correct, and, fortunately—or unfortunately—quite a lot of the minutes are quite heavily redacted because of commercial confidentiality on the part of the company itself. If the Committee want to see the unredacted minutes and papers, my suggestion would be for you to request them from the Department of Health and from the SaBTO secretariat. I am aware that the independent hamster studies have been submitted for publication, but I do not believe they are published yet. The sheep studies, I am sure, will be submitted for publication in due course.

Stephen Metcalfe

When this decision was being made, was that information available?

Professor Turner

Yes.

Stephen Metcalfe

So you have seen it; it just has not been published.

Professor Turner

That is correct.

Stephen Metcalfe

I am going to attempt to put words in your mouth, so stop me if I get it wrong. I think what you are saying is that the system is safe but it was not deemed to be clinically effective in great enough numbers. Is that right?

Professor Turner

Yes.

Stephen Metcalfe

Was, therefore, the decision to change your opinion from three years earlier unanimous at that meeting?

Professor Turner

Yes.

Stephen Metcalfe

It was; thank you. That is useful and we look forward to having a look at the redacted minutes in due course. Are there any other ways of removing prions from blood supply and also, presumably, from instruments and anywhere else that they may be found? Are there good systems or procedures in place to do that?

Professor Turner

I will not speak to surgical instruments because they are outwith my expertise, but, in broad terms, the kind of intensity of disinfection one would need to destroy the prion agent would destroy cellular material. So, from the perspective of blood components, there is no disinfection that will not destroy the product, which is why companies worked, quite rightly, on trying to remove the product rather than disinfect it.

Dr Salmon

I will have to speak for surgical instruments, though forgive me in that I do not pretend in any way to be an expert either. You will have received some evidence from the decontamination science working group, and this summarises quite nicely the potential things that you can do to reduce prion infectivity. It perhaps should be remembered that, although a residual prion infectivity is extremely resistant to heat, actually heat does reduce it. But in terms of reducing that residue of infection, which is what represents the risk from a number of types of surgery, it has been made clear that, if the practice could be changed to keeping surgical instruments wet before they went through the washer disinfectors, this would represent progress. Of course, this would represent something of a sea change in the way work had been done, because, historically, to reduce the risk of more conventional infections to the staff, they had been encouraged to dry them out. So you are having a process change here. As to the systems for detecting protein so that we can have a better idea of the efficacy of cleaning processes that are being developed, I understand there is potential for developing coatings for instruments, though I think that would have to be a long‑term solution, and there are some novel detergents. You will recall hearing from Professor Collinge last time about one of those. Again, with all of these, as I understand it—and, as I say, I would counsel you to talk directly to experts in decontamination and sterile supplies if you want to pursue this—the problem is not so much in getting products that may work, or work to a degree, but getting them in a way that they can be introduced into what is in effect an industrial‑scale process.

Stephen Metcalfe

Thank you very much.

Stephen Mosley

Dr Salmon, your advisory committee has recently considered the fact that not everybody who is at risk of CJD has been notified of that risk. When you were discussing it, you did decide that those people should not be notified of this risk. Could you explain how your committee reached that decision?

Dr Salmon

Yes, I can. As I say, one of the many things we will have gleaned from the earlier session is that bearing news to someone that they are at increased risk of vCJD for public health purposes is not a simple task. Although some people may be very sanguine about that information, for others it has a very difficult and destructive effect. As I say, we heard some very important testimony, I think, in that regard. There are a number of difficulties in identifying the group of the multiply transfused—those who have received large numbers of transfusions—that are really even more extensive than those of identifying haemophiliacs. They are not by and large under single centres. They may have been multiply transfused for a variety of reasons. Much of the activities would have been done locally and so there is no easy, centralised record keeping that you could go to. Of course, because we are talking about a rather heterogeneous group of people in a rather heterogeneous set of circumstances, it is even more difficult to be certain of what the theoretical risk might be. I don’t like this phrase “theoretical risk,” and I noticed that some of the Haemophilia Society did not like it, but I can’t think of a better one. When that was weighed up, a larger proportion of the committee felt that the disbenefits of pursuing that course of action would outweigh any benefits—not theoretical benefits—from preventing infection. As I make clear, this was not a unanimous decision and there is an important minority of the scientists involved who thought that just to remove some of the risk from some of the people whom you could identify more easily—in effect, that would have been people with certain haemoglobin disorders who do tend to be under centralised clinics—would have been worth doing. So we felt the only scientifically honest thing to do here was to convey both sides of the argument to the Department of Health, which, after all, has scientists in-house—the chief medical officer and the chief scientific adviser. Although we accept that this, in some ways, vitiates the usefulness of an expert committee, I suppose it at least does illustrate that some of those concerns that we somehow represent a monolith that just reflects back received wisdom is not in fact the case.

Stephen Mosley

In October last year the British Medical Journal published some research funded by the Department of Health that showed that one in 2,000 people tested positive for the abnormal prions. Those people are at risk, they have been tested and they have the abnormal prions. Should those people be notified that they are at risk?

Dr Salmon

If it was possible to establish who they were or if we had come to know of them by some other route, the answer would have been yes. The fact is, though, in terms of the construction of that study, the samples were absolutely unlinked from the information about who the individuals were, using techniques that were originally developed to do anonymous blood surveys at the start of the AIDS epidemic. It was done precisely because there would have been no treatments that could have been offered, and the implications of this advice are rather uncertain. Even if we felt that this might be a desirable thing to do, the way the study was set up intentionally leaves us in a position where it cannot be done.

Stephen Mosley

Okay. Moving on to something slightly different, it has been suggested to us that “at risk” individuals should be subject to post mortem examinations to determine the level of abnormal prions. Do you—and I am asking all three of you now—think that would be in the public interest? Would that be useful?

Dr Salmon

Perhaps I will start. I think this was the suggestion of Dr Sheila Bird, who is a very brilliant biostatistician and very passionate about public health causes. I do not think it is a terribly practical suggestion because I do think people expect a degree of autonomy about how they dispose of their bodies or how they dispose of the bodies of their relatives. I see no problem in encouraging that group of people to come forward for post mortem. That said, I think the gentleman who was giving evidence at the far end in the earlier session made a very telling point in that, if we could arrive at the point where we had a reliable blood test, that would probably represent a simpler and more efficient route to assessing the risk of this generalised group.

Professor Turner

This is not really a SaBTO issue, so I will give a personal view, and that is that I would strongly encourage such people to agree to a post mortem. But in terms of respect for the autonomy of people, for it to be compelled would for me personally be a step too far.

Dr MacLennan

I entirely concur. Again, this is a personal opinion, but I would not want to force a post mortem on people. To encourage that to happen would be the best route.

Dr Salmon

I might say this represents partly a personal issue but it was a reflection of the Spongiform Encephalopathy Advisory Committee at the time. We felt it was regrettable that an agreement was not able to be made with the coronial system and the coroners so that where people were going to have post mortems anyway the brain tissue could not be examined for evidence of prion diseases. Much as I have a great deal of confidence in the figures that are issued by the CJD Surveillance Unit for the characteristic forms of the disease, there does exist a scientific question to what extent there might be atypical forms, particularly in older populations, and this would have been a potential way to have got a handle on that. So, as I say, the fact that an agreement could not be reached with the coroners was very regrettable, and that was an observation that the Spongiform Encephalopathy Advisory Committee, whose responsibilities we have taken over in the ACDP, made at the time.

Stephen Mosley

Expanding on that a bit, we heard in the earlier session that some family members were sometimes prevented from doing their own testing or using other testing systems on people. From your own perspective, does that sound right, should that happen, or do you think people should be able to use their own testing methods and people outside the UK to do the tests if necessary?

Dr Salmon

Let’s put it this way, and let me perhaps preface these remarks by saying that I am neither a select scientist nor a Government official. As I stated at the outset, I am a retired public health doctor. I do not altogether recognise the accounts of my colleagues in the CJD Surveillance Unit and the MRC Prion Unit from the evidence session you got before. I have always found them to be extremely conscientious and committed individuals, who have given their professional lifetime to addressing these diseases. In many ways, for that reason, they would be the people, if it were my choice, I would have chosen to have sent my specimens to. One of the problems that you have—well, it is not a problem; it is a good thing—is that, mercifully, this remains, in terms of clinical diseases, a rare disease, and where you have a rare disease, if you wish to make progress, you do have to concentrate the resources. I am kind of saddened that this is somehow perceived as a dysfunctional monopoly. I don’t see many other solutions. You could not have a great proliferation of units, and I would worry if this material that will bring an understanding to us was to be widely disseminated round the world to groups that, potentially, could be of very varying standing.

Chair

Just carrying on with the question of testing, you heard the exchange about a test that may be 70% sensitive. Are there any circumstances in which you think that such a test would be useful?

Dr Salmon

I certainly can think of some, but I might let the blood services go first, if only because they are much more mindful of the practical difficulties than I tend to be; but I will come back.

Professor Turner

Thank you, Dr Salmon. First of all, I would say that the colleagues in the Prion Unit are to be credited on the test that they have developed because the difficulty of developing assays in this field should not be underestimated. These diseases are not like, as I said earlier, microbiological agents; they do not raise an immune response, and they do not have nucleic acids associated with them. So the normal approaches we take for HIV and hep B are not, for example, applicable in this kind of context. Looking back a decade or so ago, there were probably—I don’t know—a dozen or more different research groups and commercial companies working in this space. Now there are really only two or three research groups still working, of which the most advanced test by far is the Prion Unit assay. My personal view is that 70% sensitivity in clinical variant CJD is pretty good. Would I like 99%? Yes, I would, but that is as good as the test is at the present time, and certainly no other test currently has shown the ability to detect infectivity in the blood of people with patients with clinical variant CJD. Professor Collinge’s team have also just published on 20 January, I think, a study of US samples that showed no positives among 5,000. That gives a statistical false positive rate with 99% certainty of about 0.1%, so that is repeat reactive, which is about similar to that which we see—repeat reactivity—in other tests that we use. So I think the test has moved forward a long way. SaBTO has not taken a view on the most recent data, so I will express a personal opinion, if I may. I would have thought that the next logical step would be some form of prevalence study. There are a number of issues that need to be considered. First, the tests obviously are research‑based tests currently within the Prion Unit laboratories, and if you are going to test 25,000 or 50,000 individuals it will need to be brought into an operational high-throughput format to achieve that. We need to look at, and indeed the UK blood service is looking at, what we call confirmatory assays. These are other assays that work in a different way, which can be used specifically to test those individuals who come up positive to try and determine whether they are truly positive or false positive. I think we need to give deep consideration to the issues which, Mr Mosley, you raised around how a prevalence study would be structured. Really, I think there are two options: either the donors to the study give fully-informed consent, traceability is retained, and if they are positive they are contacted and informed, in which case I am sure they would be managed as “at risk” for public health service purposes; or it is set up as an anonymised, unlinked and unimputable study, in which case we recognise that what we are looking for is prevalence in the general population and we will not be able to re-identify and go back to those specific individuals. I think ethical consideration has to be given to which of those two strategies is appropriate.

Chair

I can certainly see the ethical issues. I want to push you a little harder on why, with its availability, a test that, let us say, is 70% is not routinely used. I presume that a test that is closer to 100% is going to generate fewer false negatives and false positives than something that is lower down the spectrum. Am I right in saying that applying this test now would inevitably produce more samples that were subsequently deferred and, therefore, would have cost implications?

Professor Turner

If we accepted the sensitivity of 70%, that means that one may miss 30% of people who are infected but not showing up in the test. My personal view would be that it would be nice if it was better, but at least you would pick up those 70% of individuals; so that would be good. The false positive rate—that is, what we call the specificity, the 5,000 normal US samples—looks quite good. We would certainly want to have in place confirmatory assays so that, first of all, we minimise the number of people we were wrongly telling they were positive, and, secondly, that, when we did approach a person to inform them that they were positive, we were very clear that that was a true result. Studies that we have done with blood donors show in broad general terms that, if they thought we had a very good test and that when we said they were positive they were positive and when we said they were negative they were negative, they would accept that as they accept testing for HIV and hep B and so on and so forth. If they felt it was a poor test, then there would be great concern among the donors that they were being tested in that way. From a practical perspective, right at the moment, one of the significant issues for the Prion Unit assay test, of course, is that it is a very research, labour‑intensive test. UK blood services test around 7,500 individuals a day, 2 million to 2.5 million a year. We could not apply that test as it is currently formatted into that context, and I think this is principally what Professor Collinge is referring to when he says he needs to try and get across that valley of death from a research‑grade test into something that is manufactured by a test‑making company to the kind of scale, standards and robotics and so on that you need for that magnitude of testing.

Dr Salmon

I am glad I let Marc go first because it is precisely some of these operational issues that I did not feel unduly confident to comment on. In terms of the test as it exists now, I certainly think there will be a great deal of scope for using it in a research context, as he suggests, either as a population prevalence study or, conceivably, on a sample of blood donors. The actual detail needs quite a bit of thinking through, but we are at the stage where we ought to be thinking about how we would do that. I notice that Public Health England have what, in a sense, amounts to a précis or almost a research proposal in their evidence. While I suspect it constitutes a bit of an advert, none the less I would commend the Committee members to have a look at it because I think it sets out rather nicely the sorts of things we could do. Before I finish on this, the Department of Health seemed to be committed to this inasmuch as on page 2 of their evidence they mention that, “A blood test for vCJD may be advantageous for both health protection and possibly prevalence study purposes.” Then, on page 4, if I can find it, in paragraph 63 they regard as a key issue maintaining a balance in the costs and benefits “of additional risk reduction” and the “appropriate definition and handling” of individuals defined as “at increased risk,” both of which you would have thought were things that required a blood test. So I see the commitment there, but it takes a bit of decoding, and I suppose I would just express slight regret that a statement of support for developments of this nature, whoever makes them, was not a bit more explicit.

Chair

So you would like to see more action from the Government in, specifically, the Department of Health.

Dr Salmon

I think the Department of Health have to front a lot of these things. You may recall, as I mentioned before, I consider that they are possibly constrained rather by sections of Government that are even higher than they are, but I think this is one area where they could usefully make a very explicit statement of intent, yes.

Chair

Is that agreed across the panel? I know, Dr Salmon, in your retired position, you are feeling more comfortable—

Dr Salmon

Exactly. I was about to make the point, Chair, that I am in a privileged position.

Professor Turner

I would say it is a shared responsibility now for UK blood services, Public Health England, the Department of Health and others to look at the most recent published data from Professor Collinge’s group and consider whether it is practical to run a prevalence study.

Dr MacLennan

I have to say this is not my main area of expertise at all, but, going back to your question of whether a 70% sensitive test is worth implementing, I do not see that it is an issue because it is 70%, but obviously all of the other criteria would have to be addressed first to make sure that this is a useful test within the blood services that does not create too many false positives, as outlined by Marc.

Chair

So there is a lot more to be done, and it is not just in terms of the victims and their families that there are cost-benefits in getting tests in place that can deliver the kind of answers that you as clinicians would want.

Dr Salmon

I think that is a very fair summary, Chair.

Chair

Thank you very much for your evidence today. Oral evidence: Blood, tissue and organ screening, HC 990 21 [1] The witness later clarified that, “I do realise, however, that I have unwittingly misinformed the committee. In discussing the independence of the committee I claimed that the minutes of ACDP were made available on the web. In fact, although this is ACDP's intention and indeed we resolved to do this at our most recent meeting on 10 February, this hasn't been done hitherto. The confusion was mine. I sit and have sat on various advisory committees, some of which currently do publish their minutes and simply got muddled. That said, there have been for some time annual summaries of ACDP's work published on the web and these quote extensively from minuted discussions and the minutes are anyway, disclosable under Freedom of Information legislation. Thus, I feel that the sentiment of what I expressed, concerning the committee's independence, was perfectly accurate. Nevertheless, for the record, I recognise that the detail should be accurate.” [2] The witness later clarified that, “In summer of 2011 there was a transmission of hepatitis B (HBV) from a donor with very low level viraemia which was not picked up in the routine nucleic acid screening. The recipients of the red cells and FFP were infected.” [3] The witness later clarified that, SaBTO considered importation of clinical plasma (FFP) on 14 July, 15 July 2009, and 9 March 2012.