Mr David Curry, Chairman of the EFRA Select Committee, with Professor David King and Dr Alex Donaldson on April 25th 2001.
(The question is about the use of the Real-Time PCR device)398. I will ask a strictly scientific question now. On 9 March, Dr Alex Donaldson received an e-mail from Roger Breeze, who is the Assistant to the Head of the USDA in America, Floyd Hall, asking if he could co-operate with Pirbright, using a machine which he describes as a "real-time PCR", which, as I understand it, and I am not a scientist, is a machine which will identify a virus in the saliva, or from a nasal swab, of animals that are infected with foot and mouth before they show symptoms. Now this I was told yesterday by Professor Fred Brown, from Plum Island, who was over here for a day; and, as I understand it, he received no reply. If this machine is as accurate as Professor Brown told me, he said it is 99 per cent accurate, could it not have saved this huge, vast, expensive cull of mainly healthy animals?
(Professor King) Could I answer this, first of all, and then, of course, I will ask Dr Donaldson to deal with your specific query. The question of the so-called 'smart cycler' is one that was brought to my attention in a discussion I had, very early on, with Fred Brown; so, here, I am simply telling you that, as Chief Scientist, I got on the telephone and 'phoned the experts around the world, and Fred Brown was one of those. And Fred Brown told me about the development of the 'smart cycler' and also told me that he had already had somebody get in touch with Dr Donaldson. Of course, we have investigated the potential use of this instrument; it is a PCR-based instrument, which means that it is based on a polymerase chain reaction, where the virus contains RNA, you multiply the RNA through this chain reaction and it becomes very readily detectable, so it is a means of detecting the virus. The world's experts in this application of foot and mouth are Dr Donaldson and his team at Pirbright; they did not develop this in-field machine, that was developed in the United States for the use of the military. Now it is commercially available, but it is an untested machine and there are very serious questions to be asked about the use of that machine in the field, in particular the problem of cross-contamination. Now I have to stress that, if you are under laboratory conditions, Chairman, and you carry out these tests, you do get very accurate results. In the field, it is considerably more difficult to achieve this type of accuracy, particularly if you are going, as you want to do, to analyse a large number of animals, from animal to animal. And that cross-contamination problem has not been answered. We would like to see very distinct field tests on this instrument; but my final conclusion, from talking to all the experts, including Fred Brown, is that, unfortunately, it will not be available to us for this epidemic.
(Dr Donaldson) I will give you the background. I have not got the correspondence with me, but I have copied it to OST and I am quite happy to make the correspondence available to anyone else who might want it. I have known Roger Breeze for many years, he was a former Director of the Plum Island Animal Health Laboratory in the United States, where Dr Fred Brown is also based at the moment. In March, Dr Roger Breeze contacted me and said that he, working with the US military, had this 'smart cycler' equipment available, and he and his team would like to come to the United Kingdom and to test the equipment under field conditions to validate it during an outbreak situation; he was optimistic that it would be very helpful. He did say, in his correspondence, that the machine had not been validated for work with foot and mouth disease. I approached Jim Scudamore, Chief Veterinary Officer, and asked if this could be facilitated. Jim Scudamore's response was that he was very interested in the equipment and he would be very willing to collaborate with the USDA, but he suggested that this should be done after the epidemic had declined because there would be logistic problems in taking such equipment into the field. I sent a reply back to Roger Breeze, saying that the Chief Veterinary Officer was not willing to accommodate him at this particular point in time but would be willing to do so at a future date. I said, meantime, I would be willing to accommodate a scientist from the USDA at the Laboratory in Pirbright to test his equipment under standardised conditions, alongside PCR equipment which we already had and which is up and running and functioning. The particular attraction of what the USDA have been offering is that their equipment is portable; it is a small device, operated by a battery, which can link to a lap-top computer, and that, in turn, can convey the output of the test result through the Internet. I should point out that the piece of equipment costs in the region of £22,000, and there was no indication of what would happen to the equipment once it had been taken onto an affected farm, in other words, how it will be decontaminated. So I expressed that view, that we would be willing to collaborate, sent that back to Roger Breeze. The next communication I had was on a Thursday, saying that he, Roger Breeze, and his team would be arriving the following weekend to test out the equipment. I said that would not be convenient, that we would have to arrange a time to accommodate him in the Laboratory when we could find space and to do it properly. He, in turn, offered to show the equipment to us over the Internet. It was pointed out to me by colleagues that one of my scientific staff was about to make a visit to Plum Island and it would be an opportunity for him to see the equipment, which we understood had been developed in collaboration with Plum Island. That scientist went to Plum Island, he was hosted by Dr Peter Mason, who is the foremost molecular biologist at Plum Island, he asked to see the equipment; the response he got from Dr Peter Mason was that he had heard about the equipment but he had not seen it nor had he been involved in any validation of it. Subsequent to that there have been the pressures from Dr Fred Brown, I believe, through different channels, to have the 'smart cycler' tested. Since that time, I believe, Jim Scudamore has offered the services of MAFF. We had a visit last weekend from a Mr Mike Tass, I believe, who offered to take some of our equipment, which is portable, into the field and to test it alongside anything else that might be forthcoming, from whatever source; because I should add that the 'smart cycler' and other offers from the United States are not the only ones we have had. The normal scientific approach when pieces of equipment like this are represented is that data is provided to show that they do operate, and when that data is available through the scientific press then one can start looking at that data in relation to well-established, gold standard methods. That is the normal scientific approach. I would add and emphasise that we have no data from the Americans about the performance of their equipment for foot and mouth disease - they may have used it for other agents, I am not sure; and, I would repeat again, I have no indication that their equipment has been validated. So, I think, there we are, we are still willing to accommodate the Americans. Mr Jim Scudamore has offered, I think, to accommodate them in the field, and, well, we are willing to help if we can.
Jan 1-6 ~ "we did attempt to validate Fred Brown's test and it didn't pass the validation"
said Professor David King on the Today Programme (Dec 18)
We will remind readers again of what actually happened since Professor King doesn't seem to remember. Here is an extract of the letter sent as evidence to the Royal Society Enquiry
It was also sent to the Lessons Learned Inquiry and given by hand to Lord Whitty
...Our real time PCR assay for foot and mouth disease (W) has been validated in the laboratory: it has proven to be a pre-clinical test for infection in cattle, swine and sheep, it detects all 7 serotypes of FMD virus and differentiates this infection from other viral diseases that cause similar clinical signs. The test is more sensitive than viral culture and will detect as few as 10 virus particles....The research paper with these results appeared in the Journal of the American Veterinary Medical Association.
Some eight months after we had disclosed the existence of our x;h/lD test to Dr. Donaldson, we read in the Veterinary Record that the Pirbright Laboratory had subsequently established a relationship with Cepheid and conducted some experiments with FpvfB reagents supplied by that company (data published by Alex Donaldson and others in the Veterinary Record, 2001).
I have no idea what those reagents were because the paper does not describe them. But I can be sure that these reagents were not those developed by USDA-ARS and Tetracore because Cepheid does not have this proprietary information.
I hope there has been no confusion in Britain between the Cepheid mystery test and the real time PCR test developed at Plum Island...."
For Prof King to continue to suggest that "we did attempt to validate Fred Brown's test" is absurd. There was indeed "confusion in Britain between the Cepheid mystery test and the real time PCR test". In the Veterinary Record on 6 October 2001, "Evaluation of a portable, 'real-time' PCR machine for FMD diagnosis", Alex Donaldson and his team reported poor results, stating that:"The reagents used in the assay were recommended by the manufacturer of the instrument" - but of course they were not recommended by the manufacturer, only by Cepheid - who, of course, didn't know and were guessing. Had the real time PCR test been properly trialled with the correct reagents - in other words, if the US offer had been courteously accepted - the story of FMD in 2001 would be very different. But Professor King told the EFRA Committee that "there are very serious questions to be asked about the use of that machine in the field, in particular the problem of cross-contamination". If one studies the letter and compares it with what Professor King and Dr Donaldson were saying in March 2001 at that EFRA Committee meeting one is struck by a feeling of great regret at what may well have been a genuine but tragic mistake.