THE PENROSE INQUIRY
Final Report

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Chapter 23

Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985

Introduction

23.1 It had been known, internationally, since the mid-1940s that transfusion of blood and blood products carried a risk of transmission of infectious agents.[1] Identification of the agents giving rise to risk, and understanding of the natural history of infections resulting from transmission developed over time. The general nature of the risk was understood by fractionators when coagulation factor concentrates were developed in their modern form in the early 1970s.

23.2 This chapter examines the efforts of the Protein Fractionation Centre (PFC) in Edinburgh, in the period up to 1985, to inactivate viruses (initially hepatitis viruses and later HIV) which were present in its Factor VIII and Factor IX concentrates in this period. It describes how scientific, technical and practical difficulties in bulk production of Factor VIII and Factor IX concentrates were overcome, enabling the PFC to introduce heat-treated Factor VIII concentrate in December 1984 that was effective in controlling transmission of HIV, with more stringent heat-treating protocols developed thereafter, and heat-treated Factor IX concentrate - HT-DEFIX - in May 1985. Inactivation of the Hepatitis C virus is discussed in Chapter 24, Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987.

23.3 Superficially, the problems related to viral contamination of blood and its derivatives and viral inactivation of blood products can be expressed simply. Blood (and specifically blood plasma) can be a vector for human viruses, and can result in blood products manufactured from such plasma also being infective.[2] The aim behind viral inactivation is to remove or destroy such viruses - using heat, chemicals, radiation, or a combination of these - and so to make blood products safe for human use.

23.4 However, inactivating viruses in blood products proved to be extremely complex, scientifically, technically and on a practical level. Blood is chemically complex, as are the viruses it harbours. Technical issues can and did arise in ensuring that the active element in a blood product (for example Factor VIII) was not also destroyed or damaged along with any virus. The inactivation of viruses can also increase the cost of a product - making it economically unattractive - and can impact negatively on the resultant yield.[3] These factors can affect the likelihood that demand for a given product can be met. In addition, where a virus has yet to be identified, it can be difficult to establish with certainty that a given inactivation process has been successful. As discussed in this chapter, the PFC was confronted by these and other practical issues when attempting to inactivate non-A, non-B (NANB) Hepatitis and HIV in the period up to 1985.

Historical background

Albumin

23.5. The Cohn fractionation process was a key step in the manufacture of human blood products. An important goal behind Cohn's research was to develop a product which could act as a substitute for human plasma in the treatment of wartime casualties.[4] Albumin provided the solution. It was crucial that albumin for military use remained stable ('undenatured' in technical terms) under battlefield conditions. According to John Edsall, who was involved in Cohn's original research:

We knew that the albumin would be sent all over the world, including regions of intense heat such as the north African desert or the southwest Pacific. It had to remain undenatured by exposure to heat for months, indeed for years, if it was to serve its purpose.[5]

23.6 Human plasma proteins tend to become damaged and lose effectiveness when temperatures are raised, and this presented a practical problem. As outlined in Dr Peter Foster's paper on heat treatment:

Human proteins in their natural state exist at body temperature and are prone to damage at raised temperatures. Proteins removed from their natural environment may be even more susceptible to heat induced damage, either from heat directly or from an increase in the activity of substances, such as enzymes, which can degrade proteins. Heat causes proteins to denature and become insoluble (e.g. cooked vs. uncooked egg white) and can occur at modest temperatures, well below the boiling point of water, with different proteins differing in their ability to withstand heat.[6]

23.7 Research into techniques for improving the ability of albumin to withstand heat led to the discovery by Dr J Murray Luck in 1944 that the addition of chemicals known as 'stabilisers' could enhance albumin's thermal stability with the result that it could be heated for a longer period at a higher temperature before breaking down.[7] Further research focused on destroying bacterial contaminants. This work showed that pasteurisation (heating in solution) was possible and an albumin product which was pasteurised for 10 hours at 60°C was introduced in the USA from June 1945.[8] While albumin was the principal application of pasteurisation, other proteins, Antithrombin 3 and Factor XIII were also pasteurised with appropriate stabilisers.[9] Pasteurisation as a process was not specific to these applications in the pharmaceutical industry. It was established technology in the food industry where it was necessary to reduce or remove microbiological contaminants (for example in milk).[10]

23.8 Awareness that hepatitis could be transmitted by transfusions of blood plasma was, in Dr Foster's view, the reason for Dr Edwin J Cohn recommending studies to assess whether 'serum hepatitis' (blood-borne hepatitis) could be transmitted by albumin which had been pasteurised for 10 hours at 60°C (or whether other heating conditions were needed).[11] These studies involved treating patients with heat-treated albumin which had been spiked with, or derived from, plasma which was known to be infected with hepatitis. The results suggested that pasteurised albumin did not transmit blood-borne hepatitis virus(es).

23.9 Further studies in the 1970s, following the discovery of the Hepatitis B virus, demonstrated, firstly, that the Cohn fractionation process itself physically removed most of the Hepatitis B virus from albumin before pasteurisation. Albumin was produced from Fraction V, the final stage in the fractionation process. Virus in the source plasma was removed differentially at the successive stages of the process, reducing the virus load before the application of heat. Secondly, it was discovered that pasteurisation alone was insufficient to destroy the Hepatitis B virus. It was the combination of fractionation and pasteurisation which was effective in inactivating the Hepatitis B virus in the albumin solution.[12]

23.10 By the 1970s the combination of cold ethanol fractionation and pasteurisation for 10 hours at 60°C was thought to be effective in inactivating hepatitis in albumin. There had been only one documented example of a Hepatitis B outbreak connected to the production of albumin and this was shown to have related to the incorrect bulk pasteurisation of the product, Plasma Protein Fraction (PPF), rather than to any inherent defect in the established heating protocol.[13] PPF was albumin of slightly reduced purity. Given its apparent safety, pasteurisation for 10 hours at 60°C became the recommended procedure for the treatment of albumin.[14]

23.11 By the time the Hepatitis C virus (HCV) had been identified in May 1988, it was recognised that the most promising approach to the reduction of transfusion-associated disease was the combination of biophysical removal and biochemical inactivation of virus.[15] The characterisation of the Hepatitis C virus was incomplete, however, and it was not possible to culture the virus. But enough was known to enable the identification of viruses sufficiently similar in structure for experimental purposes. It became possible to carry out experiments which tested the degree to which the Cohn fractionation procedure and pasteurisation physically removed and/or inactivated Hepatitis C in various blood products using similar 'model' viruses as proxies for Hepatitis C.[16] The procedure followed was to spike product with virus and to test by assay the degree to which the virus had been removed by fractionation or destroyed by heat treatment (so-called 'validation studies').[17] These studies had various strands, but the key conclusions were as follows:

  • The Cohn fractionation process did not lead to the Hepatitis C in the original plasma being spread evenly among the resulting protein fractions. Most Hepatitis C was to be found in cryoprecipitate. The least amount was found in the fractions from which albumin is derived.[18]
  • Pasteurising albumin for 10 hours at 60°C inactivated Hepatitis C and HIV to a level which could be considered safe.[19]

23.12 Work on heat-treating albumin highlighted the vulnerability of human plasma proteins to damage when temperatures are raised, but also demonstrated that chemical stabilisers could be used to protect proteins from the effects of heat. In addition, it was demonstrated that the effectiveness of fractionation, with or without viral inactivation, to remove or eliminate virus infection could be tested by validation studies using model viruses. These factors came to be of general relevance as research into viral inactivation of blood products progressed.

Factor concentrates

23.13 Although using chemical stabilisers to pasteurise albumin for 10 hours at 60°C was regarded as successful in inactivating the hepatitis virus, it was widely understood that this approach could not simply be replicated for coagulation factors.[20] Dr Foster's views on the position reached at the beginning of the 1980s are summarised briefly at the end of Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s. It is necessary to discuss them in greater detail. The coagulation factors are more 'heat labile' than albumin. They are more easily destroyed or damaged by heat.[21] Finding chemical stabilisers capable of protecting factor concentrates against heat sufficient to inactivate viruses was not straightforward.

23.14 As noted in Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s, among other reasons, Dr Foster's views were influenced by early SNBTS research that had provided evidence to support the generally accepted view that Factor VIII was temperature sensitive.[22] Collaboration with Dr Alan Johnson, New York University, during the 1970s, included development of the PFC's intermediate purity Factor VIII concentrate. One aspect of this research related to the filtration of the final solution to remove impurities. A very fine membrane filter (0.22 micrometre) was used, with the solution at a temperature of 20°C. This was found to lead to a loss of Factor VIII activity. Dr Johnson suggested raising the temperature of the solution to increase solubility and speed up filtration. The manufacturing process was changed: the temperature at filtration was raised from 20°C to 30°C. There was an even greater loss of activity. According to Dr Foster:

These observations confirmed that factor VIII activity could be destroyed by even a modest increase in temperature and it seemed inconceivable that factor VIII could be heat treated at a temperature high enough to eliminate the risk of hepatitis transmission.[23]

23.15 In his witness statement Dr James Smith expanded on this point. Factor VIII is a much larger molecule than albumin, a relatively small protein. Because of its size and complexity, Factor VIII is possibly the worst candidate among coagulation factors for heat treatment. Factor VIII activity requires that the entire molecule retain its structure intact. Bonds in the molecule are easily broken by heat. Enzymes in plasma also destroy activity. Calcium, on which the integrity of the molecule depends, is readily removed by some of the solutions used in processing. Processing had to be as fast and cold as possible. It did not come naturally to a fractionator, used to handling Factor VIII with extreme sensitivity ('with kid gloves' in Dr Smith's words), to place a dry preparation into an oven at 80°C or to place a solution in a water bath at 60°C. Dr Smith added:

Unlike albumin, there is no fortunate short-cut to protecting Factor VIII (and most other plasma proteins) against heat. They need to be protected by high concentrations of salts, amino acids or sugars, at far higher than physiologically-tolerable concentrations. These protectants then have to be removed in later stages which can be quite demanding and likely to lose yield. It transpires that for Factor VIII, the preferred protectants are sugars and glycine, which at the high concentrations used make a sticky solution, difficult to work with at large scale. Even after pasteurisation, the common methods for recovering a small amount of protein from a large volume of viscous liquid were challenged to the limit in the early 1980s. In addition, these post-heating manipulations must be done in an expensive, controlled environment to avoid recontamination; there is no question of pasteurising in the final container.[24]

23.16 Dr Smith said that fractionators resisted almost viscerally the application of high temperature to Factor VIII.[25] It is important to emphasise the implications of some of the points made. Protectants were essential in the course of heat treatment, but at concentrations that required their separation from the Factor VIII proteins after heating. It was not possible, therefore, to pasteurise the final freeze-dried Factor VIII product in vial. If freeze-dried Factor VIII was to be heat-treated to inactivate virus contamination, it would require significantly different technology from pasteurisation.

Other obstacles to early progress with virus inactivation of factor concentrates

23.17 In addition to the challenges of heat treatment, in the period up to 1980 various other obstacles lay in the path of successfully inactivating viruses in factor concentrates.[26] There was a lack of common understanding of the problem of virus transmission. Dr Smith drew a distinction between haemophilia clinicians and patients on the one hand and fractionators on the other in this period.[27] Whether or not his assessment of the position was correct or fair, he had a clear perception that those concerned with the manufacture of therapeutic products had a distinctive appreciation of the risks of transmission of virus infection. As he saw it, there was little pressure from clinicians and patients to take viral hepatitis seriously in this period. The view that NANB Hepatitis could have severe long-term consequences was not widely held. (As discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985, the risk of progression to serious disease was not generally appreciated until the second half of 1985.) By 1980, the risk of Hepatitis B transmission was thought to have been tamed by donation testing, and it was expected that a vaccine would soon be available. He said that it took AIDS to get the attention of the majority of haemophilia treaters and patients on to blood-borne viruses.

23.18 When the SNBTS and Haemophilia Directors met on 30 January 1981 (for the first time since 1977) the topic of virus inactivation was not mentioned.[28] By that point, it was known to Professor John Cash and PFC scientists that Behringwerke AG had claimed that it had succeeded in pasteurising Factor VIII, though information on the company's work had yet to be published in any scientific journal that was widely available.[29] So far as the record shows, the information was not shared with the transfusionists and haemophilia specialists present on 30 January 1981.

23.19 Fractionators were, in Dr Smith's view, much more concerned about NANB Hepatitis than other specialists: in his words, they could see their entire industry going down the tubes unless they did something about the threat.[30] The agent of transmission of NANB Hepatitis was a very recalcitrant virus, with no convincing markers until the end of the decade. There were very few tools, especially for proving whether any attempt at inactivation had succeeded. Scientists were also misled by persistent claims that there might be more than one NANB Hepatitis virus.

23.20 Having regard to the evidence of Dr Smith and Dr Foster (and of Professor Willem van Aken at paragraphs 23.220 to 23.227 below), the obstacles to technological progress which they would have perceived in about 1980 were:

  • NANB Hepatitis was widely perceived to be a mild, transient illness with only very rare serious sequelae.[31]
  • It was widely believed that NANB Hepatitis was transmitted by voluntary blood donations much less frequently than by plasma from paid donors, which was the predominant component in the large pool products of commercial fractionators.[32]
  • There was no credible marker or screening test for NANB Hepatitis, at the stage of donation or in the course of manufacture.
  • At the time, understanding of the nature and structure of the Factor VIII molecule and related proteins was limited.[33]
  • There was a lack of knowledge of the agent responsible for NANB Hepatitis and the lack of a marker for NANB Hepatitis precluded spiking and validation studies to test the efficacy of a given viral inactivation procedure.[34]
  • The only way to confirm infectivity in a concentrate was to inject it into three previously untreated chimpanzees, an endangered species. The chimpanzee model was ultimately unreliable in predicting whether a heat- treated product was potentially free from NANB Hepatitis.[35]
  • It was thought by some that there were two variants of NANB Hepatitis virus whose properties differed in important ways.
  • It was thought that heat-treating Factor VIII could potentially alter its structure and lead to the formation of so-called 'neo-antigens' in patients' immune systems - that is the creation of antibodies to Factor VIII which would prevent further infusions of Factor VIII from being effective.[36]
  • There was a concern that heat­-treating Factor IX could lead to increased thrombotic reactions in patients - that is the formation of blood clots.[37]
  • It was obvious that effective pasteurisation would be at a cost in Factor VIII yield, the amount of Factor VIII activity recovered from a given quantity of frozen plasma.[38] That was an obstacle for a public service struggling to reach or to maintain self-sufficiency.
  • There was a need to balance possible decreases in yield against an increasing demand for factor concentrates.[39]

23.21 For Dr Smith, these concerns had a real and practical significance. In April 1981, he was responsible for designing the coagulation section of the, then proposed, new BPL fractionation facility for England and Wales.[40] In his field, it was beginning to be realised generally that NANB Hepatitis was a more serious problem for recipients of plasma products than hitherto appreciated. He was of the view that this was undermining broader perceptions, among patients and expert groups, of the safety of large-pool fractionation. There was no solution to the risk of transmission for large-scale production. The production of small-pool Factor VIII and Factor IX concentrates was uneconomical. Nevertheless, he planned for sufficient small-pool concentrates to be produced either aseptically or under tight environmental control, to protect infants and other previously untreated patients from NANB Hepatitis, until a solution was 'arrived at by someone'. He was buying time 'until the cavalry appeared'.

23.22 The scheme would have reduced the statistical risk for the most vulnerable.[41] Dr Smith said:

[B]y that time I was the person in the dock - or the driving seat, depending how you care to put it - who was responsible for having contingency planning and it would seem to me in 1981 that we might not be arriving at a solution to non-A non-B Hepatitis by the time we wished to move into the new building.[42]

With all his experience and expertise, he did not foresee a solution to the problem of virus inactivation at that time.

23.23 Although research was undertaken from the mid-1940s until around the 1970s with the aim of inactivating the agent responsible for the transmission of serum (blood-transmitted) hepatitis, the evidence available to the Inquiry, and noted briefly at the end of Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s, indicates that none of the methods used were effective in eliminating infectivity without causing unacceptable damage to the product in question. The methods included: (i) the application of heat; (ii) the addition of chemicals; and (iii) the application of different forms of radiation.[43] Research was also undertaken in the 1970s into the physical filtering of viruses in the production process. None of these methods was used in the routine manufacture of human plasma products.[44] There had been a measure of success in eliminating the risk of transmission of Hepatitis B, until the mid-1970s thought to be responsible for most blood-borne hepatitis, by effective screening of donors, not by treating blood and blood products.

Commercial research

23.24 By the end of the 1970s/early 1980s, however, potentially promising research was being undertaken by commercial companies. As regards Factor VIII, the research was primarily focused on either heating the product in solution (pasteurisation) or dry-heating of the product as a freeze-dried powder. Pasteurisation had the perceived advantage that - being water-based - it was likely to be more effective at destroying viruses, but equally it was more likely to damage blood proteins. As outlined by Dr Smith during his oral evidence:

Virtually all biological, chemical reactions operate with the assistance of - through the medium of water. The water which you would think is simply a background material, holding the things together, is in fact a player in virtually all the reactions. Turning to the reactions which tend to inactivate proteins or denature them, these are heavily dependent on how much water is there. In a dry-heated product you are down to less than 1 per cent of water. In a pasteurisation situation it is all water essentially. Therefore, the ... potential damage to your protein is much more severe in the aqueous pasteurisation context than it is in the dry heating context. Equally, of course, the damage you are doing to viruses, you hope, is much more severe.[45]

23.25 The use of stabilisers to protect the protein was essential. However, the choice of stabiliser was crucial since:

[I]n pasteurisation, in trying to protect your protein from what you know will be a damaging experience, you add too much of the wrong kind of stabilisers, you always fear that you have also, in doing so, failed to inactivate so much of the virus; you have protected the virus as well as the protein.[46]

23.26 It was also, to a large degree, a matter of trial and error:

It's largely empirical. There are certain classes of substance which have been used more than others: salts, amino acids, sugars, at very high concentration ... you would start with certain things, and only then, having exhausted those and all the conditions under which you might apply them, you would start to turn to rather more exotic protectants.[47]

23.27 In contrast to pasteurisation, where a product had been freeze-dried in powder form, the lack of water and the presence of a vacuum would, in principle, make it more difficult to direct heat to the core of the powder.[48]

23.28 Commercial research led to the release of a wide range of commercial heat-treated Factor VIII and Factor IX products in the USA (from 1983). Appendix 1 to this chapter tabulates the products together with the dates of licensing in the USA.[49] Commercial heat-treated products were not licensed by the UK Medicines Control Agency for release in the UK until February 1985.[50] Some products were not available in the UK. Behring's product, Haemate P, was available in small quantities from 1980 in Germany and some other places.[51] It was not licensed in the UK and was not available here at any time.[52]

23.29 These products, which were difficult to develop, were not widely used.[53] Each additional step in the manufacturing process carried a yield penalty. With the exception of pasteurisation, they were not effective in destroying the agent(s) responsible for NANB Hepatitis. Initial chimpanzee studies of Hemofil T suggested that it was effective in preventing transmission of NANB Hepatitis but not Hepatitis B. In human recipients, the opposite outcome was reported.[54] The animal model was not reliable.

23.30 As the tables in Appendix 1 to this chapter show, licences for heat-treated factor concentrates began to be issued in the USA in March 1983. Some at least of the procedures that were developed were protected by patents, and, in the nature of things, prior publication of the inventive steps in the processes developed was unlikely, and, to the extent that it happened at all, even more unlikely to be comprehensive. As far as the SNBTS is concerned, its first heat-treated Factor VIII product (heated to 68°C for two hours) was released in December 1984.[55]

Research at the Protein Fractionation Centre: progress in the early 1980s

1980

23.31 From the perspective of the PFC, there appear to have been few notable developments in the field of viral inactivation of factor concentrates early in 1980. Dr Brian McClelland attended a meeting of the Medical Research Council Working Party on Post-Transfusion Hepatitis on 14 February 1980.[56] However, as regards hepatitis the discussion recorded was limited to: (i) work by the German company Biotest (not Bayer as noted in the minutes of this meeting[57]) into using β-propiolactone together with ultraviolet radiation to inactivate hepatitis (this work did not ultimately lead to a successful product) and (ii) the polyelectrolyte process developed by Dr Johnson mentioned at the end of Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s.[58]

23.32 Bayer (Cutter Laboratories) filed an original application for protection of a pasteurisation process on 5 March 1980.[59]

23.33 Towards the end of 1980, however, news had started to filter through to the PFC of the apparent breakthrough by Behringwerke AG ('Behring') in the pasteurisation of Factor VIII already noted. The news was broken to the fractionation community during the First International Haemophilia Conference in Bonn, Germany between 3 and 7 October 1980[60] which was attended by Professor Cash. On his return to the UK, Professor Cash told Dr Foster that the company had claimed that it had succeeded in pasteurising Factor VIII.[61] Subsequently, on 27 October 1980, he wrote a letter to Mr John Watt in which he said:

During the meeting in Bonn I learnt, for the first time, that Behringwerke are getting rather excited - following chimpanzee studies - that their preparations of factor VIII, made from HBsAg positive plasma (starting at 90 ng/ml), appear to be safe. The reason given is that they are heat treating the product for 10 hours at 60°C in the presence of glycine and sucrose. Apparently the glycine and sucrose protect the VIII from denaturation. Sounds unbelievable: thought you might be interested.[62]

23.34 Dr Foster said in his witness statement that he was 'quite shocked' when he heard of this claim. The notion that Factor VIII might be able to be heat-treated under conditions that would destroy hepatitis viruses was inconceivable to him.[63] In his oral evidence, he said that on hearing the news he was, 'completely gobsmacked'.[64] Dr Robert Perry was not directly involved, but it was clear from his evidence that the claims were widely discussed within the SNBTS and the PFC and that there was a sense of incredulity that the process could take place.[65] Dr Foster was asked whether, intuitively, treating Factor VIII at 60°C would not work. He said:

I can't admit that I ever considered that. It was just so - literally inconceivable. I didn't sit down and say, 'Would this work or would it not work?' it was something I didn't even consider, it was inconceivable.[66]

23.35 Dr Frank Boulton did not believe that it could possibly be true and expected that it would be found out to have been a mistake.[67] When Dr Foster and others reported some of their own research in this area later,[68] Dr Garrott Allen wrote, expressing surprise, commenting on his own failure, and asking for details.[69] The value of the Behring discoveries was that they demonstrated that in principle Factor VIII could be pasteurised, if suitably protected, in a high purity product. The PFC could not copy the Behring patented process: it would have to produce its own.[70]

23.36 The reasons for Dr Foster's disbelief mirror the general points outlined above by Dr Smith.[71] According to Dr Foster, the established view at the start of the 1980s remained that plasma proteins would be damaged by the level of heat needed to kill viruses. That also accorded with Dr Foster's first-hand experience of working with Factor VIII, as noted at the end of Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s, at paragraph 20.75. He had found that Factor VIII from human plasma was considerably more sensitive and more difficult to work with than any of the other proteins that he had encountered.[72]

23.37 Professor Cash appears to have been the first SNBTS official to become aware of Behring's progress on the heat treatment of Factor VIII.[73] At the end of 1980, however, the specific details of the process were not available to the PFC. After the meeting in Bonn, Behring disclosed certain details in an internal Behring journal called Die gelben Hefte (the Golden Notebook).[74] The journal would not have been readily available in the UK. Dr Foster first received a copy of this article when attending a conference in Budapest in 1982.[75] Professor Pier Mannucci saw a copy of the article in 1980. He wrote:

I, like other clinicians, was unimpressed with the claim because clinical evidence was meager and the design of the study retrospective and poor.[76]

Behring's product, Haemate P, was first licensed in Germany in 1981, where it was claimed to be the first effectively virus-inactivated Factor VIII product. The claims advanced for the Behring process are set out in the Preliminary Report at paragraphs 11.45-11.47.

23.38 In summary, by the end of 1980 Behring had carried out research into the pasteurisation of Factor VIII which appeared to have promise, but an unacceptably low yield. A yield of about 8% of the initial plasma was confirmed in 1981.[77] The details of this research do not appear to have been made public at this time. Behring's approach to publication was described by Dr Smith as a 'teasing process'. The manufacturer would not disclose enough to invalidate his patent, but would hint at developments to come.[78] However, the PFC was aware of the general development.

1981

23.39 Limited information about the procedures used by Behring were published in 1981 in the journal Haemostasis.[79] Details of the procedures were ultimately published in April 1981 in an article in the German journal Arzneimittel Forschung/Drug Research.[80] Dr Foster obtained a reprint of this document in May 1981 from the Behring trade stand at a symposium in Cambridge on 'Advances in Blood Transfusion' which was organised for Transfusion Directors by Travenol Ltd and which was by invitation only.[81] The article was in German and was translated into English by Dr Werner Zolg, a German post-doctoral researcher at Edinburgh University who was at that time involved in a collaboration on a different project with Dr Alex MacLeod - a research scientist at the PFC.[82]

23.40 Shortly afterwards, Dr Foster became ill and did not return to work until mid-October 1981. During this period, Dr MacLeod obtained the translation from Dr Zolg and, on his own initiative, on 2 September 1981 started a set of experiments aimed at reproducing Behring's findings.[83] The view in the PFC, differing from Professor Mannucci, was that Behring was a well-respected company, and, if they said a process was feasible, it was worth pursuing even if one remained sceptical about the yield and about proof that the viruses were sufficiently inactivated.[84] According to Dr Foster:

The early research of Dr MacLeod was essentially exploratory and aimed to confirm the findings of Behring and to establish whether or not the approach taken by Behring might be feasible and suitable for the PFC to pursue.[85]

A particular focus for this research was on identifying stabilisers and conditions which might allow pasteurisation to be developed without breaching Behring's patent.[86]

23.41 Thus, by the end of 1981, as a response to Behring's work, research into the pasteurisation of coagulation factors had begun at the PFC. However, the published yield of eight per cent was a serious draw-back from the point of view of the PFC. In Dr Perry's recollection, the low yield meant that the process had no practical applicability in Scotland (where all coagulation factor production, of necessity, came from the limited Scottish donor population).[87]

23.42 On 17 December 1981, Professor Cash wrote to Mr Watt, Dr Perry, Dr Foster, Dr Prowse, Dr Boulton, Dr Pepper and Dr G S Gabra intimating the setting up of the SNBTS Factor VIII Concentrate Study Group (Factor VIII Study Group) and inviting them to be members. The group was to have as its remit the exploration of:

[N]ew developments in the widest possible sense with regard to the production of factor VIII concentrates and thereby create the opportunity for cross fertilisation and for co-ordinated research within the SNBTS.[88]

23.43 This group later formed an important forum for the discussion of matters relating to viral inactivation.

1982

The PFC continues its research into heat treatment options and Behring's pasteurisation process

23.44 The first meeting of the Factor VIII Study Group took place on 28 January 1982. The minutes of the meeting indicate that Dr Christopher Prowse mentioned pasteurisation in the context of inactivating viruses.[89] He said that the HQ laboratory unit of the SNBTS was carrying out experiments using gamma-irradiation.[90] Viral inactivation was not highlighted in the list of current research priorities, however, and Dr MacLeod's research into Behring's process was not referred to.[91] During the meeting, Professor Cash recommended the setting up of a separate sub-committee with a view to improving 'the safety of the product, eg by irradiation to remove viral infectivity'.[92]

23.45 This sub-committee became known as the Safety Action Group and held its first meeting on 9-10 February 1982.[93] A discussion document set out what was known and what might be attempted. The meeting summarised the existing knowledge within the SNBTS as regards methods of viral inactivation as well as outlining proposals for action and resources required. Gamma-irradiation was discussed as was the possible use of a combination of b-propiolactone and ultraviolet irradiation.[94] Behring's pasteurisation method was also mentioned, and it was noted that:

An alternative to g-irradiation is heating (pasteurisation). This has been attempted by Behringewerke who now market 'Faktor VIII HS' in which HS implies, "safe from hepatitis". Unfortunately only one paper has been published (in German) and no details are given of solution compositions or yields. However, estimates by P.F.C. indicate 8% yield which is rather low.[95]

23.46 Although Behring's work was discussed, once again no mention was made during this meeting of the fact that the PFC had already begun investigations, under Dr MacLeod, into whether Behring's findings could be confirmed. Dr MacLeod's work was not included in the proposals for action. The Inquiry has asked whether the lack of a mention of Dr MacLeod's research in this meeting and the earlier meeting of the Factor Vlll Study Group could be interpreted as meaning that this research was not a priority for the PFC at this time, or that Professor Cash was not aware of the research.[96] Dr Foster said that, in his view, this was not the case. He explained that:

The first meeting of the Factor Vlll Study Group was held on the 28th January 1982, some two weeks before Dr MacLeod had completed his preliminary evaluation. I am sure that Dr Cash was aware of our work on pasteurisation when he arranged the first meeting of the Factor Vlll Study Group but, as the exploratory experiments of Dr MacLeod were incomplete, it is understandable that he did not include this topic in the agenda of the first meeting of the Group.

Similarly the meeting of the Safety Action Group of 9-10 February 1982 ... preceded the report of Dr MacLeod.[97]

23.47 Dr Perry's evidence to the Inquiry also explains that any perceived lack of focus on pasteurisation at this time should be seen in the context of the more general goals of the Factor VIII Study Group:

The Factor VIII study group was an important development in SNBTS and was established to coordinate all available resources in SNBTS to meet the challenges of self-sufficiency and to establish this as a national priority. I attended this meeting together with Dr Foster and Mr Watt from PFC. At this time the PFC work on virus inactivation was only at a preliminary stage without any clear reportable outcomes. My recollection from the meeting is that safety issues were discussed in general leading to agreement to establish a safety sub group. Whilst this is not recorded in the report of the meeting this would not necessarily be unusual for such internal reports. The importance of product safety was certainly recognised in these discussions but so was the recognition that any method likely to improve safety would reduce product yield. Thus consideration of FVIII processing yield and FVIII content of plasma were considered essential prerequisites to progress on product safety if the goal of self sufficiency was to be achieved and maintained.[98]

23.48 So, even at this early stage, there appears to have been a recognition that improvements in safety had to be balanced against the general goal of self-sufficiency and the need to improve yield to offset any losses caused by viral inactivation.[99]

23.49 Dr MacLeod's initial findings on his preliminary studies, following the methodology in the Drug Research paper, were summarised shortly thereafter in a PFC R&D report of 10 February entitled 'Preliminary studies on the heat treatment of PFC FVIII concentrate'.[100] The document reported briefly on the initial PFC experiments with heating Factor VIII using glycine and sucrose as stabilisers and concluded that further purification of the PFC's Factor VIII concentrate seemed necessary in order to be able to pasteurise the product.

23.50 Dr Foster's view was that:

The immediate challenge was therefore two-fold. To discover a means of increasing purity to allow the pasteurisation process to be applied, whilst at the same time substantially increasing the yield ... to enable the SNBTS to provide the quantity of factor VIII concentrate required.[101]

23.51 This became a major consideration of the Safety Action Group at the PFC.[102] An account of their discussions between February and July 1982 is given in the Preliminary Report at paragraphs 11.57-11.68. In the background was a commitment to self-sufficiency that implied that any strategy that led to failure to meet the escalating demand for product for all of Scotland's patients was not viable.[103] Self-sufficiency was, in Dr Perry's words, 'the only game in town'. He said:

[T]hat culture and that ethos really pervaded everything we did. And for very good reason. It was clearly understood why we had that particular position .... [E]very bottle of product or every vial of product, every dose of product that we could make from Scottish donors avoided the need to import material from what we perceived and believed were less safe parts of the world, and particularly the American commercial material. So it wasn't just a sort of random process of pride or national pride that we would be self-sufficient, there was a very good reason underlying it. And certainly I internalised that at a very early stage. Every morning I woke up, basically the reason for going to work was to make sure that we could avoid having to import product from areas that were believed to be less safe than Scottish donors. So where it actually came from, I think certainly pre-dated me. I think certainly Professor Cash - and this is from me reading the sort of historical archives. There were discussions when he took over as national medical director that, I think, one of the clear discussions he had before taking up the post was, you know: is part of the job here to establish self-sufficiency? And I think the answer to that was yes .... [L]eading from that process were discussions between Professor Cash and George MacDonald in the West of Scotland and various other haematologists and haemophilia directors, where they sought to establish what that meant, and the figure that I always had in mind was 2.75. That was the magic figure.[104]

23.52 There were no policy statements or documents to that effect. But:

It was in the fabric of the building, it was in the fabric of everything that was discussed, that, you know, the PFC was established at great expense to the taxpayer and its job was to meet the needs for Scottish patients. So, you know, I guess I'm just a single point in this process, but for me it became very clear very early on what we were there for and that included - and in a sense, failing to supply was - it sounds a bit romantic but failure to supply was not an option .... [I] think it would have been seen as an admission of failure of delivery against our mission and purpose. Certainly that's how I perceived it anyway.[105]

Dr Perry did not think that the Common Services Agency (CSA) and its committees lived and breathed self-sufficiency to the extent the SNBTS did.[106]

23.53 Further meetings of the Factor VIII Study Group and the Safety Action Group followed throughout spring/summer 1982. The meeting of the Safety Action Group of 30 March 1982 proposed that work should be carried out into filtration, that Dr MacLeod's research into Behring's pasteurisation process should be pursued and that Dr Duncan Pepper should investigate aspects of irradiation. Practical aspects of these strands of proposed research (laboratory accommodation, access to infected material, which animals could be used to test for infectivity - so-called 'animal models' - and funding) were also discussed.[107] The issue of possible animal models was also discussed during the Factor VIII Study Group meeting on 3 June 1982.[108] It was also dealt with in more detail during the meeting of the Safety Action Group on 23 June 1982, which investigated the possibility of infecting Tamarin monkeys with known NANB Hepatitis infected material and carrying out titrations to measure the effectiveness of various inactivation processes: heat, gamma-irradiation, adsorption, purification and the use of detergent.[109] Therefore, by the middle of 1982, the PFC was continuing its examination of the options for viral inactivation. However, no one option had yet been chosen.

23.54 Dr Bruce Cuthbertson characterised much of the work of the Safety Action Group as 'blue sky thinking'.[110] However, the discussion focused on what were seen at the time as real possibilities. For example the animal studies were seen as a serious prospect in May 1982. SNBTS scientists in this respect reflected the ambition of the organisation, notwithstanding that it was a small operation in a small country.[111] Dr Smith had a more positive view of the work of the group:

I would like to reaffirm just how wide-ranging SNBTS's experiments were. In fact, on theoretical grounds, it would seem to most people far more likely that radiation would distinguish between proteins and an assembled entity like a virus. This simply did not happen. Nature did not cooperate in this case but it does exemplify the lengths that this study group went to in exploring every avenue.[112]

Protein Fractionation Centre obtains further information on current viral inactivation research at an International Congress in Budapest

23.55 Dr Foster attended the International Society of Haematology/International Society of Blood Transfusion Congress in Budapest between 2-5 August 1982 and produced a detailed report which, among other things, summarised information about recent viral inactivation research publicised during the conference.[113]

23.56 Behringwerke did not present at the conference. However, it did provide copies of certain documents as part of a trade stand which was held in conjunction with the Congress.[114] These included:

  • A Behring paper on Factor VIII published on 16 July 1982 which emphasised the variation in purity and Factor VIII activity of a range of commercial products as compared to Behring's highly purified product.[115]
  • A typewritten version of the paper, referred to at paragraph 23.37 above, on the Behring pasteurisation process which had been published in Die gelben Hefte in 1980.[116]

23.57 The introduction to the typewritten paper on the Behring pasteurisation process stated that:

Until recently it has been impossible to eliminate the danger of hepatitis from certain plasma products, in particular clotting factor concentrates. When using factor VIII concentrate for haemophilia it was therefore necessary to weigh the benefits against the hazards. Now, however, thanks to a new manufacturing process, a safe Factor VIII concentrate is available. Experimental and clinical trials have confirmed its freedom from hepatitis risk.

23.58 It also emphasised the medical need for a safer product, noting that:

Haemophiliacs, because they require lifelong replacement therapy with coagulation factor concentrates, are exposed to considerable risks of hepatitis. Twenty years ago, before the introduction of effective replacement therapy, haemorrhage was the major hazard, but today its place has been taken by chronic liver disease.

23.59 The paper included a discussion of the various perceived options for reducing the risk of hepatitis transmission, indicating that: (i) vaccines and immunoglobulins were not available for NANB Hepatitis; (ii) single donor cryoprecipitate derived from medically supervised regular donors would have solved the problem only for a very small number of patients; and (iii) the combination of β-propiolactone and ultraviolet irradiation, which had been used in Factor IX, was not applicable to Factor VIII. Consequently:

In view of these facts we endeavoured to work out a method for producing hepatitis-free Factor VIII concentrate. We chose heat sterilisation, because it had been used for albumin for many years and was of established value. The removal of hepatitis risk by the albumin production process is based essentially on three stages: 1. Screening of all donor plasmas by a third generation test and rejection of HBsAg-positive donations. 2. Elimination of hepatitis virus (BV) during the fractionation process. 3. Inactivation of any residual virus particles by heating the final product to 60° for 10 hours. The Factor VIII molecule is highly susceptible to elevated temperatures and the heating process was made feasible only by addition of stabilizers which protect the molecule from thermal inactivation.[117]

23.60 The paper outlined experiments which had been carried out to establish whether the viral inactivation protocol had been effective, concluding that:

In the light of the experimental and clinical results it may be said that the possibility of transmission of hepatitis B by Factor VIII HS can be ruled out. Furthermore, non-A/non-B hepatitis has so far not been observed and the characteristic ... signs have not been seen. However, long-term observation is being continued so that a definitive statement can be made.[118]

23.61 Thus, although there was no final proof at this stage that the Behring product was free from NANB Hepatitis, the company claimed to have had encouraging indications of possible success.[119]

23.62 In addition to receiving more information on the Behring process in Budapest, Dr Foster learned that Biotest were making progress with β-propiolactone and ultraviolet treatment; and that an independent research company, Rubenstein and Rubenstein, were pursuing dry heat treatment. He also became aware of Hyland/Baxter's announcement that it had developed a heat-treated product. In his report, Dr Foster indicated that Hyland's method 'was said to involve pasteurisation'.[120] However in his evidence to the Inquiry, Dr Foster indicated that 'at the time I didn't know what it was and it was only later that we discovered it was a dry heat process'.[121] More specifically, in his written evidence Dr Foster stated that:

The method of heat treatment was not disclosed at the Congress. Some months later, Dr Chris Prowse of the SNBTS learned from Dr Henry Kingdon, the Medical Director of Hyland/Baxter, that the procedure involved dry-heat treatment at 60°C. What had been done to enable the Hyland/Baxter Factor Vlll concentrate (Hemofil) to withstand this degree of heat treatment was not disclosed and, to the best of my knowledge, has never been disclosed.[122]

23.63 At the time Dr Foster regarded Hyland's product as having potential, noting in his report that:

The Hyland product is perhaps the most interesting. If the yield indicated (200 iu/l) is confirmed this is probably higher than the present method of manufacture for Hemofil and therefore represents a definite break-through in FVIII stabilisation. Will this ever be published?[123]

23.64 However, when asked at the Inquiry how he would characterise the information from Hyland, Dr Foster remarked that it should be viewed as 'tantalising' and that 'it was a heat-treated product that gave no indication as to whether it might deal with viruses or not .... So the questions were still waiting to be answered'.[124] Dr Smith commented in his written statement that the paper would have served to increase interest in pasteurisation, and perhaps increase its priority.[125] As outlined in more detail below, the product was ultimately found to transmit NANB Hepatitis.[126]

23.65 Dr Foster described the work carried out by Rubenstein,[127] using labile factors in their freeze-dried state, as 'very interesting'.[128] But he thought that freeze-drying was also likely to protect the virus and infectivity data were essential. In his written evidence, Dr Foster indicated that it was at this conference that he first became aware of the possibility of heat-treating freeze-dried factor concentrates, commenting that:

It was also at the 1982 ISBT Congress that I first learned of the concept of applying heat treatment to coagulation factor concentrates in the freeze dried state (ie. dry-heat treatment). These were listed in the programme as poster presentations at which the authors would be present to answer questions on their work. In the event, the posters were not displayed nor were the authors present at the poster session to answer questions.[129]

Pasteurisation selected as preferred viral inactivation option

23.66 The Factor VIII Study Group met again on 14 October 1982 and discussed the activities of the Safety Action Group. The minutes of the Safety Action Group record that:

Heat Treatment was now the first option of the group in view of developments which had occurred since the last meeting. Dr Alex McLeod [sic] (PFC) would continue studies of heat process using high purity product. Edinburgh BTS to assist if necessary.[130]

23.67 A number of witnesses were asked the reason for the decision of the Factor VIII Study Group to focus on the heat treatment of a high-purity product.[131] In his written evidence Dr Perry stated that:

By October 1982 SNBTS had eliminated irradiation and virus removal as options for increasing FVIII safety. Irradiation in particular led to complete destruction of the product at doses necessary to achieve a sufficient degree of virus inactivation.

Therefore heat (pasteurisation) was selected as the preferred option not only because of the reported success of Behring but also because other lines of research had proven unsuccessful.[132]

23.68 Dr Foster explained in his witness statement that the reasons for prioritising heat treatment were as follows:

a). Although I was not a member of the Safety Action Group, I believe that there were three principal reasons why pasteurisation was, by 14 October 1982, 'the first option of the group'.

b). The first reason concerned the promising results that had been presented by Behring at the ISBT Congress in August 1982.

c). The second reason was the discovery of a suitable means of reducing the fibrinogen content of Factor Vlll. This discovery had been made at PFC in conjunction with Dr Milan Bier of the University of Arizona and involved the addition of zinc,[133] which preferentially caused fibrinogen to precipitate, whilst leaving factor Vlll in solution (Bier M & Foster PR. USA Patent 1983, No. 4,406,886). This discovery enabled the purity of factor Vlll to be increased prior to pasteurisation with little loss of yield and addressed the need for an increase in purity which Dr MacLeod had identified in his report of 10th February 1982. This was the 'high purity product' that was noted in the minute of the meeting of the Factor Vlll Study Group of 14th October 1982.

d). The third reason was the promising results that Dr MacLeod had obtained using sorbitol instead of sucrose to stabilise factor Vlll during pasteurisation [Preliminary Report para 11.86], which reduced the loss of factor Vlll during the heat treatment process.[134]

23.69 Witnesses were also asked whether the decision to focus on heat treatment could have been due to the PFC's existing knowledge of and experience in the pasteurisation of albumin.[135] In his evidence to the Inquiry Dr Foster explained that, although the heat treatment of albumin 'represented a bench-mark against which new procedures could be compared',[136] it could not simply be copied for other coagulation factors since 'the chemical stabilisers were not able to stabilise other plasma proteins, including the coagulation factors'.[137]

23.70 Dr Perry, in his written evidence, commented that it was not correct to assume that the choice of pasteurisation by either Behring or the SNBTS was based simply on prior experience with equipment and facilities for albumin production.[138] He, too, emphasised that albumin was a relatively stable protein in the liquid state. Pasteurisation of albumin involved the addition of non-toxic stabilisers which did not require to be removed following pasteurisation. In contrast coagulation factor proteins were known to be unstable in the liquid state and were rapidly destroyed at elevated temperatures. There were no known stabilisers which could prevent destruction of the coagulation proteins present in the concentrates when exposed to elevated temperatures. In developing virus-safe coagulation factor products with acceptable yield, pharmaceutically suitable stabilisers capable of protecting unstable coagulation factor proteins from the effect of heat, and reducing the concentration of other heat-labile proteins in the product, were required, as were processing methods (including potentially the removal of stabilisers after pasteurisation). These were complex scientific problems. Dr Perry said:

Following the discovery by Behring of suitable stabilisers, SNBTS embarked on a programme to develop a similar process which was capable of delivering an acceptable product yield and which did not infringe the Behring patents.

SNBTS (and probably Behring also) selected pasteurisation at 60 degrees for 10 hours because such established processes were already known to produce safe albumin products and it was thought likely that such processes would similarly deliver safe coagulation factors.

The availability or otherwise of equipment to carry out the specific pasteurisation step in the overall process was a relatively minor consideration.[139]

As noted above at paragraph 23.67, Dr Perry also said that SNBTS research into the use of gamma radiation and methods of physically removing virus from Factor VIII had proven unsuccessful.

23.71 Dr Cuthbertson's written evidence gave a slightly more positive view of the attractions of the existing albumin process of heating for 10 hours at 60°C noting that 'it was not surprising that Behringwerke chose this time and temperature combination for their process and it had clear attractions for the PFC in that pasteurisation equipment was already available in the PFC facility'.[140] However, Dr Cuthbertson also indicated that 'the outstanding safety record which applied to albumin could not be directly extrapolated'[141] to Factor VIII and that the key issue was finding stabilisers which would preferentially protect Factor VIII (but not viruses) from heat.[142]

Cooperation between Protein Fractionation Centre and Blood Products Laboratory

23.72 Shortly after the Factor VIII Study Group meeting of 14 October 1982, correspondence followed between the PFC and the BPL regarding heat treatment. Dr Foster wrote to Dr Smith of the BPL on 19 October 1982:

On the FVIII front we are still grinding away at the yield problem and have started to look again at the high purity situation. We are currently pursuing precipitation by metal-ions, which is something we stumbled on with Milan Bier a few months ago. The early results are interesting but its going to be stuck on the lab bench for a long time yet. Everyone is getting very hot about pasteurisation, especially since Budapest. The little work that we have done suggests that higher purity material is needed and so far FVIII (using Duncan's CAG assay) has always gone into the solids phase![143]

Dr Smith replied on 3 November 1982 indicating that:

We are doing a little on heating factor VIII, but only for the moment on the gentle conditions for fibrinogen removal. I cannot see us doing the infinitely factorial experiments and infusions required to 'solve' factor VIII and would appreciate any small signal of success from your efforts.[144]

23.73 In his written statement Dr Smith outlined the background to this comment noting that:

Brief heating at temperatures around 60°C, without stabilisers, was being considered as a means of precipitating fibrinogen as a solid while leaving most F.VIII in solution - by no means an original idea, but we were ready to try almost anything short of voodoo. There was no intention to inactivate NANBH. The letter goes on to say that BPL was in no shape to start serious work on pasteurisation (anticipating a very long haul) and that I would be very pleased if PFC's work might offer some encouragement.[145]

23.74 When asked during the Oral Hearings what the ultimate aim of the BPL's research was, Dr Smith gave the following explanation of the attempt to remove fibrinogen:

[A]ll the time we had been working with Factor VIII, you are yearning to get rid of fibrinogen, and over ten years we were working continuously on every possible avenue which presented itself to us or in some publication to achieve that ....

So although this looks like pasteurisation in pursuit of killing non-A non-B Hepatitis, the aim of the gentle heating was solely to try and find a shortcut to reduce the amount of fibrinogen at a cost in Factor VIII which might be acceptable. It did not work.[146]

It was an attempt to achieve a more pure product with all the advantages that that would bring.

23.75 There were close working relationships between the BPL and the PFC. The relationship went beyond Dr Smith and Dr Foster. Dr Cuthbertson and Dr Perry had close relationships with Dr Smith and Dr Snape, and later Dr Harrison.[147] But the relationship between Dr Smith and Dr Foster was particularly close. Mr Watt had heard Dr Foster speak at University College, London in 1970. He suggested to Dr Smith, then at the SNBTS, Edinburgh, that he should visit and discuss Dr Foster's research. Dr Foster gave further details of this stage which are set out later. He was recruited by Edinburgh and in and after January 1973 worked closely with Dr Smith until he left in 1975. They agreed to maintain close contact.[148] Their contacts, at professional level, were known to other managers at the PFC and the SNBTS and news and information gathered was passed on.[149] Dr Perry noted that Dr Smith and Dr Foster were both recognised experts in their field and thought that there was nothing surprising or remarkable about the degree of disclosure.[150] Dr Cuthbertson never had any sense of being constrained in his contacts with colleagues in England. He said:

I think in those days probably at scientific and technical level we had slightly more freedom than we later had to actually indulge personal communications. I mean, it was well enough known that at senior management level there was not a meeting of minds between the directors of the two institutions but I think we all just worked round that rather than through it, if that makes sense.[151]

Dr Richard Lane and Mr Watt did not always see eye to eye. Within the SNBTS tensions between Mr Watt and Professor Cash did not inhibit scientific work either.[152] Externally, within the constraints of commerciality, there was free exchange of data and information with scientists in industry.

23.76 Meanwhile, initial experiments led by Dr MacLeod into the pasteurisation of factor concentrates had led to what he referred to as 'good results' using sorbitol or sorbitol/glycine as stabilisers.[153] More work was, however, needed and investigations were underway into whether the SNBTS process was sufficiently distinctive and could be protected by patent.[154]

23.77 Later in the year there was more correspondence between the PFC and the BPL on the subject of heat treatment, with Dr Foster writing to Dr Smith on 1 December 1982 outlining heat treatment experiments which the PFC had carried out on Factor IX. He enclosed a copy of Behring's patent, and an abstract relating to Hyland's work. He also discussed at some length the PFC's freeze-drying experiences.[155]

23.78 When asked to describe the nature of cooperation between himself and Dr Foster at this time, Dr Smith explained in his written evidence:

I would characterise it as decidedly lopsided at this point, insofar as virus inactivation in F.VIII was concerned. BPL was in a delicate transitional condition and had few resources to tackle the problem seriously.

It was a correspondence between scientists with a clear sense of their responsibilities. We were both well aware of a degree of tension between the upper layers of our respective organisations but agreed (without as I recall having to discuss the question) that this must not be an obstacle to pooling what information we could each gather.

It will also be evident from [Dr Foster's letter of 1 December 1982] that, during my tenure at BPL Elstree, PFC visitors were welcomed and technical information shared openly. My colleagues and I invariably received an equally warm welcome from everyone at PFC and the rest of SNBTS.[156]

23.79 Dr Smith added during his oral evidence:

[T]here were very few telephone conversations. Most of the things we wanted to share with each other involved detailed evidence, as you see, and we would not present each other with rumours or rumours of rumours, which we knew would simply tend to confuse the other. We would wait until we had something which we could stand by and provide in sufficient detail to be useful to the other. We were not in each other's pockets or on the phone every other day. Most of it was done by detailed letters and topping up the background with the occasional visits.[157]

23.80 Dr Foster characterised the nature of cooperation between himself and Dr Smith as follows:

a). I had a very good relationship with Dr Smith and always found him to be extremely co-operative.

b). I first met Dr Smith in 1970 when he visited me at University College London to discuss my PhD research. After joining the PFC in January 1973, I worked closely with Dr Smith until he left in August 1975. Before leaving the PFC, Dr Smith gave a number of seminars in which he very generously shared his knowledge and expertise. I then visited Dr Smith at the PFL (Oxford) in 1976, when we agreed to maintain close communication.

c). One way of learning of progress elsewhere was to attend international conferences and symposia. As it was difficult for any one person to attend all of the conferences, Dr Smith suggested that we should share reports if one of us had attended a conference that the other had missed. Dr Smith did not attend the 1982 ISBT Congress and it was because of this arrangement that I sent my report ... to him.[158]

d). I believe that it was on reading my report of the 1982 ISBT Congress that Dr Smith first learned that research was being undertaken on pasteurisation and dry-heat treatment of coagulation factors. It is therefore not surprising that only 'a little' research on heat treatment was being undertaken at PFL (Oxford) at November 1982.[159]

23.81 The Inquiry also asked what degree of importance viral inactivation had in the research and development priorities of the BPL at this point. Dr Smith's response in his written evidence indicated that the Director of the BPL, Dr Lane, viewed NANB Hepatitis as 'a very serious problem in recipients of plasma products', but that 'there were many obstacles to tackling the problem, other than the local ones of resources in a difficult period at Elstree'.[160]

Clinical trials and commercial heat-treated products

23.82 A meeting took place at the BPL on 15 December 1982 to discuss the 'implications for the Haemophilia and Blood Transfusion Services of Commercial Introduction of "Hepatitis-Safe" Factor VIII and IX'. The minutes of the meeting reported on the expected introduction of commercial heat-treated concentrates into the UK market and expressed a need for, 'centralised, fully controlled prospective trials of "HS" materials, best operated through a properly executed National Clinical Trial lodged with the Regulatory Authority'. It was proposed that: (a) random exploitation of the haemophilia service by commercial organisations for the study of 'hepatitis-safe' products should be discouraged; (b) the haemophilia services should create a formal basis for controlled clinical trial of alleged 'hepatitis-safe' products in line with the requirements of the Medicines Act; (c) the haemophilia services, the PHLS and the NBTS should combine resources in a manner likely to advance economic treatment of NHS haemophilia patients with safe products.[161]

23.83 Professor Cash's reaction to the proposals illustrated the difficult relationships between representatives of senior management from time to time. He described it as a 'very difficult' meeting. He felt that English colleagues were party to a proposition that UK clinical trials of the new products should be encouraged, to the advantage of England. He thought that the proposals were a sophisticated marketing exercise set up by US fractionators, and that the meeting had been designed to undermine the Scottish service's commitment to self-sufficiency and, though less obviously, collaboration between BTS and SNBTS scientists.[162]

23.84 In his view the Scots were considered to be troublesome, not only by the commercial sector, but by the DHSS. Professor Cash believed that Scottish opposition to such a proposal would have been known. He was also somewhat upset that his co-operation was being sought when he had pressed without success for some years for a closer relationship between the two fractionators in research and manufacture.[163] He was anxious that the UK's small cohort of previously untreated patients should not be used to test US products and so be lost to clinical testing of domestic products. He recognised that the products required to be tested, but thought that that might be done in Italy or New York.[164]

23.85 Professor Cash's evidence reflected his attitude at the time. He believed there was a lack of commitment at the level of senior management of the National Blood Transfusion Services in the two countries to integration of research and production. Professor Cash commented that relationships between Mr Watt and Dr Lane were seriously strained.[165] He thought Dr Smith had left the PFC after falling out with Mr Watt.[166] He himself had serious disagreements with the BPL management.[167] Professor Cash was never sure how far Dr Smith had the support of senior management with regard to his collaboration with Dr Foster.[168] Professor Cash commented that he had lost control at the meeting, and that discussion had become heated.[169]

23.86 Following this meeting, Professor Cash sent Dr Lane a letter dated 17 December 1982,[170] with a copy to Dr Harold Gunson, in which he outlined his objections to the course of action proposed. In his letter Professor Cash indicated that:

I do not believe it is in the best interests of the NHS Fractionation Centres, at this time, to encourage the commercial manufacturers to undertake clinical trials with a view to obtaining product licences ....

I would therefore conclude that, at the present time, it is in our (British Transfusion Services) best interests to permit the commercial people all the freedom they desire. I fully sympathise with the sentiments expressed at our meeting, but I am totally convinced that the proposed action is tactically wrong at this time, and will have serious consequences for us all if pursued.

The solution to our problem rests, as I said at the meeting on the 15th December, in thinking and acting very much more positively - I refer to the problem of getting BPL and PFC to work together at all levels. I now deeply regret that the joint PFC/BPL meeting on factor VIII concentrates that I proposed in a letter to you dated 19th December, 1980 did not take place. However, we must now surely consider this as 'water under the bridge' and get down to the urgent task of bridge building. I'm bound to conclude that up to the present time we, as professionals, have failed and the time has come for a joint meeting of the top managers. I include in this context senior members of our respective employing authorities. It is my intention to see what I can do to build these bridges. I do not regard the existing furtive arrangements, as regards factor VIII, between Jim Smith and Peter Foster, however good they may be, as a sound basis upon which the NHS fractionators can combat the commercial people.

23.87 Dr Lane replied to Professor Cash on 21 December 1982 suggesting that it had been agreed that: 'Arthur Bloom and Charles Rizza should inform the Haemophilia Directors of their reasonable right to know the proper basis supporting manufacturers' claims of safety for products in connection with hepatitis-reduced Factor VIII now about to reach the UK market' and informing Professor Cash that: 'since you clearly have altered your view since the meeting, it would seem right that your letter should have been addressed to the Chairman or at least copied to him, since he might feel that further discussion was necessary'.[171] Professor Cash replied on 29 December 1982, in more conciliatory terms, suggesting that 'perhaps the best way forward would be for you to discuss the matter with Harold and feel entirely free to further discuss the problem with Arthur, if you so wish'.[172]

23.88 The correspondence between Professor Cash and Dr Lane following the meeting of 15 December 1982 indicated a degree of tension between the BPL and the PFC concerning the approach to be taken with regard to the likely introduction of commercial heat-treated products and, more generally, as regards cooperation/bridge-building between the BPL and the PFC on viral inactivation (and in particular the relationship between Dr Foster and Dr Smith).[173] There is a problem with Professor Cash's position generally that was highlighted by Professor van Aken: there was a conflict of interest inherent in Professor Cash advising government on the approach to adopt to commercial producers in a competitive market, and in heading the SNBTS which was a producer of products in that market.[174] The Netherlands had a different administrative and licensing structure.[175]

23.89 Professor Cash's conclusion that it was in the best interests of the British Transfusion Services to permit commercial producers all the freedom they desired, which might have included sale of commercial products without clinical trials in the UK, might have conserved the British haemophilia population for trial of domestic products, but that would have been a particularly partial case to advance.

23.90 Professor Bloom and Dr Rizza wrote to the Haemophilia Centre Directors on 11 January 1983 indicating that the Hepatitis Working Party was discussing plans for clinical trials of these products.[176] On 10 January, the Public Health Laboratory Service (PHLS) wrote to the DHSS enclosing a draft letter intended for publication in The Lancet supporting prospective trials of commercial products.[177] It appears that by the end of March 1984 clinical trials had been completed of one product, Hemofil HT, at St Thomas' hospital in London.[178] The Scottish response to the invitation to participate in clinical trials of the commercial products is discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985, at paragraphs 15.143 to 15.144. Professor Christopher Ludlam refused to participate.[179] Professor Cash promoted a Scottish study of patients who had received PFC heat-treated products. The difference in interests between Scotland and the rest of the UK, which had its origins in the dependence of England and Wales on imported products and Scotland's commitment to self-sufficiency, was implicit in these developments.

Evidence on state of cooperation between Dr Foster and Dr Smith

23.91 Professor Cash also expanded in his written evidence on what was meant by the mention in his letter of 17 December of 'the existing furtive arrangements' between Dr Foster and Dr Smith, noting that:

There is no doubt that when I look in 2010 at the proposition that Peter Foster and Jim Smith's interactions were 'furtive', an apology is due. I'm afraid the temperature in this meeting got too high and some of us became extremely anxious that all the SNBTS had stood for was to be swept aside by market place considerations. I suspect that Jim Smith and Peter Foster were aware that in 1980 I had sought to persuade Jim's boss (Dr Lane) that we really ought to be making collaboration between BPL and PFC open, intensive and a high priority, and that this proposal had been rejected. Despite this, and at that time unknown to me, Dr Smith elected to work closely with former PFC colleagues.[180]

23.92 During his oral evidence Professor Cash was asked whether 'furtive' was perhaps simply the wrong word and replied as follows:

Yes, I have no hesitation. I think the fundamental problem I had - and it wasn't about Peter and Jim Smith - it was about: how did the SNBTS as a whole - this working group that we talked about - get engaged in the area of fractionation? And that was difficult because it was heavily controlled by John Watt and so on, and I felt that Peter and Jim were often in bed. So I didn't regard them as being furtive ....[181]

Professor Cash added that he supported what was going on, and that Dr Smith and Dr Foster were getting on with the work.[182]

23.93 Professor Cash's concerns appear to have been related not to the state of the cooperation between Dr Foster and Dr Smith itself, but rather to the lack of a formal structure surrounding their cooperation. Professor Cash also appears to have been impressed by Dr Foster's abilities, going so far as to note at one point during his evidence - admittedly with exaggeration - that, 'if we had had 25 Peter Fosters, we would have been fractionating on the moon'.[183]

23.94 Dr Foster's written evidence to the Inquiry also expressed the view that the issue raised by Professor Cash at the time was the lack of a formal structure for cooperation rather than any breakdown in cooperation with the BPL and Dr Smith.[184]

23.95 Dr Foster's written evidence indicated, however, that his preference was 'to exchange information with Dr Smith and his staff on a less formal basis than Professor Cash may have preferred', although he 'would have been happy to accept a more formal arrangement, if this had been requested'.[185] When asked to expand on this point during the Oral Hearings, Dr Foster said that with scientists who are dealing with the same problems, talking face-to-face was the best way to proceed in terms of communications, over the phone and having meetings, and obviously in correspondence, and in reciprocal visits to each other's facilities.[186]

23.96 When asked, both Dr Foster and Dr Smith confirmed that, in their view, the reporting between the PFC and the BPL was reciprocal. Dr Foster noted in his written evidence that:

To the best of my knowledge the exchange of information between the SNBTS and the BPL/PFL was reciprocal, except when precluded by a requirement for confidentiality, such as the arrangements between the PFC and Dr Johnson ... and the period when BPL were planning to patent the process used to prepare 8Y ....[187]

26.97 Dr Smith's response was:

I would have continued to inform PFC without constraint of anything notable coming out of our still very tentative work on pasteurisation, and later dry-heating, in 1983. But I cannot document that.[188]

23.98 Dr Perry said:

Although there continued to be no formal collaboration or reporting between Scotland and England the established cooperation continued particularly between senior operational managers at PFC (myself and Dr Foster) and their counterparts at BPL (Drs Smith and Snape).[189]

Dr Perry's most important contribution on this issue was that it did not have any impact on the local PFC development programme, which continued to focus on the development and preparation of a pasteurised product for initial clinical trial.[190] He emphasised that it was important to recognise that the pursuit and maintenance of self-sufficiency and product yield were of high priority for the SNBTS, particularly in light of the knowledge that the eventual introduction of NHS heat-treated products would, as a result of yield penalties, potentially reduce the overall amount of Factor VIII available to patients.[191]

23.99 Notwithstanding the written exchanges, and the background of difficult relationships among senior management of the public sector organisations which they reflect, Dr Smith and Dr Foster continued their dialogue.[192] In addition, there were more formal joint projects involving the two organisations.[193] In the ordinary course of business, the exchange of information was reciprocal except where there was a requirement for confidentiality, arising from external contracts or from patent proceedings.[194]

23.100 On a wider front, informal contacts with scientists in the pharmaceutical industry provided intelligence on developments that were not widely publicised. Dr Prowse of the PFC had thus heard that Baxter/Hyland's product disclosed at Budapest was dry heat-treated.[195] After testing, the dry heating applied to Hemofil T proved less effective than pasteurisation.[196] That was consistent with information circulating informally within the industry, and within UK Government circles, in 1983 and 1984.[197] It appears that while regulatory reporting on Hemofil awaited completion of the formal studies required by International Society of Blood Transfusion (ISBT) protocols, dissemination of the adverse results was a priority for researchers.

23.101 Against this background of increased industry interest in heat treatment, the PFC (Dr Cuthbertson and Dr Pepper) did some experiments in dry heat treatment of Factor VIII.[198] Meanwhile, work on pasteurisation continued. There was considerable activity at the beginning of 1983 (summarised in paragraphs 11.96 to 11.115 of the Preliminary Report), leading up to the agreement of Professor Forbes and Professor Ludlam on 22 March 1983 to take part in clinical trials of the PFC Factor VIII product as part of a strategy for developing heat-treated products for general use.[199] However, within a few weeks AIDS among haemophilia patients in the USA was widely publicised and the context changed from elimination of NANB Hepatitis. Developments in 1983 are considered in the context of that new threat.

23.102 The change of emphasis was reflected in the Netherlands also. Professor van Aken said of the early 1980s:

The growing concern was mainly related to AIDS and with regard to non-A, non-B hepatitis that was at that time more or less, I would say, accepted as a side effect of transfusion and of the administration of plasma components. That had not the same urgency as it gradually got later on because in the beginning, when I came in board in CLB on the board, that was not the main concern we had. The first real concern about transmission of the diseases, of viral diseases, was AIDS.[200]

Research at the Protein Fractionation Centre: Progress in 1983 and 1984

1983

23.103 In the first few months of 1983 the PFC continued its work on the pasteurisation of Factor VIII. Dr Foster reported on developments to Dr Smith and the PFC appears to have been keenly aware that commercial companies were likely to launch heat-treated Factor VIII in the near future.[201] In a memo to Mr Watt, Heads of Department, Section Managers and Dr MacLeod dated 11 January 1983, Dr Foster explained that 'this could well have major implications for the NHS ... and it is therefore recognised that there is some urgency in demonstrating that the NHS has the capability to manufacture products of this kind'.[202] Clinical trials of small amounts of high purity zinc-precipitated Factor VIII which had been heated at 60°C for 10 hours were planned with the aim of developing a product with a 'reduced risk of transmitting hepatitis'.[203] During the meeting of the Haemophilia and Blood Transfusion Working Group on 22 March 1983, it was decided that Professor Charles Forbes and Professor Ludlam were to carry out these trials in coordination with Professor Cash.[204]

23.104 As regards Factor IX, research into heat treatment to reduce the risk of hepatitis was reported to be underway.[205] However, it was noted that animal studies would be needed in order to confirm that heat-treated Factor IX was not thrombogenic.[206]

Recognition by fractionators of the risks posed by AIDS

23.105 During the first few months of 1983 the focus of the PFC's research and development programme remained on methods which could inactivate hepatitis in blood products. However, a subtle shift had begun to take place. Fractionators were becoming alive to the possible risks which AIDS might pose to the blood supply (and hence the possible enhanced need for viral inactivation processes which could deal with such risks).

23.106 This issue of AIDS was referred to very briefly (admittedly with a question mark) as a 'problem' in a presentation entitled 'Methods for Preparing Non-infective Blood Products' given by Dr Foster to the Haematology Department of the Royal Infirmary of Edinburgh (RIE) on 8 March 1983.[207] When asked to expand on what this meant, Dr Foster explained that he was beginning to think that AIDS might be caused by an infectious agent that would potentially have to be taken into consideration in research on virus inactivation: research was not going to be focusing exclusively on hepatitis.[208]

23.107 AIDS was also discussed (in general terms and in the context of high-risk donors) during the meeting of the Haemophilia and Blood Transfusion Working Group on 22 March 1983, the minutes of which note that members were reminded of the recent articles both at home and abroad about AIDS, and that there was concern that AIDS might appear in the UK.[209] However, there is no record that the potential impact of AIDS on the PFC's viral inactivation programme was discussed. According to Dr Perry, the apparent lack of a cross-reference between AIDS and heat treatment in this discussion was unsurprising as, in his view, 'at that time it was far from established or accepted that AIDS had a virus aetiology'.[210] Dr Foster was of the same view, although his oral evidence on his presentation of 8 March 1983, referred to at paragraph 23.106 above, indicates a degree of ambivalence. He stated in his written evidence:

At this time (22 March 1983), the cause of AIDS was not known. Even if an infectious agent was assumed to be responsible, neither the nature of the infectious agent, nor its sensitivity to heat were known. Therefore there was no basis, other than speculation, for a 'cross-reference' between the topics of heat treatment and AIDS.[211]

23.108 Dr Perry advanced another possibility for the lack of a cross-reference between AIDS and heat treatment in the minutes of this meeting. According to Dr Perry, the failure to make a connection between these two issues in the minutes did not necessarily imply that the meeting had not discussed the two potentially related topics. He suggested instead that it seemed more likely that any such discussion had been inconclusive and therefore had not been recorded.[212] Professor Cash, in contrast, was of the view that the lack of a reference was to be expected indicating that, 'heat treatment was a process that was assumed might inactivate all viruses transmitted by plasma products. Thus in March 1983 a specific link between the two would have been taken for granted'.[213]

23.109 Only a few weeks later, in May 1983, the potential impact of AIDS on the PFC's strategy had become more apparent. On 3 May 1983 Dr Foster sent a memo entitled 'Heat Treatment of FVIII. A strategy' to Mr Watt and the PFC's Heads of Department.[214] The memo indicated that:

Until very recently the objective of our heat treatment programme was to cope with the hepatitis problem in haemophiliacs.

Because severe haemophiliacs have already been heavily exposed to untreated products then only mild and moderate haemophiliacs could benefit from a treated product (in the foreseeable future). It was estimated that the mild/moderate group could use up to 30% of the total FVIII. This estimate, plus the fact that these patients are presently likely to be treated with single donor cryoprecipitate have determined our present strategy i.e. that we will:

(1) Plan for 4-6 pilot scale lots during 1983.

(2) Design a full-scale plant to handle 30% production for 1984/85 at the earliest.

(3) Mild and moderate haemophiliacs can continue to receive single donor cryo meanwhile.

The possibility that another more serious infectious agent (AIDS) is now involved suggests that we may need to review this strategy. In the new scenario:-

i) The haemophiliacs most at risk are the severes rather than the mild and moderates.

ii) There is already evidence of a panic recourse to cryoprecipitate.

In the absence of any hard data, heat treatment (of everything) looks at the moment to be the most likely possibility that we have to face up to. If this is so then we will have to plan to pasteurise all of the FVIII (rather than 30%) and we may also want to review the timescales noted above.

23.110 The memo indicated further that decisions will probably be taken according to a 'worst case' hypothesis and suggested that:

There may therefore be a case for accelerating our heat treatment programme. While I do not disagree with point (2) above it may be possible to introduce an intermediate stage, still using the pasteurisation cabinets. We probably have most of the equipment to do this already.[215]

23.111 A worked example followed outlining how this 'intermediate stage' would operate in practice based on an input of 1000kg of fresh frozen plasma.

23.112 Two days later, on 5 May, Mr Watt wrote to Professor Cash.[216] His letter outlined the existing pilot-scale approach to heat treatment and preliminary results of heat treatment studies which showed that heating for a shorter period at a higher temperature (70°C for less than an hour) was more effective in killing virus than heating for 60°C at 10 hours. The letter also advocated an acceleration of the pasteurisation programme, noting that:

In view of recent news exposure of (?) [sic] infectivity of Factor VIII concentrates we have made a re-assessment of heat treated concentrate based on a careful step-by-step appraisal of a series of pilot-scale lots.

In most areas of the development I believe we now possess sufficient data to allow, by adopting a few calculated risks, this programme to be speeded up substantially .... My colleagues are engaged in a costing for the expedited programme in case public opinion rather than science may dictate the best course of action.[217]

23.113 Professor Cash responded to this letter on 1 June 1983 noting that he considered the last part of Mr Watt's letter (ie the proposal to accelerate the heat treatment programme) to be the most important and that 'as you say, public opinion may eventually press us heavily'.[218] However, the letter also indicated that there were insufficient funds:

Right now we must conclude that with the existing set of instructions the Agency [the CSA] has received from SHHD with regard to the way it is to spend its development monies, and noting the reaction of the Deputy Chief Medical Officer to the concept that heat treated factor VIII is related to the interests of the Medicines Inspectorate, then there are no funds available in 1983-1984 for your proposals. However, in the light of the current pressures (AIDS etc.) the Department may wish to reconsider its instructions to the CSA and/or find additional monies (less likely!). In any event, I think we can be certain that a full and separate case will be required by the SHHD as soon as possible and your Report on PFC's needs will be of considerable importance.

23.114 The letter drew Mr Watt's attention to two 'inextricably linked items' ('implications for PFC of optimal additive blood bags' and 'pilot stage of heat-treatment of factor VIII') and went on to ask Mr Watt to 'take these two items' and 'put them together in a single package (story) directed towards the heat treatment of factor VIII' - ie a proposal which could be put before the SHHD.

23.115 The Inquiry asked various witnesses questions focused on gaining an understanding of: the circumstances which led Dr Foster to write his memo of 3 May 1983; the plans outlined in this memo; the subsequent correspondence between Mr Watt and Professor Cash; and the plan to seek more funds from the SHHD for the acceleration of the pasteurisation programme.[219]

23.116 In his written evidence,[220] Dr Foster explained that the trigger for his memo was the report in The Lancet of 30 April 1983 of AIDS infections in 11 haemophiliacs in the USA and three in Spain who had been treated with commercial factor concentrates.[221] According to Dr Foster, 'these reports caused me to consider the potential implications for our strategy on the development of heat treatment, should it be found that this syndrome was caused by an infectious agent'.[222] Severe haemophiliacs were more at risk of AIDS as they 'received much more treatment'.[223]

23.117 Dr Smith's view was that, at this time, most fractionators thought it likely that AIDS was caused by a blood-borne virus, indicating that Montagnier and Barré-Sinoussi's seminal article of 20 May on the isolation of the HIV virus[224] offered 'strong support' for this 'working hypothesis'.[225] The Montagnier/Barré-Sinoussi article post-dated Dr Foster's memo and could not have been something he would have been aware of in preparing his memorandum of 3 May.[226] Dr Smith further explained in his oral evidence that the insight that he had at this time (based on information probably provided by Dr Cumming) was that:

[There was] a huge overlap between the sexually transmitted diseases and the blood borne diseases. So anyone with that mindset would tend to be making a conclusion perhaps before the evidence really justified it.[227]

23.118 Professor Cash also confirmed in his written evidence that the threat of AIDS was becoming clearer by May 1983, noting that:

As far as I recall, by May 1983 we were a little more certain that AIDS was transmitted by plasma products and that the clinical consequences were very much more serious than viral hepatitis. It follows that Dr Foster's reported efforts to accelerate our heat treatment programmes were entirely appropriate.[228]

23.119 In his oral evidence, Dr Foster explained how the plan outlined in his memo of 3 May 1983 was intended to operate. He noted that he had difficulty recollecting exactly what he meant by the introduction of an 'intermediate stage' for the acceleration of the heat treatment programme.[229] However, when asked, he indicated that the phrase should be read as meaning a plan which could advance heat treatment as quickly as possible[230] and that, in practice, this meant a 'temporary arrangement pending the fully engineered process design' (ie pending the design of a full-scale plant).[231] The plan would, therefore, have amounted to a wholesale move to pasteurisation using the existing pasteurisation cabinets, albeit on a temporary basis.[232]

23.120 Dr Foster gave further background information in his written statement. He indicated that the original plan for the pasteurisation process involved 'heating large volumes of protein in a concentrated sugar solution' in a single large vessel, but that:

[E]arly large-scale experiments demonstrated that the heating-up and cooling-down of the mixture took a very long time, during which more factor VIII was destroyed than had been experienced in small-volume laboratory experiments.[233]

23.121 To prevent this loss of Factor VIII, Dr Foster considered the design of a re-circulating system in which the solution would be passed through a heat exchanger to accelerate heating-up and cooling-down. However, according to Dr Foster, this was not straightforward. An alternative process was adopted which involved 'dispensing the mixture into 1 litre bottles which could then be heat-treated in the PFC spray cabinet that was used to pasteurise albumin'. Dr Foster explained that this procedure enabled pilot-scale production of Factor VIII to be accelerated.[234] This pilot-scale process did not extend to the wholesale switch to pasteurisation using pasteurisation cabinets which was proposed in his memorandum of 3 May 1983.[235] As outlined further below in the discussion of the events of 1984, wholesale switch to pasteurisation ultimately never occurred.

Funding issues

23.122 The Inquiry posed various questions to witnesses aimed at clarifying the outcome of Professor Cash's request in his letter of 1 June 1983 for the PFC to put together a funding proposal for the heat treatment programme.

23.123 In summary, the position appears to have been as follows:

  • At the end of May 1983, the Blood Transfusion Service Sub-Committee of the Common Services Agency (CSA) agreed that a funding proposal for the 'pilot stage of heat treatment of factor VIII' should be submitted to the SHHD as a bid against certain of the money available to meet the costs of the recommendations arising from the Medicines Inspectorate inspection of the PFC.[236] The reason for attempting to link heat treatment to the recommendations of the Medicines Inspectorate appears to have been largely a pragmatic one, based on the fact that a large sum of money (circa £650,000) had already been allocated for compliance with the Medicines Inspectorate's recommendations relating to the quality of the PFC's facility.[237]
  • A proposal was duly submitted by the CSA to the SHHD in June 1983.[238] The funding sought for the heat treatment of Factor VIII was for capital of £74,000 for equipment and £13,400 revenue.[239]
  • In September 1983, the SHHD responded that the expenditure on heat treatment was not a requirement arising from the recommendations of the Medicines Inspectorate, but asked the CSA to consider making a separate submission for funding.[240]
  • On 22 February 1984, the Blood Transfusion Service Sub-Committee approved a separate submission to the SHHD for funding for the heat treatment of Factor VIII.[241]
  • On 23 May 1984, Dr Albert Bell of the SHHD wrote to Mr Alexander Murray (also SHHD) outlining the policy case for the heat treatment of Factor VIII, concluding, '[I]t is not for me to say how this development should be financed but I can say that it is a genuine technological advance and a failure to bring it about would be very difficult to defend'.[242]
  • Formal authorisation of a sum of £90,000 for the heat treatment of Factor VIII was ultimately made by the SHHD in mid-August 1984.[243]

23.124 There was, therefore, a delay of more than one year between the submission of the initial request for funding for heat treatment of Factor VIII and the authorisation of the amount requested, arising largely from these administrative exchanges.[244] Funding was one of the few aspects of the SNBTS operations in which the CSA and its committees had an active role.

23.125 An important question is whether this delay in the authorisation of funding resulted in a delay to the heat treatment programme. According to the witnesses asked this question by the Inquiry, the heat treatment development programme was not delayed. Dr Perry stated in his written evidence that: 'my recollection is that notwithstanding the above funding issues concerning scale up of production and its routine introduction the development programme continued to progress at pilot scale within existing resources'.[245] Dr Foster echoed this view in his oral evidence:

Q. But just before we drop for today the question of funding, do you have any memory of its also being an obstacle ... that money had to be found?

A. No, it didn't seem to me to be an issue. I thought this is so important that I thought, 'If this is what it costs, this is what it costs and the money will come through,' and I left that to Mr Watt and Professor Cash to sort out. It wasn't something that seemed to me to be an obstacle.[246]

23.126 During his oral evidence, Professor Cash 'instinctively' concurred with Dr Foster's view.[247]

23.127 Both Dr Perry and Dr Foster also explained that, in their view, the key factor which determined the progress of the pasteurisation project in the latter half of 1983 was the organisation and conduct of clinical trials and not funding.[248]

Progress at PFC

23.128 Meanwhile, on 13 June 1983 Professor Cash wrote a letter to Professor Ludlam asking him to carry out clinical trials of the first batch of pasteurised Factor VIII (batch NY 761).[249]

23.129 On 15 June 1983 a meeting of the Factor VIII Safety Action Group was held, which was attended by Dr Bruce Cuthbertson, Dr Bobby Sommerville and Dr Duncan Pepper. The minutes of the meeting provide a detailed overview of the research which the PFC was undertaking at this time, which involved heating at 60°C for 10 hours followed by a 30 minute period at 70°C and testing for virus kill (using vaccinia, polio 2 and herpes simplex as model viruses) and Factor VIII loss.[250] The research was summarised as follows:

Considerable progress has been made at P.F.C. in producing heat treated FVIII and clinical trials should start towards the end of the summer in Glasgow and Edinburgh. No infectious model for non-A, non-B has been produced yet. The putative 'AIDS' virus must be considered as a potential hazard in FVIII concentrates.[251]

23.130 On 27 June 1983 Dr Foster met Dr Johnson at a World Federation of Hemophilia meeting in Stockholm and learned of a potentially promising method which could be used to increase the purity of Factor VIII.[252] Dr Foster explained in his written evidence that the process:

[I]nvolved the chromatographic purification of factor VIII, in which chemicals were added to subtly modify the conformation of the factor VIII molecule to promote its attachment to a conventional ion exchange matrix.[253]

23.131 In practical terms this meant that:

[I]t was conceivable that the increased purity promised by the method of Dr Johnson would enable the volume of solution to be pasteurised to be reduced about 50-fold, making the pasteurisation in 1 litre bottles potentially feasible for full-scale manufacture as well as for pilot-scale processing.[254]

23.132 Dr Foster passed on this information to Mr Watt who wrote to Dr Johnson on 1 August 1983, proposing collaboration (initially on a confidential basis) and outlining various procedural issues which would have to be dealt with.[255] The letter to Dr Johnson also intimated Mr Watt's decision to leave the PFC on grounds referred to as 'multifactorial'.[256]

Infectivity of Hyland product

23.133 Meanwhile, on 1 July 1983, Dr Diana Walford of the DHSS wrote to Dr Harold Gunson of the Regional Transfusion Centre (RTC) in Manchester indicating that three chimpanzees given Hyland's dry-heated Factor VIII product had developed hepatitis.[257] It would appear that the reference to hepatitis in this letter meant Hepatitis B.[258] The suggestion was that Hyland's product might not be hepatitis-safe. It is not clear at exactly what point this information filtered through to the PFC for the first time. However, it is clear that Hyland had already proposed a study during the World Federation of Hemophilia meeting in Stockholm in June to evaluate whether its dry-heated Factor VIII product transmitted hepatitis.[259] Professor Mannucci of the University of Milan took part in this study which was carried out in Milan, Heidelberg, Paris and London, and noted in his 2003 memoirs that:

[I]t was evident from the follow up of the first few patients enrolled in our study that a large number of them had developed hepatitis. Such information was verbally communicated by me to a large number of hemophilia treaters who met in Barcelona on the occasion of the Congress of the European Society of Haematology in September 1983.[260]

23.134 The ultimate outcome of the research carried out by Professor Mannucci and others into the safety of the Hyland product, which was published in July 1985, was that patients given Hyland's dry-heated product had a high prevalence of NANB Hepatitis and an absence of Hepatitis B, whereas for chimpanzees the results were the reverse (ie an absence of NANB Hepatitis and a prevalence of Hepatitis B). So, in simple terms, the fact that a chimpanzee which had been given Hyland dry-heated Factor VIII was free from NANB Hepatitis provided no guarantee that the product would not transmit NANB Hepatitis to humans. The conclusion of Professor Mannucci's research was therefore that, 'the animal model is not reliable for NANB hepatitis transmission studies'.[261]

23.135 The results of the research were already widely known before publication in 1985. By late summer 1983, knowledge of the failure of the Hyland dry-heated product to inactivate hepatitis appeared to be fairly widespread. By January 1984, the SNBTS was certainly aware that the Hyland product was infective as evidenced by the minute of the meeting of the Factor VIII Study Group of 12 January 1984 which indicated that 'the current Hyland product ... is still infective'.[262]

Progress in England

23.136 By late July 1983, consideration by the authorities in England of their own approach to heat treatment was ongoing. A report by Dr Craske, which was subsequently incorporated into the annual report of the UK Haemophilia Centre Directors Hepatitis Working Party for 1982-83, included a general overview of the viral inactivation landscape outlining the various forms of viral inactivation which were being developed (ie using chemicals, pasteurisation and dry heat treatment), and the commercial heat-treated products which were likely to become available. The report commented that it was possible that Factor VIII concentrate prepared from plasma donations obtained in the USA might be contaminated with a putative infectious agent associated with the cause of AIDS.[263] It did not, however, suggest a specific direction which should be taken.

23.137 An unpublished Central Blood Laboratories Authority (CBLA) paper on heat treatment dated 26 July 1983 did comment on the direction which was likely to be taken in England, though for marketing rather than purely scientific reasons.[264] It noted that pasteurisation was 'more homogeneous and efficient' than dry heat treatment, but that it was 'associated with more molecular damage of heat unstable proteins than occurs by the dry heat route' and appeared to favour dry heat treatment on the basis that this 'will allow BPL to present to clinical managers of haemophilia a product carrying equivalent weight of claims for safety as those of rival commercial organisations'. The report also indicated that 'it [had] been shown possible to maintain greater than 95% of factor VIII activity in the finished product after heating at 75°C for ten hours or heating at 60°C for 24 hours' and that this dry-heated product was 'being advanced with high priority to enable manufacture to become routine by the late summer 1983'. At this point, therefore, shortly before Mannucci was giving preliminary indications of the lack of efficacy of the dry-heated Hyland product in Barcelona, dry heat treatment was the preferred viral inactivation process in England.

23.138 Various witnesses commented critically on aspects of the CBLA report of 26 July 1983. Dr Smith did not know who had written it and indicated that the date for routine manufacture of 'summer 1983' was 'extraordinarily optimistic' as by 'late summer 1983 we only had our very first results on dry heating'.[265] Dr Smith also pointed out that, while correct in principle, the reference to pasteurisation being 'associated with more molecular damage' had to be read loosely as one would not pasteurise or dry heat in the same medium and account would have to be taken of other elements used to protect Factor VIII in the pasteurisation process.[266] Dr Foster shared this view indicating that the statement on the molecular damage caused by pasteurisation was a 'bit of a generalisation' and that it failed to take account of the amount of heat applied or the use of stabilisers in the pasteurisation process.[267] Similarly, Dr Cuthbertson indicated that the reference to 'heating at 75°C for ten hours or heating at 60°C for 24 hours' was too simplistic noting that 'it's not simply a question of heat and time, it's a question of the stabilisers, the format that the product is in and a whole range of other complex things that lead to the level of inactivation that you finally get'.[268]

Scottish developments

23.139 Returning to Scotland, on 23 August 1983, Dr Foster updated Dr Smith on the progress of the pilot-scale pasteurisation programme for Factor VIII and explained that, since Factor VIII survived 'fairly well' for up to one hour at 70°C, an amended regime of 9.25 hours heating at 60°C followed by 0.75 hours at 70°C would be followed in the next trials.[269] According to Dr Foster, Dr Smith visited the PFC on 8 September and 2 November 1983 to discuss coagulation factor research and development and the heat treatment of coagulation factor concentrates.[270]

23.140 Research into heat treatment continued at the PFC during the second half of 1983. Progress at the end of the year was summarised as part of a more general report by Dr Foster entitled Progress Report on Studies to Improve Yield and Quality of FVIII Concentrate dated 20 December 1983. As regards pasteurisation, the report explained that:

Extensive studies have been carried out on the stability of FVIII:C and a range of model viruses to heating in solution in the presence of sorbitol and glycine.

Compared to an albumin control ... the sugar solutions ... showed substantial stabilisation of virus (vaccinia and mumps). Improved heating conditions have been identified to achieve further viral inactivation ....

Even more severe heating results in substantial loss of FVIII activity and the improved conditions are probably the best that can be achieved without an unacceptable loss of yield.[271]

23.141 The report also indicated that the PFC was carrying out experiments in dry heating, using the same model viruses. Dr Cuthbertson indicated in his witness statement that he carried out the dry heating experiments together with Dr Pepper on 21 November 1983. He described the work:

Vials were either left unheated as controls or were heat treated at 60 or 70°C. The vials heated at 70°C were completely insoluble, so it was not possible to assess the extent of viral inactivation. The vials heated at 60°C were tested and showed a modest degree of inactivation of vaccinia virus, which was significantly less than that found in our pasteurisation studies.[272]

The report commented that 'initial results suggest that the viral kill is less than that achieved by heating in sugar solutions at 60°C for 10hrs'.[273]

23.142 Dr Cuthbertson was asked by the Inquiry to provide further information and documentation describing these experiments.[274] He duly provided his handwritten summary of the experiments[275] together with a typewritten copy for ease of reading.[276] In his oral evidence, Dr Cuthbertson explained that the purpose of the experiments was to see whether dry heating would give equivalent inactivation to what the PFC was seeing in the liquid process. It was a kind of control. The temperatures applied, 60°C and 70°C, were chosen because they were the temperatures used for the pasteurised product.[277] Dr Cuthbertson also explained in more detail the difference in viral inactivation between the dry-heated and wet-heated products, noting that in the dry-heated product heating led to 'a 3 log reduction, whereas in the ... liquid product, we were looking at an 8 log reduction' and adding, in reference to the dry-heated product, that:

Just to put that into perspective, an 8 log reduction means 100 million viruses per inoculum being inactivated, whereas this shows about 10,000 viruses per 0.1 ml being inactivated. So the difference in them, because it is a logarithmic scale, is enormous. So it was a much less effective virus inactivation process than the liquid process that we were studying and for that reason we kept going with the liquid process at that time.[278]

1984

23.143 On 5 January 1984, Dr Smith sent Dr Foster a memorandum outlining details of the results of the PFL's experiments on the dry heat treatment of Factor VIII.[279] The memorandum commented on the impact of different heating conditions on solubility and Factor VIII activity and indicated that the experiments showed 'the promising preservation of factor VIII:C[280] and solubility of one batch'.[281] The Inquiry asked whether what was disclosed in this memorandum was new and what effect, if any, this news had on those working at the PFC.[282] Dr Foster's response in his written statement was that:

The memorandum from Dr Smith to myself, of 5th January 1984 ... concerned the ability of the current BPL Factor VIII concentrate to withstand dry heat treatment under different conditions. Although these data were more extensive than those that had been obtained by the SNBTS, the results were consistent with those of Dr Cuthbertson and Dr Pepper and were not regarded as representing new findings.

The absence of any data from BPL concerning the inactivation of any viral markers, meant that the data from Dr Smith were of limited value. Virus inactivation data were available for pasteurisation, from laboratory studies with marker viruses by the SNBTS, as well as studies in animals and in patients by Behring, all pointing to pasteurisation being more likely to succeed in making coagulation factor concentrates safe with respect to non-A, non-B hepatitis than dry-heat treatment. Consequently the information from Dr Smith did not alter the opinion in Scotland that pasteurisation should continue to be the main focus of research on virus inactivation.[283]

23.144 Dr Smith indicated that:

There does appear to be some gap in technical correspondence, but Dr Foster and I both understood perfectly well that we were pursuing different approaches in the short term, for our respective pressing reasons. For example, during this period PFC was greatly preoccupied with preparing a pasteurised product for clinical trial. My letter would not be intended in any sense to divert PFC from pasteurisation ... simply to show that the Oxford and larger-scale Elstree products were capable of withstanding heat treatment, as Rubinstein predicted. I had no information (and at the time little hope) that this treatment would inactivate NANBH, which remained the goal of pasteurisation.[284]

23.145 Thus, on Dr Smith's approach, the information in his memorandum did not indicate that the BPL results suggested that the procedure reported would inactivate NANB Hepatitis, and only alerted the PFC to the fact that the BPL's Factor VIII could survive certain forms of dry heat treatment.

23.146 On 11 January 1984, Professor Ludlam wrote to Professor Cash reporting that the clinical trial of the PFC's pasteurised Factor VIII (batch NY 761) had led to an adverse reaction in one patient:

I write to let you know the outcome of infusing the heat treated factor VIII. The above batch of material was given to a single severe haemophiliac on three separate occasions ....

Infusions were accompanied by reactions on all three occasions. On the first the recipient had a short episode of diarrhoea beginning an hour after the infusion. On the second and third occasion he felt ill towards the end of each infusion. He developed transient central chest pain, pallor and [retching]. There was no change in his pulse, BP or temperature. To ascertain whether this was likely to be an organic reaction to the concentrate we gave him a 'placebo' infusion of ordinary SNBTS factor VIII. He was told that it was the heated material and the infusion protocol was identical. He had no adverse reaction to this standard product.[285]

23.147 Professor Ludlam therefore concluded that that batch of material 'genuinely gave rise to significant and unacceptably adverse reactions in the recipient'.

23.148 Professor Cash replied on 16 January 1984 agreeing with Professor Ludlam's conclusions, and expressing the hope that a further batch, with improvements in heat treatment and lower sorbitol content, would be available in April.[286] On 25 January 1984, Dr Gillon wrote to Dr Boulton expressing the view that sorbitol was unlikely to be the cause of the adverse reaction.[287]

23.149 The information regarding the possibly adverse outcome of the clinical trial had already been intimated at the meeting of the Haemophilia and Blood Transfusion Working Group on 14 November 1983. During this meeting Professor Ludlam appears to have mentioned that the patient experienced, 'minor adverse reactions', possibly implying that the severity of the reactions was less than the 'significant and unacceptable reactions' outlined in the letter of 11 January 1984.[288]

23.150 The Inquiry asked witnesses for an explanation of the difference in the description of the adverse reaction in the letter of 11 January and the memo of 14 November 1983.[289] Professor Ludlam's response in his written statement was as follows:[290]

At the meeting of the Haemophilia Directors with SNBTS at SHHD on 14th November the Minutes record that I reported that there had been 'minor adverse reactions on each occasion' when the heated product was infused. This was how the Minute-taker recorded what he thought had been said and may not have accurately recorded what had actually been stated. I have no recollection of exactly what I said. I might have indicated that the reactions were 'minor' but this does not make them acceptable. A 'major' reaction would have been an anaphylactic one in which there is severe hypotension and is immediately life-threatening - this occasionally is seen with infusion of blood products especially cryoprecipitate.

Further details of the infusions and the reactions are given in my letter of 11th January 1984 in which I recorded that 'Infusions were accompanied by reactions on all three occasions ....' The reaction to each infusion was sufficiently marked that an injection of piriton (antihistamine commonly given to reduce 'allergic' reactions) was given on each occasion ....

23.151 Dr Cuthbertson's view in his written statement was that the reaction was probably not severe, but was not one which would be considered acceptable. He noted that Professor Forbes agreed to trial the product with additional patients, which was not consistent with a severe reaction.[291] However, a later letter from Dr Foster to Professor Ludlam dated 10 February 1984 indicated that Professor Ludlam was the only clinician who had been given an 'inferior batch' to test, the implication being that this could have been the reason for the adverse reaction.[292] Therefore, according to Professor Ludlam the description of the adverse reaction as 'minor' during the meeting of the Haemophilia and Blood Transfusion Working Group on 14 November 1983, may have been due to an inaccurate recording by the minute taker, or may have been accurate and consistent with the letter of 11 January 1984. According to him, the fact that he was prepared to arrange a control experiment with unheated product was evidence that the reactions were 'clinically significant'.[293]

23.152 On 12 January 1984 the Factor VIII Study Group met.[294] Dr Cuthbertson presented the results of the PFC's research into the viral inactivation of Factor VIII (including the results of viral inactivation experiments using model viruses) and referred to the BPL's work on dry heat treatment and the fact that this work suggested that, 'there is no yield penalty for dried FVIII if it is heated to 60°C for 3 days'. As indicated above, mention was also made of the fact that Hyland's heat-treated product was infective.

23.153 The Inquiry asked witnesses whether the information on the failure of Hyland product had an impact on the perceived significance of the BPL's progress in dry heating Factor VIII and whether there was any suggestion within the PFC of changing to dry heat treatment at this time.[295] Dr Foster's response in his written statement[296] was that the failure of the Hyland product was indeed considered to be evidence against dry heat treatment, as were the disappointing levels of viral inactivation which Dr Cuthbertson and Dr Pepper had found when carrying out their own dry heat experiments in November of 1983.[297] Dr Foster also pointed out that the fact that the BPL's dry heat treatment experiments lacked any measurement of viral kill was a factor in the PFC's decision to continue with its prioritisation of pasteurisation.[298] Dr Perry's answer was to the same effect. He emphasised that there was no information available worldwide to suggest that heat treatment of freeze-dried product at 60°C would be capable of inactivating an AIDS virus.[299]

23.154 Dr Cuthbertson agreed with this view, noting that the failure of the dry heat-treated Hyland product to inactivate NANB Hepatitis 'made this process look less promising, whereas the virus inactivation data on the SNBTS pasteurised product were very promising indeed' and that for this reason, it was concluded that the PFC should continue with pasteurisation as the primary heat treatment process.[300]

23.155 At this time the firm focus of the PFC was, therefore, on continuing its research into the pasteurisation of Factor VIII. Work in this regard continued in the early part of 1984. Events of note included:

  • Further clinical trials of heat-treated Factor VIII and the conclusion of a successful trial (with no adverse reactions) by Professor Forbes of Glasgow Royal Infirmary by March 1984.[301]
  • The availability for formal clinical trial of a pilot batch of pasteurised Factor VIII at the end of April 1984.[302]
  • Further collaboration between Dr Foster and Dr Smith in May of 1984.[303]

23.156 At this point the target date for the introduction of pasteurised Factor VIII for clinical use was April 1985.[304] That target date was described by Dr Foster in his written evidence as 'extremely ambitious for the installation and commissioning of such a large and complex manufacturing process' adding that this is why 'the focus shifted in August 1984 to the incorporation of Dr Johnson's purification procedure in order to substantially reduce the volume of solution to be pasteurised ...'.[305]

23.157 The PFC's research into, and focus on, the pasteurisation of Factor VIII continued during the summer of 1984. The collaboration with Dr Johnson of New York University on the development of a high purity Factor VIII product, which it was hoped would allow for pasteurisation in one litre bottles, had stalled due to the delay in applying for a patent and the University's concerns that details of the procedure should not be disclosed before an application was filed.[306] However, on 14 June 1984, Dr Foster met with Dr Johnson in New York and an agreement was made that details of the procedure should be disclosed to the PFC prior to the patent being filed.[307] This agreement paved the way for further work to be carried out at the PFC into the development of a high purity Factor VIII product. Such work included an evaluation by Dr Foster of Dr Johnson's proposed ion-exchange[308] reagent and the setting up of a meeting between Dr Johnson and Dr John Curling of the pharmaceutical company Pharmacia at the ISBT Congress in Munich to look at alternative reagents. The alternative reagent chosen, Q-Sepharose, was delivered to the PFC on 22 August 1984.[309] According to Dr Foster, it was found to be 'very promising', although 'it became clear that further work would be required to fine-tune the chromatography process before it could be integrated into the pasteurisation process'.[310] Due to the additional scientific input needed, Dr Ronald McIntosh was moved from his work on immunoglobulins to take the lead on the high purity project.[311] As indicated above, one of the main aims behind this project was to reduce the volume of solution to be pasteurised, and so facilitate the change from experimental to commercial production.

23.158 Arrangements for clinical trials of pasteurised Factor VIII were progressing and in June 1984 Professor Cash prepared a report on the activities of the Factor VIII Study Group which contained a separate report outlining 'Preliminary Clinical Evaluation Studies' for heat-treated Factor VIII.[312] The annex explained that:

Preliminary in vivo and in vitro studies (carried out in Edinburgh and Glasgow), using a 60°C for 10 hours heating procedure demonstrated that the sugar appeared to prevent denaturisation of factor VIII. The proposed new studies will be performed using product exposed to the optimal heat treatment (includes a period at 70°C) and are designed to assess biological acceptability, clinical efficacy and residual infectivity.

It is proposed that all heat-treated product made available for patient use until further notice will be issued exclusively for these clinical evaluation studies.[313]

23.159 The separate report also contained a detailed plan/protocol as to how such studies should be structured as regards assessment of biological acceptability, clinical efficacy and residual infectivity.

23.160 On 26 June 1984, Professor Cash wrote to Dr Perry outlining the process for the future issue of the product for clinical evaluation. The letter indicated that this was to be on a named patient basis.[314]

23.161 On 25-26 June 1984, Dr Smith and other members of staff from the PFL and the BPL visited the PFC to observe the preparation of a pilot-scale batch of SNBTS pasteurised Factor VIII concentrate and took photographs of the process.[315] Dr Foster indicated in his written statement that this was evidence of continuing interest by the BPL and the PFL in pasteurisation in the summer of 1984.[316] Dr Smith confirmed this during his oral evidence. It was suggested to him that progress with dry heat treatment in England was still taking place against the backdrop of a preference, at least in theory, for pasteurisation, as offering a more efficient form of heat treatment. He said:

Very definitely. We were quite near achieving what looked like success in recovering Factor IX from pasteurisation and on Factor VIII we were still working well into the early summer of 1984 on pasteurisation. I think that's the point at which Lowell Winkelman and I went up to [PFC] to see their scaled-up pasteurisation process, and I think even to take photographs.[317]

23.162 An abstract outlining the PFC's proposed pasteurisation process for Factor VIII (heated at 60°C for 9.5 hours followed by 70°C for 0.5 hours with glycine/sorbitol stabilisers) was drawn up for the 18th Congress of the International Society of Blood Transfusion held in Munich between 22 and 27 July 1984.[318] The abstract also noted that:

A FIX concentrate has been pasteurised in a similar manner giving about 60% recovery of clotting activity over the heating step with no increase in thrombogenicity ....[319]

23.163 After the summer of 1984, the focus of the PFC's heat treatment programme remained on the pasteurisation of Factor VIII and its clinical evaluation. Dr Foster commented on progress:

During 1983/84, a total of seven pilot batches of pasteurised Factor VIII concentrate (ZHT) were prepared at the PFC for clinical evaluation with the final batch (batch number ZHT-007) being processed on 24/25 September 1984.[320]

23.164 Thus, by the autumn of 1984 the PFC remained committed to the introduction of a pasteurised Factor VIII product and was actively working towards the introduction of such a product. However, significant developments occurred towards the end of 1984 which, together, would have a crucial impact on the PFC's existing viral inactivation strategy.

23.165 On 1 September 1984, Dr Rachanee Cheingsong-Popov, Professor Robin Weiss, Professor Richard Tedder and others published the results of a major study of the prevalence of antibodies to HTLV-III in UK subjects.[321] Haemophilia clinicians responded to the information that an assay for HTLV-III/HIV antibodies was available by submitting samples from their own patients for testing. By the end of October, there was growing awareness among haemophilia clinicians in the UK generally that HIV infection could be contracted from Factor VIII and that transmission could be associated with domestic as well as imported products.[322] Professor Ludlam submitted samples to Professor Tedder. Independently, Professor Forbes submitted samples from west of Scotland patients to Dr Gallo's laboratory in the USA.

The Edinburgh Cohort

23.166 It is not known when SNBTS scientists received information about the west of Scotland results. Information about the results in Professor Ludlam's patients was received first, probably at the end of October 1984. A group of patients treated with standard production PFC Factor VIII at the RIE over the period March to May 1984 (ie the so-called 'Edinburgh cohort') had become infected with HIV.[323] Various witnesses were asked when exactly this information was passed on to the PFC, as this was not clear from the documentation available to the Inquiry.

23.167 The SNBTS had the information over the weekend 26 to 29 October 1984. Professor Ludlam told Dr McClelland on the evening of 26 October.[324] There had been a meeting of the PFC Heads of Department on the morning of 26 October.[325] Dr Perry thought that he could not have known that the patients had seroconverted, or potentially seroconverted before 26 October.[326] Dr Cuthbertson remembered Dr McClelland telephoning him with the news. He remembered a review of all of the available information a week later.[327] Dr Foster first learned of the infections in late October 1984, when Dr Cuthbertson received a telephone call about it. He had thought he had overheard a conversation between Dr McClelland and Dr Cuthbertson.[328] But he thought later that it may have been Dr Boulton who passed on the news to the PFC, explaining that he now knew that Dr McClelland had been ill.[329] The precise date on which the PFC got to know of the events cannot be specified. But it must have been around the weekend beginning 26 October.

23.168 The response was fast. In the course of a few weeks, the PFC shelved its pasteurisation programme, experimented with dry heating of Factor VIII, and adopted dry heating for all of its intermediate Factor VIII product. Coinciding with the outbreak of HIV infection in Edinburgh emerging intelligence on the effectiveness of dry heating to kill HIV caused a rapid reassessment of priorities. It was apparent that there was a current problem that had to be dealt with. But, before narrating the events which followed, it is appropriate to take note of the wider research environment at the time.

Information about heat inactivation of retroviruses

23.169 In October 1984 a 'haemophilia meeting' took place in Cardiff.[330] Notes of the meeting were received at the PFC on 6 November 1984. During this meeting, Professor Mannucci discussed the European trials of the dry-heated product Hemofil T. As outlined above, the trials demonstrated that the product was infective for NANB Hepatitis and that the attack rate was 70%.[331] However, as far as AIDS was concerned, Professor Mannucci reported that after one year no patients treated with the product had apparently seroconverted.[332] AIDS was still not reported as a major threat to haemophilia patients.

23.170 On the other hand, it was being suggested that HTLV-III was heat-labile. Prior to the Cardiff meeting, an article published in The Lancet on 29 September 1984 reported substantial inactivation, after several hours of dry heat treatment at 68°C, of a murine (ie mouse) retrovirus which had been added to Factor VIII concentrate.[333] Dr Foster indicated in his written statement that he was aware of this publication in The Lancet and noted that, 'as the AIDS virus was also known to be a retrovirus ... these data suggested that HIV might be destroyed by dry-heat treatment at 68°C'.[334]

23.171 This research on the murine retrovirus was later referred to in the USA Centers for Disease Control (CDC) Morbidity and Mortality Weekly Report (MMWR) published on 26 October 1984, which indicated that:

A recently published study evaluated the thermostability of murine retroviruses inoculated into factor concentrates, using a cell transformation assay. After 48 hours at 68 C (154.4 F), viral titers dropped from 108 to two infectious particles/ml.[335]

23.172 The MMWR report also referred to studies carried out by the CDC, in cooperation with Cutter laboratories (a subsidiary of Bayer) in which 'AIDS virus was added to factor VIII concentrate (virus titer 10[5]) and the factor was lyophilized and heated to 68 C (154.4 F)'. The report concluded with a statement which was later to prove crucial that 'virus was undetectable after 24 hours of heat treatment'.[336] Although the PFC subscribed to the MMWR, Dr Foster explained during his oral evidence that the journal 'took a couple of weeks to arrive' and that, therefore, the PFC were not yet aware of this research when information about the outbreak in the Edinburgh Cohort was received.[337]

Protein Fractionation Centre response to the discovery of infection in the Edinburgh Cohort

23.173 Dr Foster indicated in his written statement that, upon overhearing the telephone conversation in which Dr Cuthbertson was given news of the HIV infections, he immediately called Dr MacLeod to his office to ask him to identify R&D samples of Factor VIII concentrate that were already available which could be used for heat treatment experiments.[338] According to Dr Foster, Dr MacLeod responded immediately coming to Dr Foster's office, 'before Dr Cuthbertson had put the phone down'.[339] Dr Foster also indicated that Dr Macleod returned with a list of available samples and that they 'drew up a plan of investigation to obtain as much information as possible on the impact that the various additives might have on the ability of the PFC Factor VIII concentrate (NY) to withstand dry heat treatment at 68°C'.[340] When asked when this plan was drawn up and whether this was on Friday 26 October, Dr Foster responded that:

[I]t seems to me more likely that that was the Monday morning and that it was Dr Boulton who was phoning Dr Cuthbertson on the following Monday and that that then led us to carry out these further heat treatment experiments. And I do have a set of results of some of these experiments, which are dated Tuesday, 30th, which would be consistent with that.[341]

23.174 Dr Foster explained in oral evidence that there were two relevant sets of experiments - the experiments carried out by Dr MacLeod which involved samples prepared with different additives, and also experiments with existing product carried out by Mr McQuillan of the quality control department.[342] According to Dr Foster, it was the results of Mr McQuillan's tests which were available on Tuesday 30 October.[343] Dr Foster indicated that these involved dry heating Factor VIII to 68°C (and also to 60°C)[344] and explained that it is possible that these experiments were discussed on the Friday afternoon (ie following the Heads of Department meeting on the morning of Friday 26 October), in light of the publication by Levy and others in The Lancet (see paragraph 23.170 above) that the murine retrovirus could be inactivated at a temperature of 68°C.[345] Dr Foster also noted in his written statement that he had:

[S]pecified that heating at 68°C be included, not only because of the publication by Levy et al. of 29 September, but also because this was the highest temperature to which a Factor VIII concentrate (Koate HT of Cutter/Bayer) had been dry-heat treated, in addition to having obtained regulatory approval in the USA ....[346]

23.175 Dr Foster commented further in his written statement that the results of the experiments by Mr McQuillan indicated that 'PFC's Factor VIII concentrate (NY) could withstand dry-heat treatment at either 60°C for 24 hours or at 68°C for about 3 hours'.[347] In his oral evidence he explained that these were the first dry heat treatment experiments to have been carried out by the PFC since the experiments of Dr Cuthbertson and Dr Pepper in November 1983.[348]

23.176 On Wednesday 31 October, the day after the PFC's dry heating results were available, Dr Foster, Dr Perry and Dr Ronald McIntosh travelled to the Netherlands to attend a Plasma Fractionation Conference held by the transfusion centre in Groningen on 1-2 November 1984.[349] The Groningen meeting proved to be a crucial event as, according to Dr Foster, it was there that the PFC became aware, for the first time,[350] of the findings of the CDC/Cutter, which had been published in the MMWR on 26 October 1984, that, 'HIV could be substantially inactivated by dry-heat treatment at 68°C for 1 hour'.[351] These findings were contained in an oral presentation by Dr Jason of the CDC made on 2 November 1984.[352] During the public hearings, Dr Perry characterised the Groningen meeting and the knowledge that HIV had entered the Scottish blood supply as a 'strategy-changing moment', explaining that:

For the first time we had evidence from the Groningen meeting that the product that we were making could be inactivated fairly simply but also, and importantly, there was HIV in the UK and certainly the Scottish, blood supply.[353]

23.177 The Lindsay Tribunal report comments that the results of the research, showing HIV to be sensitive to heat inactivation, were considered highly significant by the CDC and were widely publicised, both formally and informally. There was not yet any clinical proof of the effectiveness of heat treatment against the HIV virus but there was an immediate recommendation in the USA by MASAC[354] that 'Treaters using coagulation factor concentrate should strongly consider changing to heat treating products with the understanding that protection against AIDS is yet to be proved'.[355] This increased the pressure on the manufacturers, including the BPL, to develop methods of viral inactivation. The Lindsay Tribunal found that there was no general move to the use of heat-treated commercial concentrates until after October 1984.[356]

23.178 So far as Scotland is concerned, Dr Perry said:

This ten-day period brought together, almost coincidentally, the report to Dr Ludlam and the information that we got for the first time from the Groningen meeting, from the CDC and the Cutter people, who demonstrated for the first time that HIV is fairly heat-sensitive and ... the risk/benefit balance changed overnight. It was dramatic and it was quite clear, moving from a position where everyone was very nervous about introducing heat treatment to a position where the advantages clearly outweighed any of the risks.[357]

23.179 Dr Foster commented in his written statement that the data from the Groningen meeting were discussed by himself and Drs Perry and McIntosh during their return journey from Groningen to Edinburgh and that they 'agreed to propose to Dr Cash that the SNBTS should immediately adopt dry heat treatment at 68°C'.[358] A decision was taken to follow this approach, which Professor Cash characterised in his oral testimony as a very difficult one (both emotionally and on a more practical level):

Q. Do you remember that time, November/December 1984, quite clearly?

A. Yes, I do actually.

Q. Yes.

A At least the panic and alarm and the sweat and the terror and the loneliness of it, when the boys came in and said, 'John, we think we should do this and this and this', and they are all looking at me. It is up to you, you are the medical director, to press the button. And there were two problems: were we going to accept the Groningen view that it was okay, our product was going to be okay? Point 1. The second was, which I think would be refused now: what's the legal position of pulling that product that has already been issued and heating it?[359]

23.180 As regards the issue of the legal position of rapidly introducing heat-treated product, Professor Cash alluded in his written statement to experiencing a sense of isolation at the time.[360] In an additional written statement on this point, Professor Cash commented that:

Despite a request for SHHD support (through Dr AE Bell, (SHHD)), the responsibility to permit the release of the first PFC heat-treated Factor VIII was not shared by SHHD or CSA officials .... But it was shared by clinical colleagues and, through Dr Perry, informal support was obtained from a senior NIBSC staff member.[361]

23.181 When asked to comment on this suggestion by Professor Cash, the Scottish Government explained that it had been 'unable to find any documents in which the SNBTS complained of a lack of support, or sought additional support, other than funding', noting however, that 'it would appear from the remaining records that the main contact within SHHD in relation to this issue was Dr Bell, who is no longer alive and therefore cannot be consulted'.[362] The Scottish Government also asserted that in its view, the fact that dry heat treatment was ultimately introduced is evidence that active support and funding was provided to the PFC.[363] When asked about this issue during the public hearings, Dr Perry explained that he did contact Dr Duncan Thomas, who was the Head of Haematology at the National Institute for Biological Standards and Control (NIBSC), but that this was not a formal process and was merely a question of talking him through the PFC's strategy and rationale and establishing the extent to which he thought that the rapid introduction of dry heat treatment was an appropriate thing to do.[364] Dr Perry also appeared to have few concerns over regulatory issues commenting that:

I have to say, as an operational manager in a period of enormous concern but also a belief that we could do something very quickly and very effectively, I think, even with hindsight, the concerns over the regulatory process weren't at the front of my mind.[365]

23.182 It appears that Professor Cash had a telephone conversation with Dr M E Duncan of the DHSS Medicines Division (then charged with the control of licensing of medical products) in November 1984. Dr Duncan wrote to Professor Cash on 26 November 1984 referring to the telephone conversation and confirming that 'the licensing authority wishes to encourage all companies involved in the production of Factor VIII to use a dry heat process in the course of manufacture' and that 'we are inviting each company to consider this proposal and, hopefully, to make early (abridged) application for a new product licence'.[366] The PFC did not require a licence under the Medicines Act 1968. But it appears that Professor Cash, via Dr Perry, received from Dr Duncan Thomas in the NIBSC, the 'moral support' he wanted.[367]

23.183 On returning to Scotland, Dr Foster wrote a letter to Professor Cash on 6 November 1984 in which he described the information provided during the Groningen meeting as 'encouraging'.[368] The letter included Dr Foster's notes of the meeting which, as regards inactivation of HTLV-III, contained the following information:[369]

Heat inactivation studies (probably by Cutter)
Starting level of virus 10[5] particles/ml (LAV)
Conditions Comment
68° wet heating (German method) Complete inactivation in 4 minutes
68° dry heating <10[1] particle/ml after 1 hour, complete inactivation at 24 - 78 hr

23.184 Dr Foster later confirmed, during his oral evidence, that the figure of 68°C mentioned in his notes for 'wet heating' was incorrect and should read '60°C' as this - not 68°C - was the temperature used in the pasteurisation experiments in question.[370]

23.185 In his written statement, Dr Foster explained that one of the key attractions of dry heat treatment was that it could be applied to existing stocks of Factor VIII concentrate.[371] In the SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors he said that reasons for choosing this heating protocol (68°C for two hours) were as follows:

68°C was selected by the SNBTS as it was the highest temperature that had been applied to Factor VIII concentrate by any manufacturer and was known to be well tolerated by recipients. Two hours was specified because this was the longest period of heating that samples of the existing SNBTS Factor VIII concentrate (NY) from a range of different production batches could withstand, as well as being double the period that had been reported to substantially inactivate HIV.[372]

23.186 The SNBTS Briefing Paper explained in more detail that the rationale for choosing to heat for two hours at 68°C was as follows:[373]

  • There was evidence from the USA that this degree of heat treatment could inactivate HIV.
  • As about 12 months stock of unheated Factor VIII (NY) was available, heat treatment of this stock meant that heat treated Factor VIII could be supplied from donations that had been collected at an earlier stage of the HIV epidemic, thereby enabling a product to be supplied with a lower theoretical risk than one prepared from donations collected later in the epidemic.
  • The product was immediately available for heat treatment, enabling sufficient heat-treated Factor VIII concentrate for all patients to be provided very quickly.
  • A stock of heat-treated product was available to re-fill the supply chain and to have available product in reserve for unplanned use, emergencies and other contingencies.
  • Waiting for Factor VIII concentrate to be prepared with a revised formulation, to enable the product to tolerate heating for 24 hours, would have delayed the introduction of heat-treated Factor VIII concentrate by about five months, ie the time taken to re-start production, manufacture a fresh batch of Factor VIII concentrate and to then obtain the necessary clinical data concerning efficacy and tolerability.

23.187 Following the meeting in Groningen, the PFC focused on attempting to dry heat Factor VIII to 68°C. During a meeting of the Heads of Department/Section Managers held on Tuesday 13 November 1984, Dr Perry indicated that:

[A]s a result of the amount of information being publicised through the press on the subject of AIDS, there was an immediate requirement for PFC to render all FVIII free from HTLV III virus .... R&D and QC were setting up experiments for heating FVIII at a higher temperature to kill the HTLV III virus without compromising the quality of this product and it was noted that Dr Foster had already subjected some material to this heating process ....[374]

23.188 The minutes of the meeting also noted that Dr Foster had advised that he might need access to the pasteurisation cabinet and a freeze drier for the purpose of this exercise.[375] In his written statement he explained that access to the pasteurisation cabinet (normally used for albumin processing) was needed as there was insufficient time to obtain a dry heat treatment oven, noting that:

Specialist ovens for dry-heat treatment ... had to be manufactured to order and could not be obtained for about 6 months. In order to avoid delay, the spray cabinet that was used to pasteurise albumin was utilised to heat vials of freeze dried Factor VIII, pending the purchase and delivery of a specialised oven.[376]

23.189 Dr Foster added that 'although the spray cabinet was normally operated at 60°C, it had fortuitously been designed to function up to 70°C'.[377] Dr Foster said that the successful operation of the spray cabinet was confirmed in a validation run on 14 November 1984, enabling routine dry heat treatment of Factor VIII to begin on 18 November 1984.[378] It was this spray cabinet which was ultimately used to heat sealed vials of freeze-dried Factor VIII concentrate for two hours at 68°C (see step A18 in Figure 20.2 appended to Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s).

23.190 On 22 November 1984, the PFC sent Dr Boulton (Edinburgh and South East Scotland BTS) four vials of Factor VIII which had been dry-heated for two hours at 68°C.[379] These were supplied so that solubility tests could be carried out before the planned limited release of the batch the following week once it had cleared quality control.

23.191 A meeting of Haemophilia Directors and representatives of the SNBTS took place on 29 November 1984 to discuss the implications of recent findings of HTLV-III antibodies in Scottish haemophilia patients, measures being taken by the SNBTS to prevent transmission of AIDS by blood products, and media-related matters.[380] During this meeting Dr Perry explained that it would be some time before the PFC's pasteurised product would be available and that 'having regard to the established sensitivity of retroviruses to heat, and corresponding reports of the efficacy of heat treatment at 68°C in countering HTLV III activity' dry heat treatment of Factor VIII at 68°C for two hours had commenced as a short-term measure.[381] The minutes of this meeting also noted that clinical trials of this dry-heated product were already underway. Thus, at this point a formal decision had also been taken in Scotland to dry heat Factor VIII as a short-term solution aimed at preventing transmission of AIDS.

23.192 The clinical trials referred to were intended to ensure that the product still had Factor VIII activity and that there were no unacceptable side-effects to its use. These tests could be carried out quickly. Trials to assess whether the dry-heated product did prevent HIV/AIDS transmission would have taken much longer.

23.193 On 6 December 1984, Dr Perry wrote a letter to all the Regional Transfusion Directors (ie in Belfast, Glasgow, Edinburgh, Inverness, Aberdeen and Dundee) which confirmed that the first infusions of dry-heated Factor VIII had been successful, although recovery and half-life data had yet to be received.[382] The letter also noted that arrangements had been made for dispatch of the first batches of dry heat-treated Factor VIII, with expected delivery on 10 or 11 December 1984 and that the initial quantities dispatched would provide approximately one month's supply. It was also indicated that following this initial supply, plans were in hand to supply further quantities of dry-heated product to each RTC equivalent to twice the minimum/maximum stock level so as to enable continuous supply to patients after 10 December (this second phase would start in the latter half of the week beginning 10 December and was expected to be completed before Christmas). It was also pointed out that 'in the New Year, PFC will arrange for non-heated product to be collected from RTCs' - ie a recall of non-heated products would take place in the New Year of 1985 - and that the RTCs should 'make arrangements for this material to be recalled as widely as possibly in preparation for this replacement programme'.

23.194 When asked about this general recall programme during the public hearings, Dr Perry explained that 'it was the intention that all product, right down to the patient's domestic refrigerator at home would be recalled and replaced with heat-treated material'.[383] Dr Perry also explained that the PFC arranged this through the RTCs, with the RTCs making the practical arrangements with the patients:

[T]he instruction would have gone from myself to the regional transfusion centres, who were our regional representatives, and they would have liaised with the haemophilia centres and various other holding points because they were the distribution points ... they held the records of where these products were issued to. Therefore in order to effect an effective recall, you had to recall it via the regional transfusion centre.[384]

However, he added that recall from the patients did not occur in order to carry out the initial heat treatment since the SNBTS had sufficient of its own material for this purpose and also because the patients still needed product to treat unexpected bleeds.[385]

23.195 Dr Cuthbertson also emphasised that the PFC was not directly responsible for the recall, explaining that Dr Perry wrote to the Regional Transfusion Directors who then transacted the recall from individual haemophilia treatment centres, who in turn requested the return of product from their patients.[386]

23.196 Professor Ludlam described his practice:

Patients were invited to return the bottles of unheated concentrate they had at home and heat treated concentrate was given in exchange. This change over was complete by the end of December.[387]

23.197 Following on from Dr Perry's letter of 6 December 1984, a meeting of the Heads of Department/Section Managers took place on 7 December 1984 which also confirmed that the clinical trials in question had been successful and that the product would be distributed to the RTCs in the forthcoming week.[388]

23.198 On 10 December a meeting took place in Elstree between UKHCDO Reference Centre Directors, blood transfusion colleagues and senior staff from Edinburgh and Elstree.[389] The meeting discussed heat treatment and ultimately recommended the heat treatment of NHS products. Although it is not clear what influence, if any, a negative decision by this meeting might have had on the PFC's existing strategy to dry heat its own product, it is worth noting that the meeting appears to have been a difficult one. According to Professor Ludlam's written statement:

It was not an easy decision to make because of the possible adverse effects of heat treatment on the clotting factors and other proteins in the vials which could have had a range of adverse effects on patients. This was particularly difficult because it was very uncertain how effective the heat treatment would be at inactivating the HTLVIII virus ....[390]

23.199 In oral evidence, Professor Ludlam explained further that, in practical terms the problem was that 'if we had altered the molecule slightly and 100 per cent [of patients] developed inhibitors, then we would have virtually no effective treatment for haemophilia, apart from FEIBA'[391] adding that 'a decision was nearly made not to heat-treat and it was only because two or three people were quite forceful in their views that the decision was made'.[392]

23.200 Professor Cash made a similar general point in his written statement, indicating that 'there was great concern among many of the clinicians that any form of heating might be associated with protein denaturation which could have serious consequences for the patients'.[393]

23.201 Later, on 17 December 1984, Professor Cash wrote to the Scottish Haemophilia Directors informing them that they would be receiving supplies of the first-generation heat-treated Factor VIII within the next day or so and requesting them to monitor clinical efficacy and the development of neo-antigens and to take serum samples to test for HTLV-III antibody.[394] Professor Cash's letter elicited a critical response from Professor Ian Hann of the Royal Hospital for Sick Children at Yorkhill in Glasgow who queried, in a handwritten letter to Professor Cash dated 19 December 1984, whether adequate studies of 'neo-antigen formation, efficacy and other safety issues' had been made and whether the PFC would know in the near future whether heat treatment had been effective.[395] When asked to expand on this letter during the public hearings Professor Hann explained that:

Certainly I was very nervous about this approach. Without going into great detail, one normally does not launch a product or a drug in children with very, very limited information. Especially when there is a risk of neoantigen formation, therefore severe reactions which could be even life-threatening. There could be a significant risk of the development of inhibitors, which is a disaster, making patients not responsive to treatment, et cetera.[396]

23.202 He added:

As it turned out, everything was okay, but I just wanted to express the fact that (a), it was very impracticable to do what was being asked, (b), it wasn't necessarily covering all the types of checks that I would like to see with regard to the liver function tests, et cetera and (c), that it really ought to have been instituted, and I would have preferred to see a bit more evidence that there were no neoantigens, et cetera, and that there was some evidence of safety rather than, 'Here it is, get on with it'.[397]

23.203 Therefore, in summary, by the end of 1984 the PFC had taken a strategic about-turn due to the threat of AIDS and (notwithstanding the lack of clear-cut evidence that such a process would be successful) had chosen to dry heat existing Factor VIII for two hours at 68°C and to recall existing unheated product.

23.204 At the time, this strategy was seen as a temporary arrangement and, as outlined elsewhere in this Report, further developments (for example dry heat treatment for 24 hours at 68°C) followed. At the time it was not clear whether the heating protocol had been successful in inactivating HIV. However, a later look-back study discussed by Dr Robert Cuthbert and others reported that two of the first batches of PFC Factor VIII heated in November 1984 at 68ºC for two hours had been prepared using a donation which was later found to be infected with HIV. It had not subsequently transmitted HIV.[398] The Inquiry is also not aware of any HIV infections associated with Factor VIII heat-treated using this protocol. Therefore, looking back at this period, the evidence suggests that the heat treatment protocol chosen by the PFC (ie 68ºC for two hours) was effective in inactivating HIV. As outlined elsewhere in the Report, it was not, however, effective at inactivating NANB Hepatitis.

General issues

Why did the Protein Fractionation Centre not switch to dry heat treatment earlier?

23.205 As outlined above, up until the autumn of 1984 the PFC planned to pasteurise Factor VIII - initially to deal with the threat of NANB Hepatitis and later to deal with the emerging threat of HIV. In late October/early November 1984 this strategy changed and the PFC switched its efforts to dry heat treatment of Factor VIII, which ultimately proved successful at inactivating HIV. Given that the Edinburgh Cohort became infected with HIV in the spring of 1984, one of the key questions for the Inquiry is whether the PFC should have made this switch at an earlier point in time - for example in January 1984.

23.206 The Inquiry put this question in the following terms to all of the major witnesses who gave evidence:

In retrospect, the infection of the group of people known as the Edinburgh Cohort would have been prevented if PFC had moved to dry heat treated product at the beginning of 1984. It appears that the equipment necessary to do so was either already installed or already obtained. What are the reasons why this did not take place?[399]

At one level, the question was clearly hypothetical. Confirmation that the cause of AIDS was indeed viral, and was to become known as the Human Immunodeficiency Virus, was not available until April 1984, and the first (experimental) test of possible exposure to the virus was not available until August or September 1984. It was important, however, to avoid limiting the issue by prescribing an over-narrow reference period.

23.207 The Inquiry also posed a similar question to the expert witness, Professor van Aken.

23.208 As outlined below, the overwhelming response of the witnesses heard by the Inquiry was that the PFC was correct not to introduce dry heat treatment at the beginning of 1984, and that there were rational reasons for not doing so.

Dr Foster

23.209 Dr Foster's response to this question in his written statement, with references to paragraphs of the Preliminary Report, was as follows:

a) In my opinion, dry-heat treatment was not introduced by the SNBTS in January 1984 for the following reasons:

  • the cause of AIDS was not known (paragraph 8.84),
  • the virus responsible for AIDS had not been discovered (paragraph 8.84),
  • that the virus responsible for AIDS could be inactivated by heat treatment was not known,
  • that the virus responsible for AIDS could be inactivated by dry-heat treatment, under conditions that SNBTS Factor VIII concentrate could withstand, was not known,
  • the SNBTS was already preparing pilot batches of a heat treated product (ZHT) for clinical evaluation, similar to a number of other manufacturers,
  • no manufacturer in the world had switched from unheated to heat treated Factor VIII concentrate, although some manufacturers were heat treating a small proportion of their Factor VIII,
  • it was known that dry-heat treatment had not inactivated agent(s) responsible for non-A, non-B hepatitis (paragraph 11.160),
  • there was concern[400] that patients might react adversely to heat treated products ....[401]

23.210 Dr Foster also made the following additional points in his statement: (i) to the best of his knowledge Scotland was the first country to switch completely to heat-treated Factor VIII and the only country to recall unheated Factor VIII at the end of 1984/start of 1985; (ii) it was not until 26 January 1985 that a peer-reviewed paper was published which reported that HIV was relatively heat-sensitive;[402] (iii) although the BPL issued some batches of dry-heated Factor VIII in early 1985, unheated Factor VIII continued to be issued in England and Wales by the BPL until 1 May 1985.[403]

23.211 During the public hearings Dr Foster was also asked whether an additional reason for not dry heating at the start of 1984 was the fact that it was not then known that HIV had infected the Scottish blood supply.[404] Dr Foster said:

[I]n January 1984, even if we had known that HIV was in the blood supply, we didn't know how to prevent it and what you are suggesting is based on hindsight.[405]

23.212 When asked what the PFC would actually have done in these hypothetical circumstances, Dr Foster explained that:

I am sure we would have sat down and done everything we could have thought of. I doubt we would have done something speculative in terms of some treatment that we had no knowledge would or wouldn't work, which might harm patients.[406]

23.213 Thus, according to Dr Foster, even if it had been clear at the start of 1984 that HIV had entered the donor pool, given that it was not known then how to inactivate the virus it is unlikely that this knowledge would have led to speculative dry heat treatment.

Dr Smith

23.214 Dr Smith's response to this question was as follows:

May I be allowed to speculate, since I was not party to PFC's decision-making but was swimming in the same soup at the time? ....

  • Prior to November 1984, there was no reason to believe that dry-heating would succeed in preventing transmission of AIDS, and in fact almost all the early dry-heated (commercial) concentrates caused confirmed transmissions of HIV at later dates. In the wake of Hyland's experience, there was no likelihood that NANBH would be inactivated if dry-heating were applied to PFC's F.VIII at that time.
  • I am not sure that, in early 1984, it was generally perceived that AIDS had entered the UK donor population. No test was generally available, validated for application to large populations of donors.
  • In about May 1984, three patients in England were given mildly-heated (60°C, 72h) Factor VIII, and by the end of 1984 had contracted neither AIDS nor NANBH. [T]his anecdotal experience had no impact on BPL's policy. If in fact the information was considered significant enough for me to share with SNBTS, I would not have expected it to affect PFC policy.
  • At the beginning of 1984, clinical trial of PFC's pilot-scale batches of pasteurised F.VIII was still being considered successful ... and there were detailed plans for scale-up and national issue in a credible time-scale .... There was reason to expect that this pasteurised F.VIII would transmit neither AIDS nor NANBH. For several reasons, it is extremely difficult to envisage running two candidate products full-pelt in a unit with limited resources, so a choice had to be made (England did not have the luxury of choice ... and was perhaps lucky in that - but only with hindsight). It should not be inferred that PFC made the 'wrong' choice at that period, or that PFC was slow to modify its position when the evidence moved on, later in the year.[407]

23.215 Dr Smith was asked during the public hearing to expand on the second bullet point in his written statement and whether the assessment of risk would have been different if it had been known that HIV had entered the donor population at the start of 1984. Dr Smith responded as follows:

Q. [I]f it had been known at the start of 1984 that AIDS was in the donor population, the assessment of the risk and the timescale within which some sort of viral inactivation process would be required would have necessarily have been different. Would you agree with that?

A. Yes, and I could be wrong. This is my recollection from the time but it is a long time ago and, generally perceived, is rather loose. But I have said it here, this would be a factor, how you perceived the balance of risk/benefit in going to heat treatment, which was still being perceived by some people as very dangerous.[408]

23.216 Dr Smith was also asked whether the assumption that HIV had not entered the donor pool at the start of 1984 was realistic:

THE CHAIRMAN: In retrospect, was there not a degree of naivety in treating the donor population as in some way hermetically sealed within the boundaries of the United Kingdom? Didn't people travel in those days?

A. Yes, they did, and already by 1983 the Fletcher and Rizza paper had shown that there was no safety from non-A non-B but there were inhibitions against - AIDS was being seen as, like TB and leprosy and syphilis in previous times, as a kind of dirty disease, and you do not want readily to think that your patients or your donors are in that category. This is just psychopathology. It's not good reasons for it. But when I say 'perceptions', I don't know how many percentage of which groups - treaters, patients, transfusionists - would have subscribed to that view.[409]

Dr Perry

23.217 Dr Perry's written statement indicated that it was only with the benefit of hindsight that one could suggest that dry heat treatment could have been implemented earlier and referred to similar arguments to those mentioned above in support.[410] Dr Perry's statement also referred to the following additional arguments which, in his view, supported his position:

  • That the PFC studies carried out in late 1983 indicated that dry heat treatment of the PFC's existing Factor VIII product (i.e. the experiments carried out by Dr Pepper and Dr Cuthbertson on 21 November 1983),[411] rendered the product insoluble;
  • That the formal regulatory position in the UK and elsewhere was that there was inadequate evidence of any benefit (in terms of virus safety) from dry heat treatment (for either AIDS or Hepatitis) to justify the licensing of commercial dry heat treated products; and
  • That, at that time, the modern 'precautionary principle' was less developed compared with today with the result that interventions on blood or plasma product safety required a greater body of scientific evidence to justify their implementation.[412]

23.218 Dr Perry was also asked, during the public hearings, to explain why there appeared to be a belief at the start of 1984 that HIV had not arrived in Scotland (and by implication entered the Scottish blood supply). Dr Perry answered as follows:

[W]e must remember that although HIV is a well-known entity for everybody in this room now, at that time it was a new disease, it wasn't understood, there were still alternative ways to describe the AIDS condition and its causation and so on, and little, if anything, was known about the epidemiology and the extent to which it was travelling around the world .... With hindsight, it could have been clearly proposed or suggested that HIV could indeed be in the UK population. We just hadn't seen any evidence of it.[413]

23.219 As regards the issue as to whether the PFC's strategy would have been different if it had been aware of HIV infection at the start of 1984 Dr Perry offered the following thoughts:

[M]y best guess is that even if we had had evidence of HIV in the donor population, at that point in time that in itself wouldn't have been sufficient to take what would have been seen at that time as a very dramatic step in terms of potential damage to a Factor VIII product. We might have known that HIV was in the donor population but we would have had no knowledge whatsoever of our ability to inactivate it using heat treatment.[414]

Dr Cuthbertson

23.220 Dr Cuthbertson's written statement also commented that, in his view, 'it is only with the benefit of hindsight that it can be concluded that earlier introduction of heat treatment was a sound option', and that 'more rapid introduction of dry heat treatment was not justified on the basis of knowledge at the time and we could have easily introduced a less safe product with reduced yield which still had the capacity to transmit HIV'.[415] Dr Cuthbertson's arguments mirror those outlined above and also make mention of what Dr Cuthbertson refers to as 'Regulatory constraints' - the understanding that the DHSS did not wish to grant licences to commercial dry heat-treated products at this time due to safety concerns.[416]

Professor van Aken

23.221 Professor van Aken provided the Inquiry with a report in which he reviewed the introduction of dry heat treatment of Factor VIII by the PFC and considered the question whether the PFC could or should have introduced this process at the start of 1984.[417]

23.222 In his report, Professor van Aken referred to the World Health Organization's 2004 'Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood and plasma products'[418] which stipulate that the ability of a process to inactivate/remove viruses should take into account:

- the reduction of virus titre achieved;

- for inactivation processes, the rate of inactivation;

- the robustness of the inactivation step in response to changes in process conditions;

- the selectivity of the process for viruses of different classes; and

- validation studies, which need to be well documented.[419]

23.223 According to Professor van Aken, these requirements meant that the safe introduction of a change in the manufacturing process of plasma products such as Factor VIII required: (i) knowledge about the nature and characteristics of virus(es) to be inactivated; (ii) validation studies and studies in experimental animals, and (iii) yield, manufacturing consistency and integrity of the final product with regard to protein function/structure.[420]

23.224 As regards the first requirement (knowledge about nature and characteristics of virus(es)) and HIV, Professor van Aken's view was that the first indication of the cause of AIDS did not arise until the publication of Professor Gallo's article in May 1984.[421] Therefore, according to his view, at the start of 1984 there was insufficient knowledge regarding the cause of AIDS and consequently:

[I]f heat treatment for inactivation of HIV [had] been introduced in early or mid 1984 (or earlier) it would not have been based on evidence but rather on speculations about the origin of the virus.[422]

23.225 When asked during the public hearings why commercial companies appeared to have pushed ahead with dry heat treatment in 1983 before all the necessary information was available, Professor van Aken indicated that the commercial companies had taken a 'pragmatic approach'. He said that commercial companies were able to do so since, unlike public fractionators who were confined to their home country, they operated on a worldwide basis and could, therefore, tailor their approach to different attitudes in different markets. If one country had a particularly stringent approach to the regulation of new products the commercial companies could move to another (less stringent) country.[423] Professor van Aken also pointed out that it was not possible simply to copy the protocols used by commercial companies as the heating conditions were either confidential or patented.[424] In his view, another key difference was the fact that public fractionators were often aiming at a policy of self-sufficiency and were therefore more concerned about the impact of heating on yield than commercial companies.[425] Upon further questioning, Professor van Aken also indicated that the fact that the commercial companies' source plasma may have been of a lower quality than that of public fractionators was likely to have been a factor which made them more likely to use heating protocols even when the evidence was not yet definitive.[426]

23.226 As regards validation studies, Professor van Aken made the point that sufficient HIV virus to allow these studies to take place was only available in mid-1984.[427] Therefore, before this period work had to be done using model viruses, and that would not necessarily have been as accurate as validation using the actual virus.[428]

23.227 As regards requirement three (yield, manufacturing consistency and integrity of the final product), Professor van Aken explained during the public hearings that the issue was ensuring that the product was still effective after heat treatment and also that it had not been changed in such a way that it might cause harm to patients.[429]

23.228 On the basis of these arguments, Professor van Aken's conclusion on the question of whether the PFC should have introduced dry heat treatment more quickly was as follows:

The answer to the question 'Should/could PFC have moved more quickly to introduce the dry heating of factor VIII concentrate?' is NO for the following reasons:

- the procedure (the proper conditions) to inactivate blood borne viruses, in particular those present in plasma, by dry heating were not known until the later part of 1984;

- the characteristics of the viruses to be inactivated (HIV and HCV) were not known until the beginning of 1984 (HIV) respectively 1989 (HCV);

- cell lines producing sufficient quantities of HIV and HCV[430] to perform validation studies (virus spiking experiments) in the laboratory were not available until mid 1984;

- methods to improve the yield of factor VIII and to determine that the structure of factor VIII (or other clotting factors) after heating is still intact were not yet available.[431]

Why did the Protein Fractionation Centre not follow through with the proposed acceleration of pasteurisation in 1983?

23.229 As mentioned above, on 3 May 1983 Dr Foster wrote a memorandum suggesting that the PFC's existing pasteurisation programme should be accelerated in order to meet the 'worst case' scenario of having to deal with HIV/AIDS.[432] The Inquiry asked Professor van Aken to comment on the suggestion of taking a decision on the basis of a 'worst case scenario' and asked whether he was aware whether other fractionators were also considering such an approach at the time. Professor van Aken provided a written response to this question in a separate report which was discussed during the public hearing.[433]

23.230 In his report, Professor van Aken explained that in mid-1983 it was not known if a virus was responsible for AIDS and that Dr Foster's suggestion was, therefore, likely based on a presumption to this effect. Professor van Aken also indicated that in mid-1983 evidence that heat would be an effective means of inactivating the agent which caused AIDS was also lacking. According to Professor van Aken, it was therefore, 'by no means certain that pasteurisation would be a method to improve the safety of plasma products like factor VIII concentrate'.[434]

23.231 He also indicated that initial pasteurisation attempts in several laboratories had resulted in low yields and that any pasteurisation programme would have to take this, and the possible impact on self-sufficiency, into account. He also pointed to the possible risk of neo-antigen formation as a second negative effect of any pasteurisation of Factor VIII. This could result in the creation of inhibitors in patients, thus complicating their future treatment. Professor van Aken explained further that these considerations were part of the discussion that took place among fractionators in various different countries and that some chose to carry out heat treatment even though important evidence was not available whereas others, such as the Central Laboratory of the Blood Transfusion Service (CLB) in Amsterdam, did not. In the case of the CLB, his report notes that a decision was made in accordance with recommendations of haemophilia physicians in the Netherlands to restrict the manufacture of Factor VIII so as to have sufficient material for the production of freeze-dried cryoprecipitate (reflecting the view that the risk of virus transmission from small pools of cryoprecipitate would be less than from large plasma pools used to make Factor VIII).[435]

23.232 Professor van Aken's report concluded as follows:

Acceleration of the pasteurisation program by PFC would most likely have led to a low factor VIII yield and consequently fewer products for haemophilia treatment. To compensate such losses a very large increase in the collection of donor plasma in Scotland would have been necessary. In addition the risk of side effects, such as neoantigen formation by pasteurisation, would have made the treatment of a certain number of haemophilia patients more complicated. This leads me to conclude that although acceleration of the pasteurization program by PFC might have seemed an option in 1983, it is unlikely that (as part of a 'worst case scenario') this would have provided a solution for PFC.[436]

23.233 When asked during the public hearings to comment on his statement that it was 'by no means certain that pasteurisation would be a method to improve the safety of plasma products like factor VIII concentrate', Professor van Aken explained that he thought that Dr Foster's plan to pasteurise all product was logical, given the amount of time which had already been committed to the project.[437] However, he also indicated that he personally was not convinced that 'this was the way to go,' whilst explaining that this was 'his bias' and that he found it difficult to give a clear or explicit answer given the underlying element of speculation at the time.[438] He also stressed that in the Netherlands the patient organisations were particularly concerned about the potential loss of yield which could be caused by heat treatment and that their preference was for yield/supply over safety.[439]

23.234 Thus, in conclusion, Professor van Aken's view was that there were certain difficulties with the proposed plan to accelerate pasteurisation of Factor VIII. However, given the inevitably speculative nature of taking such a decision, and the differing considerations inherent in the decision-making process between the Netherlands and Scotland, he found it difficult to give a clear-cut answer as to whether the PFC's plan to pasteurise was a reasonable one or not.

Should the Scottish National Blood Transfusion Service have been encouraging clinicians not to let their patients try the commercial heat-treated products?

23.235 The Inquiry asked Professor van Aken to give a view on whether the SNBTS should have encouraged clinicians not to let their patients try commercial heat-treated products. In other words, was Professor Cash correct to oppose the introduction of formal clinical trials for commercial heat-treated products as outlined in his letter of 17 December 1982 to Dr Lane?[440]

23.236 In his written statement Professor van Aken explained that such a set of circumstances would be unlikely to have occurred in the Netherlands as the CLB did not offer opinions about commercial products or encourage clinicians to stop or decrease the use of such products. Instead it provided information on its own products, with the Dutch haemophilia physicians having more of an advisory role. Professor van Aken further explained, in this context, that the Dutch association of physicians treating haemophilia patients agreed in January 1983 on the following advice for haemophilia treatment:

1) if possible use cryoprecipitate (notably for newly diagnosed patients and children of less than 4 years);

2) if factor VIII concentrate needs to be used, prescribe factor VIII concentrate prepared from plasma of Dutch donors (use commercial concentrates only in case of a severe side effects following the use of Dutch concentrate);

3) for the treatment of haemophilia B patients use only factor IX concentrate prepared from plasma of Dutch donors.[441]

23.237 When asked during the public hearings to comment further on Professor Cash's position as expressed in his letter to Dr Lane, Professor van Aken said that, coming from a small country, he understood Professor Cash's fear that clinical trials of commercial products could reduce the number of patients available for any SNBTS trials.[442] However, he also pointed out that he did not think that it was the role of a fractionator to take this stance, noting that:

[I] always have felt that we have to be very cautious when you were going to direct or try to give directions for what other products, what other commercial products should or should not be used, because you are in a competitive market and in my experience it doesn't work when you are trying, as a manufacturer, to influence. That you have to leave to the government or to physicians treating haemophiliacs, but as a producer that is not your personal responsibility. I interpreted that Dr Cash was director here of the SNBTS. So he was in fact the director of a producing institution. And therefore I would be more restrictive. I would try other ways to do this instead of so openly giving a recommendation how it should be done.[443]

Should commercial heat-treated products (Hemofil T) have been adopted in advance of locally produced products?

23.238 As outlined above, the commercial heat-treated product Hemofil T (dry heat for 72 hours at 60°C), which was licensed in the USA by the US Food and Drug Administration (FDA) in March 1983,[444] was later found not to have led to HIV seroconversions. The product was not granted a licence in the UK until February 1985.[445]

23.239 The Inquiry asked Professor van Aken whether, in his view, Hemofil T should have been adopted in the UK in advance of locally produced heat- treated products. There are two aspects to the question: whether the product should have been granted a licence earlier, and whether it should have been prescribed on a named patient basis. Professor van Aken discussed the first of these.

23.240 He explained in his report that Hemofil T was later found to transmit NANB Hepatitis (the outcome of Professor Mannucci's 1985 study mentioned above). According to Professor van Aken, looking back, this was one reason to justify the lack of a licence since:

If the marketing efforts of commercial companies such as Hyland would have led to introduce such a product for haemophilia treatment in the UK it would subsequently have created uncertainty and critique when it was shown that the claim of non-transmission of NANB hepatitis proved to be unjustified.[446]

23.241 Professor van Aken explained that his view was that the adoption of heat-treated products was justified when it could be established that the agent responsible for AIDS was inactivated by the heating procedure. In his view, since the safety of commercial plasma as source material for the manufacturing of Factor VIII was questionable, 'it was prudent not to introduce commercial factor VIII concentrate until it was shown that such products were safe'.[447] Professor van Aken also argued that alternative products such as cryoprecipitate were available which, because they were prepared from small pools of plasma from non-remunerated donors, were less risky than Factor VIII concentrates prepared from very large pools of remunerated donors.

23.242 Given the above arguments, Professor van Aken concluded that:

[T]he adoption of commercial heat treated products in the UK in advance of locally produced products would have been justified once there was sufficient and reliable data from clinical studies demonstrating the safety and efficacy of such commercial products. Hemofil-T did not meet such criteria.[448]

23.243 The issue of the safety, or otherwise, of Hemofil T as regards HIV was also discussed with Dr Foster during the Inquiry's public hearings.[449] Dr Foster referred to a report which he had drawn up for the Archer Inquiry[450] entitled, 'Response to Questions raised at the Inquiry in Contaminated Blood and Blood Plasma Products'.[451] The report explained, amongst other things, that:

(i) it was known in September 1983 that Hemofil T had transmitted NANB Hepatitis;

(ii) the UK Committee on the Safety of Medicines had rejected a licence application for Hemofil T in September 1983;

(iii) it was not until February 1985 that reports became available that 18 patients treated exclusively with Hemofil T were HIV-negative (according to Dr Foster, although these results were encouraging they did not prove that HIV had been inactivated as there was no evidence that the batches in question were infected);

(iv) a January 1986 study on the inactivation of viruses in Factor VIII did not contain any data on Hemofil T.[452] According to Dr Foster, to suggest, as had been suggested at the Archer Inquiry, that it was known in May 1983 that the HIV virus could be inactivated by a particular heat treatment protocol, such as that used for Hemofil T, reflected a misunderstanding.[453]

Did Mr Watt's resignation have an impact on the heat treatment programme?

23.244 As outlined above, Mr Watt, the Director of the PFC, decided to leave the PFC in the summer of 1983. This decision was officially communicated to Professor Cash by letter dated 4 July 1983 in which Mr Watt outlined the reasons for his resignation. The reasons included personal matters (including increased domestic commitments and medical issues), as well as a desire on the part of Mr Watt to finish his career as a consultant working in the field of fractionation in a role outwith the PFC.[454] Professor Cash subsequently drew up a confidential document entitled 'Replacement of the Director of PFC (Preliminary Notes)', dated August 1983.[455] In this document, Professor Cash discussed certain problem areas which, in his view, had arisen during Mr Watt's management of the PFC (in particular the lack of management control which the National Medical Director had over the Director of the PFC) and suggested possible solutions. From the tone and content of this confidential report, it is clear that Professor Cash viewed the relationship between himself and Mr Watt as not being in good repair. Although the original plan was that Mr Watt would leave at the end of March 1984, it is evident from a memo from Dr Perry to the Heads of Department and Section Managers dated 30 December 1983 that Mr Watt actually left at the end of December 1983[456] with Dr Perry taking over as Acting Director.[457]

23.245 The Inquiry asked various witnesses for more details on the impact of Mr Watt's departure and, more importantly, whether his departure adversely affected the PFC's viral inactivation programme.[458]

23.246 In his oral evidence Professor Cash confirmed that he was of the view that Mr Watt's departure did not affect the heat treatment programme. The main reason for this was that 'Peter Foster, the solid rock, was still there, as far as that programme was concerned'.[459] As regards the departure of staff, Professor Cash explained that two staff at a senior technical level ultimately left the PFC to work with Mr Watt's consultancy.[460]

23.247 Dr Foster stated in his written evidence that he learned on Monday 11 July 1983 on his return from Stockholm that Mr Watt had resigned. He was informed by a colleague that Mr Watt was planning to establish a company to fractionate animal plasma and that he was seeking to recruit staff from the PFC.[461] When asked, Dr Foster informed Professor Cash that he had not been approached by Mr Watt and that, if approached, he had no intention of leaving the PFC. According to Dr Foster:

It was evident to me that Dr Cash was worried that the PFC might be damaged by the loss of key staff. Later, he told me that he had discussed the matter with Mr Watt, who had indicated that he intended to recruit only a small number of staff from the PFC to avoid any damage to the PFC. Nevertheless, I believe that it was concern over the potential loss of key PFC staff that led to Mr Watt leaving at the end of December 1983, rather than at the end of March 1984.[462]

23.248 In his written statement Dr Foster also expressed the view that Mr Watt's resignation did not adversely affect the virus inactivation programme, stating that:

I do not believe the resignation of Mr Watt adversely affected the virus inactivation programme or influenced the SNBTS strategy. According to his CV,[463] Mr Watt continued to be a member of the Biologicals sub-committee of the Committee on Safety of Medicines until 1986. In March 1984 this committee approved an application from Behring for a licence for its pasteurised Factor VIII and, in July 1984, rejected an application for a licence from Armour for its dry-heat treated Factor VIII. I do not know the advice, if any, that Mr Watt offered at these meetings, but the fact that the SNBTS strategy was consistent with both of these decisions does not suggest that Mr Watt would have encouraged the SNBTS to take a different position if he had remained in post.[464]

23.249 In oral evidence Dr Foster said that the departure of staff to Mr Watt's consultancy did not impact on the heat treatment programme. A few people at section manager, senior technical level left the PFC to join him when he had established his own business. In particular, a person who managed one of the quality control laboratories and also a person who managed one of the areas in production at a senior technical level joined Mr Watt. But these losses were coped with within normal turnover of staff arrangements.[465]

23.250 Dr Perry was also of the view that Mr Watt's resignation did not adversely affect the viral inactivation programme, stating that:

Mr Watt resigned in July 1983 and following his earlier than planned departure in December 1983 I was appointed as acting Director of PFC.

It is not possible to meaningfully judge the general impact of his departure but by this time the PFC programme on heat treatment was well advanced and there are no specific instances of delays or failures of the development programme attributable to his departure.[466]

23.251 In line with Dr Foster, Dr Perry also explained in his oral evidence that, in his view, the departure of two staff to Mr Watt's consultancy did not adversely affect the heat treatment programme, stating that:

[I] don't think there were any, what you might describe as absolutely key individuals, that left taking with them intellectual capability or intellectual property. I think that the programme that had been established prior to Mr Watt's departure carried on, ably led by Dr Foster.[467]

23.252 Dr Perry also provided background to his appointment as Acting Director of the PFC in January 1984, explaining that Professor Cash asked him informally to take on the role and that this was followed up on a formal basis by the secretary of the CSA, Mr Mutch, with confirmation of the permanent role being made a year later in 1985.[468]

Discussion and conclusions

23.253 The transmission, in the spring of 1984 (discovered in the autumn of 1984), of HIV infection to haemophilia patients treated in Scotland at the RIE with PFC Factor VIII concentrate was an event of critical importance for this Inquiry. It had a devastating impact on the lives of the patients involved, and on the lives of their families. Most of the patients infected with HIV had died before the Inquiry was instructed. The circumstances in which the patients came to be infected are discussed in Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2. As is clear from the evidence that has been analysed in this chapter, discovery of the transmission of HIV was a factor that immediately and significantly impacted on the PFC's research and development and production priorities. And what proved to be an effective response, dry heat treatment of Factor VIII concentrate, was quickly put into effect.

23.254 The evidence sought from documents, written statements and oral testimonies from witnesses, could not be narrowly specified: in fairness to patient interests and to the manufacturers, it was necessary to explore the background in depth. But there were some obvious questions that provided focus for the investigation and presentation of the evidence:

  • Was there a risk of HIV infection in blood donated in Scotland that affected the safety of PFC products?
  • When was such a risk was understood to exist?
  • Was or should that risk have been taken into account by the SNBTS and the PFC in the processing of blood products?
  • More specifically, should the threat of AIDS have caused the PFC to accelerate its heat treatment programme in or around May 1983?
  • Was adherence to the pasteurisation programme until October/November 1984 justified? In particular was that course justified after January 1984?
  • Was there sufficient liaison/cooperation between the fractionation services in Scotland and England over the period 1980 to 1984 in relation to viral inactivation?
  • Did any management problems impact on the PFC's viral inactivation programme?
  • Would closer collaboration, and UK-wide policy guidance, have avoided the pursuit of different courses by the Transfusion Services in Scotland and England, and would it have been more effective?
  • Did the PFC have sufficient resources/staff and access to information/academic research for its viral inactivation programme?
  • Should commercial heat-treated products have been adopted in advance of locally produced products or could/should the PFC have bought in a commercial heat-treated process[469] instead of developing its own?
  • In general, was the approach taken to viral inactivation at the PFC in the period 1980 to 1984 reasonable?
  • In general, was the degree of priority accorded to viral inactivation by the PFC during this period reasonable?

The risk of HIV infection in blood donated in Scotland that affected the safety of Protein Fractionation Centre products

23.255 As discussed in Chapter 33, An Investigation into the Systems in Place for Informing the Patients about the Risks - HIV/AIDS, it was understood within the SNBTS by May 1983 (though not reflected in uniform action throughout Scotland) that certain groups of individuals presented a risk of transmission of the presumed infective agent causing AIDS if they donated blood, and were therefore asked not to present themselves as donors. The advice was based on reports of the US experience rather than on reported cases of transmission in the UK involving any of the groups identified. The aetiology of AIDS, and therefore the precise nature of the risk, was not at that stage well understood. The preparation and issue of leaflets reflected apprehension that there might be a risk rather than knowledge of an existing risk.

23.256 By late July 1983, the Central Blood Laboratories Authority had concluded that AIDS was likely to include in its aetiology transmission of an infective virus, and noted that this had prompted more activity in the area of blood products pasteurisation.[470] At this stage it was thought that domestic products presented a low risk.[471] The view of the Biological Sub-Committee of the Committee on the Safety of Medicines, who at that stage were opposed to the withdrawal of imported products, was that:

Efforts are ... being made to secure UK independence of foreign suppliers of clotting factor concentrates. This should reduce markedly, although not eliminate, the risks to recipients of these products, and the Sub-Committee strongly supports this aim.[472]

23.257 At that time virus inactivation of Factor VIII and Factor IX products was a 'promising future development', and the assessment of risk was related to the presumed low level of infection in domestic blood donations. As stated in paragraph 8.45 of the Preliminary Report, self-sufficiency was seen as part of the answer to the problem of AIDS. The possibility that the agent of transmission was already present in the UK blood supply had not been specifically acknowledged.

23.258 The death of a haemophilia patient in England in August 1983 was associated with imported products.[473] A further patient had received English therapy. The products he had received were under investigation, but no link had been established. An article by Dr Peter Jones in the British Medical Journal, published on 10 December 1983, noted that two AIDS cases had been reported in haemophilia patients in the UK.[474] At the end of the year there was media comment on the number of AIDS cases.[475] Apprehension that there was a present risk arising from UK products was beginning to appear in some quarters.

23.259 A meeting arranged by the NIBSC to examine the infectious hazards of blood and blood products, with particular reference to hepatitis and AIDS, was held on 9 February 1984.[476] It was reported that the most recent information indicated that two UK patients and nine other European patients with haemophilia had contracted AIDS. A report by the Centres for Disease Control and Prevention (CDC) had identified 31 recipients of blood transfusion in the USA who had contracted AIDS. Association with UK products was not reported.

23.260 It was not until the development of tests for anti-HIV and the report of research by Dr Cheingsong-Popov, Professor Weiss, Professor Tedder and others was published on 1 September 1984 that any data on the prevalence of anti-HIV seropositivity among 'at risk' groups in England were available.[477]

23.261 The period when the SNBTS and the PFC might have acknowledged that the domestic product might be infected with HIV runs from the turn of the year 1983-84 until early September 1984. During that period the risk to haemophilia patients in Scotland was real: the Edinburgh Cohort patients were infected by PFC product.

23.262 However, on the evidence as a whole, there was no basis on which it could be inferred that an actual present risk was known, or should have been known, to the SNBTS, the PFC, or, indeed, the haemophilia clinicians. They shared, with colleagues in England and Wales, the understanding that there was a potential risk. The second and third questions have to be considered in that context.

Steps taken by The Scottish National Blood Transfusion Service/Protein Fractionation Centre to take account of the potential risk of transmission of HIV in the processing of blood products

23.263 As the narrative of the evidence shows, the PFC's research relating to virus infection concentrated on hepatitis until early 1983. Then there was the beginning of a subtle change of focus as the possible risks which AIDS might pose to the blood supply began to be understood. From then the scientists realised that research would focus, not exclusively on hepatitis, but also on AIDS. By March 1983 recognition of the importance of AIDS was tentative: explanations of the absence of a formal record of discussion of the subject at the Haemophilia and Blood Transfusion Working Group meeting on 22 March 1983 demonstrate that opinion had not become firm on the relevance of the topic.[478]

23.264 Dr Foster's memorandum of 3 May 1983 marked the beginning of a substantial shift towards recognising the relevance of the AIDS risk. By the end of the year there had been a substantial programme of research, set out in paragraphs 23.128-23.132 and 23.139-23.142 above. The potential risk was clearly taken into account and influenced the programme of research into the formulation and processing of the PFC's products.[479]

Should the threat of AIDS have caused the Protein Fractionation Centre to accelerate its heat treatment programme in or around May 1983?

23.265 This question was prompted by Dr Foster's memorandum of 3 May 1983. It implies that, in acknowledging the potential risk from AIDS, not only should the direction of research have been altered, but that the progress of that research should have been accelerated. Dr Foster identified the issues clearly. NANB Hepatitis was thought to have infected all severely affected haemophilia patients because of the inherent infectivity of large-pool concentrates. So long as the focus was on hepatitis, strategy could focus on those who had received little treatment, and a proportion only of total production had to be treated for virus inactivation. With AIDS, those who needed most treatment were exposed to the greatest risk of infection. It would not be possible to differentiate, and all production would require to be heat-treated. It was possible that the timetable would require to be reviewed.

23.266 Mr Watt's letter to Professor Cash dated 5 May 1983 supported the speeding-up of the programme.[480] The initial request sought funding from the budget set aside to cover costs arising from compliance with the Medicines Inspectorate recommendations. Unfortunately, this request was turned down. The subsequent submission for funds was successful. However, it was not until August 1984 that the funding issue was resolved. If the scientists at the PFC had waited until the resolution of that issue, there would have been a very considerable delay in progress.

23.267 That did not happen. There was progress, and the question whether there should have been acceleration must be considered in the light of the evidence of what happened in fact rather than on the implementation of the specific scheme put to Professor Cash.

23.268 A batch of pasteurised Factor VIII was sent out for clinical trial on 13 June 1983. There was a review of the research programme on 15 June. By that time, the heating protocol had been developed to specify pasteurisation at 60°C for 10 hours and at 70°C for half an hour. Tests of virus kill were in place using model viruses, and loss of Factor VIII activity was being monitored. In the light of experience, an amended regime of heating at 60°C for 9.25 hours followed by 0.75 hours at 70°C had been developed for testing in the next round of trials. Dr Foster's report dated 20 December 1983 on progress in the studies to improve yield and quality of Factor VIII concentrates included comment on extensive work on the stability of FVIII:C (activity) and a range of model viruses used in heating in solution in the presence of sorbitol and glycine in conditions which were, in his opinion, probably the best that could be achieved without an unacceptable loss of yield.[481]

23.269 There is no basis in the evidence on which it could be found that that programme could have been accelerated to any significant extent. On the contrary, the evidence indicates that progress was acceptable.

23.270 The scientific witnesses were generally in agreement that the funding issue did not affect progress which went ahead according to the development programme. Dr Perry's evidence was that despite the funding issues, the programme was carried out. Dr Foster's evidence illustrates an aspect of the conduct of business at the PFC which was to arise in other contexts. The scientists got on with the work they considered relevant and important, and left questions of administration and funding to others. In their separate views, what did hold up progress of the pasteurisation programme in the latter part of 1983 was the organisation and conduct of clinical trials (in part another administrative issue) and not funding.

23.271 As narrated in paragraphs 23.155 to 23.156, research and development work was well advanced in the early part of 1984, and an ambitious target for the installation and commissioning of the necessary production facilities had been set. The impression reasonably gained from the evidence as a whole is that the scientists made good progress, conscious of the threat of AIDS as it was understood at the time, and that there is no basis on which they could have accelerated the work.

Was adherence to the pasteurisation programme until October/November 1984 justified, and in particular was that course justified after January 1984?

23.272 By December 1983, Dr Foster was reporting good progress in the pasteurisation of Factor VIII in the presence of sorbitol and glycine. The CBLA report of 26 July 1983 had indicated that pasteurisation was more homogeneous and efficient than dry heating.[482] The adverse comments on pasteurisation in the report were subject to significant criticism by the witnesses who gave evidence to the Inquiry. It is not possible to treat the comments on pasteurisation in the CBLA report as substantial or as likely to be material to a decision whether to persist with pasteurisation in 1983. Until the end of the year there is no reasonable criticism that can be made of the PFC's pursuit of a solution to the problem of virus inactivation that employed 'wet' heating (pasteurisation).

23.273 In January 1984, Dr Smith sent Dr Foster a memorandum on the PFL's experiments on the dry heat treatment of Factor VIII. Findings reflected in the memorandum were set out in paragraph 11.156 of the Preliminary Report. Written and oral evidence now available to the Inquiry provides a fuller insight into the report and its significance. Dr Smith's evidence (paragraph 23.144) indicates the limited scope of the memorandum, and is in line with Dr Foster's understanding. The two English facilities had demonstrated, at laboratory scale at Oxford and large-scale at Elstree, that the English Factor VIII products could withstand heat treatment, as Rubenstein had predicted at the International Society of Haematology/International Society of Blood Transfusion Congress in Budapest in August 1982. It had not been demonstrated that the treatment applied would inactivate NANB Hepatitis, and Dr Smith at that time had little hope that it would. Dr Foster considered that the results, though more extensive, were consistent with the PFC's own findings on dry heating. His view was that, without evidence of inactivation of any viral markers, the data were of limited value. The SNBTS had data from laboratory studies using model viruses, and published data from Behring, which pointed to the relative effectiveness of pasteurisation in making concentrates safe from transmission of NANB Hepatitis viruses.

23.274 In the light of this evidence, the PFC was fully justified in pursuing the pasteurisation project undeterred by the information provided by Dr Smith in January 1984.

Was there sufficient liaison/cooperation between the fractionation services in Scotland and England over the period 1980 to 1984 in relation to viral inactivation? Did any management problems impact on the PFC's viral inactivation programme?

23.275 It is not inevitably the case that closer collaboration would have been of advantage to either service. If that had involved restricting the scope of research, the benefit of having two independent, and skilled, teams of investigators could have been lost. The issue is, rather, whether there was sufficient contact and exchange of information to ensure cross-fertilisation of research, giving each team the benefit of the other's work.

23.276 The Inquiry considered two factors that might have influenced the exchange of information between Scotland and England: firstly, any formal structures providing links between the two transfusion services and their fractionation facilities; and secondly, the nature of personal contacts and communications between staff at the PFC and the BPL.

23.277 As far as formal links were concerned, the transfusion services in England and Scotland and their associated fractionation facilities reported to different government departments and Ministers. While collaboration in specific research and development projects was arranged from time to time, there were no formal structures in place to ensure communication between the PFC and the BPL/PFL or to coordinate their work generally.[483]

23.278 Professor Cash maintained that he had been anxious to foster collaboration. In oral evidence, he said:

It has always been my belief that had the two organisations (BPL and PFC) been able to pool their limited R&D resources, and perhaps some manufacturing resources, it may have ... made a significant difference, throughout the 1980s, to the availability of desirable plasma products in the UK.[484]

23.279 In his view it was in the public interest that there should be formal links.[485] Consistent attempts to try and forge closer relationships between the Scottish and English transfusion services, in different areas, were a constant theme of his tenure as national medical director.[486] He believed that there was a critical shortage of research staff - the background to the comment in paragraph 23.93 about the value of Dr Foster.

23.280 In a paper for the chairman of the CSA dated January 1984, Professor Cash provided some background information describing the comparative roles of the Central Blood Laboratories Authority (CBLA) and CSA. Having described the position generally, he wrote:

[T]he formal relationships between BPL (originally managed by the Lister Institute) and the SNBTS have not been satisfactory over the years.

23.281 Professor Cash told the Inquiry that:

[A]t CSA, the Department of Health level, major efforts were made by some well meaning people to get these organisations together at a supramanagement, strategic level; frankly we failed. With the one exception, and that is when DHSS decreed that BPL were to go up to Scotland to get the virus inactivation validation studies done. That was the only occasion.[487]

23.282 The Inquiry explored whether, in the absence of any other structural links, the CBLA Central Committee on Research and Development in Blood Transfusion, which first met in 1983, might have provided a more formal route for the exchange of information.

23.283 Professor Cash knew about the Central Committee On Research and Development: it was never going to bridge the gap between the SNBTS and the BPL/PFL because, in his view, it did not enjoy the support of the DHSS or the SHHD.[488] Dr McClelland, who was a member of the committee, 'was under the impression that this was essentially an English committee ... set up to advise the CBLA'.[489]

23.284 For his part, Dr Perry's recollection was that the committee 'was never recognised as a UK committee and certainly never exercised any formal influence over the activities of the SNBTS - although the SNBTS took account of its actions and recommendations in its own planning processes'.[490] His impression was that the committee's role was 'primarily observational and reactive in relation to ... decisions taken elsewhere'. Dr Foster had not been aware of the Committee and did not believe that PFC representation on it would have led to the earlier introduction of Z8.[491]

23.285 As far as personal contacts and communications were concerned, the Inquiry heard evidence that the relationship between senior managers at PFC and BPL had sometimes been difficult, whether from personal differences or from disagreements about strategy.[492]

23.286 In spite of this, and in spite of the absence of formal links between the organisations, there was real and substantial collaboration between them at the level of the scientific officers engaged with research. The close working relationships that existed between scientific staff at the PFC and the BPL have already been discussed at paragraph 23.75 above.

23.287 For his part, Dr Foster resisted the suggestion that organisational problems affected relationships between the scientific officers. He had no personal experience of difficulties. He said:

[W]henever I met Dr Lane, it was always a very pleasant experience and I have to say I didn't meet him that often and I was always encouraged by Mr Watt to interact with colleagues at BPL and at PFL quite freely, and that was, to my knowledge, always reciprocated and I was never ordered to disengage this liaison at any time. I was aware that Mr Watt and Dr Lane had different views and that's understandable, that they were - at this time people did have different views but Mr Watt was very much trying to take forward the plan that English plasma be processed in Scotland and I don't think Dr Lane saw things the same way. So there was a point there, where they clearly disagreed and that's conceivable that that might have led to some friction but that's really all I can talk to. That's all I'm aware of.

Q. From your position as head of research and development at PFC, how were your relations with your counterpart or counterparts down south?

A They were always excellent ... shortly after I joined PFC, I was given a task by Mr Watt to lead a delegation from PFC to BPL to help people to meet their counterparts, and there were maybe 10 or 12 people from PFC went down to BPL, they met their counterparts, that was reciprocated by visits from BPL, and we always encouraged our staff to communicate with their counterparts and that was always the situation and remained the situation [throughout] my employment.

Q. So there was communication, not only between yourself and Dr Smith but also the staff beneath you as well?

A. Yes, very much so. All of my staff were encouraged to deal with their counterparts because we saw ourselves in the wider sense part of the same organisation. We all worked for the NHS and we were in an area where it's really highly specialised. So to find somebody who is dealing with the same problems and same issues is not something that happens every day. So to have, if you like, another branch of the same organisation where you can talk to somebody was really a very good thing to have. So we did encourage that and I think that happened at BPL as well. And I'm not aware of anybody saying, 'Please stop doing this,' either at BPL or PFC.

23.288 Dr Foster was asked about Professor Cash's attempts to institute more formal relations. He said:

I can understand why Professor Cash perhaps was seeking something more formal because the relationships that we had were to a large extent informal and it did depend on the individual personalities, and if I had left or Dr Smith had left and someone else had come [along], things might have been different. So Dr Cash might have wanted something more formal to have a structure in place. So I can understand that but from my perspective it wasn't necessary, but if Dr Cash had said, 'Please do this more formally,' we would have done.

Q. So certainly we saw the use of the words 'formal relationships' in Dr Cash's briefing notes and he did recognise in the notes that there was communication, dialogue and liaison between yourself and Dr Smith.

A. Yes, and if we had been asked to do it more formally then we would have had no difficulty with that.[493]

The exchange provides a clear indication of the approach adopted by Dr Foster to collaboration, as well as illustrating the balanced views he held about relationships in a wider context. There is no basis for apprehension that the apparent inability of senior management to develop formal structural arrangements for the exchange of information had any impact on scientific research and development at this stage.

23.289 Indeed, Professor Cash accepted, in relation to the development of Z8, that given the relationships between Dr Foster and Dr Smith in particular, there was not a wide gap between the SNBTS and the BPL/PFL.[494] Their personal liaison was the best opportunity for exchange of information in the circumstances.[495]

23.290 Dr Foster acknowledged that there were two occasions on which the CBLA's interest in the protection of intellectual property rights might have inhibited the exchange of information temporarily.[496] The PFC may have withheld information for similar reasons. Dr Foster said:

I did apply for a patent application for the method of thawing plasma, which I had designed, and that patent was awarded and so it's conceivable that that information wasn't given to BPL immediately but it was published shortly thereafter. The only other example I can think of is when we were working with Dr Johnson and, of course, we had to sign confidentiality arrangements with him and we weren't allowed to discuss that with anyone else.[497]

23.291 The advice he had received from patent lawyers was that one should not breathe a word about an invention to anyone before filing because of the risk of prior disclosure undermining the application. Dr Smith received similar advice.[498] He commented that proprietary information released under a confidentiality agreement never featured in exchanges between the PFC and the PFL.[499]

23.292 The UK as a whole, and for present purposes Scotland in particular, were fortunate indeed in benefiting from the relationships among the scientists engaged in their respective research projects in virus inactivation, despite the lack of formal structures. The active collaboration that resulted made good the lack of formal structures and met the needs of this period.

Would closer collaboration, and UK-wide policy guidance, have avoided the services in Scotland and England pursuing different courses and have been more effective?

23.293 Any answer to this question must be speculative to a degree. It is impossible to know how UK policy would have been developed, or how policymakers would have obtained the information required to instruct policy, or how policy would have been formulated. More particularly, since there would inevitably have been competing priorities, it is impossible to know how such issues would have been resolved, or what the outcome would have been. Pooling of knowledge and thought, such as Professor Cash envisaged, might have added intellectual mass to the single project and accelerated progress. Alternatively, if the two services had been compelled to limit their researches to one common approach, the distinctive contributions of each might have been lost. Avoiding the pursuit of different courses would not necessarily, or obviously, have been to the advantage of the UK as a whole or Scotland in particular.

23.294 So far as the second aspect of the question is concerned, it is possible to be more positive. It was the ability of Scottish scientists to pursue their own research that resulted in the development of effective heat inactivation at the end of 1984, enabling the SNBTS to provide the first comprehensive national supply of heat-treated Factor VIII in the world. At that stage, the Oxford and Elstree facilities were not carrying out model virus studies. Scotland was able to validate the effectiveness of the processes. While it is impossible to say where a fully integrated joint research programme would have reached by this stage, there is no basis in evidence for a view that a UK policy decision directing collaboration between the two services would have resulted in more effective research progress than was achieved in Scotland.

Did the Protein Fractionation Centre have sufficient resources, including staff, and access to information and academic research for its viral inactivation programme?

23.295 Research links with the universities were not explored in detail in oral evidence, since there was no suggestion that there were barriers on the side of the public facilities that prevented access. In the mid-1980s there were close links between the SNBTS and Heriot-Watt University which were referred to in evidence. Professor Charles Brown conducted a research programme in biochemistry. One of his students was Dr Valerie Hornsey. The supervisors of her PhD studies on monoclonal antibodies, completed in 1988, included Dr Prowse and Dr Pepper. Dr Hornsey went on to join the SNBTS. Interaction of this kind with higher education institutions was not, and is not, uncommon in Scotland. However, as noted in Chapter 20 Haemophilia Therapy - The Period up to the Early 1980s, at paragraph 20.73, Dr Foster failed in his attempts to encourage research groups at a number of UK universities to undertake fundamental research into ways of eliminating the risk of coagulation factor concentrates transmitting hepatitis. Collaboration requires both parties to be convinced of the value of the research proposed.

23.296 Whether access to academic research was sufficient might theoretically have been an issue, but it did not arise for extended examination on the evidence available to the Inquiry. Given the published research output of SNBTS scientists, there is good ground for the view that they were themselves at the forefront of academic research. The fact that SNBTS scientists were invited to provide supervision of academic research projects supports that view.

23.297 Human and other resources are, almost as a matter of tradition, stretched in the public service. Professor Cash would no doubt have been willing at any time to invest more had the funds been made available. Questions were to arise later about resources, in connection with the development of products effectively heated to kill Hepatitis C. So far as this period is concerned, the evidence of Dr Foster and Dr Perry (paragraph 23.125) was that lack of resources did not delay research. Dr Foster's characteristic view was that it was not an issue for him and his research colleagues: it could be left to Mr Watt and Professor Cash to sort out.

23.298 The answer to the question, at the end of the day, is that the work was done, it was done effectively, and it was done with remarkable expedition. Additional resources would no doubt have been welcome, but lack of resources did not inhibit progress.

Should commercial heat-treated products have been adopted in advance of locally produced products or could/should the Protein Fractionation Centre have bought in a commercial heat-treated process instead of developing its own?[500]

23.299 It is necessary to define a time-frame for this question. Licences for heat-treated factor concentrates began to be issued in the USA in 1983, as set out in paragraphs 23.28 to 23.30 above and Appendix I to this chapter. The products licensed in the USA that have to be considered were:

  • Baxter/Hyland's Hemofil T, licensed in March 1983
  • Armour's HT Factorate, licensed in January 1984
  • Alpha Therapeutic's Profilate HT, licensed in February 1984
  • Cutter's Koate HT, licensed in February 1984

23.300 Commercial heat-treated products were not licensed by the UK Medicines Control Agency for release in the UK until February 1985. Before that date, Scottish Haemophilia Centres purchased and infused heat-treated commercial products on a named patient basis. Assuming that the products used after licensing in the USA were heat-treated, Edinburgh used Factorate in 1984. Glasgow Royal Infirmary used Hemofil in 1984. Yorkhill used Factorate in 1984. None of these regions used any commercial product in 1985 and 1986. Aberdeen, Dundee and Inverness did not use commercial products over the material period. Haemophilia clinicians were not excluded from the commercial market. Indeed in England and Wales commercial purchases accounted for the majority of Factor VIII used at this period. The PFC's first heat-treated Factor VIII concentrate was issued in December 1984.

23.301 The question can only relate to the general adoption of imported heat-treated products, and necessarily assumes that UK licensing might have occurred earlier than February 1985. There is no basis on the evidence for a finding that the UK licensing process at this time was other than in accordance with normal practice, or unduly delayed.

23.302 There were other factors in the short period between US licensing and the production of the PFC's heat-treated product. As noted in paragraph 23.28, Behring's product, Haemate P, was available in small quantities from 1980 in Germany and some other places. It was not licensed and was not available in the UK. Initial chimpanzee studies of Baxter/Hyland's product Hemofil T suggested that it was effective in preventing transmission of NANB Hepatitis but not HIV. In human recipients, the opposite outcome was eventually reported.

23.303 Some at least of the procedures that were developed by commercial companies were protected by patents and, in the nature of things, prior publication of the inventive steps in the processes developed was most unlikely to have occurred at all and, if it happened, even more unlikely to have been comprehensive. Publication of a final specification would almost invariably take a period of years from filing of the original application.

23.304 Dr Foster's paper following the Congress of the International Society of Haematology/International Society of Blood Transfusion in Budapest in August 1982 reported that there was at that time no final proof that the Behring product was free from NANB Hepatitis. The method of heat treatment of Hemofil T was not disclosed at the Congress. When, months later, Dr Prowse heard that the process involved dry heat treatment at 60°C, the methodology employed was not disclosed and to Dr Foster's knowledge has never been disclosed. Clinical trials of Hemofil T in 1982-83, including trials at St Thomas' Hospital in London, had shown that the product was less effective in inactivating virus than pasteurisation. That information was circulating informally within the industry, and within UK Government circles, in 1983 and 1984 (see paragraph 23.100). In October 1984, Professor Mannucci disclosed that, as far as AIDS was concerned, no patients treated with the product had apparently seroconverted after one year from treatment with Hemofil T (see paragraph 23.169). This was the first time that there was any evidence that dry heating inactivated, or might inactivate, the HIV virus. Events moved swiftly from then. By December 1984, dry heat treatment was operational in Scotland.

23.305 In order to have advanced the provision of effectively heat-treated products so as to have ensured their supply in Scotland before the end of December 1984 as a matter of general prescription, the SNBTS would have required to be satisfied that the products were safe and effective to a degree that indicated that domestic research should be suspended or discontinued. The evidence has not disclosed any rational basis on which that could have been decided. Nor could one form or express any view on the likely reaction of the regulatory agencies if a licence application had been made.

In general, was the approach taken to viral inactivation at the Protein Fractionation Centre in the period 1980-84 reasonable? In general, was the degree of priority accorded to viral inactivation by the Protein Fractionation Centre during this period reasonable?

23.306 These two questions relate to the work of the scientists explored in the evidence narrated in this chapter. They can be answered unequivocally in the affirmative.

Appendix 1

Commercial heat-treated coagulation factor products 1983-1991

Factor VIII

ARMOUR PHARMACEUTICAL COMPANY
Product FDA licence Method Temp Time
HTFactorate January 1984 Dry Heat 60°C 36 hours
HTFactorate Generation II 1984 Dry Heat 60°C 36 hours
Haemate-P[501] May 1986 Pasteurised 60°C 10 hours
Monoclate 1987 Dry Heat 60°C 36 hours
Moncloate-P 1990 Pasteurised 60°C 10 hours
ALPHA THERAPEUTIC CORPORATION
Product FDA licence Method Temp Time
Profilate HT February 1984 Dry Heat[502] 60°C 24 hours
HT-Profilate September 1985 Dry Heat 60°C 24 hours
Profilate HT HP May 1988 Dry Heat 60°C 24 hours
Profilate SD July 1989 Dry Heat 60°C 24 hours
Moncloate-P 1990 Pasteurised 60°C 10 hours
BAXTER, HYLAND
Product FDA licence Method Temp Time
Hemofil T March 1983 Dry Heat 60°C 72 hours
Hemofil CT October 1985 Dry Heat 60°C 72 hours
CUTTER BIOLOGICAL, MILES Inc
Product FDA licence Method Temp Time
Koate HT February 1984 Dry Heat 60°C 72 hours
Koate HS April 1986 Pasteurised 60°C 10 hours
IMMUNO AG
Product FDA licence Method Temp Time
Kryobulin TIM N/A Dry Heat under steam pressure 60°C 10 hours

Factor IX

ALPHA THERAPEUTIC CORPORATION
Product FDA licence Method Temp Time
Profilnine HT October 1984 Dry Heat 60°C 20 hours
AlphaNine December 1990 Dry Heat 60°C 20 hours
BAXTER, HYLAND
Product FDA licence Method Temp Time
Proplex SX-T October 1984 Dry Heat 60°C 144 hours
Proplex T January 1986 Dry Heat 60°C 144 hours
CUTTER BIOLOGICAL, MILES Inc
Product FDA licence Method Temp Time
Konyne HT October 1984 Dry Heat 68°C 72 hours
Konyne 80 April 1991 Dry Heat 80°C 72 hours

1 Maunsell, 'Transmission of hepatitis during blood transfusion', British Medical Journal, 1 December 1945; 783 [LIT.001.0246]

2 As explained elsewhere in this Report, the risk of infectivity rises where large plasma pools are used as the source material for a given blood product.

3 In the case of Factor VIII, the amount of Factor VIII activity recovered from a given quantity of frozen plasma.

4 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1319

5 Edsall, 'Stabilization of serum albumin to heat, and inactivation of the hepatitis virus', Vox Sanguinis, 1984; 46:338-340 [SNB.008.5701]

6 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1319

7 Edsall, 'Stabilization of serum albumin to heat, and inactivation of the hepatitis virus', Vox Sanguinis, 1984; 46:338-340 [SNB.008.5701]

8 Dr Foster - Day 41, page 60

9 Dr Smith - Day 59, pages 47-49

10 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1763-64

11 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1319 and Dr Foster - Day 41, page 63

12 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1320

13 Professor van Aken's report on Stable Plasma Protein Solution and the transmission of HCV [PEN.001.0306] at 0307; Professor van Aken - Day 2, pages 47-49; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1321

14 Dr Foster - Day 41, pages 64-65 and SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1321

15 Alter et al, 'Photochemical decontamination of blood components containing hepatitis B and non-A, non-B virus', The Lancet, 24/31 December 1988; 1446-50 [LIT.001.3984]; Chapter 16, Knowledge of Viral Hepatitis 3 - 1986 Onwards

16 See Professor van Aken - Day 2, pages 29-33 for a discussion of culturing and the use of model viruses.

17 For more information on virus spiking and Hepatitis C see Professor van Aken's report on Stable Plasma Protein Solution and the transmission of HCV [PEN.001.0306] at 0307

18 Professor van Aken - Day 2, pages 35-39; Yei S et al, 'Partitioning of hepatitis C virus during Cohn-Oncely fractionation of plasma', Transfusion, 1992; 32/9 [LIT.001.3218] at 3221

19 Professor van Aken - Day 2, pages 44-45

20 See above at 23.7

21 Dr Foster - Day 41, pages 64-65; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1321

22 Dr Foster - Day 41, pages 87-89; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1339-40

23 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1340

24 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1568-69

25 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1567

26 For these and other obstacles identified, see: Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1567; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1323–24]; and Professor van Aken's statement on the introduction of dry heat treatment of Factor VIII concentrate [PEN.012.1932] at 1932

27 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1554

28 Minutes of meeting [SNB.001.5055]

29 See paragraph 23.33 below

30 Dr Smith - Day 59, page 25

31 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1567

32 Ibid [PEN.012.1551] at 1567

33 Dr Foster - Day 41, pages 102-103

34 Note that HIV had yet to become a concern for fractionators at this point in time.

35 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1567; Dr Foster - Day 41, pages 72-75; See Kasper et al, 'Recent evolution of clotting factor concentrates for hemophilia A and B', Transfusion, 1993; 33:422-434 [SGH.002.1947] at 1950

36 Professor van Aken - Day 47, pages 12-15. These antibodies are otherwise referred to as 'inhibitors'.

37 For details see Kasper et al, 'Recent evolution of clotting factor concentrates for hemophilia A and B', Transfusion, 1993; 33:422-434 [SGH.002.1947] at 1948; Professor van Aken-Day 47, pages 23-24

38 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1567; Dr Smith - Day 59, pages 28-29; Dr Foster - Day 41, page 71

39 Dr Foster - Day 41, page 71; Dr Smith - Day 59, pages 28-29

40 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1556-57

41 Dr Smith - Day 59, page 67

42 Dr Smith - Day 59, pages 63-64

43 Dr Foster - Day 41, pages 65-66; For more details see SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1321

44 Dr Foster - Day 41, page 66; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1322

45 Dr Smith - Day 59, pages 31-32

46 Dr Smith - Day 59, page 32

47 Dr Smith - Day 59, page 32

48 Dr Smith - Day 59, pages 30-31

49 For further details see: Kasper et al, 'Recent evolution of clotting factor concentrates for hemophilia A and B', Transfusion, 1993; 33:422-434 [SGH.002.1947] at 1950; and SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1323

50 Dr McClelland's statement on the use of blood products in Scotland [PEN.015.0307] at 0320 and SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1323

51 Professor Cash - Day 43, pages 14-15

52 Dr Perry - Day 45, page 13; Dr Cuthbertson - Day 46, page 19

53 Dr Foster - Day 41, pages 70-71; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1323

54 Kasper et al, 'Recent evolution of clotting factor concentrates for hemophilia A and B', Transfusion, 1993; 33:422-434 [SGH.002.1947]. Colombo et al, 'Transmission of non-A, non-B hepatitis by heat-treated Factor VIII concentrate', The Lancet, 6 July 1985; 1-5 [LIT.001.0369]

55 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1340-41

56 Dr McClelland's statement on viral inactivation to 1985 [PEN.011.0062] at 0062

57 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1446

58 Dr Foster - Day 41, pages 109-110; Minutes of MRC Working Party on Post-Transfusion Hepatitis, 14 February 1980, paragraphs 3.3 and 3.4 [DHF.002.4845] at 4847; Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1446

59 Fernandes P and Lundblad JL 1982. Pasteurized therapeutically active protein compositions. US Patent 4.440,679, filed 20 December 1982 and issued 3 April 1984 [SNB.004.5922]. Continuation of application number 127,351, filed 5 March 1980.

60 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1447

61 Ibid [PEN.012.1438] at 1447

62 Professor Cash's letter [SNB.007.2646]

63 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1448

64 Dr Foster - Day 41, page 114

65 Dr Perry - Day 45, page 11

66 Dr Foster - Day 41, page 116

67 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1449

68 Welch et al, 'Non-A, non-B hepatitis from intravenous Immunoglobulin’, The Lancet, 19 November 1983 [LIT.001.3924]

69 Dr Allen's letter of 7 December 1983 to Dr Welch [SNB.007.4036]; Dr Foster's reply dated 22 February 1984 [SNB.007.4287]; Dr Foster - Day 41, pages 117-118; Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1449-50

70 Dr Pepper's statement on viral inactivation to 1985 [PEN.013.1391] at 1394

71 See paragraph 23.15

72 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1448-49. For the full explanation of Dr Foster's disbelief on hearing the news regarding Behring's heat treatment process see Dr Foster's statement at 1448-50 and Dr Foster - Day 41, pages 114-117

73 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1447

74 Heimburger et al, 'Factor VIII concentrate - now free from hepatitis risk; progress in the treatment of haemophilia', Die gelben Hefte, 1980; 4:165-174 [SNB.004.5880]

75 Dr Foster - Day 41, pages 112-113

76 Mannucci, 'AIDS, hepatitis and haemophilia in the 1980s: memoirs from an insider', Journal of Thrombosis and Haemostasis, 2003; 1:2065-69 [LIT.001.1101]

77 Heimburger et al, 'A Factor VIII concentrate, highly purified and heated in solution', Haemostasis, 1981; 10/1:204 [SNB.007.3300]

78 Dr Smith - Day 59, page 20

79 Heimburger et al, 'A Factor VIII concentrate, highly purified and heated in solution', Haemostasis, 1981; 10/1:204 [SNB.007.3300]

80 Heimburger et al, 'Faktor VIII-Konzentrat, hochgereinigt und in Lösung erhitzt', Arzneimittel Forschung/Drug Research, (31) 619-622 [SNB.008.6794]

81 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1451 and Dr Foster's supplementary statement on viral inactivation to 1985 [PEN.012.1797] at 1798

82 Dr Foster - Day 41, pages 121-122; Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1451-52; for Dr Werner Zolg's translation see [SNF.001.0881]

83 Dr MacLeod prepared a report on this work dated 10 February 1982 [PEN.012.1489]

84 Dr Foster - Day 41, page 115; Dr Perry - Day 45, page 12

85 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1452

86 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1761

87 Dr Perry - Day 45, pages 11-12

88 Professor Cash's letter of 17 December 1981 [SNB.001.3587]

89 Minutes of the Factor VIII Study Group, 28 January 1982 [SNF.001.3813] at 3813

90 Minutes of the Factor VIII Study Group, 28 January 1982 [SNF.001.3813] at 3817-18; Dr Pepper's statement on viral inactivation to 1985 [PEN.013.1391] at 1393

91 As already noted, Dr MacLeod did not report his work until 10 February 1982 [PEN.012.1489]

92 Minutes of the Factor VIII Study Group meeting, 28 January 1982 [SNF.001.3813] at 3818-19

93 Factor VIII Study Group: First report of the Safety Action Group, 16 March 1982 [SNB.005.8387]

94 Preliminary Report, paragraphs 11.57-11.58

95 Factor VIII Study Group: First report of the Safety Action Group, 16 March 1982 [SNB.005.8387] at 8390

96 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1532

97 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1452

98 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1762

99 Dr Perry - Day 45, pages 17-18

100 Dr MacLeod's report [PEN.012.1489]

101 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1453; see also Dr Perry - Day 45, pages 17-19

102 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1453

103 Dr Perry - Day 45, pages 18-19

104 Dr Perry - Day 45, page 32-33

105 Dr Perry - Day 45, page 34

106 Dr Perry - Day 45, pages 34-35

107 Minutes of the Factor VIII Study Group meeting, 30 March 1982 [SNF.001.3793] at 3796

108 Minutes of the Factor VIII Study Group meeting, 3 June 1982 [SNB.001.3902] at 3905

109 Report of the meeting of the FVIII Safety Action Group on 23 June 1982 [SNB.001.3917]

110 Dr Cuthbertson - Day 46, page 30

111 Dr Cuthbertson - Day 46, pages 34-36

112 Dr Smith - Day 59, page 35

113 Dr Foster's report on the conference [SNB.010.4452]

114 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1453

115 Kröniger et al, 'Factor VIII concentrates: problems and protein-chemical characterization', Die Medizinische Welt, 1982; 33:1027-1033 [SNF.001.0921]. Note that the paper made no explicit claims that the Behring product was hepatitis safe.

116 Heimburger et al, 'Factor VIII concentrate - now free from hepatitis risk; progress in the treatment of haemophilia', undated typescript [SNF.001.0929]

117 Ibid [SNF.001.0929] at 0932

118 Ibid [SNF.001.0929] at 0941

119 See also Preliminary Report, paragraphs 11.74-11.78

120 Dr Foster's report on the Budapest conference [SNB.010.4452] at 4456

121 Dr Foster - Day 41, page 129

122 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1454

123 Dr Foster's report on the Budapest conference [SNB.010.4452] at 4459

124 Dr Foster - Day 41, page 128

125 Dr Smith - Day 59, pages 34-35

126 Preliminary Report, paragraph 11.160

127 Dr Foster's supplementary statement on viral inactivation to 1985 [PEN.012.1797] at 1798-99

128 Dr Foster's report on the Budapest conference [SNB.010.4452] at 4459

129 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1453-54

130 Minutes of Factor VIII Study Group meeting, 14 October 1982 [SNB.001.3932] at 3932

131 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1532

132 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1763. See also Dr Cuthbertson's statement [PEN.013.0025] at 0029 for similar reasoning.

133 For more details on zinc precipitation see 'SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors' [PEN.013.1309] at 1332-33

134 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1454-55

135 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1533

136 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1457

137 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1455

138 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1763-64

139 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1764

140 Dr Cuthbertson's statement on viral inactivation to 1985 [PEN.013.0025] at 0029

141 Ibid [PEN.013.0025] at 0029

142 Dr Cuthbertson - Day 46, page 43; see also Dr Smith's written statement [PEN.012.1551] at 1568 'JKS Note 2' where he emphasises the difficulty of removing the stabilisers from the resultant solution.

143 Dr Foster's letter to Dr Smith [SNB.007.3253]

144 Dr Smith's letter to Dr Foster [SNB.007.3267]

145 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1555-56

146 Dr Smith - Day 59, page 51

147 Dr Cuthbertson - Day 46, page 43

148 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1457

149 Dr Perry - Day 45, pages 24-25

150 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1771

151 Dr Cuthbertson - Day 46, page 46

152 Ibid

153 Memorandum from Drs Foster and MacLeod to Mr Watt, dated 12 November 1982 [SNF.001.3497]

154 Preliminary Report, paragraphs 11.87-11.89

155 Dr Foster's letter to Dr Smith [SNB.007.3341]

156 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1556

157 Dr Smith - Day 59, page 62

158 Dr Foster's report on the Budapest conference [SNB.010.4452]

159 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1457

160 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1556

161 Minutes of meeting [DHF.003.0059]. The meeting was attended by Professor A Bloom, Dr C Rizza, Dr H Gunson, Dr J Craske, Dr R Lane and Dr M Harvey, as well as Professor Cash of the PFC and Dr Smith of BPL/PFL. See also Preliminary Report, paragraph 11.90.

162 Professor Cash - Day 43, page 37

163 Professor Cash - Day 43, pages 18-27; Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1917

164 Professor Cash - Day 43, pages 28-29

165 Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1915

166 Ibid [PEN.012.1912] at 1916

167 Ibid [PEN.012.1912] at 1916-19

168 Ibid [PEN.012.1912] at 1915

169 Professor Cash - Day 43, page 31

170 Professor Cash - Day 43, pages 31-32; Professor Cash's letter [SNB.004.3163]

171 Dr Lane's letter [SNB.004.3160]. It is clear from [SNB.004.3159] that the Chairman of the meeting held on 15 December 1982 was Arthur Bloom.

172 Professor Cash's letter to Dr Lane [SNB.004.3159]

173 Professor Cash - Day 43, page 36; Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1917-18. See also Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1765-66

174 Professor van Aken - Day 47, page 65

175 Professor van Aken - Day 47, pages 66-68

176 Professor Cash - Day 43, pages 49-51; Professor Bloom and Dr Rizza's letter [DHF.003.0892]. Note that the date recorded on the letter (11 January 1982) would appear to be incorrect and that a date one year later (11 January 1983) appears correct: see Inquiry Counsel's explanation - Day 27, pages 47-51

177 Letter from PHLS to DHSS [DHF.001.7106]

178 Professor Cash - Day 43, pages 39-42; Colombo et al, 'Transmission of non-A, non-B Hepatitis by Heat-treated Factor VIII Concentrate', The Lancet, 6 July 1985; 1-5 [LIT.001.0369]. And see Memorandum to Haemophilia Centre Directors of 29 March 1984 [DHF.002.8963]

179 Professor Ludlam's letter to Miss Spooner of 10 April 1984 [SNF.001.3211]

180 [PEN.012.1912] at 1919

181 Professor Cash - Day 43, page 44

182 Professor Cash - Day 43, pages 44-45

183 Professor Cash - Day 57, page 138

184 See also Dr Perry's statement on viral inactivation to 1985 for a similar view - [PEN.012.1759] at 1766

185 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1460

186 Dr Foster - Day 41, pages 140-141

187 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1461

188 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1558

189 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1767. Dr Perry agreed during his oral testimony (Day 45 - page 35) that the order of Drs Smith and Snape should be reversed so at to reflect the correct counterparts at the PFC and the BPL. Dr Perry also noted that Dr Snape was the quality assurance manager at the BPL.

190 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1766

191 Dr Perry - Day 45, pages 28-29

192 Dr Foster - Day 41, pages 140-141

193 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1459-60

194 Dr Foster - Day 41, page 141; Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1461

195 Dr Foster - Day 41, pages 142-143

196 Dr Foster - Day 41, pages 143-145; Mannucci, 'AIDS, hepatitis and haemophilia in the 1980s: memoirs from an insider', Journal of Thrombosis and Haemostasis, 2003; 1:2065-69 [LIT.001.1101]; Colombo et al, 'Transmission of non-A, non-B Hepatitis by Heat-treated Factor VIII Concentrate', The Lancet, 6 July 1985: 1-5 [LIT.001.0369]

197 Dr Foster - Day 41, pages 145-148

198 Dr Foster - Day 41, page 143

199 Minutes of Haemophilia and Blood Transfusion Working Group, 22 March 1983 [SNB.001.5183]

200 Professor van Aken - Day 47, pages 74-75

201 See letter from Dr Foster to Dr Smith dated 20 January 1983 including technical details of the PFC's work on pasteurisation [SNB.007.3407]

202 Dr Foster's memorandum [SNB.005.8435]. See also the minutes of the meeting of Directors of the SNBTS and Haemophilia Directors of 21 January 1983 [SNB.001.5160] at 5163, where a similar view was expressed.

203 Minutes of the meeting of Directors of the SNBTS and Haemophilia Directors of 21 January 1983 [SNB.001.5160] at 5163

204 Minutes of Haemophilia and Blood Transfusion Working Group, 22 March 1983 [SNB.001.5183] at 5184

205 Minutes of the meeting of Directors of the SNBTS and Haemophilia Directors of 21 January 1983 [SNB.001.5160] at 5164

206 Minutes of the meeting of Directors of the SNBTS and Haemophilia Directors of 21 January 1983 [SNB.001.5160] at 5164. See also the memo from Dr Foster to Mr Watt and Dr Perry dated 17 February [SNB.007.3474] in which Dr Foster proposed setting up a dog colony to test for thrombogenicity. For further details of the period January-April 1982 see Preliminary Report, paragraphs 11.96-11.115.

207 Dr Foster's presentation [SNB.007.3503] at 3507

208 Dr Foster - Day 41, pages 150-151

209 Minutes of Haemophilia and Blood Transfusion Working Group, 22 March 1983 [SNB.001.5183] at 5184

210 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1768

211 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1461

212 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1767-68

213 Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1920-21

214 Dr Foster's memorandum [SNB.007.3635]

215 The memo included Dr Foster's tentative suggestions as how such a process would operate [SNB.007.3635] at 3636

216 Mr Watt's letter [SNB.007.3638]

217 Mr Watt's letter [SNB.007.3638] at 3640

218 Professor Cash's response [SNB.007.3708]

219 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1534, paragraphs 17-18

220 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1461

221 Gordon, 'Factor VIII products and disordered immune regulation', The Lancet, 30 April 1983; 991 [LIT.001.0911]; Lissen et al, 'AIDS in haemophilia patients in Spain', The Lancet, 30 April 1983; 991 [LIT.001.0403]

222 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1461-62

223 Dr Foster - Day 41, pages 153-154

224 Barré-Sinoussi et al, 'Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)', Science, 1983; 220:868-871 [LIT.001.0058]

225 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1559

226 Dr Foster - Day 41, page 159

227 Dr Smith - Day 59, page 72

228 Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1921

229 Dr Foster - Day 42, pages 2-3

230 Dr Foster - Day 42, page 3: 'I was looking to see how we can advance this as quickly as possible'.

231 Dr Foster - Day 42, page 5

232 Dr Foster - Day 42, page 4

233 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1462

234 Ibid [PEN.012.1438] at 1462

235 Dr Foster - Day 41, pages 11-12

236 Minutes of Blood Transfusion Service Sub-Committee, 25 May 1983 [SGH.001.9769] at 9770 and 9775

237 Professor Cash - Day 43, pages 66-69; Dr Perry - Day 45, pages 54-56; and Dr Cuthbertson's oral evidence - Day 46, pages 47-48 and his written statement [PEN.013.0025] at 0033

238 Letter from Mr Wooller, CSA, to Mr Murray, SHHD, dated 6 June 1983 [SNB.003.7641]

239 Dr Perry - Day 45, pages 47-49; Annex to Mr Wooller's letter of 6 June 1983 [SNB.003.7643] 7645

240 Letter from Mr Wastle, SHHD, to Mr Wooller, CSA, dated 20 September 1983 [SNB.011.1251]; Professor Cash - Day 43, pages 74-76; See also papers for the Blood Transfusion Service sub-committee of 23 November 1983 [SGH.001.9496] at 9497

241 Minutes of Blood Transfusion Service Sub-Committee, 22 February 1984 [SGH.001.9972] at 9974

242 Dr Bell's letter [SGF.001.1986]

243 Letter from Dr Perry to Mr Wooller, dated 13 August 1984 [SNB.007.4523] and Mr Wooller's response, dated 17 August 1984 [SNB.007.4527]

244 Dr Perry - Day 45, pages 39–56 and Professor Cash - Day 43, pages 56–79 for more details on the issue of funding.

245 Dr Perry - Day 45, pages 54-55; Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1769

246 Dr Foster - Day 42, page 14

247 Professor Cash - Day 43, page 79

248 Dr Perry - Day 45, pages 57-58; Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1769; Dr Foster - Day 42, page 13

249 Professor Cash's letter to Professor Ludlam [SNB.006.5498]

250 Minutes of FVIII Safety Sub-Committee, 15 June 1983 [SNF.001.3730] at 3731

251 Minutes of FVIII Safety Sub-Committee, 15 June 1983 [SNF.001.3730]; Preliminary Report, paragraphs 11.130-11.134

252 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1364

253 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1465

254 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1462

255 Mr Watt's letter to Dr Johnson [SNB.007.3794]

256 For further details on Mr Watt's departure from the PFC and the possible impact this may have had on the PFC's heat treatment programme, paragraphs 23.244 to 23.252 below.

257 Letter from Dr Diana Walford, DHSS, to Dr Harold Gunson dated 1 July 1983 [DHF.002.5668]

258 Dr Foster - Day 41, page 145. The fact that the chimpanzees had developed Hepatitis B can be derived from the conclusion to Professor Mannucci's research - see paragraph 23.134 below.

259 Dr Foster - Day 41, pages 143-144

260 Mannucci, 'AIDS, hepatitis and haemophilia in the 1980s: memoirs from an insider', Journal of Thrombosis and Haemostasis, 2003; 1:2065-69 [LIT.001.1101] at 1103

261 Colombo et al, 'Transmission of NANBH by heat-treated factor VIII concentrate', The Lancet, 1985; 2:1-4, [LIT.001.0369] at 0371. See Dr Cuthbertson - Day 46, pages 59-61 for discussion of the failure of the chimpanzee animal model.

262 Minutes of Factor VIII Study Group, 12 January 1984 [SNB.007.4059] at 4063; See also Dr Foster - Day 41, page 146 and Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1467-68

263 UK Haemophilia Hepatitis Working Party Annual Report for 1982-83 [SNF.001.0948]; Preliminary Report, paragraphs 11.148-11.150

264 CBLA report [DHF.002.4489]

265 Dr Smith - Day 59, page 117

266 Dr Smith - Day 59, page 118

267 Dr Foster - Day 42, page 33

268 Dr Cuthbertson - Day 46, pages 58-59

269 Dr Foster's letter to Dr Smith [SNB.007.3841]

270 SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1364

271 Progress Report on Studies to Improve Yield and Quality of FVIII Concentrate, 20 December 1983 [PEN.012.1500] at 1503

272 Dr Cuthbertson's statement on viral inactivation to 1985 [PEN.013.0025] at 0036; see also Dr Foster - Day 42, page 38

273 Progress Report on Studies to Improve Yield and Quality of FVIII Concentrate, 20 December 1983 [PEN.012.1500] at 1504

274 Dr Cuthbertson's statement on viral inactivation to 1985 [PEN.012.1692] at 1693

275 Dr Cuthbertson's handwritten notes [PEN.012.1669]

276 Transcript of Dr Cuthbertson's notes [PEN.012.1673]

277 Dr Cuthbertson - Day 46, pages 65-66

278 Dr Cuthbertson - Day 46, page 67

279 Dr Smith's memorandum [SNB.007.4052]; Preliminary Report, paragraph 11.156

280 ie Factor VIII activity.

281 Dr Smith's memorandum [SNB.007.4052] at 4053

282 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1536

283 Dr Fosters's statement on viral inactivation to 1985 [PEN.012.1438] at 1468-69

284 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1562

285 Professor Ludlam's letter to Professor Cash [SNB.001.5311]

286 Professor Cash's reply to Professor Ludlam [SNB.006.4695]

287 Dr Gillon's letter to Dr Boulton [SNB.007.4127]

288 Minutes of the Haemophilia and Blood Transfusion Working Group, 14 November 1983 [SNB.001.5188]

289 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1537

290 Professor Ludlam's statement on viral inactivation to 1985 [PEN.012.1688] at 1689

291 Dr Cuthbertson's statement on viral inactivation to 1985 [PEN.013.0025]

292 Dr Foster's letter to Professor Ludlam [SNB.007.4147]

293 For similar arguments to Professor Ludlam's see Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1771

294 Minutes of Factor VIII Study Group, 12 January 1984 [SNB.007.4059]

295 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at [PEN.012.1537]

296 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1468

297 See paragraphs 23.141 to 23.142

298 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1468-69

299 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1772-73

300 Dr Cuthbertson's statement on viral inactivation to 1985 [PEN.013.0025] at 0037

301 Letter from Professor Forbes to Professor Cash dated 15 March 1984 [SNB.007.4335]

302 Letter from Dr Perry to Professor Cash dated 27 April 1984 [SNB.007.4383]; Preliminary Report, paragraph 11.174

303 Letter from Dr Smith to Dr Foster dated 22 May 1984 [SNB.007.4402] and letter from Dr Foster to Dr Smith dated 24 May 1984 [SNB.007.4403]

304 Cost estimate for the production of heat-treated Factor VIII concentrate, SNBTS, February 1984 [SGH.002.0068] at 0069

305 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1469-70. For an additional statement indicating that the PFC April 1985 goal was ambitious, see Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1563. See also Dr Cuthbertson's statement on the same topic [PEN.013.0025] at 0037 for the argument that the proposed timescale was sensible given the number of safety and quality control steps which were needed before issuing a product to patients.

306 Using the chromatographic purification process first discussed between Dr Johnson and Dr Foster on June 27 1983 at a World Federation of Haemophilia meeting in Stockholm. See paragraphs 23.130 to 23.131 above.

307 Dr Foster - Day 42, page 18; Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1463

308 Ion-exchange is a process used to separate or purify proteins where selected proteins are bound to a solid matrix and then removed.

309 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1463

310 Ibid

311 Ibid

312 Report on the activities of the Factor VIII Study Group [SNB.007.4169]

313 Preliminary Clinical Evaluation Studies report [SNB.007.4407] at 4408

314 Professor Cash's letter to Dr Perry [SNB.007.4447]. 'Named patient basis' meant that, if a clinician considered that a patient would benefit from a medication prior to it being licensed, the clinician could request access to the medication for this patient from the manufacturers - see Professor Leen, Day 33, pages 20-21

315 Dr Foster - Day 42, page 39 and Dr Smith - Day 59, page 115

316 Dr Foster's statement on viral inactivation to 1985 PEN.012.1438] at 1469

317 Dr Smith - Day 59, page 115

318 MacLeod et al, 'Pasteurisation of Factor VIII and Factor IX concentrates', Abstracts of 18th Congress of the International Society of Blood Transfusion, Munich, 22-27 July, 1984 [SNB.008.6696]

319 MacLeod et al, 'Pasteurisation of Factor VIII and Factor IX concentrates', Abstracts of 18th Congress of the International Society of Blood Transfusion, Munich, 22-27 July, 1984 [SNB.008.6696] at 6677

320 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1464

321 Cheingsong-Popov et al, 'Prevalence of antibody to human t-lymphotropic virus type iii in aids and aids-risk patients in Britain', The Lancet, 1 September 1984 [LIT.001.0417] at 0419. See Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2, at paragraphs 10.3 to 10.5

322 See Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2, at paragraph 10.15

323 The topic is discussed more fully in Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2, from paragraph 10.16

324 Dr McClelland's statement on viral inactivation to 1985 [PEN.011.0062] at 0063

325 Minutes of PFC Heads of Department meeting, 26 October 1984 [SNB.010.3479]

326 Dr Perry - Day 45, page 106

327 Dr Cuthbertson - Day 46, page 76

328 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1472

329 Dr Foster - Day 42, page 54

330 The Inquiry has been unable to discover the exact date of this meeting.

331 Note of Dr Mannucci's talk on safe treatment of haemophilia at Cardiff meeting [SNB.004.9164]

332 Note of Dr Mannucci's talk on safe treatment of haemophilia at Cardiff meeting [SNB.004.9164] at 9166

333 Levy J et al, 'Recovery and inactivation of infectious retroviruses added to Factor VIII concentrates', The Lancet, 29 September 1984:722-723 [LIT.001.0434]

334 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1473; See Dr Foster - Day 42, pages 48-52 for further discussion.

335 'Update: Acquired Immunodeficiency Syndrome (AIDS) in Persons with Hemophilia', MMWR, 1984; 33/42:589-591 [LIT.001.0460]. Results from the studies were published in a peer-reviewed journal in August 1985 - McDougal et al, 'Thermal inactivation of the acquired immunodeficiency syndrome virus, human T lymphotropic virus-III/lymphadenopathy-associated virus, with special reference to antihemophilic factor', Journal of Clinical Investigation, 1985; 76/2:875-877, [SNB.010.6169]

336 'Update: Acquired Immmunodeficiency Syndrome (AIDS) in Persons with Hemophilia', MMWR, 1984; 33/42:589-591 [LIT.001.0460] at 0461

337 Dr Foster - Day 42, page 63

338 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1472

339 Dr Foster - Day 42, page 55

340 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1473

341 Dr Foster - Day 42, page 56

342 Dr Foster - Day 42, page 59

343 Ibid

344 Dr Foster - Day 42, page 61

345 Dr Foster - Day 42, page 51

346 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1474

347 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1472

348 Dr Foster - Day 42, page 60

349 Dr Foster - Day 42, page 62

350 Dr Foster - Day 42, page 63

351 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1474

352 Dr Foster - Day 42, page 61; SNBTS Briefing Paper on the Development of Heat Treatment of Coagulation Factors [PEN.013.1309] at 1366

353 Dr Perry - Day 45, page 110

354 The Medical and Scientific Advisory Council of the US National Hemophilia Foundation

355 Lindsay Tribunal (1999). Report of the Tribunal of Inquiry into the Infection with HIV and Hepatitis C of Persons with Haemophilia and Related Matters, page 62. http://health.gov.ie/blog/publications/report-of-the-tribunal-of-inquiry-into-the-infection-with-hiv-and-hepatitis-c-of-persons-with-haemophilia-and-related-matters/ [Last accessed 21 January 2013]

356 Lindsay Tribunal (1999). Report of the Tribunal of Inquiry into the Infection with HIV and Hepatitis C of Persons with Haemophilia and Related Matters page 154. http://health.gov.ie/blog/publications/report-of-the-tribunal-of-inquiry-into-the-infection-with-hiv-and-hepatitis-c-of-persons-with-haemophilia-and-related-matters/ [Last accessed 21 January 2013]

357 Dr Perry - Day 45, pages 110-111

358 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1472

359 Professor Cash - Day 43, page 108

360 Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1927

361 Professor Cash's additional statement on viral inactivation to 1985 [PEN.012.1909] at 1910. There is no evidence that a specific request for support on this matter at that time was made to the CSA.

362 Letter from Scottish Government to Inquiry Team, 4 May 2011 [PEN.012.1731] at 1732

363 In the light of the evidence already recited, this assertion cannot be accepted as accurate or justified on any objective view.

364 Dr Perry - Day 45, page 116

365 Dr Perry - Day 45, page 117

366 Dr Duncan's letter to Professor Cash [PEN.013.0125]. For a discussion of the background to the licensing process see Professor Cash's additional statement on viral inactivation to 1985. [PEN.012.1909] and Professor Cash - Day 43, pages 111-114

367 Professor Cash - Day 43, pages 109-110

368 Dr Foster's letter to Professor Cash [SNB.007.4557]

369 Dr Foster's notes on the Groningen meeting of 1-2 November 1984 [SNB.008.6528] at 6529-30

370 Dr Foster - Day 42, pages 62-63

371 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1464

372 SNBTS Briefing Paper [PEN.013.1309] at 1345

373 SNBTS Briefing Paper [PEN.013.1309] at 1345-46

374 Minutes of PFC Heads of Department meeting, 13 November 1984 [SNB.010.3475] at 3476

375 Ibid

376 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1464. See also Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1777-78

377 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1465

378 Ibid [PEN.012.1438] at 1465

379 Letter from Mr McQuillan to Dr Boulton, dated 22 November 1984 [SNB.007.4592]

380 Minute of meeting of Haemophilia Directors and SNBTS representatives, 29 November 1984 [SNB.001.5256]

381 Minute of meeting of Haemophilia Directors and SNBTS representatives, 29 November 1984 [SNB.001.5256] at 5257

382 Dr Perry's letter to Regional Transfusion Directors [SGH.002.6506]. Shortly thereafter, the recovery and half-life data were found to be acceptable - see message from Dr Boulton to Dr Perry [SNB.007.4656]

383 Dr Perry - Day 45, pages 101-102

384 Dr Perry - Day 45, pages 103-104

385 Dr Perry - Day 45, page 102

386 Dr Cuthbertson - Day 46, pages 84-85

387 Professor Ludlam's note on long-term safety monitoring for transfusion transmitted infections [PEN.012.0351] at 0355

388 Minutes of PFC Heads of Department meeting, 7 December 1984 [SNB.010.3462] at 3463

389 DHSS note from 10 December 1984 meeting [DHF.003.0898] and Note of Haemophilia Reference Centre Directors' meeting, 10 December 1984 [SNF.001.3850]

390 Professor Ludlam's note on long term safety monitoring for transfusion transmitted infections [PEN.012.0351] at 0355

391 ie Factor VIII Inhibitor Bypass Activity.

392 Professor Ludlam - Day 44, pages 9-10

393 Professor Cash's statement on viral inactivation to 1985 [PEN.012.1912] at 1927

394 Professor Cash's letter to Haemophilia Directors [SNB.007.4685]

395 Dr Hann's letter to Professor Cash [SNB.007.4689]

396 Professor Hann - Day 21, page 59

397 Professor Hann - Day 21, page 59

398 Cuthbert et al, 'Efficacy of heat treatment of Factor VIII concentrate', Vox Sanguinis, 1988; 54:199-200 [LIT.001.0664]

399 Inquiry's schedule of questions on viral inactivation to 1985 [PEN.012.1531] at 1538-39

400 Dr Foster's statement includes a reference to a letter from Professor Cash to Mr Watt, dated 22 April 1983 [SNB.007.3625]

401 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1475-76

402 Spire et al, 'Inactivation of lymphadenopathy-associated virus by head, gamma rays and ultraviolet light', The Lancet , 1985; 1:188-189 [SNB.007.4724]

403 For these and other additional background arguments see Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1476-77

404 Dr Foster - Day 42, page 77

405 Dr Foster - Day 42, page 78

406 Dr Foster - Day 42, page 81

407 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1565-66

408 Dr Smith - Day 59, pages 137-138

409 Dr Smith - Day 59, page 139

410 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1778

411 Dr Perry - Day 45, page 115. See paragraphs 23.141 to 23.142 above. NB - the protocol used by Drs Pepper and Cuthbertson was 70°C for 72 hours and not 68°C for 24 hours as reported in Dr Perry's written statement.

412 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1778. It should be noted that Dr Perry's point regarding the precautionary principle does not accord with his description of the lack of regulatory procedures - see above at paragraph 23.181 and Dr Perry - Day 45, pages 116-117. See also Dr Perry - Day 45, pages 83-84 where Dr Perry makes the argument that today's regulatory procedures are much more stringent than those of the early 1980s.

413 Dr Perry - Day 45, page 112

414 Dr Perry - Day 45, page 114

415 Dr Cuthbertson's statement on viral inactivation to 1985 [PEN.013.0025] at 0043

416 Ibid

417 Professor van Aken's statement on the introduction of dry heat treatment of Factor VIII concentrate [PEN.012.1932]

418 Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood and plasma products, WHO Technical Report, Series No. 924, Annex 4 2004, http://www.who.int/bloodproducts/publications/WHO_TRS_924_A4.pdf. [Last accessed 23 January 2013]

419 Professor van Aken's statement on the introduction of dry heat treatment of Factor VIII concentrate [PEN.012.1932] at 1934-35

420 Ibid [PEN.012.1932] at 1935-36

421 Gallo, 'Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk of AIDS', Science, May 1984; vol. 224 [LIT.001.3769]

422 Professor van Aken's statement on the introduction of dry heat treatment of Factor VIII concentrate [PEN.012.1932] at 1935

423 Professor van Aken - Day 47, page 46

424 Professor van Aken - Day 47, page 47

425 Ibid, page 47

426 Ibid, page 51

427 Professor van Aken's statement on the introduction of dry heat treatment of Factor VIII concentrate [PEN.012.1932] at 1936

428 Professor van Aken - Day 47, pages 52-55

429 Ibid, page 55

430 It was only cell lines for HIV which were available in 1984 (ie not for HCV). Professor van Aken corrected this mistake in his oral evidence, Day 47, page 56.

431 Professor van Aken's statement on the introduction of dry heat treatment of Factor VIII concentrate [PEN.012.1932] at 1937

432 Dr Foster's memo [SNB.007.3635]

433 Professor van Aken's statement on the acceleration of the existing pasteurisation programme [PEN.012.1928]

434 Ibid [PEN.012.1928] at 1928

435 Ibid[PEN.012.1928] at 1929. Compare Dr Smith's evidence at paragraph 23.21 above of planning for the BPL at April 1981.

436 Professor van Aken's statement on the acceleration of the existing pasteurisation programme [PEN.012.1928] at 1929

437 Professor van Aken - Day 47, page 58

438 Professor van Aken - Day 47, page 59. See also Page 60 where Professor van Aken admitted that he did not know enough about the pasteurisation developments to be comfortable giving a definitive answer, and pages 60-61 where Professor van Aken indicated that the PFC did more pasteurisation research than the Dutch CLB.

439 Professor van Aken - Day 47, page 62

440 Professor Cash's letter to Dr Lane [SNB.004.3163]

441 Professor van Aken's statement on the acceleration of the existing pasteurisation programme [PEN.012.1928] at 1929-30. Professor van Aken's statement also notes that there was one blood bank in the Netherlands which had a different policy and which recommended the use of commercial heat-treated products. For further discussion of the situation in the Netherlands at this time see Professor van Aken - Day 47, pages 66-70.

442 Professor van Aken - Day 47, page 65

443 Professor van Aken - Ibid

444 Kasper et al, 'Recent evolution of clotting factor concentrates for hemophilia A and B', Transfusion, 1993; 33/5: 422-434 [SGH.002.1947] at 1954

445 SNBTS Briefing paper on the development of heat treatment of coagulation factors [PEN.013.1309] at 1323; HC Hansard, Vol 75, Col. 117, 12 March 1985 [SGF.001.0854]

446 Professor van Aken's statement on the acceleration of the existing pasteurisation programme [PEN.012.1928] at 1930

447 Ibid [PEN.012.1928] at 1930

448 [PEN.012.1928] at 1930-31

449 Dr Foster - Day 42, page 46

450 Independent Public Inquiry into Contaminated Blood and Blood Products - http://www.archercbbp.com/report.php [Last accessed 14/12/2014]

451 Dr Foster's report to the Archer Inquiry [PEN.012.1506]

452 Ibid [PEN.012.1506] at 1507

453 Dr Foster - Day 42, page 48

454 Mr Watt's letter to Professor Cash [SNB.011.1214]

455 Professor Cash's note on replacement of the Director of PFC [SNB.011.1217]

456 Dr Perry's memorandum of 30 December 1983 [SNB.009.4290]

457 See letter from Professor Cash to Mr Mutch (Secretary CSA) dated 23 May 1984 confirming that Dr Perry was Acting Director of the PFC [SNB.011.1688]

458 See the Inquiry's Schedule of Questions [PEN.012.1531] at 1535 - paragraphs 21-22

459 Professor Cash - Day 43, page 83

460 Professor Cash - Day 43, pages 83-84

461 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1467

462 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1467

463 Mr Watt's curriculum vitae [PEN.012.1491]

464 Dr Foster's statement on viral inactivation to 1985 [PEN.012.1438] at 1466

465 Dr Foster - Day 42, pages 30-31

466 Dr Perry's statement on viral inactivation to 1985 [PEN.012.1759] at 1770

467 Dr Perry - Day 45, page 61

468 Dr Perry - Day 45, pages 64 and 67

469 See Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1573 for a very brief mention of this point.

470 CBLA paper on AIDS, dated 26 July 1983 [DHF.002.4489] at 4490

471 Summary of main points from a consideration of AIDS and licensed blood products by CSM(B), 13 July 1983 [DHF.002.8865]

472 Ibid [DHF.002.8865] at 8866

473 Haemophilia Centre Directors AIDS Investigation - Surveillance of AIDS patients in patients with blood coagulation disorders; Update 10.9.83 [SNB.001.7556]

474 Jones, 'Acquired immunodeficiency syndrome, hepatitis and haemophilia', British Medical Journal, 10 December 1983; 6407:1737-38 [LIT.001.0243]

475 The Guardian, 9 December 1983 [SGF.001.0944]

476 Draft minutes of NIBSC meeting on the infectious hazards of blood products, 9 February 1984 [SNB.004.8628]

477 Cheingsong-Popov et al, 'Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain', The Lancet, 1 September 1984; 477-480 [LIT.001.0417]

478 See paragraphs 23.107 and 23.108 above

479 Dr Foster's memorandum to Mr Watt of 3 May 1983 [SNB.007.3635] referred to in paragraphs 23.109 to 23.111

480 Mr Watt's letter [SNB.007.3638] at 3640

481 Progress Report on Studies to Improve Yield and Quality of FVIII Concentrate, 20 December 1983 [PEN.012.1500]

482 CBLA report on AIDS [DHF.002.4489]

483 In the 1980s there was collaboration in virus inactivation studies of 8Y, and on the thrombogenicity of heat-treated FIX concentrates, for example, [PEN.013.1309] at 1338-39

484 Professor Cash - Day 57, page 135; See also Professor Cash's statement on viral inactivation from 1985 to 1987 [PEN.017.1085] at 1089

485 Professor Cash's statement on viral inactivation from 1985 to 1987 [PEN.017.1085] at 1091; See also Professor Cash - Day 57, page 145

486 Professor Cash - Day 57, page 138

487 Professor Cash - Day 57, page 137

488 Professor Cash - Day 57, pages 143-144

489 Dr McClelland's statement on viral inactivation from 1985 to 1987 [PEN.017.0003]

490 Dr Perry's statement on viral inactivation from 1985 to 1987 [PEN.017.1219] at 1227

491 Dr Foster's statement on viral inactivation to [PEN.017.1556] at 1568-69. Z8 was a PFC Factor VIII concentrate, heated at 80°C for 72 hours, introduced in 1987.

492 Meeting between CSA and CBLA, 20 January 1984: Background notes for Chairman [SNB.006.5138] at 5140; Dr Perry's statement on viral inactivation from 1985 to 1987 [PEN.017.1219] at 1227; Professor Cash - Day 43, page 22; Dr Cuthbertson - Day 46, pages 45-46, Dr Foster - Day 57, pages 4-5

493 Dr Foster - Day 57, pages 5-7

494 Professor Cash - Day 57, page 144

495 Professor Cash's statement on viral inactivation from 1985-87 [PEN.017.1085] at 1090; See also Professor Cash - Day 57, page 145

496 Dr Foster's statement on viral inactivation 1985-87 [PEN.017.1093] at 1106; See also Dr Foster - Day 57, page 9

497 Dr Foster - Day 57, page 10

498 Dr Smith - Day 59, pages 84-85

499 Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1560; See also Dr Smith - Day 59, page 82

500 See Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1573 for a very brief mention of this point.

501 Manufactured by Behringwerke, Marburg, Germany.

502 Dr Foster - Day 41, pages 69-70; Sometimes described as a wet process, the Factor VIII was suspended in liquid, and not dissolved: it was properly a dry process.

24. Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987 >