THE PENROSE INQUIRY
Final Report

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Chapter 24

Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987

Introduction

24.1 This chapter considers the steps undertaken at the Protein Fractionation Centre, Edinburgh (PFC) between 1985 and 1991 to inactivate virus in blood products so as to prevent transmission of non-A, non-B Hepatitis (NANB Hepatitis)/the Hepatitis C virus (HCV).

The international context

24.2 As discussed in Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985, developments in factor concentrate technology in Scotland at the end of 1984 and in 1985 were focused on an immediate response to the discovery of HIV infection in Scottish patients treated with SNBTS Factor VIII concentrate, particularly in the group of patients that came to be known as the Edinburgh Cohort. The experimental work that led to heat treatment of intermediate Factor VIII concentrate to inactivate that virus was prompted by information obtained at the Groningen Conference at the beginning of November 1984. Research and development do not, and did not, take place within hermetically sealed national boundaries.

24.3 The international context provides an important focus for discussing developments in viral inactivation in the period covered by this chapter. In Appendix 1 to Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985, early developments in commercial heat-treated products were summarised without comment on their effectiveness. For the purposes of this chapter, the effectiveness of commercial production methods to inactivate viruses, and in particular NANB Hepatitis/HCV, is relevant. It is also material to identify, so far as possible, the dates when commercial manufacturers of blood products, who tended to have greater resources for research and development than state fractionators, were able to produce Factor VIII and IX concentrates that were sufficiently virally inactivated to prevent transmission of NANB Hepatitis/HCV.

24.4 Dr Peter Foster led the necessary research in Scotland at the PFC. He gave evidence to the Inquiry that, over time, three methods of virus inactivation became accepted as being effective in inactivating NANB Hepatitis/HCV, namely (1) pasteurisation at 60°C for 10 hours, (2) solvent detergent treatment, and (3) dry heat treatment at 80°C for 72 hours (albeit pasteurisation and solvent detergent treatment have been associated with occasional transmission of virus, including Hepatitis C).^[1] The Factor VIII and IX products which were accepted as safe from the transmission of NANB Hepatitis/HCV, together with such information as was available about the licensing and availability of the products in the UK are set out in Tables 24.1 and 24.2:^[2]

Table 24.1: Factor VIII products effective in inactivating NANB Hepatitis/HCV

Table 24.2: Factor IX products effective in inactivating NANB Hepatitis/HCV

24.5 The list was based on information contained in an article by Kasper and others, published by the journal Transfusion in 1993.^[5] While Dr Foster did not know precisely when the production or supply of the products in the list took place in the UK, he considered that the dates when the products were available in this country would be close to either: (a) the earlier of the date on which a USA FDA licence or a UK licence was granted for the manufacture of the product; or (b) the date that a UK licence was granted for supply of the product in the UK.^[6]

24.6 During the Oral Hearings reference was also made to a product known as NYBC/Melville Biologics Coagulation Factor VIII-SD (a solvent-detergent product using Tri-n-butyl-phosphate and sodium chloride) which was referred to in table 5 of the 1993 Kasper paper. The product was licensed in the USA in 1985. Dr Foster said that Melville Biologics was the name of a facility operated by the New York Blood Centre which manufactured the product. He said that while it appeared in due course that the product would have been safe from Hepatitis C, it was not available in the UK.^[7]

24.7 Within the UK, the Plasma Fractionation Laboratory and the Blood Products Laboratory (PFL/BPL) were able to supply Factor VIII concentrate (8Y) to England, Wales and Northern Ireland from September 1985. Over time, the product was found to be safe from transmission of NANB Hepatitis/HCV. It can be seen from the above tables that, with the exception of the Behringwerke pasteurised product (which resulted in low product yields and was not generally available in the UK), the PFL/BPL were the first fractionators able to produce a Factor VIII product that events were to show did not transmit NANB Hepatitis/HCV (albeit, as discussed at 24.22 below, they were not able to produce sufficient product to meet the needs of all haemophilia patients in England and Wales).

24.8 In Scotland, the PFC was able to make available for clinical trial in December 1986 a Factor VIII concentrate (Z8) which, over time, was found not to transmit NANB Hepatitis/HCV. That product was available for use from April 1987. That date compares favourably with the achievements of commercial manufacturers in providing safe products, as shown in Table 24.1. In addition, unlike the position in England, PFC were able to supply a sufficient quantity of product to meet the needs of all Haemophilia A patients in Scotland.

24.9 Both the PFC and the PFL/BPL were able to supply a Factor IX concentrate (respectively, DEFIX and 9A) to meet demand from Haemophilia B patients from October 1985. These products were also found, over time, to be safe from the transmission of NANB Hepatitis/HCV. Table 24.2 indicates that a safe NHS product was available many years before commercial manufacturers supplied Factor IX concentrates that were safe from the transmission of NANB Hepatitis/HCV.

Events in England

24.10 As explained by Dr Jim Smith, Head of Research and Development at the PFL and the BPL, in 1984 the PFL was investigating, on a very small scale, the PFC's zinc/heparin precipitation process.^[8] The aim of this process was to create a purer Factor VIII product by precipitating out (removing) the proteins fibrinogen and fibronectin.^[9] There were two main reasons for seeking higher purity - firstly, to create a product which would dissolve more readily^[10] and which could be administered to patients in smaller quantities of higher potency, and, secondly, to reduce the overall volume of product to be pasteurised, thus making it more straightforward to heat.^[11]

24.11 Dr Smith said that, when carrying out an experiment into this process, a PFL technician accidentally used a far greater quantity of heparin than was specified and, surprisingly, found an unusually heavy precipitate of fibrinogen and a high Factor VIII recovery.^[12] Further research at the PFL showed that even better results could be obtained using heparin alone at much higher concentrations than had been used in the PFC's original zinc/heparin process.^[13]

24.12 This serendipitous discovery proved to be a key point in the development of 8Y and further work was carried out during 1984 to refine the steps in the process. Dr Smith explained that the heparin step allowed the PFL to:

[E]liminate a fiddly adsorption step in our current scheme and, after adding another precipitation method^[14] conveniently emerging from our front-end work at the time, a ten-fold purification over the current product was achieved.^[15]

24.13 He added:

It often takes a long time to develop formulation and drying of a new concentrate, but we were fortunate to find a simple formulation which freeze-dried using the cycle applied to the current product. This very dry concentrate could then be heated at quite high temperatures without loss of solubility and with an acceptable loss of Factor VIII.^[16]

24.14 Although the PFL had conducted experiments on both wet and dry heating in the course of 1984,^[17] the decision was taken in England, as in Scotland, to introduce immediate dry heating of the PFL/BPL's existing Factor VIII product upon hearing the news in November 1984 from the conference in Groningen that HIV could be inactivated by being dry heated to 68°C for one hour. Dr Smith explained that on his return from the meeting in Groningen, a small informal group at the PFL decided that the small, high-precision oven at the PFL would be used to heat retrospectively all batches of the current Factor VIII held in stock at the PFL and the BPL, at 70°C for 24 hours (or, if that proved unsatisfactory, 60°C for 72 hours).

24.15 The references to heating all batches of current PFL/BPL Factor VIII at 70°C for 24 hours and 60°C for 72 hours related to the existing English dry heat-treated intermediate purity products known as 8CRV (produced at the PFL) and HL (produced at the BPL), which were broadly equivalent to the PFC's intermediate purity product, NY.^[18] Batches which withstood heating at 60°C for 24 hours were known as HT1 and batches which survived heating to 70°C for 72 hours were known as HT2.^[19] Dr Smith said that HT1 and HT2 were issued for general use in January 1985.^[20] He indicated that the rationale for releasing HT1 and HT2 before 8Y was to try to protect haemophiliacs from HIV in the period up until 8Y could be released.^[21]

24.16 Dr Smith said that the BPL did not recall Factor VIII products that had already been issued in order to heat them. He stated:

[W]e did not do what some of the commercial companies did, which was to recover stocks of product from the haemophilia centre and even, I believe, from the fridges of haemophiliacs, their home treatment supply. I don't believe we ever went that far or we even went back to the transfusion centres, which distributed our material. I believe we only retroheated the stocks in our own holding rooms.^[22]

24.17 As well as deciding in November 1984 to heat the existing intermediate purity Factor VIII product at 70°C for 24 hours, a decision was also taken at the PFL to complete the scale-up of production of the new high purity 8Y Factor VIII concentrate. It was further decided to prepare batches, dry heated at 80°C for 72 hours, for clinical trials with the intention that, if successful, production of 8Y would be transferred to the BPL. This would enable sufficient quantities of the product to be produced to supersede the existing intermediate purity product, heated at a lower temperature.^[23]

24.18 Dr Smith was asked at the public hearing whether the decision in November 1984 to proceed with the high purity 8Y product that could be heated at 80°C was taken with a view to inactivating HIV or NANB Hepatitis. He said it was certainly done to put HIV kill beyond all reasonable doubt. It was hoped that the product 'could do a bit more damage to non-A non-B', but he had 'no hopes, to tell the truth, that this would deal with non-A non-B Hepatitis'.^[24]

24.19 The first pilot-scale production batch of the high purity 8Y product (80°C for 72 hours) was manufactured in November 1984. The product was rapidly scaled-up by the PFL from one litre in November 1984 to 300 litres by the end of January 1985, at which point there was sufficient material to begin clinical trials.^[25] Dr Smith's recollection was that Phase 1 clinical trials of the PFL product for safety and efficacy were carried out in March 1985, with Phase 2 clinical trials for virus safety starting in April 1985.^[26] Once the BPL had successfully produced its first batches of 8Y, trials followed with its product.^[27]

24.20 Full-scale production of 8Y commenced at the BPL in April 1985^[28] with general release of the product to Regional Transfusion Centres in England in September 1985.^[29]

24.21 Factor VIII concentrate had never before been able to be heated at such high temperatures and the ability of Dr Smith's team to do so was a considerable achievement. Research facilities at the PFL were relatively 'basic' when compared with commercial producers (or, indeed, when compared with facilities at the PFC) and Dr Smith pithily explained, there was:

[A]mazement ... that two men and a boy working in a dustbin under socialised medicine could have come up with a solution before large pharmaceutical companies.^[30]

24.22 During the Inquiry hearings, Dr Smith's attention was drawn to a letter dated 24 July 1985 from Dr Richard Lane, the Director of the BPL, to Haemophilia and Regional Transfusion Directors in England and Wales, and to a passage stating that BPL's output of 8Y at that time could only meet about one third of demand for Factor VIII.^[31] Dr Smith indicated that he did not have the information to make such a calculation.^[32] However, he agreed that there was not enough 8Y in September 1985 to meet the total demand for Factor VIII in England and Wales for treatment of all haemophilia patients if 'total demand' included potential demand from patients using commercial products.^[33]

24.23 Dr Lane's letter contained a suggestion that the 8Y heat treatment process might be effective against NANB Hepatitis, indicating that:

Clinical trials at six Haemophilia Centres are in progress to gain evidence of reduction or elimination of viral transmission, and several patients have safely passed the point at which first evidence of NANBH virus transmission would normally occur with unheated Factor VIII.^[34]

24.24 Over time, further reports became available which gave increasing reassurance that 8Y might not transmit NANB Hepatitis.

24.25 On 9 May 1986, Dr Smith presented a paper to an international symposium in Melbourne, Australia, giving interim results for 33 patients in England who had received 8Y and who had been followed up with regular liver function tests.^[35] The paper expressed a degree of optimism that the product did not transmit NANB Hepatitis, noting that:

Although these are only interim results on a limited number of batches, we think we are justified in thinking that the severe heating has been more effective in preventing transmission of NANBH than the milder heating accorded to the Hyland and Armour products in studies published last year.^[36]

24.26 The paper also advocated caution, however, by noting that:

It is too early to know whether NANBH transmission has been eliminated by severe dry heating or whether we may see transmission by only a few batches ....^[37]

24.27 On 30 September 1986, Dr Smith provided further clinical results on the routine use of 8Y and 9A in England. The results were contained in an interim report, Surveillance of previously untreated patients for possible virus transmission by BPL Factor VIII and Factor IX concentrates, 8Y and 9A, prepared for a meeting of the UK Haemophilia Centre Directors Organisation (UKHCDO) in Edinburgh on 10 October 1986.^[38] The report explained that in the spring of 1985 all Haemophilia Centre Directors in England were issued with a protocol for the detection of NANB Hepatitis, Hepatitis B and HIV in susceptible patients receiving BPL 8Y and 9A and were invited to collect data on this basis.^[39] The summary of the results Dr Smith provided was restricted to patients who had no previous history of treatment with large-pool concentrates. It indicated that: (i) none of the patients 'had any ALT or AST above 2.5 times the upper limit of the normal range'; (ii) no case of HIV seroconversion had been reported; and (iii) no evidence of infection with Hepatitis B had been seen.^[40] The report concluded:

These data, showing no clinical or laboratory events attributable to transmission of the three main blood-borne viruses, may further encourage HCDs to use 8Y and 9A in previously untreated patients.^[41]

24.28 In his written evidence to the Inquiry Dr Smith indicated that these results were reason to be, 'a little more upbeat, but not much', explaining that the data in question were criticised throughout 1986-87 and that 'using the only product "which hasn't failed yet" does not necessarily denote confidence that it is going to be 100% successful'.^[42]

24.29 Dr Smith further explained that 'the number of clean follow-ups at the end of 1986 was too small to either support or disprove the proposition that 8Y was statistically significantly safer from NANB Hepatitis transmission than commercial concentrates heated less severely'.^[43] He 'came to believe in the next few years that 8Y was probably safe, by sheer weight of good follow-ups and in particular the exposure of many batches of widely different provenance' but he considered that liver enzyme tests (ie ALT tests) were unreliable and would not have vouched for 8Y's safety 'until application of the highly specific anti-HCV test' in 1993.^[44]

24.30 Dr Foster advised the Inquiry that he was given a copy of the interim report by Dr Smith on 9 October 1986^[45] and confirmed that this was the first occasion on which he saw written data on 8Y's evaluation.^[46] However, asked when it seemed to him to be likely that 8Y was free from NANB Hepatitis, Dr Foster said he had doubts whether the data could be used to say that 8Y was 'likely' to be free from NANB Hepatitis at this time.^[47] He explained that in science one tends not to use words such as 'likely' and that products were either safe or unsafe. Dr Foster accepted, however, that safety could be measured statistically.^[48]

24.31 Dr Robert Perry was also asked when he thought that it seemed likely that 8Y was free from NANB Hepatitis. He advised that it was not until Dr Smith's report in September 1986 that 8Y's freedom from NANB Hepatitis would have been described as likely. He added the caveat, however, that 'even at this stage such a conclusion would have been regarded as cautionary and unconfirmed'.^[49]

24.32 Dr Bruce Cuthbertson also shared this view, stating in his written evidence that:

The letter from Dr Smith ... is the first evidence that I am aware of that 8Y could be potentially effective in significantly reducing the risk of NANBH .... The data available in Dr Smith's letter of September 1986 clearly showed a reduction in infectivity with NANBH, but was not yet conclusive of a lack of infectivity.^[50]

24.33 Asked to expand on his views, Dr Cuthbertson explained:

[C]learly there is a difference between the product which has a reduced risk from one which is absolutely free of evidence of infectivity. I think that's the point I was trying to get over in this text, that from the early work, it was clear that the risk of non-A non-B Hepatitis from the product was substantially less than from conventional unheated products. The infection rate with them was close to 100 per cent, whereas from the early evidence, a number of patients had not developed clinical evidence of non-A non-B Hepatitis. But to actually demonstrate freedom from infectivity is a very difficult process and takes time - or certainly took time then, when we were relying on indirect biochemical tests as a means of assessing infectivity.^[51]

24.34 On 16 September 1987 Dr Smith drew up a report for a UKHCDO AGM on 25 September 1987.^[52] The report indicated that a two-year study, which was 'stricter' than the previous study, had shown a 'near zero' incidence of NANB Hepatitis transmission by 8Y or BPL's dry-heated Factor IX product, 9A.^[53] Even at that stage, however, Dr Smith remained of the view that the effectiveness of severe dry heating in inactivating NANB Hepatitis had not been established. His report concluded:

It is not possible to determine the true incidence of transmission of NANBH by 8Y and 9A from this imperfect evidence, but the apparent near-zero incidence justifies the inclusion of a further series of patients in a more formally controlled prospective trial, to be co-ordinated by Dr Rizza and Dr Kernoff.^[54]

24.35 By 1988 further evidence was accumulating that 8Y was free from NANB Hepatitis. In particular, a paper by Dr Brian Colvin and others published in The Lancet in October 1988 reported that 32 patients who had been treated with 8Y had not developed NANB Hepatitis. The paper indicated that an additional, more rigorous, study was necessary, but noted that these data demonstrated that '80°C is highly effective in inactivating NANBH in coagulation factor concentrates'.^[55]

24.36 In 1993, once more sensitive and specific tests for HCV were available, a paper by Rizza and others reported that 27 previously untreated patients (PUPs) in England had received 24 batches of 8Y and that no evidence of infection by Hepatitis C, Hepatitis B or HIV had been found following these transfusions, thus finally confirming that 8Y was free from these viruses.^[56]

Developments in Scotland

1985

The development of a high purity Factor VIII product and pasteurisation

24.37 As indicated in Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985, (paragraphs 23.185 to 23.203) at the end of 1984 the PFC dry-heated stocks of its existing intermediate purity NY Factor VIII product at 68°C for two hours in an attempt to inactivate HIV, in response to the report from Groningen that HIV could be inactivated by dry heating at 68°C for one hour. This was regarded as an interim measure, which, in view of the extreme urgency brought about by the discovery that HIV had been transmitted by SNBTS Factor VIII concentrate, could be implemented immediately.

24.38 Production of new batches of Factor VIII by the PFC had largely been suspended between October 1984 and January 1985 to allow for improvements required by the Medicines Inspectorate to be carried out at the plant.^[57] The PFC's policy (and therefore the policy for Scotland) at the beginning of the year was intimated formally in a letter by Dr Perry to Dr Duncan Thomas, from the National Institute for Biological Standards and Control (NIBSC), dated 8 January:^[58]

• All FVIII issued from PFC had been heat-treated since mid-December 1984;
• PFC would recall all existing regional stocks of non-heat treated FVIII for heating and reissue;
• The heating conditions applicable at that date were 68°C for 2 hours in the dry state. Those conditions were the best that could be achieved with the existing product without compromising solubility, and in the knowledge that a joint CDC/Cutter study had suggested that they might provide 4-5 logs inactivation of HTLV III virus;
• Analytical specification and in vivo characteristics were identical to the unheated precursor;
• There was no significant deterioration as a result of the changes;
• Plans were well advanced for the manufacture of a new product, with a modest reformulation involving the addition of carbohydrate, which would be subjected to more extreme conditions of temperature and time.

24.39 Developments were in hand on the last point. When the PFC recommenced production on 20 January 1985, sucrose was added to all intermediate purity Factor VIII to enable heating at 68°C for 24 hours with the objective of achieving a greater margin of safety against HIV. It was correctly thought, however, that the 68°C/24 hours product was unlikely to be free from risk of transmitting NANB Hepatitis.^[59]

24.40 Despite the introduction of dry heat treatment of the existing intermediate purity Factor VIII product in an attempt to inactivate HIV, a progress report produced by Dr Foster for the meeting of the SNBTS Factor VIII Study Group in February 1985 commented that the development of a high purity product that could be pasteurised 'would seem to be still the preferred option'.^[60]

24.41 Dr Foster's progress report explained that the aim at that stage had been to apply pasteurisation to the high-purity Factor VIII product under development in collaboration with Dr Alan Johnson of New York University (NYU). PFC had been sufficiently impressed with the NYU process that in October 1984 a decision had been taken to shelve further research into the existing zinc heat-treated method (ZHT) 'so that maximum effort could be given to the newer method'.^[61]

24.42 When asked to explain the attractions of the NYU process and pasteurisation, Dr Foster said:

[T]he objective was to have a product that was safe from non-A non-B Hepatitis, and at that time pasteurisation was the front runner in terms of the knowledge that existed, in terms of what might be safe, and in order to make that process work in our production operation, I wanted to increase the degree of purification so that I could reduce the volume of pasteurisation by maybe 50- or 100-fold, and the Johnson process would allow me to do that and that's why we gave priority to that at that time.^[62]

24.43 Dr Foster explained that the NYU product was significantly more pure than the PFC's existing intermediate Factor VIII product NY, pointing out that, '[for] the NYU product, we were looking for an increased purification of the order of 100- to 200-fold'.^[63]

24.44 While expressing a preference for wet heat treatment (pasteurisation), the progress report commented that 'recent information concerning HTLV-III' had led to dry heating of the existing product. It commented that 'severe heating of the freeze dried powder may be possible (Smith, unpublished results)'.^[64] The mention of 'severe heating' in the report was a reference to the work by the PFL/BPL on 8Y discussed above. The impression given at that stage, however, was that resort to dry heat treatment of the PFC's product was a temporary measure.

24.45 Dr Ronald McIntosh, a biochemist at the PFC during the relevant period, also gave evidence to the Inquiry as to the rationale for the move, in late 1984, from developing the ZHT process to developing the NYU process. He explained that there were significant problems with the ZHT process, including: the need to add large percentages (20-40%) of carbohydrate stabilisers to allow for satisfactory Factor VIII recovery (resulting in a solution with a large volume that was very viscous and hence difficult and time-consuming to process); the precipitation step (where Factor VIII was recovered from the high concentration of stabilisers) was difficult to control; and lower yields for ZHT than the existing intermediate Factor VIII product (which would have had a negative impact on the PFC's policy of self-sufficiency).^[65]

24.46 Dr McIntosh was asked whether it would have been practical to ramp up the ZHT process to achieve full production. Dr McIntosh replied:

It would not have been feasible. The difficulties in processing such large volumes of viscous solution and also adding additional processing steps to fit into the available working schedule in production, would have made it very difficult to do.^[66]

24.47 In contrast to the problems with ZHT, the NYU process appeared more promising. Dr McIntosh indicated in his oral evidence that the NYU process 'would allow us to get the purification that was needed to aid pasteurisation, without compromising yield'.^[67] He explained in more detail the initial research carried out on the NYU process between late 1984 and the middle of 1985, indicating that various changes were made to the process with the aim of making it compatible with the requirements for Factor VIII production at PFC.^[68] These included: the addition of a zinc heparin precipitation step derived from the ZHT process to filter out unwanted fibrinogen and fibronectin; the use of an ion exchange gel different from the gel used by Dr Johnson; the substitution of calcium with other salt combinations which were physiologically more acceptable; and the development of a more stable formulation.^[69]

24.48 Although pasteurisation was, in principle, still the PFC's preferred option for viral inactivation at the start of 1985, the PFC appears to have carried out relatively little pasteurisation work in the first few months of the year. In that regard, another report for the meeting of the SNBTS Factor VIII Study Group on 7 February 1985, Update Paper on Viricidal Action Since Last Meeting One Year Ago, indicated that the PFC's work on pasteurisation was 'in abeyance' at this time.^[70] This was apparently due to the shelving of the ZHT project (see above) and because of pressure on the PFC to complete dry heat treatment of all existing intermediate purity NY Factor VIII batches (ie the interim measure to inactivate HIV introduced at the end of 1984 as an emergency response to the infection of Edinburgh patients with HIV which temporarily diverted attention from NANB Hepatitis).^[71]

24.49 The February 1985 Update Paper noted that a 'watching brief' would be kept on detergents and organic solvents as potential methods of viral inactivation. Dr Foster said that the PFC was aware of the research being carried out elsewhere into the use of solvent detergent as a method of viral inactivation.^[72] He explained, however, that this method was only effective against viruses that had 'lipid envelopes', and that given that the structure of the NANB Hepatitis virus or viruses was not clear at the time, the solvent detergent method was less obviously attractive than heat treatment. Dr Foster also noted that an additional downside to the solvent detergent method was that it involved adding and then removing toxic chemicals from the product, which at the time could not readily be applied to the PFC's manufacturing processes.

24.50 Another report for the February 1985 meeting of the Factor VIII Study Group, prepared by Professor John Cash, noted that preliminary clinical evaluation studies (bioacceptability, clinical efficacy and residual infectivity) were planned for SNBTS Factor VIII products, both pasteurised (60°C for 10 hours and an additional period at 70°C) and dry heated (68°C for 24 hours), and outlined the PFC's rationale for examining both wet and dry heat treatments. The report commented that:

The need to assess both dry and wet heat arises because the former is less costly and subject to lower yield penalties. However the wet heat is likely to be more virucidally effective.^[73]

24.51 At this time, research into the heat treatment of Factor IX was also continuing. These studies were carried out in collaboration with the BPL.^[74] Difficulties had been encountered in arranging animal model studies using dogs, which were needed to test for thrombogenicity. According to a report by Professor Cash in March 1985:

Despite considerable efforts over the last 2 years it has only very recently been possible to make arrangements for animal model (thrombogenicity) testing. These were recently begun and provided all goes well it is anticipated that a heat treated product will be available for preliminary clinical evaluation by late Spring of 1985. The product currently the candidate for heat treatment is DEFIX.^[75]

24.52 A meeting of the SNBTS and Haemophilia Directors took place on 7 March 1985.^[76] A paper drawn up for this meeting by Professor Cash summarised the position as regards heat treatment of Factor VIII by PFC. It explained that the current product was a reaction to AIDS. The period from November 1984 to March 1985 had been difficult. Professor Cash reported:

It has been a period in which disaster struck in Australia and in which both UK transfusion services were implicated in the transmission of HTLV-III viruses.^[77]

24.53 The standard routine SNBTS issue, Dry (Intermediate) HT (68°C for two hours) involved the dry heat treatment of the existing intermediate product without the addition of stabilisers.^[78] According to the paper, it was anticipated that this product would remain the standard SNBTS Factor VIII product until autumn 1985 and that preliminary clinical evaluations of the new dry-heated product (68°C for 24 hours with the addition of stabilisers) would be completed by the end of May 1985. The paper indicated that work on the high purity NYU product was 'proceeding satisfactorily' and that, 'decisions have not yet been made with regard to the heat treatment regime but at the present time wet heat treatment is favoured'.^[79]

24.54 Dr Perry also drew up a paper for this meeting, which summarised progress in heat treatment work at the PFC.^[80] Dr Perry's paper indicated that current heat-treated material (68°C/2 hrs) was available for the treatment of all haemophilia patients in Scotland and Northern Ireland and that an ongoing programme was underway to subject all existing stocks (including those recalled from Regional Transfusion Centres) to these heating conditions, with stocks anticipated to last until autumn 1985.^[81] The paper noted that clinical trials of the intermediate purity NY Factor VIII product, dry-heated at 68°C for 24 hours, should be planned and implemented so as to ensure continuity of product supply later in the year.^[82] By this date, it had been established that this product could be heated in the dry state to 68°C for 24 hours without reducing solubility. On 4 March 1985, Dr Perry had written to Dr Frank Boulton intimating that two batches of this product would be available for clinical trials within two weeks.^[83] One hundred vials of two separate batches were arranged to be sent on or around 13 March 1985.^[84] At the meeting, Dr Perry informed members that the new intermediate Factor VIII concentrate, dry-heated at 68°C for 24 hours, was ready for clinical evaluation. It was remitted to a Working Group to facilitate clinical evaluations in Scottish centres. It was also proposed that the Working Group should look into involving hospital Ethical Committees in evaluation proposals.^[85]

24.55 By late March 1985 a degree of progress had been made as regards the clinical trials mentioned in Dr Perry's paper. On 2 April 1985, Professor Cash wrote to Professor Arthur Bloom with arrangements for trials of the latest product heat-treated at 68°C for 24 hours.^[86] Professor Bloom, who had been hesitant about committing resources to the Scottish project earlier in the year,^[87] responded with proposals on 10 April 1985.^[88]

24.56 However, the plan to proceed to clinical trials of safety and efficacy in Scotland led to some disquiet among haemophilia clinicians in the absence of compensation arrangements for participants in the trial.^[89] In response to a request from Dr Boulton to test the 68°C/24 hours material, Professor Christopher Ludlam indicated in a letter dated 19 March 1985 that if compensation arrangements were not put in place he would have to seek ethical approval before continuing with the trial (Professor Ludlam's letter noted that it would take some time to gain such approval).^[90] There also appears to have been a degree of reluctance from the Glasgow Royal Infirmary in undertaking clinical trials.^[91]

24.57 The discussions in March 1985 highlight a feature of SNBTS policy in relation to the rolling out of new products reflecting technological developments. All existing stocks, heat-treated at 68°C for two hours were to be used until exhausted in the autumn. The new formulation, prepared for heating at 68°C for 24 hours, would be held unheated pending trials of the preliminary batches, and issued (after dry heat treatment) in July or August when sufficient clinical experience of the product had accumulated. The policy of exhausting existing supplies before new (and, theoretically, superior) products were released was to become a recurrent theme.

24.58 Professor Cash wrote to Professor Ludlam on 22 March 1985, expressing concern that his decision on trial of the product was likely to impact on progress, and commenting on the risk that delay could affect supplies of Factor VIII in mid-1985.^[92] Professor Ludlam replied on 4 April 1985 expanding on his position as regards compensation arrangements and indicating that he was prepared to assist once he had received the full product specification.^[93] However, the letter notes that Professor Ludlam would be, 'looking for concrete guidance from the Department' (that is, guidance from the SHHD on compensation arrangements).^[94] Dr Boulton reacted to these developments in a letter to Professor Cash dated 19 April 1985. In his letter Dr Boulton queried Professor Ludlam's version of events, but indicated that he would contact Professor Ludlam once he had full details of the product, so as to come up with a 'mutually acceptable protocol'.^[95] There appears to have been some progress thereafter. On 29 April, Professor Ludlam wrote to Professor Cash that he had sought ethical approval and was arranging for four haemophilia patients to 'come up' in the very near future.^[96]

24.59 On 15 May 1985 a meeting of the Haemophilia and Blood Transfusion Working Group took place.^[97] Dr Perry reported that the PFC continued to manufacture FVIII, including 2% sorbitol, dry-heated at 68°C for 24 hours. Preliminary clinical evaluation studies had been good, and he said that the PFC could now proceed to heat all unheated stocks of FVIII. Meantime, as noted above at paragraph 24.15, the PFL and the BPL had already proceeded with production and release for general use of HT1 and HT2 in January 1985. At the Edinburgh meeting of the British Society for Haemostasis and Thrombosis on 26 March 1985 progress with the BPL's product prepared by heating freeze-dried concentrate at 60°C for 72 hours was reported, together with information on the outcome of trials.^[98] Prospective studies on three surgical patients had shown no evidence of transmission of NANB Hepatitis. Development work proceeded at PFL on 8Y. From December 1984, the PFL had scaled up 8Y for clinical trail for safety and efficacy. Trials were conducted satisfactorily in February 1985 by which time 8Y had become the sole Factor VIII product manufactured at the PFL. Haemophilia Directors were informed in March 1985 that 8Y was available for clinical trial. The BPL followed through with manufacture of 8Y in May 1985.^[99] The English Factor VIII development programme was now clearly ahead of Scottish work on dry heat treatment of FVIII.

24.60 On 15 May, there was further discussion of heat treatment of Factor IX. It had been reported in February that dog studies of thrombogenicity had been instructed.^[100] The minutes of 15 May disclose that Dr Perry informed the meeting that:

[T]he heat treatment of Factor IX was a high priority project and that dog tests were underway at Cambridge. PFC expected initial clinical evaluation studies to begin in 2/3 months' time. Dr Cash was pleased to inform members that the first results received from Cambridge looked promising and tests had shown no trace of DIC in the heat treated product.^[101]

24.61 However, progress had not been sufficient to satisfy demand for Factor IX. In May 1985, when the SNBTS stopped supplying its unheated Factor IX, Haemophilia Directors purchased heated commercial Factor IX from the USA.^[102]

24.62 On 4 July 1985, results from Professor Bloom, added to results from Edinburgh, indicated excellent validation of the biological efficacy of the PFC's 'latest batch' of heat-treated Factor VIII.^[103] The product would have been dry-heated for 24 hours at 68°C (the 'second generation' Factor VIII^[104]) in May 1985, if it was the same as the Edinburgh test material.

24.63 On 15 July 1985 Dr Perry sent a letter to Dr Lane, Director of BPL, which indicated that both the PFC and the BPL were involved in the clinical evaluation of their respective heat-treated Factor VIII products and noted that, as regards PFC's 68°C/24 hours product, the PFC was 'primarily concerned with half-life and recovery since it is unlikely that we will achieve freedom from NANB'.^[105] The letter also included a copy of the PFC's heating protocol with the explanation that:

[S]ince we anticipate future trials of a product subjected to more substantial conditions of viral inactivation, I believe it would be helpful if we exchanged our respective trial protocols with a view to achieving commonality wherever possible.^[106]

24.64 Over the summer of 1985, further research continued. It was not expected that Factor VIII heated at 68°C for 24 hours would clear the product of NANB Hepatitis. New equipment had been ordered to achieve higher temperatures in the production process. The first heat treatment cabinet commissioned for the purpose was received and commissioned by the SNBTS in July 1985.^[107] It was used thereafter for the dry heat treatment of Factor VIII concentrate at 68°C and Factor IX concentrate at 80°C. This equipment made it possible to proceed to more effective heat treatment.

24.65 On 16 August 1985, at a meeting of the PFC Heads of Department/Section Managers, Dr Perry reported that heat-treated Factor IX product, DEFIX (dry heat treated at 80°C for 72 hours) 'had now been issued for routine use at Edinburgh Centre and further issues would be made to remaining centres in September/October 1985'.^[108] On 26 August 1985, he wrote to the Scottish Transfusion Directors and NIBTS Director intimating that the PFC had almost exhausted their stocks of the original heat-treated product (68°C for two hours) and that the 'new' product would be issued within the next two months.^[109]

24.66 On 4 September 1985 the PFC commenced routine issue of its intermediate purity NY Factor VIII, dry heated at 68°C for 24 hours.^[110] The 68°C/2 hours product continued to be released until 13 September 1985 after which it was recalled.^[111]

24.67 By October 1985, the PFC's heated Factor IX product (HT DEFIX), dry heat-treated at 80°C for 72 hours, was routinely distributed to all centres.^[112] Existing stocks of unheated Factor IX were subsequently recalled and destroyed.^[113]

24.68 Over the second half of 1985, there were several technological developments at the PFC. Where necessary these will be described in some detail. In addition to the need for new ovens, they included new equipment for purification, specified in October 1985, and delivered by Pharmacia, the manufacturer, in mid-1986;^[114] and the development of innovative freeze-drying procedures and associated equipment arising from study of the BPL's production methods for 8Y.^[115] The implementation of developments in scientific research required sophisticated hardware.

24.69 The lead time from discovery to full production was unavoidably long in some cases. In this, as other areas of research and development, laboratory scale experiments with small quantities of material might provide proof of principle, but scaling up to routine production of hundreds of litres of material safe for therapeutic application in patients required proof of practicability and effectiveness at each successive stage in the production process. And the equipment required for novel manufacturing processes often had to be custom-designed and made.

Dr McIntosh's discovery

24.70 By October 1985 there was sufficient volume of the NYU high purity Factor VIII product being developed by the PFC for work to progress to freeze-drying experiments.^[116] Initial experiments were carried out on the high purity product using the established process for freeze-drying the PFC's intermediate purity NY Factor VIII.^[117] However, this freeze-drying process led to the destruction of the high purity NYU product.^[118] Dr McIntosh explained that freeze-drying using the standard production cycle 'completely failed' and that 'the primary drying conditions were much too warm, so the product literally boiled instead of sublimation occurring'.^[119]

24.71 As a result of this failure, the PFC was forced to design a new freeze-drying process from first principles in order to freeze-dry the high purity NYU product.^[120] The key features of the re-designed freeze-drying process were: (i) a much lower primary drying temperature and a longer primary drying phase and (ii) a defined time and temperature in the secondary drying phase (as opposed to removing product when it was judged that it had dried sufficiently^[121] under the existing 'pressure hold test').^[122]

24.72 On 21 October 1985, Dr McIntosh conducted a freeze-drying and heat treatment experiment based on this new process on a sample of high purity NYU Factor VIII prepared in the PFC's research laboratory.^[123] A sample from a standard vial of intermediate purity Factor VIII was also included as an experimental control.^[124] Although the high purity product tolerated the new freeze-drying process, it failed to withstand dry heat treatment at 80°C.^[125] In contrast, the intermediate purity product was found to have withstood both the freeze-drying process and dry heat treatment at 80°C.^[126] Dr Foster included a description of the experiment in a memo to Dr McIntosh dated 22 October 1985.^[127] This memo did not mention the experimental control,^[128] but indicated that the heated NYU high purity product 'looked overheated', did not re-dissolve properly and had no Factor VIII activity. A list of possible areas to research was set out.^[129] Dr Foster explained that the result of the experiment was 'very surprising' as he had 'expected the high purity product to be able to withstand dry heating at 80 and even to be able to withstand heating beyond 80'.^[130] There had been no expectation that the intermediate purity product would be able to withstand heating to that temperature. The expectation until that point was that increased purity was the key to heating at higher temperatures.

24.73 In the following weeks, the PFC conducted further investigations into the reasons for the unexpected result of the experiment and the possibilities regarding dry heat treatment. The initial experiment was repeated;^[131] and on 11 November 1985 Dr Foster drew up handwritten laboratory notes detailing further dry heat treatment experiments (80°C/72 hours) involving the PFC's existing intermediate purity Factor VIII (referred to by its product code NY 776) and the high purity product (product code NYU 195), and took photographs of the results.^[132] On 21 November 1985, Dr McIntosh carried out an experiment to examine the feasibility of dry heating intermediate Factor VIII at high temperatures (ie the ZHT product purified using zinc/heparin precipitation).^[133] Notes of these experiments were made on an existing method sheet for the ZHT product, with the elements related to the pasteurisation step deleted by hand.^[134] When asked during the Inquiry hearings to explain what this experiment involved Dr McIntosh said:

[T]his is one of the early experiments ... taking the - as I call, front end of the ZHT process and not carrying on into pasteurisation but freeze-drying that material, preparing that material for freeze-drying in such a way that it could be terminally dry heat-treated.^[135]

24.74 Dr McIntosh confirmed in oral evidence that these experiments were the first laboratory scale experiments on the product that would, in due course, become known as Z8.^[136]

24.75 Meanwhile, on 13 November 1985 Dr Foster wrote to Dr Smith at the BPL enclosing some recent PFC publications. He also said:

One question I've been meaning to ask you; what are the freeze drying conditions for your new FVIII concentrate (especially during primary drying). We have some preliminary data that suggests that drying conditions may be particularly critical for the subsequent sensitivity of both protein and virus components to heating (not unexpected).^[137]

24.76 Dr Foster said that this question about the freeze-drying procedure for 8Y, which was known to tolerate dry heat treatment at 80°C/72 hours, arose from Dr McIntosh's discovery in the laboratory scale experiment that intermediate purity Factor VIII tolerated dry heat treatment at 80°C/72 hours.^[138] This discovery led Dr Foster to consider that the freeze-drying process might be important in relation to the ability of Factor VIII to tolerate dry heat treatment.^[139] Although Dr McIntosh's discovery was surprising at the time, Dr Foster indicated during the Inquiry hearings that once he had had the opportunity to consider it further he came to the conclusion that, on reflection, it was not entirely surprising that the freeze-drying procedure might influence the subsequent heat treatment step given that it was not unusual in fractionation for the success of a manufacturing step to be influenced by a preceding step or steps.^[140]

24.77 Dr Smith responded to Dr Foster in a letter of 11 December 1985 which included details of the freeze-drying conditions at the BPL for 8Y.^[141] Dr Foster said that the information supplied by Dr Smith 'confirmed that the new freeze drying cycle devised at the PFC was similar in design to that being used to freeze dry 8Y, consistent with this being the key aspect of the 8Y process, rather than the degree of purification'.^[142]

Change of direction

24.78 By late 1985 work at the PFC had progressed far enough that it was possible to re-assess the various options regarding heat treating Factor VIII. In particular, on 18 December 1985 Dr Foster sent a memorandum entitled FVIII Progress and Options to Dr Perry. The memorandum explained that it was 'a brief summary of where we are at with the NYU [high purity] FVIII project and the various options that are available to us to achieve a product heated at 80°C for 72 hours'.^[143]

24.79 The NYU project was summarised first and it was explained that the latest attempt at heating the product on 17 December 1985 had given a negative result (the speculative suggestion was that this was due to a problem with the product's 'ionic strength').^[144] Three options for the NYU project were set out:^[145]

• Option 1.1. Heat material at high ionic strength but with lysine added to provide extra stabilisation.
• Option 1.2. Reduce the ionic strength to a subcritical level (with or without lysine).
• Option 1.3. Recover the whole FVIII molecule instead of FVIIIC. It was noted that this would entail a loss of purity of 25%-50% and that it would be an 'ideological' step backwards.

24.80 The memorandum also set out three options for the development of PFC's existing intermediate purity NY Factor VIII product.^[146] These options were:

• Option 2.1. Heating the existing product at 80°C for three days, which apparently could be achieved by using a more conservative freeze-drying regime.^[147]
• Option 2.2. Purifying the existing product a little further so that the solution could be concentrated by ultra-filtration so as to reduce fill volume and hence the freeze-drying time (this could apparently be achieved by zinc precipitation of cryoprecipitate).
• Option 2.3 Copying the BPL method. It was noted, however, that, 'a fair amount of work would be needed to finish this project off and it is not an attractive proposition for transfer to production'.^[148]

24.81 The memorandum indicated that, 'unfortunately all of these options compete for resources, particularly FVIII assays, still the rate limiting factor',^[149] and concluded with the recommendation to:

[G]ive options 1.1 and 1.2 top priority but to continue on 1.3 and 2.2 so that we can either change tack on the NYU project if progress is slow or produce a modification of our existing product if pressure on heat inactivation demands it.^[150]

24.82 Dr Foster was asked during the Inquiry hearings whether his preference at the time was to continue to give priority to the NYU high purity project, but to have option 2.2 (further purification of the intermediate product) as a back-up plan. He confirmed that this was the case and explained that, in his view, pasteurisation was still his preference for the high purity product as there 'was more evidence to support it in terms of achieving a safe product'.^[151] In addition, however, a high purity product would also be compatible with alternative viral inactivation techniques such as dry heat treatment or solvent detergent.^[152] He added:

[O]ne of the factors in my thinking at this time was the knowledge that the haemophilia directors were very keen on having higher purity products and they were concerned about the possibility that there might be some immune disturbance in patients as a result of the lower purity products. So that was an added aspect to consider with this higher purity material.^[153]

24.83 Dr Foster indicated that the statement, 'if pressure on heat inactivation demands it', was a reference to work carried out by Dr Alfred Prince in the USA which had questioned the effectiveness of dry heat treatment against HIV^[154] and pointed out that for the PFC this was a potential concern, explaining that, 'looking back now, we kind of see non-A non-B as equal or even perhaps of more concern but at this point in time it was HIV that was driving everyone's thinking'.^[155]

24.84 The question of which option or options to proceed with was discussed at a meeting between Drs Foster, McIntosh, Perry and Cuthbertson on 23 December 1985.^[156] Other than a brief diary entry by Dr Foster on this date, which simply refers to 'FVIII meeting', there was no formal record of the meeting.^[157]

24.85 During the Inquiry hearings, Drs Foster, McIntosh, Perry and Cuthbertson were each asked for their recollections of this important meeting.^[158] All indicated that the purpose of the meeting was to discuss Dr Foster's memo of 18 December and the two main heat treatment options - ie continuing with the high purity NYU process or moving to severe dry heat treatment of the PFC's intermediate Factor VIII product.^[159] There appears to have been a degree of urgency in holding this meeting as it was scheduled immediately before the Christmas holidays when the PFC would not have been in production (a non-urgent meeting would normally have been left until the New Year).^[160]

24.86 Dr Foster explained that his view before the meeting had been that the PFC should continue to prioritise the high purity NYU process, whilst exploring alternatives.^[161] In contrast, Dr McIntosh was of the opinion that the PFC should pursue severe dry heat treatment (80°C/72hours) of the PFC's intermediate purity NY product (purified a little further) on the grounds that: (i) laboratory experiments had shown that the product could be freeze-dried and heated at high temperatures; and (ii) dry heating would be more straightforward than pasteurisation (both in terms of equipment and staffing) and could be fitted into the PFC's current manufacturing and staffing processes more easily.^[162] Dr Cuthbertson shared Dr McIntosh's view for similar reasons, but also on the basis that dry heat treatment would take place in the final sealed container which would reduce the risk of cross-contamination.^[163] Dr Cuthbertson also indicated that 8Y's apparent success in England was another factor in favour of dry heat treatment.^[164] For his part, Dr Perry went into the meeting with an open mind. While dry heat treatment was likely to be the simpler route, he was conscious of the 'presentational issue' that early commercial dry-heated products, heated at lower temperatures, had not turned out to be safe. The dry heat treatment process had the potential to be discredited due to previous failures.^[165]

24.87 At the end of the meeting a decision was made to recommend the prioritisation of the severe dry heat treatment of PFC's intermediate purity product.^[166] Dr McIntosh was to lead the development of the project and Dr Perry would inform Professor Cash, as head of the SNBTS, of the group's recommendation.^[167]

24.88 In his written evidence to the Inquiry, Dr Foster summarised the reasons for the PFC changing its Factor VIII strategy as follows:

• a pre-publication report from the USA [the Prince report noted above] which found HIV to be more resistant to dry heat treatment than earlier experiments had indicated ... leading to uncertainty over the margin of safety being provided by the current SNBTS dry heat treated Factor VIII concentrate,
• a problem of instability that had been identified on the scale-up of SNBTS high purity NYU Factor VIII product, which required to be solved,^[168]
• difficulty in dry heating high purity Factor VIII product at 80°C,
• recognition that the sophisticated equipment required for the production of high purity Factor VIII could not be obtained quickly^[169] and that its operation would require revised staffing arrangements, the establishment of which was uncertain,^[170]
• that full scale production of 8Y had been achieved successfully at the BPL,
• that the 8Y produced at the BPL had been found to be satisfactory in terms of clinical efficacy and tolerability.^[171]

1986

Research on Z8 prioritised

24.89 Although it appears to have been understood that Dr Perry and Professor Cash would meet in early 1986 to discuss the proposed new heat treatment strategy, the Inquiry has been unable to find any record of such a meeting and neither witness could recall such a meeting having taken place.^[172] Despite that, in their evidence to the Inquiry, both Dr Perry and Professor Cash were of the view that such a meeting must have taken place some time at the start of 1986. Professor Cash indicated that the PFC would have required to discuss its proposed change of strategy with him as he was the 'ultimate decision maker' for the SNBTS.^[173] Although there is a degree of uncertainty as to exactly when and how Professor Cash approved the proposed change of direction at the PFC, it seems highly likely that at some point in early 1986 Professor Cash must have approved the new strategy to develop an intermediate purity Factor VIII product that could be severely dry- heated.

24.90 Dr Perry drew up a report for a meeting of the Haemophilia Directors in March 1986.^[174] The report, dated 10 January 1986, mentioned the BPL's 8Y product, indicating that, 'preliminary clinical data indicates that this material is non-infective with respect to HTLV III, NANB and Hepatitis B'.^[175] The report referred to the PFC's NYU high purity product and noted that, '[A] programme of in-vitro characterisation and animal studies has been initiated and it is likely that the product will be ready for Phase I clinical studies in April 1986'.^[176]

24.91 No mention was made in Dr Perry's report, however, of the decision made at the meeting on 23 December to prioritise the development of an intermediate purity Factor VIII product that could be severely dry-heated.

24.92 When asked during the public hearings why the report did not mention that important change in strategy, Dr Perry suggested that the report may have been drawn up before he had had a chance to speak to Professor Cash, or that Professor Cash may have been away in January of 1986.^[177] He considered it equally possible that the report was drafted in late 1985, before the meeting on 23 December had taken place.^[178] Dr Perry further explained that the reference in his report to the high purity NYU product being ready for Phase I clinical trials in April 1986 was 'perhaps an over-optimistic statement' and that, in any event, any trials would have been of a pilot production scale product rather than a full production scale product.^[179]

24.93 It appears likely that Dr Perry was correct in speculating that his report was drafted before the meeting on 23 December 1985 and, because of the Christmas break, was not typed up until 10 January 1986.^[180] In any event, the outcome of the meeting on 23 December was reflected in an addendum produced by Dr Perry to his report.^[181] While the addendum is undated, it appears to have been sent to Professor Cash on either 25 January 1986 or 18 February 1986.^[182] The addendum indicated that research had shown that the PFC's intermediate purity product could tolerate severe heat treatment and that:

This information will enable a non-infective product to be achieved using intermediate-purity material without compromising the development of the very high purity product ....^[183]

24.94 Various advantages of the new strategy were mentioned in the addendum including that it would allow: (i) non-infective product to be introduced more quickly and (ii) the high purity product to be properly assessed and phased in without undue haste (the implication being that work on the high purity product had not been completely abandoned).^[184] It was also noted that it was likely that the intermediate dry heated product, 'will be available for evaluation in April 1986'.^[185] When asked about this projection, Dr Perry said that it could have only been in relation to a product 'somewhere between laboratory and pilot scale manufacture' and that he must have written the addendum relatively early in 1986 as 'if [he] had been writing it in March' then his April estimate 'would have been wildly off course'.^[186] Dr Foster also commented on the issue of the April 1986 evaluation date in his written statement to the Inquiry.^[187] He advised that he had suggested this date to Dr Perry, but that it was incorrect because he had assumed that pilot scale material would be used for clinical trials as this had been the approach previously taken with the pasteurised ZHT product. However, in the event, trials were not carried out until full-scale production Z8 was available.^[188] In addition, various unexpected problems occurred in the development and production of Z8 (as discussed at paragraph 24.125 below).^[189]

24.95 Although it is unclear when exactly a final management decision was taken to prioritise the severe dry heat treatment of the PFC's intermediate purity product, it is clear that the PFC continued research, led by Dr McIntosh, into this process at the start of 1986. The Inquiry recovered handwritten notes of experiments undertaken by him during January and February 1986.^[190] A significant development was the introduction of ultra-filtration (in substitution for size-exclusion chromatography) in formulating the supernatant from the zinc-precipitated material to become a finished product.^[191] The development of full scale ultra-filtration equipment for manufacturing purposes and the sequencing of production processes had occupied time and resources in 1985.^[192] Freeze-drying equipment and procedures also presented difficulties.^[193]

24.96 From February 1986 the change of direction at the PFC began to be recorded in contemporaneous documents. In his notes for the March 1986 meeting of the Haemophilia Directors and Transfusion Directors, for example, which were drawn up in February 1986, Professor Cash indicated that difficulties had arisen as regards the heat treatment of the high purity product and that:

As a consequence it is anticipated that there will be some delay in it reaching phase 1 (recovery and ½ [life]) studies. Accordingly, a decision has been taken to introduce an interim solution: a product which is only 2-3 times purer than the existing intermediate VIII but which can be dry heated at 80°C for 72 hours.^[194]

24.97 While this document is further evidence that work on the high purity product had not been abandoned completely, Dr Foster said that at this time Dr McIntosh was focusing almost entirely on severe dry heat treatment, rather than high purity work.^[195] Dr Cuthbertson echoed this point. He said that the high purity process had been put 'on the backburner' and that even if there had been a desire to develop the high purity project rapidly there was insufficient assay capacity in his testing laboratory to focus on two research and development projects simultaneously in addition to routine testing of manufactured products for quality control.^[196]

24.98 During this period, contact with the PFL in England continued and, on 26 February 1986, Dr Smith wrote to Dr Duncan Pepper with details on what he described as 'the last significant stage of 8Y' as well as his thoughts on 'very fast freezing'.^[197] Freeze-drying was also discussed during a meeting of the SNBTS Coagulation Factor Study Group on 27 February 1986 in which mention was made by Dr Perry of plans for 'improved freezing' and improved freeze-drying of the intermediate purity product which was to be heated at 80°C for 72 hours.^[198]

24.99 At the meeting of Haemophilia Directors and SNBTS Directors on 5 March 1986, the switch to developing severe heat treatment of the intermediate purity product was discussed with the Haemophilia Directors.^[199] It was at this stage, following a memorandum sent by Dr Foster to Dr Perry and Dr McIntosh dated 5 March 1986 that 'Z8' was selected as the name for the product (intended to be heated at 80°C for 72 hours).^[200] Dr Foster had become concerned that the multiplicity of PFC Factor VIII products under consideration might cause confusion outside the PFC. He listed two ZHT products heated at 68°C, the 80°C product that was named Z8, and a fourth 'PFC, NYU FVIII', the high purity product on the ZHT base, which he proposed should be named 'REAL 8'.

Spring 1986 - work on Z8 continues

24.100 Further work relating to the development of Z8 continued throughout the spring of 1986. A meeting took place at the PFC between individuals from the BPL and the SNBTS on 17 March 1986 at which the two organisations exchanged information about progress in research and development and agreed further collaboration.^[201] Discussion was summarised by Dr Perry in a note dated 24 March 1986.^[202] During this meeting virus inactivation studies were discussed and it was agreed that the BPL would send samples of 8Y to the PFC, which had more specialist facilities, to carry out studies into levels of virus inactivation.^[203] At the meeting Dr Smith outlined clinical trial results for 8Y. It was noted by Dr Perry that:

While results cannot be considered conclusive at this stage ... no cases of virus infection have occurred (attributable to 8Y material) after 12 months experience of 8Y in virgin haemophiliacs.^[204]

24.101 At the Inquiry's public hearings Dr Smith said that by March 1986 there was evidence that heating Factor VIII at 80°C instead of 60°C was beneficial as regards HIV.^[205] However, as regards NANB Hepatitis he said that he considered that Dr Perry's summary of the March meeting relating to the perceived safety of 8Y was based probably on a very brief review of the facts and that it was too optimistic.^[206] Dr Smith accepted that, logically, the preliminary results reported gave what he called 'a slightly larger margin of safety'. However he stressed that he was not of the view at the time that this could be viewed as significant statistically or that there was a 'high probability of the product being safe'.^[207] While initial results from its use suggested that 8Y had a greater margin of safety in respect of the transmission of NANB Hepatitis, Dr Smith was of the opinion that there was insufficient evidence of freedom from infection in 1986 to enable any robust scientific conclusions to be made.^[208]

24.102 Dr Foster was asked about his knowledge of the clinical results for 8Y at this period.^[209] He said that he was aware of the general view that the clinical trial of 8Y was proceeding well,^[210] but that he was not specifically kept up to date with the emerging clinical data available from the routine use of 8Y. He would have expected Dr Smith to inform him of any bad news, and the lack of any such news was reason for cautious optimism.^[211]

24.103 At the BPL/SNBTS meeting on 17 March 1986 mentioned above, there was also discussion of the likelihood that freeze-drying conditions might affect the efficacy of heat treatment.^[212] On 24 March 1986 Dr Foster received further details of the freeze-drying cycles for BPL's Factor VIII and Factor IX products as requested.^[213]

24.104 Between March and May 1986 work on developing Z8 continued. Dr McIntosh indicated that during this period the PFC was involved in 'further work on freeze-drying and on the formulation of the ultra-filtered material'.^[214] The scale-up of the ultra-filtration stage in preparation for Z8 manufacture was a large part of this work and would have involved familiarising staff with new ultra-filtration equipment.^[215] On 25 April 1986, the first virus inactivation experiments were performed on samples of Z8 produced in the research laboratory and dry-heated at 80°C.^[216]

24.105 Steps were also underway at the PFC to carry out virus inactivation experiments on 8Y on behalf of the BPL. On 9 May 1986, for example, Dr Cuthbertson sent Dr Lane of the BPL an outline of the protocol (using model viruses) which the PFC intended to use in evaluating virus kill in 8Y.^[217]

24.106 In May 1986, Drs Cuthbertson, McIntosh and Foster of the PFC presented a paper at an international conference in Sydney, Australia. A summary of the paper emphasised the importance of freeze-drying for successful heat treatment, noting that:

During heating in the freeze dried state we have noted that the stability of FVIII and FIX concentrates is influenced profoundly by changes to freeze drying conditions and product formulation. Unfortunately these parameters have been omitted from publications concerning virus inactivation, making it impossible to properly interpret results and their relevance to manufacturing procedures.^[218]

Pilot-scale production of Z8 and plans for clinical trials

24.107 On 23 June 1986 the first pilot scale production of Z8 (80°C for 72 hours) was carried out at the PFC using around 200 litres of plasma.^[219]

24.108 At this time, efforts were also under way in relation to setting up clinical trials and planning for the introduction of new heat-treated products as they became available. On 27 June 1986 Dr Boulton wrote to Professor Cash indicating that:

I have again spoken to Christopher Ludlam who continues to assert his willingness to participate in studies of new factor VIII materials for patients, both virgin and multi-transfused.

Apparently a few weeks ago he was asking Brian McClelland if VIIIY^[220] could be made available in the event of a 'virgin' haemophiliac being presented. He tells me that he would be happy to treat such patients with a product prepared by the SNBTS that has been subjected to an 'equivalent' heat-treatment regime.^[221]

24.109 Professor Cash responded to Dr Boulton's letter on 1 July 1986, explaining that:

You may be under some misunderstanding with regard to the type of studies we require. I can best emphasise the point by stating that we have already agreed that until such times as we have a product which is to be the definitive product for at least 5 years we won't consider further the awesome task of a NANB study on virgin haemophiliacs. In the meantime we will require to consider ½ life and in vivo recovery studies (on small numbers of non-virgin patients) ....^[222]

24.110 On 2 July 1986, Dr Perry wrote to Dr Boulton intimating that the PFC was poised to launch another Factor VIII product, heated at 80°C for 72 hours (Z8), which, he said, 'should therefore be comparable to 8Y' and better than anything available commercially. The comment was clearly intended to respond to Dr Boulton's letter dated 27 June (paragraph 24.108). Dr Perry suggested that virgin haemophilia patients might have access to this product before the stocks of existing products were exhausted, though that had not been formally agreed.^[223] Dr Boulton was prompted to ask about PFC's plans, and a telephone conversation ensued.

24.111 On 4 July 1986 Dr Boulton wrote to Dr Perry enclosing notes of the projected production sequence as he understood it from the telephone conversation between them.^[224] Dr Perry responded to Dr Boulton's letter on 7 July 1986, adjusting some of the detail recorded.^[225] Full scale production of Z8 was expected to begin in September 1986. Half life and recovery studies on 'non virgin' haemophilia patients would be required between September and December 1986. It was planned to begin production of the PFC's high purity NYU product (which Dr Foster proposed to name 'REAL 8') in January 1987 with supply in September 1987 after stocks of Z8 had been used up. On this projection there would be no PFC product virucidally comparable to the BPL's 8Y until September 1986. Dr Perry intended to supply Z8 for 'virgin' patients from September 1986, removing the need to 'go south' for such patients. In the immediate future, until September 1986, he thought that they could probably get supplies of 8Y for special cases, and expressed the view that it would be preferable to obtain and supply English material through the PFC. At this stage production of Z8 was still seen as an interim measure with the development of a high purity Factor VIII product continuing as the eventual aim.

24.112 On 28 July 1986 production of the second pilot scale preparation of Z8 was carried out.^[226]

24.113 On 30 July 1986 a meeting of a steering group, 'New FVIII Product Manufacture', took place which decided that no further 'old-style FVIII' (ie the 68°C/24 hours product) would be made for the time being and noted that a large-scale production run of the new Z8 product had been approved to take place on 4 August 1986.^[227] The cessation of 68°C/24 hours production and the date for the first large-scale run of Z8 were both a little earlier than Dr Perry had forecast in his discussion with Dr Boulton.

24.114 Dr Perry said that the routine manufacture of NYFVIII (68°C/24hr) was discontinued in July 1986 to allow the the PFC to focus its development and manufacturing resources on the final development stages of Z8 with a view to building up working stocks of Z8 for distribution through the batch dedication system. At this point it was estimated that sufficient stocks of NYFVIII were available to meet planned requirements until the spring of 1987, which was therefore the estimated date for the transition from NYFVIII to Z8.^[228]

24.115 In his briefing paper on the development of heat treatment, Dr Foster stated that:

By July 1986, progress in the pilot studies was encouraging and there were good stocks of existing 68°/24-hour heat-treated Factor VIII concentrate available. It was therefore decided to cease production of the existing product to release production staff and facilities in order to fast track the development of Z8 at large scale. Preparation of the first production trial batch of Z8 was begun in August 1986.^[229]

24.116 Dr Perry explained that PFC's production strategy was based on a phased development plan involving the progressive development and introduction of heated products, without interruption of supply. The strategy required that the PFC should continue to routinely manufacture NYFVIII (68°C/24hr) until the Z8 product had been developed, validated at scale, transferred to routine production, and safe working stocks established.^[230]

24.117 Dr Perry further explained the rationale behind the switch to Z8 production in the summer of 1986 indicating that, 'we had a high level of confidence that we were on the right track. We had a very high level of expectation that the development would be successful within the sort of timescales that we had established'.^[231]

24.118 At the Inquiry hearings these comments were echoed by Dr McIntosh who said that, 'production of the previous product, NY [heated at 68°C for 24 hours], had been suspended or halted, to give us full access to production, and a decision was made to prepare material [ie Z8] at as large a scale as possible but for experimental purposes'.^[232]

24.119 In mid-1986, therefore, the SNBTS's priority project was the production of Z8, considered to be 'virucidally equivalent' to the BPL's 8Y, as an interim solution to the transmission of virus infection, retaining the longer term objective of developing a superior pasteurised product. It was implicit in the development process that trials would be required of successive products, at least for half-life and in vivo recovery. Apart from the difficulties inherent in the development and production of effective products, there was growing resistance from haemophilia clinicians to exposing their patients to trials without adequate insurance against adverse reactions. It is important to set Scottish experience at this time in a wider context.

24.120 In June 1986, the World Hemophilia Federation Conference was held in Milan. Dr Smith attended and produced notes. A copy was available in Scotland.^[233] Reports of the discussions of a range of products underlined doubt about their effectiveness. Armour's product Factorate, issued before January 1986, was withdrawn in July 1986. Other heat-treated products such as Travenol (60°C for 72 hours) and Cutter (68°C for 72 hours) were not withdrawn, but were gradually replaced in the period after 1 January 1987. It seems likely that this development was prompted primarily by the search for a form of viral inactivation effective against the risk of transmission of NANB Hepatitis, although general misgivings about the effectiveness against the risk of transmission of HIV of dry heat treatments at temperatures in the region of 60°C may have contributed to the development.

24.121 Pasteurised products began to appear. Alpha Profilate was a heat-treated, wet method product, heated at 60°C for 20 hours. Armour were licensed in the USA to market Haemate P, the pasteurised heat-treated Factor VIII developed by Behringwerke. Cutter was licensed to manufacture Koate HS, a heat-treated pasteurised product. The wider, worldwide, market appeared to have been moving towards pasteurised products at this time, though further change was imminent. On 21 July 1986, Immuno distributed a circular intimating that dry-heated products had been discontinued: all products would be subject to steam treatment for the future, and that included FEIBA. This was a period of considerable uncertainty worldwide. Developments in Scotland have to be seen in that light. Retaining the option of pasteurisation while prioritising dry heat treatment was not out of line with international developments.

24.122 As approved on 30 July (paragraph 24.113), the first large-scale production run of PFC Z8 took place on 4 August 1986.^[234] On 7 August 1986 satisfactory viral inactivation studies were carried out comparing the effects of heating Z8 at 75°C and 80°C on model viruses.^[235] On the same day Dr Perry wrote to Dr Boulton indicating that two batches of Z8 (the pilot-scale batches, prepared in June and July 1986)^[236] had been successfully manufactured and noting that, 'assuming all is well on the QA front, we are well on target to make product available for clinical trial end of August/beginning of September'.^[237] He said that discussions could start with Professor Ludlam regarding clinical trials of Z8. In the event, as noted below at paragraph 24.131, early production batches could not stand heating at 80°C and were heated at 75°C until January 1987 and released for use.^[238] Around this time Dr Smith passed to Dr Foster a memo outlining changes to the freeze-drying regime for 8Y.^[239]

24.123 On 20 August 1986 a meeting of the CSA Blood Transfusion Service Sub-Committee took place at which the issue of 'compensation of volunteers' was discussed.^[240] The minutes of the meeting noted that the National Medical Director (Professor Cash) had had 'a useful dialogue with the Legal Adviser concerning arrangements for the compensation of volunteers and agreed that the General Manager [of the CSA] should now pursue the bringing forward of firm proposals'.^[241]

24.124 On 22 August Dr Boulton wrote to Dr Perry enquiring as to the availability of the Z8 product and wondering how to approach Professor Ludlam to conduct in vivo half-life and survival studies.^[242]

An eleventh-hour problem

24.125 Dr Perry responded to Dr Boulton's letter on 29 August 1986, explaining that:

While we now have material which can be used for trial (beginning September) in Dr Ludlam's patients, I am not, at this stage, convinced that it has a proper GMP [Good Manufacturing Practice] pedigree or that it represents our definitive process. We have recently encountered an eleventh hour problem with freeze-drying which we are now addressing with some considerable urgency. The result of this is that we will not be able to meet the target dates of early September for clinical trials.^[243]

24.126 In his briefing paper Dr Foster explained that the 'eleventh hour problem' resulted from the switch from pilot-scale production to full-scale production. While only a small number of vials of Z8 had been produced in each pilot batch, the number of vials produced by full-scale production completely filled the freeze-dryer. That affected the conditions in the freeze-dryer with the result that a significant number of vials failed to withstand 80°C dry heating.^[244]

24.127 It was observed that vials with frozen plugs of a uniform, fine crystal structure could withstand dry heating to 80°C, whereas those with larger crystals or a mixture of fine and large crystals did not withstand heating to that temperature.^[245] Dr Foster explained that as differences in crystal structure are determined by the rate of freezing it was postulated that the uniform formation of fine crystals in the vials which had survived heating might be the result of 'super-cooling', a condition at which the vial contents remain liquid below the freezing point of the solution. In this situation a small disturbance in the fluid is sufficient to cause instantaneous crystal formation resulting in fine crystals.^[246]

24.128 On 25 September 1986 Dr McIntosh carried out further experiments using a production-scale dryer in order to investigate the super-cooling hypothesis, following which he concluded that super-cooling had, indeed, occurred.^[247] Efforts then followed to develop a freeze-drying cycle which, in the words of Dr McIntosh, 'would induce supercooling ... in a reproducible way and in a uniform way across the batch'.^[248] This was reported in a meeting of the PFC Development Review Group of 15 October 1986 where it was noted that the Z8 process 'requires further developments in formulation and freeze drying to enable heating at 80°C/72hr to be achieved reproducibly'.^[249]

24.129 On 14 October 1986 a further meeting of the SNBTS Coagulation Factor Study Group took place. The minutes of the meeting included an update on Z8 and a summary of steps taken in respect of its 'Introduction to Routine Production'.^[250] The summary explained that heating to 80°C/72 hours of various lots of Factor VIII in a full-scale, large-production dryer had resulted in losses of Factor VIII activity ranging from 30% to 70%. It was noted that:

Failure at full scale production was due to varying performance of the freeze drier and a change in product composition .... In an effort to overcome these problems work was continuing in the following areas:

1. Modifications to procedure to improve extraction.

2. Establishment of freeze drying parameters to cope with 'worst case scenario.'

3. Reduction of weight of cryo/L plasma to 1984 levels.^[251]

24.130 Dr Foster reviewed the Z8 studies undertaken, including the efforts made to overcome the difficulties with the performance of the freeze dryer. Heating at 75°C for 72 hours was reported. It was thought that there were difficulties in the production and issue of a product heated to 75°C/72 hours and it was agreed that Professor Cash would write to Dr Boulton seeking the co-operation of the Haemophilia Directors in undertaking a small study of recovery and half-life of this product.^[252]

24.131 In the light of this meeting, Professor Cash indicated to Dr Perry in a letter dated 15 October 1986 that it was appropriate for the PFC to commence production of a 75°C/72 hours dry-heated product, while continuing to work on the development of an 80°C/72 hours product.^[253] According to Dr McIntosh, the decision to try to release a product heated to 75°C first was due to the fact that the PFC had not yet been able to develop a product with a crystalline structure which could tolerate heating at 80°C.^[254] Given this, the PFC was of the view that heating to 75°C (which was achievable) would be a suitable interim solution and was an improvement on the existing 68°C/24 hours dry-heated Factor VIII.^[255]

24.132 On 13 November 1986 Professor Cash wrote to Dr Boulton explaining the plan to commence production of 'a new factor VIII concentrate which will be called Z8' and which 'will be dry heat treated at 75°C for 72 hours'.^[256] The letter asked Dr Boulton to 'liaise with Chris Ludlam, Charles Forbes and Elizabeth Mayne with a view to obtaining t/2 and % recovery data on the product'.^[257] This was followed by a letter from Dr Cuthbertson to Dr Boulton on 26 November 1986 enclosing a copy of the draft specification for Z8.^[258] On 1 December 1986 Dr Perry noted, during a Clinical Trial Review meeting, that the 75°C/72 hours product was now available for half-life and recovery studies in Edinburgh, Glasgow and Northern Ireland and that Dr Boulton was coordinating this study.^[259] On 1 December Dr Boulton wrote to Dr Perry, acknowledging receipt of Professor Cash's letter and the Z8 specification; and explaining that he wished to supply Professor Forbes in Glasgow directly with the product rather than following the usual course of sending the product via Law BTS.^[260] On 12 December 1986 Dr Crawford of the Glasgow and West of Scotland Blood Transfusion Service (Law Hospital) wrote to Dr Perry expressing a degree of disquiet as regards the possible direct transfer and asking Dr Perry to contact Dr John Davidson (Glasgow Royal Infirmary, haematology laboratory)^[261] with a note of any Z8 supplied to Professor Forbes.^[262] Dr Perry passed on this message to Dr Boulton in a letter dated 23 December 1987 and asked Dr Boulton to contact Dr Davidson 'with a note of that material which will be issued to Charles Forbes ... when you know how much to send to Dr Forbes'.^[263]

24.133 According to PFC records, the first clinical grade batch of the 75°C/72 hours product was 'placed at issue' (ie certified as fit for clinical use)^[264] on 2 December 1986,^[265] the batch in question having been manufactured in October 1986 and then having undergone standard quality control procedures.

24.134 Towards the end of 1986 research was continuing at the PFC into improving freeze-drying techniques. On 16 December 1986 Dr Foster wrote to Dr Smith indicating that the PFC had been involved in 'intensive work on freezing and freeze drying over the last 3 months' and that two problems had arisen when scaling up the Z8 process, namely: (i) the large production dryer performed differently to the small production and pilot dryers; and (ii) variations in final product total protein had arisen which had led to major batch-to-batch differences in solubility.^[266] There were also substantial differences within batches when product was heated to 80°C. The letter explained that the PFC believed that they had now overcome all of these problems by means of a special freezing technique and by designing the freeze-drying cycle more carefully. The technological solution, which involved super-cooling to ensure an amorphous crystalline structure, was a so-called '2-stage freezing process'.^[267]

24.135 On 8 December 1986, Dr Smith sent Dr Foster, on a confidential basis, a paper on the effects of plasma conditioning on subsequent cryoprecipitation and cryoextraction.^[268] He explained that the 8Y process reflected know-how not yet 'sewn up' by patent. The studies based on information from empirical observations by Scottish scientists now had a measure of analytical support and theoretical underpinning. Dr Foster said as much in a reply dated 16 December 1986.^[269]

24.136 By the end of December 1986 the 75°C/72 hours product was released to Dr Boulton for distribution to centres participating in the clinical trial. On 22 December Dr Perry sent a memorandum to Dr Cuthbertson headed 'Z8 for clinical trial', in which he asked Dr Cuthbertson to 'send 200 vials of the selected batch to Dr Boulton who will subsequently distribute it to participating Centres'.^[270] Twenty units of the product were issued on 22 December 1986, and a further 180 units were released on 24 December.^[271]

24.137 At a meeting of the Z8 steering group on 22 December 1986 it was noted that 'all batches manufactured in 1986 will be heated at 75°C/72 hours with 20 vials from each batch being heated at 80°C/72 hours'.^[272] At this point, the two-stage freezing process had also been used successfully to manufacture certain batches of Z8 at 80°C/72 hours. There was a partial release for clinical trial of a batch of 80°C/72 hours product, manufactured in December 1986,^[273] in February 1987.^[274]

Compensation for clinical trials

24.138 On 5 December 1986 Dr Boulton wrote to Professor Cash noting that he had received the specifications of Z8 and had discussed the situation with Professor Ludlam who 'still has some reservations'. Professor Ludlam was concerned about patients who suffered as a result of being infused with the trial material and Dr Boulton felt he would be unwilling to agree to trials without a specific commitment by the SHHD to compensate them.^[275] This was followed by a letter from Professor Ludlam to Professor Cash on 11 December 1986 which indicated that Professor Ludlam had 'obtained ethical approval to undertake recovery and survival studies in haemophiliacs' but was 'awaiting an appropriate commitment from either the PFC, the SHHD or the DHSS concerning the question of indemnity'.^[276] The letter also commented that Professor Ludlam had 'raised this a long time ago with the SHHD and there [had] been no response' and that there was 'great disquiet' about this issue among colleagues at other Haemophilia Centres.^[277] On 30 December 1986 Professor Cash telephoned Dr Archibald McIntyre of the SHHD and followed this up with a letter in which he stated that he would very much appreciate a formal response from the SHHD that patients receiving coagulation factor concentrates as part of a trial would receive compensation in the same way as 'blood donors who undergo immunisation/boosting for the procurement of anti-Rh (D) immune plasma'.^[278]

1987

24.139 The issue of compensation for clinical trials of Z8 continued into 1987. On 5 January Professor Ludlam wrote to Professor Cash explaining that he was 'unwilling to test further blood products on patients' until he received 'written assurance that appropriate compensation will be available'.^[279] The letter further noted that the SHHD had known of Professor Ludlam's concerns since 1983; that 'in such a serious matter more than verbal assurances are essential'; and that Professor Ludlam would be delighted to resume testing once he received 'written assurance from an appropriate authority'.

24.140 On 7 January 1987, Professor Cash sent a copy of Professor Ludlam's letter to Dr McIntyre of the SHHD.^[280] He also responded to Professor Ludlam directly, assuring Professor Ludlam of his 'fullest support on this matter', but emphasising that since existing Factor VIII (68°C/24 hours) would become exhausted 'some time in February 1987' it would be helpful for Professor Ludlam to respond to the following questions:

Given written (SHHD) assurance that appropriate compensation will be available to patients/relatives in the context of clinical assessment of Z8:

(a) Would you be prepared to use your best efforts to undertake recovery and t/2 life studies as quickly as possible, bearing in mind the PFC supply position?

(b If Z8 proved to have acceptable recovery/t/2 life and there were no untoward (clinical) effects in the patients studied in (a) above would you be prepared to use Z8 immediately thereafter for routine clinical purposes?

(c) If time runs out on us (i.e. we can't complete the Z8 in vivo recovery/t/2 studies before PFC stocks of factor VIII are exhausted) is it your intention to ask the Lothian Health Board to purchase product or would you prefer us to start up (if possible) the old intermediate (NY) factor VIII process again and thus maintain a no change position?^[281]

24.141 On the same date, Professor Cash wrote to the Scottish Haemophilia Centre Directors enclosing a copy of Professor Ludlam's letter of 5 January 1987 and his response and asked them whether they were of the same view as Professor Ludlam.^[282]

24.142 Professor Ludlam responded to Professor Cash's letter on 9 January 1987 explaining that given written assurance from the SHHD as regards compensation he 'would be happy to organise immediately the appropriate infusion studies' but that if Z8 was initially released on a 'named patient basis' he would require that the SHHD 'extends its indemnity until a product licence is obtained'.^[283] Professor Ludlam also indicated that if there was a delay in releasing Z8 before PFC stocks of Factor VIII ran out he would favour a return to 'the old intermediate (NY) factor VIII'.^[284]

24.143 Meanwhile, an internal SHHD minute from Mr Alexander Murray dated 12 January 1987 explained that stocks of the existing Factor VIII product (NY) would shortly be exhausted, that a new Factor VIII product (Z8) had been developed but that the Haemophilia Directors had refused to carry out clinical trials on the new product unless suitable compensation arrangements were in place in respect of patients who suffered harm from the product.^[285] Mr Murray explained that the DHSS faced a similar problem with the English Haemophilia Directors in respect of heat-treated Factor VIII produced by BPL. Mr Murray had alerted the Treasury (who would require to fund or agree to SHHD funding any compensation scheme) of the difficulties and to the fact that the SHHD would be making an approach to them. There then followed correspondence on the question of clinical trials between the SHHD, the DHSS and the Treasury.^[286]

24.144 On 13 January 1987, Drs Bruce Bennett and Audrey Dawson (Haemophilia Directors, Aberdeen Royal Infirmary) replied to Professor Cash's letter of 7 January indicating that they shared Professor Ludlam's view that the SHHD should give written assurance on compensation before the Z8 trial began.^[287] Similarly, on 15 January 1987 Dr Heppleston phoned Professor Cash to indicate that the Haemophilia Directors in Dundee would also require SHHD assurance in respect of compensation.^[288] Professor Ian Hann of the Royal Hospital for Sick Children (Yorkhill, Glasgow) responded to Professor Cash on 19 January 1987 noting that he agreed with Professor Ludlam that 'as usual the administrative process here has dragged on for too long' and that he believed strongly that children should not be used in the trials, 'especially as I do not know what Z8 is'.^[289]

24.145 Professor Ludlam's letter of 9 January appeared to have given Professor Cash some confidence as to the timeframe for the introduction of Z8 and on 13 January 1987 Professor Cash advised Professor Ludlam that:

Right now, assuming SHHD deliver the necessary assurances, we'll keep your team in reserve to test the 80°C/72 hours material which will very soon be with us. In the meantime Charles Forbes has agreed to look at the 75°C/72 hours product.

All being well we should just slip past the rocks I felt some days ago we were destined to founder on.^[290]

24.146 By letter dated 5 February 1987 the Treasury confirmed to the DHSS and the SHHD that it agreed that arrangements for compensation along the lines of the Association of the British Pharmaceutical Industry (ABPI) procedures could apply to clinical trials of heat-treated Factor VIII product.^[291] Mr Murray advised Professor Cash of that by letter dated 6 February 1987.^[292]

24.147 On 11 February 1987 Professor Cash responded to Mr Murray's letter indicating that he was 'delighted with the news', but also noting that Mr Murray:

[M]ight also wish to consult with Duncan McNiven^[293] [sic] as he will be aware of the particular point made by the haemophilia Directors, with regard to their perceived need for cover during the period a product is being made available for patient treatment on a named patient basis.^[294]

24.148 The mention of the Haemophilia Directors in Professor Cash's letter appears to relate to a meeting of the SNBTS and Haemophilia Directors which took place on 9 February 1987. According to the minutes of this meeting, Mr Duncan Macniven of the SHHD informed the meeting that:

The Department had consulted with Treasury, and ... a scheme similar to that already in force for the production of Anti-D would operate in the new factor VIII trials. Any claims would be considered by a 3 man panel and the ABPI guidelines^[295] would apply.^[296]

24.149 However, it was also pointed out that, 'the new agreement would only apply to the initial trials of the new factor VIII' and not to its 'administration for therapeutic purposes'.^[297] The minutes of the meeting also included a report from the SNBTS which noted that:

Plans are now well advanced for the introduction of a new factor VIII which is of higher purity and higher yielding. Further batches manufactured since January 1987 have been dry heated at 80°C for 72 hours to inactivate virus ... Dr Ludlam wished success to PFC's efforts to make a purer product still, and he and Dr Forbes agreed to accept the new product for trial.^[298]

24.150 According to Professor Ludlam's recollection, the minutes of this meeting (in particular the exclusion of compensation for therapeutic use) were not a correct record of the agreement which had been reached with the SHHD that cover would be granted from the first test infusion of a new Factor VIII product until the granting of a product licence.^[299] In order to clarify this point, on 23 February 1987 Professor Ludlam wrote to Mr Murray querying what Mr Murray meant by 'clinical trial' and asking whether the SHHD interpreted this as meaning the period between the first test injection and the issuing of a full product licence.^[300] On 26 February 1987 Dr Forrester minuted Mr Murray advising that:

I believe the answer to Dr Ludlam has to be that the Department is not yet in a position to follow the ABPI guidelines beyond the stage of where the injections begin to be given for treatment and not purely for reasons of testing. Furthermore, I understand that a full product licence may never be obtained from CSM, a body which is in any case not able to grant a licence at all. I told Dr Ludlam informally recently of my doubts whether the full product licence procedure would ever go into action.

I understand today from Dr Perry that trials have already begun in any case.^[301]

Commencement of clinical trials

24.151 Although Professor Ludlam still had queries about the precise scope of the compensation arrangements, clinical trials of Z8 were commenced in late February/early March 1987. These clinical trials, being Phase I trials, were to test the clotting and other properties of the product and could be completed in a few patients over a relatively short period. Phase II trials, which investigated whether the product was safe from the transmission of viruses, including NANB Hepatitis, would require to study use of the product by more patients over a far longer period.^[302] It appears that it was initially intended that Phase I trials of Z8 would take place in Northern Ireland, Glasgow and Edinburgh. The Inquiry has, however, been unable to find any record of trials having taken place in Northern Ireland and there is no record of Z8 having been supplied to Northern Ireland for this purpose.^[303] Although the evidence is not conclusive, it seems likely that clinical trials of Z8 took place in Glasgow in late February 1987. That is a reasonable inference from: (i) the Minutes of a Meeting of the Heads of Department/Section Managers of the PFC held on 17 February 1987 which refers to 'the Glasgow Centre [having] received 75°C product for trial';^[304] (ii) a handwritten note dated 25 February 1987 from Dr Christopher Prowse of the Royal Infirmary of Edinburgh (RIE) to Dr Perry stating, as regards 'the Z8-80 trial material', that 'I understand Glasgow have done 2 or 3 infusions successfully (from Dr Forbes). Your best contact there may be Dr Gordon Lowe';^[305] and (iii) a letter from Dr Perry to Professor Lowe of the Glasgow Royal Infirmary dated 30 March 1987 which appears to suggest that Professor Lowe had carried out infusions of Z8. The letter stated:

I understand that you have now infused this material into patients and that these infusions were uneventful.

I would be most grateful if you could provide me with a summary of this 'trial' (T½, recovery etc) so that I am in a position to release this new product for general use.^[306]

24.152 Dr Perry said that he was unable to find a reply to this request, the date(s) when the trial took place or the results of any trial.^[307] The Inquiry has been unable to unearth any further details of the clinical trial of Z8 in Glasgow, including whether product for the trial was sent to Glasgow directly from the PFC or via Dr Boulton at the Edinburgh Regional Transfusion Centre.^[308] Dr Boulton said that he was 'unable to recall anything about the reported issue of any "Z8" from the Edinburgh and SE Scotland Transfusion Centre to any Scottish Haemophilia Centre'.^[309]

24.153 Clinical trials of Z8 took place in Edinburgh in February and March 1987. In his handwritten note dated 25 February 1987 to Dr Perry, Dr Prowse enclosed data on haemophilia patients infused with the 'Z8-80 trial material' and pointed out that Dr Susan Howe (RIE) could answer any queries on 'clinical monitoring sheets'.^[310] Dr Howe subsequently wrote to Dr Perry on 31 March 1987 enclosing the latest data on 'haemophiliacs infused with Z8-80 trial material' and indicated that 'no further infusions are planned until Dr C Ludlam returns from holiday in three weeks time', (ie at the end of April).^[311]

Z8 released for use

24.154 By the end of March the issue of the precise scope of compensation for clinical trials of Z8 remained unresolved. On 12 March 1987 Professor Ludlam wrote to Dr John Forrester of the SHHD referring to the draft minutes of the SNBTS/Haemophilia Directors Meeting of 9 February 1987, reiterating his view that the compensation envisaged should apply to 'all clinical trial infusions' and asking Dr Forrester to clarify this matter 'as it will be difficult to use the material therapeutically without this undertaking'.^[312] On 25 March 1987 Dr Forrester circulated a minute within the SHHD, Compensation Arrangements for Participants in Trials of PFC Products.^[313] The memorandum indicated that Dr Forrester had met Professor Ludlam on 24 March and explained that the SHHD's position remained that participants who receive Factor VIII for 'reasons of treatment as well as trial' would not be covered by the compensation arrangements.

24.155 At this point, the issue of the phasing out of the existing 68°C/24 hours product and the introduction of Z8 into the PFC's batch dedication system came to the fore.^[314] A report drawn up by Dr Perry for the SNBTS's Supply and Demand meeting on 7 April 1987 noted that:

[T]here exists the need to phase out old product and phase in the new Z8. The following proposal is presented for consideration.

(a) Batch dedication is maintained.

(b) Residual NY and Z8 (75°/72 hrs) stocks are fed into the batch dedication system as normal.

(c) An additional lane(s) is created at each RTC of Z8 (80°/72 hr) to make available material for special patient cohorts (eg virgins, elective surgery, mild haemophiliacs) prior to consumption of existing stocks of old material.

This will ensure equity of new product distribution whilst at the same time recognising the needs of special patient groups.^[315]

24.156 In other words, it was intended that there would be a phased introduction of Z8. Existing stocks of the 68°C/24 hours product (NY) would be exhausted under the PFC's standard batch dedication system before a switch to Z8 was made. It was also recognised, however, that certain patients (eg previously untreated patients) should receive Z8 at an earlier date.^[316] Dr Perry's report noted that 'at present rates of demand it is estimated that Z8 will become available for all patients by July 1987'.^[317]

24.157 Around this time (April 1987), Phase I trials of Z8 had been successful and it was concluded that the product could be released for clinical use. In particular, on 10 April 1987 Professor Cash wrote to Dr Perry explaining that 'Dr Cuthbertson and I have reviewed the raw data from the Edinburgh patients and I am satisfied that PFC may now move to issue Z8 for routine clinical use'.^[318] During the Inquiry hearings Dr Perry indicated that it was likely that Dr Boulton would have presented a report to Professor Cash on the studies and that Professor Cash, in his role as SNBTS National Medical Advisor, would have considered this report and authorised the release of Z8.^[319] Professor Cash's letter was followed on 15 April 1987 by the release to Glasgow of 830 units of the 75°C/72 hours Z8 product for clinical use.^[320] On 22 May 1987, 368 units of the 80°C/72 hours Z8 product were released to Glasgow.^[321] The last issue of the existing 68°C/24 hours (NY) product was made on 13 May 1987.^[322]

24.158 The gradual introduction of Z8, in terms of the batch dedication scheme, followed in the period May-July 1987.

24.159 Although reference was made to Z8 being released for 'routine' use, given that no product licence or clinical trial certificate had been issued, it appears that Z8 was prescribed to patients on the basis of the 'named patient' exemption in the Medicines Act 1968 (which applied to medicinal products 'specially prepared' for a doctor 'for administration to a particular patient').^[323]

Compensation arrangements extended

24.160 The issue of compensation for trials of Z8 continued to be discussed. The minutes of a meeting of the SNBTS Directors on 10 June 1987 record that 'in Mr Murray's absence Dr Forrester explained that the SHHD had extended the Treasury Compensation Scheme to Z8' and that 'Miss Corrie and the CSA Secretary were working together on draft proposals for revision of the current compensation scheme'.^[324] The minutes also noted that 'Dr Forrester recommended that the agency should get the ABPI guidelines extended to cover all SNBTS products for all trials involving volunteers of any product given for non-therapeutic reasons'. On 10 June 1987 Mr Murray, SHHD, wrote a letter to Mr Donald (the General Manager of the CSA) indicating that the Treasury had granted approval for a compensation scheme for Factor VIII trials in line with ABPI guidelines. The letter stated:

The Department has sought Treasury approval to appropriate arrangements for compensation in the event of injury during clinical trials of Factor VIII. We sought cover for those haemophilia patients participating in clinical trials to ascertain the quality and efficacy of new batches of Factor VIII which have been subjected to the improved heat-treatment process.

Treasury approval has now been received to a compensation scheme adhering to the guidelines recommended by the Association of the British Pharmaceutical Industries.^[325]

24.161 Professor Ludlam remained dissatisfied, however, that the compensation scheme was limited to use of the product during clinical trials and did not extend to its use in the period after trials had been concluded and before a product licence was obtained. On 11 June 1987 he wrote to Dr Forrester reiterating that he did not view the draft minutes of the meeting of Haemophilia/SNBTS Directors on 9 February 1987 as a correct record of the meeting and that he was of the view that Mr Macniven had given an undertaking that all infusions of Factor VIII would be covered by the compensation scheme.^[326] Professor Ludlam also wrote to Dr Boulton on 11 June indicating that he had been led to believe that the issue of Z8 to patients had begun and expressed concern that that had taken place without 'a Product Licence from the CSM' or a 'Clinical Trials Exemption Certificate'.^[327] Professor Ludlam's letter indicated that it was unclear 'who is responsible for any adverse side effects' and emphasised that in his view the minutes of the meeting of Haemophilia/SNBTS Directors on 9 February 1987 were incorrect and that the SHHD compensation arrangements should apply to all test infusions to assess clinical efficacy (ie Phase II trials) and not just half-life tests (ie Phase I trials).^[328] The letter described the decision to introduce Z8 as a 'fait accompli' and Professor Ludlam indicated that he was forced 'either to accept the situation ... or to go over to the purchase of commercial factor VIII'.^[329]

24.162 In a letter of 25 June 1987 Professor Cash advised Professor Ludlam that he was in no doubt that the minutes of the meeting of Haemophilia/SNBTS Directors on 9 February 1987 were correct and that the SHHD's compensation scheme only included cover for half-life studies.^[330] He also indicated that the reason for introducing Z8 was due to the shortage of the PFC's current 68°C/24 hours product, which was the result of 'the long delay in establishing the t/2 studies' and that Professor Ludlam's mention of giving patients the option of using commercial products was 'opening a Pandora's box'.^[331] The letter closed by stating that, 'we're taking every possible step to expedite the licensing of Z8'.

24.163 Professor Ludlam responded to Professor Cash's letter on 30 June 1987, outlining in more depth (albeit in a conciliatory manner) his concerns as regards compensation and the introduction of Z8 and stating that, 'as Z8 is under clinical trial I must reserve the right to use another product if the patient refuses to accept the trial material, but I need not make this explicit'.^[332] Professor Cash responded to this letter on 13 July 1987 suggesting that he and Professor Ludlam meet to discuss the various issues.^[333]

24.164 In the meantime, on 6 July 1987 Professor Ludlam wrote to the Medical Defence Union^[334] and a contact (Dr Leonard) at the relevant Ethics Committee^[335] outlining his (Professor Ludlam's) understanding that (i) the current issue of Z8 could be considered as a Phase II clinical trial to assess clinical efficacy; (ii) there was no clinical trial certificate; and (iii) that current SHHD compensation policy would not cover patients who experienced a severe reaction. Dr Leonard responded on 8 July 1986 indicating that Professor Ludlam should convey to the SHHD his misgivings about the use of Z8 when it 'has not received the appropriate ABPI cover'.^[336]

24.165 Shortly thereafter, the compensation arrangements were extended, as Professor Ludlam had wished, to cover the continued prescription of Z8 beyond the Phase I trial. On 8 July 1987, Professor Cash wrote to Mr Macniven noting that 'there is now a need for ... the creation of a new concept ... - compensation for products undergoing trials when the product is being given for therapeutic purposes (Type II)'.^[337] On 9 November 1987, following further correspondence between the various parties,^[338] Mr Macniven responded to Professor Cash explaining that the SHHD had reassessed its position and had concluded that the existing compensation arrangement should now also apply to therapeutic trials.^[339] Professor Cash passed on Mr Macniven's news to Professor Ludlam who replied on 19 November indicating that he was 'delighted' that the SHHD had agreed to extend compensation to cover therapeutic trials of Factor VIII.^[340] Although further discussion followed regarding the technicalities of the compensation scheme,^[341] by November 1987 the underlying issue of compensation for the continued use of Z8 (and, indeed, other products manufactured by SNBTS) had finally been resolved.

1988 to 1991

Evidence of viral inactivation in Factor VIII concentrates heated to 80°C for 72 hours

24.166 Although Z8, heated to 80°C for 72 hours, had been introduced from the middle of 1987 there was still work to be done in order to confirm the effectiveness of viral inactivation.

24.167 A formal Phase II clinical trial for Z8 in 'virgin' patients was set up in 1988.^[342] Professor Ludlam explained that the trial was:

[A] national study to monitor patients who received Z8 for the first time under the protocol laid down by the ISTH,^[343] which was a very rigorous protocol - fortnightly blood samples for, I think, the first 16 weeks and then monthly for two months, looking at ALT levels.^[344]

24.168 In 1989 Mrs Winkelman and others published on the method of manufacture of the BPL's 8Y Factor VIII (dry-heated at 80°C for 72 hours).^[345] The key step in the new manufacturing process was said to be the use of heparin at temperatures above ambient to precipitate fibrinogen and fibronectin. Good results were reported.^[346] In 1989 a paper by Pasi and others was published reporting that the BPL Factor VIII product 8Y appeared to have prevented transmission of HCV and HIV.^[347]

24.169 By November 1989 when Professor Ludlam provided his expert opinion to support the SNBTS's application for a product licence variation for Z8 he was able to report that:

Factor VIII Z8 has been the concentrate treatment of first choice for my patients since its introduction into routine use in 1987. This is consistent with the view of the UK Haemophilia Reference Centre Directors report ... which recognises FVIII products which have been dry heat-treated at 80°C for 72 hours as being amongst the safest available products with regards to the risk of virus transmission.^[348]

24.170 At this stage, publication was often some years after work was done. The paper by Mrs Winkelman and others referred to at paragraph 24.168 above, published in 1989, reflected work done three to four years earlier. Similarly, commercial products approved and marketed around 1989 were often the result of research and Phase I and II trials carried out several years earlier.

24.171 The results of the Scottish and Northern Irish Phase II study were not published until 1993. The paper contained the following summary:

To assess the viral safety of the Scottish National Blood Transfusion Service (SNBTS) intermediate purity Factor VIII and IX concentrates, the liver function and viral status were assessed prospectively in 13 recipients. None developed hepatitis or seroconverted to HIV or HCV. This study provides additional evidence for the efficacy of dry heat treatment at 80°C for 72 h in preventing virus transmission by coagulation factor concentrates.^[349]

Regulatory framework for viral safety

24.172 In the UK, the regulatory framework for ensuring viral safety was about to change. The first meeting of the Advisory Committee on the Virological Safety of Blood (the ACVSB) was held on 4 April 1989.^[350] The ACVSB was expected to have a role in relation to regulation: the EC Directives on blood products could have a major impact on the UK. Products that had until this time been made under Crown privilege would have to be licensed. Blood would have to be harvested from donors selected according to the Directives and certain tests for virological conditions might be mandatory. It would also have regard to NANB Hepatitis, in respect of which it was recorded that the issue of surrogate or direct testing for NANB Hepatitis was of some urgency. The activities of the ACVSB and the Advisory Committee on Transfusion-Transmitted Diseases (ACTTD) are examined elsewhere in relation to a number of topics of interest to the Inquiry and, in particular, surrogate testing and later HCV screening.

24.173 At the second meeting of the ACVSB on 22 May 1989 the UKBTS/NIBSC Guidelines (Draft March 1989), Part 5, dealt with viral inactivation, and set out a specification for the validation of virus inactivation procedures to be used during the manufacture of clotting factor concentrates.^[351]

Development of a higher purity product (S8) and clinicians' concerns about Z8

24.174 Through this time SNBTS continued with research and development work for a high purity product, now designated S8. The 'S8 Group' met on 28 February 1989.^[352] The date of the first full clinical trial production run was confirmed as 3 April 1989. However, a number of research and development issues remained to be resolved. A draft specification for the new product was prepared^[353] and circulated with the notes of the S8 Group meeting held on 10 May 1989.^[354] A forward programme was agreed.

24.175 The report of the first meeting of the Scotland and Northern Ireland Factor VIII working party, dated April 1989, commented on the PFC's Z8 product.^[355] It was thought that Z8 was not an optimal product. The working party strongly supported a project for a new higher purity concentrate (now designated S8), noting that development had progressed more slowly than originally anticipated. It was anticipated that the first infusions would occur in June and a formal Phase I study (of percentage recovery and half life) would take place at the premises of Drug Development (Scotland) Ltd in September. Thereafter a Phase II study would follow to demonstrate clinical efficiency. The report on viral safety of Z8 noted that there was no evidence to suggest the product would transmit HIV or NANB Hepatitis, and that there was substantial evidence to demonstrate HIV safety. There were said to be very few data positively to demonstrate NANB Hepatitis safety. However, the opinion of the group was that at that stage only heat treatment was preferable to a solvent detergent technique.

24.176 Professor Ludlam presented the first report of the working party to a meeting of the SNBTS and Haemophilia Directors on 21 July 1989.^[356] The new product S8 was discussed: the Haemophilia Directors expressed the hope that this product, which had the same purity as commercial products, would be available soon. Z8 had a low purity. Professor Ludlam said that there was an international movement towards high and very high purity products 'even though evidence of their value was lacking',^[357] and that Directors were coming under pressure to use them. It was pointed out that purity did not equate with safety, and was associated with lower yield.

24.177 The S8 group met on 10 November 1989.^[358] It identified priority areas for action including additional plant, assay development, stabilisers and other specific matters related to the manufacturing process. Various options for development of the high purity product were discussed, and in particular terminal heating (including both dry and wet heat and possibly solvent-detergent) as virucidal steps. It was agreed that there would be empirical and theoretical studies of variables. Existing and novel stabilisers were to be studied. Assays for detergents and solvents were to be set up. Work was to be done on viral inactivation of Hepatitis B (especially by wet heat treatment). A period of three years to clinical trials was thought to be a reasonable estimate of the time required. In relation to Hepatitis B, it was noted that a major area requiring discussion was how toxicology and safety should be tackled.

24.178 On 30 November 1989, there was a 'Z8 trouble shooting' meeting.^[359] Analysis had demonstrated increasing fibrinogen content in process cryoprecipitate resulting from coolant problems. The increase made the overall Z8 process less efficient, and led to a decline in solubility. The emerging complaint of the Haemophilia Directors about the usefulness of the product (related to its solubility) appeared to have been substantiated. Improvements were scheduled for research and development.

24.179 In 1990 the approach to manufacture changed, with development involving collaboration with the Centre Régional de Transfusion Sanguine (CRTS), Lille, in the production of purer products. Dr Prowse of the SNBTS South East Regional Centre and Department of Transfusion Medicine reported to Professor Cash, Dr Foster and Dr Pepper on the results of heat treatment at 80°C for 72 hours of Lille concentrates, including High Purity FVIII. The appearance of the FVIII product following treatment was 'clear'. Dr Prowse concluded that it appeared that terminal heat treatment could be a valid option for 'high purity' products.^[360]

24.180 Dr Prowse prepared a development proposal for a virally inactivated FVIII concentrate in a paper for the SNBTS Product Development Group in April. The PFC's recurrent problems, in which he included the critical limits in terms of freeze drying for success in severe heat treatment, and advice from Dr Smith on the difficulty in achieving severe heat treatment of products under 10mg/ml, led him to conclude that the SNBTS would need to adopt established solvent detergent technology in due course. He commented:

However, recent in-house data on heat treatment of the Lille product ... suggests it may be possible to retain in excess of 70% VIII activity at a specific activity of 100u/mg. Thus we should not abandon terminal treatment, but should continue to work on this as a 'belt and braces' approach.^[361]

24.181 Among other proposals, and having regard to time constraints, he advocated sub-licensing an established technology such as that used by the CRTS Lille. He also proposed a collaborative effort with England and Wales.

24.182 The need for a high purity product had been discussed by Professor Cash in a memorandum dated 22 May 1990.^[362] In relation to viral inactivation, he thought that terminal dry heating should not lightly be abandoned but, because there was an open invitation to acquire the CRTS Lille technology, solvent detergent had to be considered seriously. By now, the vast majority of the world's fractionators had taken that route. He proposed that the PFC 'bite the bullet' and opt for the total Lille package.

24.183 Dr Foster and Dr McIntosh visited Lille on 9-11 July 1990 and prepared a report.^[363] They had mixed impressions of the Lille operation. Some aspects of the plant impressed, but the general conclusion was that practice was not up to US or UK standards. The reporters thought that collaboration was required on a range of technical matters, and recommended a review of the SNBTS's strategy for development of a high purity Factor VIII.

24.184 On 13 July 1990, it was reported that Dr Prowse was making progress in establishing a joint venture with the NIBSC on the immunosuppressive properties of Factor VIII concentrates.^[364] This was of potential importance because there had been suggestions that, because of their lack of purity, Z8 and S8 might contain proteins which might lead to impaired immune response if administered chronically.

24.185 Discussions with Lille continued, and regulatory requirements in France were progressed in October 1990.^[365] On 30 October 1990, the SNBTS sent details of the PFC's methods for preparation of Factor VIII (S8) to Lille.^[366] The CRTS had prepared documentation for licence purposes and arrangements were made for the SNBTS to have access to that documentation if it was decided to proceed with the Lille process.^[367] This was the beginning of a new chapter in factor concentrates research and development.

24.186 There was continuing contact with the New York Blood Centre relating to licensing of solvent/detergent technology. This was a necessary treatment step in the manufacture of the Lille product. Discussions with the New York Centre established the licensing arrangements and fees required for access to its solvent/detergent technology on 21 January 1991.^[368]

24.187 On 3 May 1991 a technology exchange agreement was signed between the French and the Scottish blood transfusion services to enable the SNBTS to produce a high purity Factor VIII using CRTS technology.^[369]

24.188 There continued to be wide-ranging research and development in Scottish laboratories in 1991 and beyond. Dr Foster wrote an interesting and typically perceptive article on the history of the Protein Fractionation Centre, tracing its final stages in particular, in 2008.^[370] Chapter 11 of the Preliminary Report gave an account of some of that work.

24.189 However, the developments bearing on the issues raised by the Terms of Reference had all taken place by the end of 1990 or early 1991. Transmission of infection with HIV and HCV by SNBTS products, now subject to effective terminal heat treatment, was no longer an issue and it is not appropriate to discuss at length the evolving history of the final years of PFC research, development and production of factor concentrates.

Discussion

Should Z8 have been developed earlier?

21.190 As discussed above, in England 8Y (dry heat-treated at 80°C for 72 hours) was issued for general release to Regional Transfusion Centres in September 1985. The equivalent PFC product, Z8, was available for general use from April 1987. The question arises whether the PFC ought to have developed a Factor VIII product that did not transmit NANB Hepatitis/HCV earlier. That question involves a consideration of:

(a) The initial priority given by the PFC to developing a high purity Factor VIII concentrate (NYU) that could be pasteurised.

(b) Whether PFC ought to have taken the decision at an earlier stage to prioritise the development of an intermediate Factor VIII product that could be severely dry-heated.

(c) Whether the product that was developed (Z8) ought to have been available for clinical trials before December 1986.

(d) Whether there was a failure to address timeously Professor Ludlam's concerns in respect of compensation for patients who suffered harm in clinical trials and, if so, whether any such failure resulted in a delay in (i) the commencement of clinical trials and (ii) the availability of Z8 for use by patients.

Each of these issues will be considered in turn.

(a) The initial priority given by the PFC to developing a high purity Factor VIII (NYU) and pasteurisation

24.191 The development of a high purity Factor VIII product that could be virally inactivated by pasteurisation had priority in the PFC's research and development programme in 1984 and 1985. At that time, the PFC remained alert to the possible introduction of other viral inactivation procedures including, in particular, dry heating. There was ample evidence before the Inquiry that a focus on the development of a high purity product at that time was reasonable given the demands of the Haemophilia Directors for a higher purity product and the initially promising results of the PFC's collaboration with Professor Johnson aimed at producing an appropriate product. Pasteurisation, rather than dry heating, was also supported by evidence available at the time that wet heating of factor concentrates might be effective in preventing transmission of NANB Hepatitis (specifically the Behringwerke work discussed elsewhere in this Report); and that dry heating (at least at 68°C, the temperature in common use at the time) was not effective in preventing the transmission of NANB Hepatitis. There was also evidence that, in the case of some products, dry heating was not effective in preventing the transmission of HIV (paragraphs 24.83 and 24.120).

24.192 In his evidence Dr Foster explained that during 1985 his judgement was that 'in terms of the data that were available, the better data came from the pasteurisation process in terms of safety to patients',^[371] whilst adding that:

[W]e were positioning ourselves to change if we got new information that showed that perhaps dry heat treatment, for very severe conditions, was going to be a good option. And that, if we had to ... heat at 80 or go beyond 80, the higher purity product should be capable of doing that because it was much more highly purified than 8Y.^[372]

24.193 According to Dr Foster, the understanding, common to English and Scottish scientists, that the PFL/BPL's success in heating 8Y to 80°C was based on its higher purity confirmed that the PFC was following the correct route in focussing on a high purity product. If pasteurisation did not prove effective then severe dry heating might provide an alternative method of viral inactivation.^[373]

24.194 Dr Perry stated:

I think our belief ... was that pasteurisation remained the best option. And colleagues from the BPL to an extent actually agreed with that because there was some experience from the Behringwerke product that pasteurisation was likely to deliver a safe product. So we still felt that was the best option.^[374]

24.195 Other witnesses to the Inquiry shared this view. In particular, Professor Van Aken, who provided expert assistance to the Inquiry, was of the view that at the start of 1985 it was reasonable - given the needs of the market - for the PFC to dry heat-treat their existing intermediate purity NY product (at 68°C for 24 hours) to deal with the immediate threat of HIV while having the long-term aim of applying pasteurisation to a high purity product.^[375]

24.196 Dr Smith of the PFL/BPL gave evidence stating that 'my correspondence etc., shows that, even for someone identified closely with 8Y, pasteurisation seemed likelier than dry heating to defeat NANBH, at least through 1986 ...'.^[376] He was of the view, during the whole of 1985, that pasteurisation would have been 'the better horse to back' if the aim was to inactivate NANB Hepatitis.^[377]

24.197 The evidence on the prioritisation of pasteurisation is accepted as reliable, and persuasive of the appropriateness of the course adopted by the SNBTS. There is independent objective support for the pasteurisation option in the evidence, noted in paragraph 21.121, that from about 1986 some commercial pharmaceutical companies were beginning to market pasteurised products. The research and development priorities of the SNBTS were consistent with wider industry practice in those cases, in which the pasteurisation process must have been developed over the material period.

(b) Whether PFC ought to have decided earlier to develop an intermediate Factor VIII product that could be severely dry-heated

24.198 The initial understanding that the PFL/BPL's success in developing 8Y in England in 1984 and 1985 depended on the high purity of the product (which distinguished it from the PFC's existing intermediate purity NY Factor VIII product) changed after Dr McIntosh's discovery in October 1985 that the freeze-drying process appeared to be more important than purity in the product's ability to withstand severe dry heating. Dr Foster wrote at the time that the importance of the freeze-drying step to the product's subsequent ability to withstand heating was 'not entirely unexpected', given the interaction of all of the steps in the production process. However, this had the quality of hindsight (paragraph 24.76), inevitable in a review of what had been discovered. There was no evidence available to the Inquiry to support a view that, prior to Dr McIntosh's discovery, the PFC ought to have considered that severe dry heat treatment of an intermediate purity Factor VIII concentrate was a realistic possibility, or that the priority given to developing a high purity Factor VIII product should be reassessed. The available evidence was to the contrary effect.

24.199 Dr Perry explained to the Inquiry that the key information which triggered the change of direction at the PFC was, 'the experiments conducted by Dr McIntosh and the realisation that ... you could heat a relatively low purity product at 80 degrees for 72 hours'. He said that information was not available to the PFC before Dr McIntosh's discovery. Their belief prior to that was that 'pasteurisation remained the best option'.^[378]

24.200 In his written evidence Professor Van Aken stated:

In retrospect it may be asked if PFC should have changed its policy at an earlier stage, i.e. before December 1985. In my opinion, which is shared by Dr Smith, PFC had good arguments to pursue the wet heating of factor VIII concentrate as it was doing. Before December 1985 it was uncertain if the BPL product would be safer than the SNBTS/PFC product.^[379]

24.201 Dr Smith's evidence, as noted above, to the effect that even for someone identified closely with 8Y, 'pasteurisation seemed likelier than dry heating to defeat NANBH, at least through 1986'.^[380] and that, during the whole of 1985, his view was that pasteurisation would have been 'the better horse to back' if the aim was to inactivate NANB Hepatitis, is material.^[381]

24.202 The novelty of a discovery is not necessarily undermined by analysis after the event that suggests that the discovery could have been anticipated. The evidence that Dr McIntosh's findings, which were at the time unexpected, changed the course of events is accepted. So far as the evidence available to the Inquiry shows, until October 1985 there was no experimental or other scientific data that should have prompted the SNBTS and the PFC to change direction in their dry heating research programme.

(c) Whether the product that was developed (Z8) ought to have been available for clinical trials before December 1986

24.203 In developing the Z8 process, SNBTS scientists were able to draw on elements of the NYU process developed in conjunction with Professor Johnson of New York.^[382] Witnesses from the SNBTS and the PFC indicated that certain elements from that programme played a key role in the subsequent development of the Z8 process. Dr McIntosh, for example, was of the opinion that:

[T]he experience and expertise gained during the development of a number of the processing steps in the NYU project (e.g. cryo-precipitate processing, formulation, freeze-drying) were directly transferrable to the Z8 process.^[383]

Nevertheless, the evidence suggested that considerable research and development work was required.

24.204 Although Dr McIntosh discovered in October 1985 that vials of the PFC intermediate purity product withstood dry heat treatment at 80°C, various witnesses commented that this was a very preliminary finding in a laboratory setting and that a significant amount of further research and technological development was needed before a product so heated could be manufactured on a large scale.^[384] Dr Foster, for example, explained that the production of Z8 'required a new manufacturing process to be established from the recovery of cryoprecipitate onwards'.^[385]

24.205 Dr Cuthbertson set out in detail the steps required to introduce a new product:

The development of a new product is a very detailed process and a large number of steps must be carried out in a meticulous manner in order to ensure that the final product meets the basic pharmaceutical requirements of safety, quality and efficacy. Nowadays it is believed that the development of a new process from development, through clinical trialling to final licensing and routine issue will take of the order of 5 years. In those days, the regulatory requirements were not so rigorous, but even so, implementation of a new process required significant periods of time to include the following steps

• Development of process at R+D scale
• Understanding of safety issues (including virus inactivation studies)
• Clinical evaluation, to include

  o Freedom from adverse reactions, including use in repeat infusions

  o Acceptable recovery of clotting factor in circulating plasma

  o Development of product at pilot scale

  o Acceptable recovery in the circulation and in vivo half life

• Process scale up
• Development of effective quality control (test) and quality assurance procedures
• Demonstration that process can be adopted routinely with acceptable reproducibility (there is no point in producing a product with poor yield or poor reproducibility)
• Production of enough material at manufacturing scale, whilst ensuring that existing product is still available.^[386]

24.206 Professor Van Aken had a similar view of the need for various steps to be taken to progress from laboratory scale to pilot scale and subsequently full production scale, concluding that, 'in my opinion it is quite an achievement to successfully complete all this within one year (in fact between June and December 1986)'.^[387]

24.207 In addition, and perhaps unsurprisingly, when developing and scaling up a new product and manufacturing process, unexpected technical problems arose that required to be overcome. Dr Foster^[388] and Dr McIntosh^[389] explained that a number of unexpected technical/management issues occurred during the development and production of Z8 which delayed its introduction. In addition to the 'eleventh hour' freeze-drying problems in August 1986 discussed above, there were also problems sourcing suitable ultra-filtration pumps which would operate at a larger scale without damaging the Factor VIII^[390] and there was a need to revise the Z8 production process so that it could be performed without having to alter existing PFC staffing arrangements, and hence PFC employees' terms and conditions of employment.

24.208 The evidence that the time taken between a decision in late 1985/early 1986 to prioritise the development of Z8 and the development, production and availability of that product for clinical trials by the end of 1986 was not unreasonable is accepted. The evidence went further, to the effect that the timescale achieved was remarkably quick, in particular when judged against modern practices and timescales for the development of new pharmaceutical products. That evidence is also accepted.

(d) Whether there was a failure to address timeously Professor Ludlam's concerns in respect of compensation for patients who suffered harm in clinical trials and, if so, whether any such failure resulted in a delay in (i) the commencement of clinical trials and (ii) the availability of Z8 for use by patients

24.209 The question of compensation for patients who suffered an adverse reaction to clinical trials of PFC products was first raised by Professor Ludlam with the SHHD in late 1983 and, despite his best efforts, remained unresolved by late 1986, when Z8 became available for clinical trial. In particular, Professor Ludlam raised the issue of compensation at a meeting of the Haemophilia and Blood Transfusion Working Group on 14 November 1983 (at which Dr Bell of the SHHD was present);^[391] at the meetings of the SNBTS and Haemophilia Directors on 2 February 1984 and 7 March 1985 (at which Drs Bell and McIntyre were present);^[392] in his letter dated 19 March 1985 to Dr Boulton;^[393] and in his letter dated 4 April 1985 to Professor Cash.^[394]

24.210 When Z8 became available for clinical trials in December 1986, Professor Ludlam, with the support of the other Haemophilia Directors, refused to undertake trials of the product unless satisfactory compensation arrangements were in place for patients suffering damage as a consequence of infusion of the new product. In oral evidence to the Inquiry Professor Ludlam explained:

I had one of two options. One was to roll over and say, 'There shouldn't be compensation arrangements,' and get on and test the product or I should say, 'I won't test it'. I'm there as a patient's advocate in this instance and it seemed to me that if I didn't draw a line at this point, there might never be arrangements and there might be some terrible consequence of one of these test infusions and then one would be dependent on the CSA's goodwill. I felt it only fair to the patients that there was something a bit more explicitly available than just the hope that there would be goodwill.^[395]

24.211 SHHD witnesses gave evidence to the Inquiry to the effect that the reason why Professor Ludlam's concerns over compensation for clinical trials had not been resolved by late 1986 was, partly, because the SHHD considered that the issue was one on which the CSA should take the lead and, partly, because Professor Ludlam's concerns over compensation for patients became caught up with the wider, more complex, issue of compensation for trials involving healthy volunteers, specifically trials and immunisation procedures involving SNBTS staff members and blood donors.^[396] Reliance on a CSA lead in 1986 could only have related to the consequential financial aspects of a compensation scheme. The policy question whether a scheme was appropriate was a matter for SHHD and ministers.

24.212 Mr Murray, SHHD, agreed that, in retrospect, the time taken to deal with the question of compensation was unsatisfactory.^[397] When asked to explain in more depth why the issue took so long to resolve, Mr Murray explained that:

[I]n reviewing the papers, not from my memory but from my reading of the documentation, there would appear to be a fragmentation of attention. And we have - we have the meetings of the regional directors and those responsible for haemophilia, we have the BTS subcommittee, we have the CSA central administration, we have Scottish Home and Health Department medical officers and then we have the administrative side of the department. The answer to your question, I think, lies in those structures.^[398]

24.213 In his evidence to the Inquiry, Mr Macniven (who was in post from May 1986) indicated that a key issue was lack of focus as regards the scope of the proposed compensation scheme. He stated:

[T]he way to have resolved this much more quickly was to stick to what Dr Ludlam was asking, stick to the narrow question, which, as we demonstrated in early 1987, was relatively simply for Treasury to answer .... The delay was engendered for a number of reasons but because people were uncertain about what breadth of compensation scheme we were talking about: Were we talking about a scheme that involved all clinical trials of all possible future SNBTS products? That's a larger blank cheque for Treasury to write out, or to approve us writing out, than the narrow scheme, which they were used to, as we saw earlier, in other contexts.^[399]

24.214 There is support in the evidence for the view that the SHHD should have taken the lead in resolving Professor Ludlam's concerns in respect of compensation, and that that could have been done relatively easily by disentangling the issue raised by Professor Ludlam from the issue of compensation of healthy volunteers and donors who were trialling different products. The introduction of any compensation scheme of wide application raised issues of health policy and had financial implications that would, inevitably, have required the consent of the Treasury. When the SHHD finally did take responsibility for resolving Professor Ludlam's concerns (following Professor Cash's telephone conversation with Dr McIntyre on 30 December 1986), and consulted with the DHSS and the Treasury, they were able to obtain agreement on a compensation scheme by early February 1987 which, in turn, resulted in clinical trials of Z8 being carried out.

24.215 There was ample evidence that resolving Professor Ludlam's concerns caused delay. Dr Cuthbertson was of the view that 'there is absolutely no doubt that these concerns delayed the initiation of the clinical trial of Z8. Product was released for use in the trial in December of 1986, but the trial did not commence until March 1987'.^[400] He was not critical of Professor Ludlam and other clinicians. He considered that the compensation issues 'were legitimate concerns and that nowadays no clinical trial would be allowed to begin if such indemnity arrangements were not in place'.^[401]

24.216 Professor Cash shared Dr Cuthbertson's view on timing, indicating that the issue caused a delay of 'no more than 3 months'.^[402] Professor Ludlam agreed that the issue of compensation delayed Z8's assessment in Edinburgh by about two months. He was not in a position to draw valid conclusions about consequential delay in the introduction of Z8 for clinical use.^[403]

24.217 A separate issue that arises on the evidence is whether delay in commencing clinical trials delayed the availability of Z8 for use by patients.

24.218 The evidence of witnesses from the SNBTS and the PFC was that, with the exception of previously untreated patients, the delay in commencing clinical trials of Z8 probably did not result in a delay in patients receiving Z8. That was because, in accordance with the batch dedication system, patients already in receipt of NY Factor VIII concentrate (heated at 68°C for 24 hours) would in any event have continued to receive that product until existing stocks were exhausted. Stocks of the intermediate purity NY product did not become exhausted until April/May 1987, by which time Z8 was available for use and began to be prescribed to patients. Even if there had been no delay in resolving the compensation issue and clinical trials had been carried out in late 1986/early 1987, prescription of Z8 to existing patients would still not have begun until existing stocks of NY were exhausted in April/May 1987.

24.219 Dr Perry's evidence relating to the intention to phase in Z8 to existing patients in accordance with the batch dedication is narrated in paragraph 24.114. Underpinning the arrangement was an understanding among manufacturer and users that successive new products would be introduced through the system to established patients when stocks of the previous product had been exhausted.

24.220 Given that the batch dedication system reflected established policy, the determining factor which affected the timing of the introduction of Z8 was not when clinical trials of the product were carried out but, rather, the point at which stocks of the PFC's existing 68°C/24 hours intermediate purity NY product ran out.^[404] Dr Perry indicated that this point was reached in April 1987.^[405] Therefore, according to Dr Perry, although earlier clinical trials would have relieved some of the PFC's concerns about running out of its existing product before Z8 was ready, importantly, they would not have changed the timescale for the Scotland-wide introduction of Z8.^[406] Dr Perry's evidence was that the only patients potentially affected by delay would have been previously untreated patients who were not within the existing batch dedication system and would not have been supplied with the 68°C/24 hours product.^[407]

24.221 During the Oral Hearings both Professor Cash and Professor Ludlam agreed with Dr Perry's evidence that, given the batch dedication system, the key to the introduction of Z8 was exhaustion of the remaining stocks of the PFC's 68°C/24 hours product rather than when Z8 first became available for use by patients.^[408] In the case of patients with a significant history of factor concentrate treatment (effectively more than five units) previous exposure to NANB Hepatitis/HCV was assumed. The shift to a new product did not affect their risk of acquiring infection.

24.222 The rationale for distinguishing previously untreated patients was that they would not already have been exposed to the risk of contracting NANB Hepatitis/HCV from treatment with factor concentrate or cryoprecipitate, and therefore clearly required treatment with a safer product when it became available for use. The evidence available indicated that, but for the delay in resolving the issue of compensation, it is likely that Z8 would have been available for use by previously untreated patients some two to three months earlier than April/May 1987, that is in January/February 1987.

24.223 Professor Ludlam gave evidence that before releasing Z8 for clinical use it would have been 'necessary to have a stock of several batches, at least enough for 1-3 months' supply'^[409] and that, in his view, any delay during this period would not have disadvantaged previously untreated patients as these could have had access to 8Y:

If there was a delay of approximately 3 months (Z8 introduced for clinical use in May rather than February 1987) untransfused patients (PUPs), who would have been at risk of non-A non-B hepatitis, could have had access to 8Y (a small stock of which had been acquired in August 1986). Thus patients, therefore, should not have been disadvantaged if there was any delay in the introduction of Z8.^[410]

24.224 The Inquiry is aware of one patient (patient 'Alex') who was first treated with Factor VIII concentrate in mid-January 1987.^[411] Otherwise, the Inquiry is unaware whether any previously untreated patients contracted Hepatitis C as a result of treatment with insufficiently heat-treated Factor VIII product between January/February and April/May 1987. The total number of patients first treated between 1 September 1985 and 30 June 1987 was 29.^[412] If there are any such patients, other than Alex, who were infected between about January and April 1987, their number is likely to be very small. It is, however, a matter of considerable regret that any patient was or may have been infected in this period.

24.225 Professor Ludlam's evidence about availability of BPL 8Y for treatment of PUPs is accepted so far as Edinburgh and south east Scotland patients are concerned. As discussed in Chapter 22, Haemophilia Therapy - Use of Blood Products 1985-1987, the Inquiry failed to uncover any evidence suggesting that the availability of 8Y was known to other Haemophilia Directors, or that there were in place appropriate protocols for application to the BPL for release of 8Y for what (at the time) would have been part of an extended clinical trial programme.

Should the PFC have copied the English 8Y process?

24.226 The question arises as to why the PFC did not seek simply to copy the BPL's manufacturing processes for 8Y after the decision was taken in Scotland in late 1985/early 1986 to switch from developing a high purity, pasteurised, product to developing a Factor VIII product that could be severely dry heat-treated. The evidence received by the Inquiry, however, indicated that there were practical reasons why that was not a realistic option and that, if it had been adopted, it is unlikely to have led to the more rapid introduction of a Hepatitis C-safe Factor VIII product in Scotland.

24.227 Dr Foster explained that in 1986:

The option of directly transferring the methods and technologies used by BPL was not chosen because a number of uncertainties remained, in particular:

• use by BPL of a chemical (heparin) at a concentration which interfered with the routine method used by SNBTS for measuring factor VIII activity,
• uncertainty over the practicality and time required to replace the SNBTS method of measuring factor VIII activity with the method used by BPL,
• uncertainty over the omission of aluminium hydroxide adsorption in the BPL process and the possibility that minor process variations might result in instability to factor VIII,
• difficulties previously experienced by the SNBTS in the use of precipitation/centrifugation to recover purified factor VIII from dilute solutions,
• the need to purchase, install and become familiar with large-scale size exclusion chromatography in factor VIII processing.^[413]

24.228 None of these were trivial matters. When examined on these issues during the Inquiry hearings, Dr Foster explained that the problems outlined above were largely technical in nature and that PFC's judgment was that it would be quicker to use the existing PFC processes:

[T]he question we were faced with was, what could we do most quickly, or what did we think we could do most quickly. And that was the judgment that we made, that we could do it most quickly using procedures we were more familiar with and that were more compatible with our operation.^[414]

24.229 Dr Foster also pointed out that copying the 8Y process would have involved purchasing expensive new equipment, some of which might have had to have been specially designed and which would have required additional requests for funding.^[415] According to Dr Foster these issues could have led to delays.^[416]

24.230 A similar point was made by Dr McIntosh, who explained that there were at least eight technical differences between the 8Y and Z8 processes which the PFC would have had to have overcome in order to replicate 8Y, namely:

• Adjustments to cryoprecipitate processing involving the purchasing of different thawing vessels (the 8Y process used simple batch thawing, whereas the PFC used a continuous thin film thawing technique developed by Dr Foster).
• The purchasing of Sharples centrifuges to match those used in England.
• The reconfiguring of the PFC's coolant supply so as to function with the Sharples centrifuges.
• A change to the PFC's assay method so as to deal with the large concentration of heparin involved in the 8Y process.
• The purchasing and commissioning of chromatography columns to replace the PFC's existing ultrafiltration technology.
• The purchasing of new testing equipment to deal with the fact that 8Y was stoppered when in a vacuum.
• The need to add an additional unit operation step, which would have been difficult to fit into the PFC's existing processing time.
• Potential issues as regards the low yield of 8Y, which could have caused difficulties as regards the Scottish policy of self-sufficiency.^[417]

24.231 Dr McIntosh concluded that it would not have been straightforward to copy all the procedures used to manufacture 8Y. In oral evidence, he indicated that it would not have been feasible to pick and choose certain elements from the 8Y process, explaining that:

[N]either Oxford's understanding of their own process nor our understanding of what the key parameters were was sufficiently developed at that time in order to be able to make what would be a very sophisticated judgment to select key parameters from a process and emerge with a process design which would allow severe heat-treating at 80ºC, when this was a brand new, hitherto unachieved development.^[418]

24.232 Dr Smith provided an overview of certain difficulties the PFC would have been confronted with in attempting to copy the English 8Y process.^[419] These largely mirror those highlighted by Drs Foster and McIntosh and included:

• The fact that the high residual concentration of heparin used in the 8Y process would invalidate the PFC's Factor VIII assay.
• The fact that there was likely to be an inherent problem of trying to mimic the 8Y methodology and equipment. There would be a risk in any attempt at duplication of the 8Y methodology that it would fail to identify important variables hidden within the existing process and would therefore be unsuccessful.
• The fact that the full scale 8Y process required at least two shifts of skilled operatives, whereas the PFC did not operate shift-working.
• The use of different centrifugation technology.
• The need for the PFC to change to gel filtration from ultrafiltration.
• The relatively low yield of 8Y, which according to Dr Smith was no more than 200 IU/kg.

24.233 Dr Smith discussed these technical difficulties during the Inquiry hearings,^[420] and also explained in more depth the technical reasons why the heparin used in the 8Y process would have interfered with the PFC's existing Factor VIII assay.^[421] Dr Smith's general view was that there were very valid scientific, technical and management grounds for not trying to copy the process and that it is only with hindsight that 8Y can be regarded as providing a Hepatitis-safe Factor VIII - or as Dr Smith put it in his written evidence:

It was never a case of, 'Jim Smith has finally smuggled out the recipe for a hepatitis-free F.VIII. Stop everything you have been doing for three years, we start on Tuesday'.^[422]

24.234 Professor Van Aken was asked whether it was reasonable for the PFC to decide to develop its own process in December 1985 rather than simply copying the 8Y manufacturing process and, in his response, stressed that there were technical obstacles which the PFC would have needed to overcome.^[423] In addition, he emphasised, in line with other witnesses, that any decision to follow the 8Y process would have had to have been an 'all or nothing' decision, encompassing all aspects of the process. According to Professor Van Aken:

You cannot say, 'I'll just take this step and the rest I will continue', as you used to do so. You have to do it all or not to do. That is usually the experience, that you cannot, without getting into all sorts of surprises, just say, 'Well, I'll use this element and this element, and the rest I'll leave as it is'.^[424]

24.235 Overall, the evidence before the Inquiry was to the effect that it was reasonable for the PFC to decide not to attempt to copy the English 8Y process but, rather, to seek to develop their own Factor VIII product that could be severely dry-heated, using their own manufacturing processes and plant and building on their existing research work. That evidence is accepted.

Liaison between fractionators in Scotland and England

24.236 Communication between the PFC and the PFL/BPL was from time to time inhibited by confidentiality agreements with third parties or by the need to avoid disclosure of patentable inventions. Otherwise, the evidence available to the Inquiry was uniformly to the effect that liaison between the organisations, although mainly conducted informally, was effective in ensuring that researchers in Scotland were aware of significant developments in England and that the sharing of information between fractionators in each facility did not lead to any delay in the development and production of a Hepatitis C-safe Factor VIII product in Scotland.

24.237 As regards awareness in Scotland of the development of 8Y, for example, Dr Foster explained in his written evidence that he first became aware of the work by the PFL in May 1984 when a letter from Dr Smith alerted him to 'an intriguing alternative to zinc [precipitation]'^[425] (ie the heparin discovery outlined above) and that by late November 1984 he was generally aware of the procedures used in the preparation of 8Y, most probably as a result of informal discussions between Dr McIntosh (PFC) and Mrs Winkelman (PFL) which were communicated to him.^[426] Dr Foster's witness statement also indicated that he was aware at the end of 1984 that, 'the ability of 8Y to withstand heating at 80°C for 72 hours was believed by Dr Smith and Mrs Winkelman to be due to the higher degree of purification of factor VIII that was obtained by the 8Y process'.^[427] He also explained that Mrs Winkelman and colleagues from the PFL/BPL visited the PFC on 27 March 1985 to discuss heat treatment and that she indicated that a final decision had yet to be taken on whether to dry heat the established BPL Factor VIII (ie HL mentioned above in paragraph 24.15) at 70°C for 24 hours or 8Y at 80°C for 72 hours.^[428] Dr Foster also explained that he received a copy of the patent application for 8Y from Dr Smith on 16 April 1985.^[429] According to Dr Foster, it was not, however, until sometime in late summer 1985 (he did not know precisely when) that he learned that the PFL's 8Y process had been successfully scaled-up and transferred to the BPL.^[430]

24.238 Dr McIntosh confirmed in his written evidence that the SNBTS/PFC were aware of the major features of the 8Y process prior to receiving a copy of the patent application for 8Y in 1985.^[431] During the Inquiry's hearings Dr McIntosh indicated that he thought that he would have learned of the PFL's 8Y process in late 1984.^[432]

24.239 When specifically asked about the adequacy of the liaison arrangements, Dr Foster advised that, from his perspective, communications between the SNBTS and the BPL/PFL were 'excellent' and involved not only himself and Dr Smith, but included: Dr Pepper (SNBTS Headquarters Laboratory) with Dr Smith; Dr McIntosh (PFC R&D) with Mrs Winkelman and Mr Evans (PFL R&D scientists); Dr Cuthbertson (PFC Head of Quality) with Dr Snape (BPL Head of Quality); and Dr Perry (PFC Director) with Dr Smith and Dr Snape.^[433]

24.240 Drs Perry, Cuthbertson and McIntosh also considered that there were good relations, and a satisfactory exchange of information, between fractionators north and south of the border.^[434]

24.241 For his part, Dr Smith of the PFL/BPL indicated that while there was tension at senior (ie Director) level (at least, in the period before Dr Perry became Director at the PFC), that did not hinder fruitful co-operation between scientists or in relation to research.^[435]

24.242 On his reading of the available documentation, Professor Van Aken formed the view that 'there does not appear to have been a lack of shared information which might have impeded the progress of developing heat treated Factor VIII by PFC'.^[436]

24.243 Professor Cash initially provided written evidence to the effect that, in his view, improvements in liaison between the BPL and the PFC were desirable and that it was his belief that had the two organisations been able to pool their limited research and development 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.^[437] This was explored further during the Inquiry hearings when Professor Cash was asked whether any difficulties between the directors of the BPL and the PFC adversely affected the PFC's work on coagulation factors (in particular Z8). Professor Cash agreed that he would defer to the views of Drs Foster and Cuthbertson that such difficulties did not affect their work, albeit he remained of the general view that there were advantages to more formal arrangements for the exchange of research information.^[438]

24.244 Dr Perry acknowledged that there was an absence of a formal management structure providing a link between the PFC and the BPL, but considered that there were many examples of 'highly productive collaboration'. In the case of Factor VIII, in his view it could perhaps be argued that the lack of formal arrangements was beneficial as it allowed the BPL and the PFC to concentrate on different research and development strategies in the period up to 1985 (ie dry heat treatment and pasteurisation respectively) rather than being forced to back one process which may or may not have been successful.^[439]

24.245 This evidence is accepted. There was ample circumstantial evidence illustrating the extent of cooperation, if seldom actual collaboration, between responsible officers of the two organisations in the exchange of data and of their experimental and development findings. The SNBTS was unable to disclose confidential information obtained from Professor Johnson of New York University under contract. Dr Smith and Mrs Winkelman on the one hand, and Dr Foster and his colleagues on the other were inhibited from time to time by the need to avoid prior disclosure of the inventive steps in processes that were or were intended to be subject of patent applications. The narrow scope of the exceptions is consistent with what otherwise was an open exchange of scientific and technical knowledge. It appears to be clear that this openness was not a characteristic of relationships between senior management of the organisations, but there was no evidence to suggest that there were consequential difficulties among scientists.

Why the PFC was able to produce severely dry heat-treated Factor IX (DEFIX) earlier than severely dry heat-treated Factor VIII (Z8)

24.246 The PFC released heat-treated Factor IX (HT DEFIX, dry-heated to 80°C for 72 hours) in October 1985, whereas Z8 Factor VIII (also dry-heated at 80°C for 72 hours) was not available for clinical trials until December 1986, over a year later.

24.247 The question was not, in the event, controversial and can be dealt with briefly. Factor IX was more stable than Factor VIII and, because of its chemical composition, inherently less likely to be damaged by heating. For these reasons the heat treatment of Factor IX posed far less of a technical challenge than the heat treatment of Factor VIII.^[440] In addition, the heating of Factor IX, unlike heating Factor VIII, did not give rise to any yield constraints.^[441] Both the PFC and the PFL/BPL had potential problems arising from the risk of thrombogenicity in their heat-treated products. Solving these was a rather singular example of active collaboration between the two services. The SNBTS had access to the facilities necessary for dog studies to determine the risk of thrombogenicity. In the event the collaboration was successful. All technical problems were overcome relatively quickly.

24.248 On the evidence available, the differences between the products were such that there cannot be meaningful comparison between them in terms of the course of research and development required to resolve the issues raised by heat treatment, or in terms of the time required to reach a solution. That evidence is accepted.

Conclusions

Development of Z8

Priority of research into pasteurisation

24.249 Until it was established that the processing of PFL/BPL's 8Y Factor VIII concentrate was effective to inactivate HIV and NANB Hepatitis/HCV in source plasma, there was no scientific basis for a decision to prefer dry heat treatment over pasteurisation in the manufacture of factor concentrates.

24.250 Commercial pharmaceutical companies which had developed and marketed dry heat-treated products in the first half of the 1980s^[442] changed to pasteurisation or solvent/detergent methods of virus inactivation in products marketed in the second half of the 1980s and early 1990s.^[443]

24.251 The PFC's research aimed at production of a pasteurised product effective to inactivate HIV and NANB Hepatitis/HCV was consistent with accepted industry norms, and, if it had been pursued, would have continued to be consistent with wider industry expectations related to dry heat-treated products, without exception, until early 1988.^[444]

24.252 The PFC's decision to change direction, formalised in January 1986, reflected:

• Privileged information about the development of 8Y available to the PFC as a result of informal collaboration between scientists at the PFL/BPL and the PFC respectively.
• Dr McIntosh's discovery that the experimental control sample of PFC's standard Factor VIII concentrate withstood heating at 80°C for 72 hours.
• The insight that purity was not critical to the ability of Factor VIII to withstand heating at high temperature and for prolonged periods.
• Highly innovative research that disclosed the critical role of the crystal structure of the frozen product in making it suitable for heating at high temperature.

24.253 The random selection of a control sample that had a uniform fine crystal structure may have introduced an element of serendipity into Dr McIntosh's experiment: that is of the nature of invention.

24.254 It is also of the nature of invention that until the factors contributing to an inventive insight come together speculation about what might have been until that point is idle. One cannot anticipate invention.

24.255 The PFC's research into pasteurisation was fully justified, and was appropriate, having regard both to comparative industry practice and the progress achieved down to the end of 1985.

Should the PFC have decided to develop a Factor VIII concentrate that could be severely heat-treated earlier than it did?

24.256 The only support for dry heat treatment of Factor VIII in the mid-1980s was the success of the PFL/BPL in developing 8Y.

24.257 That was (erroneously, as it turned out) understood in Scotland until the end of 1985, and in England until at least the end of 1986,^[445] to have depended on having a high purity product.

24.258 The PFC devoted considerable time and resources in 1984 and 1985 to research and development of a high purity Factor VIII product, initially ZHT and later NYU.

24.259 According to the perceptions of the period, high purity was a necessary preliminary step towards any form of effective heat treatment.

24.260 ZHT was not fully developed by the end of 1985 when Dr McIntosh's discovery was made.

24.261 In short, there is no factual basis for any suggestion that the PFC should have decided to develop a Factor VIII product that could be severely heat-treated earlier than it did.

Progress towards clinical trials following the decision to develop a dry heat-treated product (Z8): research and development by SNBTS

24.262 The PFC applied appropriate resources in the research and development work necessary to achieve an acceptable Factor VIII product dry heat-treated to inactivate HIV and NANB Hepatitis/HCV.

24.263 Z8 was developed and made ready for clinical trials within a reasonable time.

24.264 Professor Van Aken's assessment of the success of the PFC as 'quite an achievement' is accepted.

24.265 There is no basis for adverse criticism of the work of the PFC in this respect.

Progress towards clinical trials following the decision to develop a dry heat-treated product (Z8): compensation

24.266 The demand by Haemophilia Directors (and Professor Ludlam in particular) for appropriate provision for compensation for individuals who agreed to undergo trials of and treatment with Z8 before licensing of the product was in the interests of patients and was reasonable.

24.267 The demand was limited in scope and could and should have been dealt with on its own merits with reasonable expedition.

24.268 The demand raised issues of health policy and funding which were not within the scope of CSA's delegated functions. The CSA was not equipped to deal with issues involving clinical judgement. The CSA was unlikely ever to have been an appropriate body to resolve such issues within its own budgets and competency.^[446]

24.269 The commitment of resources for compensation ought to have been dealt with by the SHHD from the outset in consultation with the Treasury.

24.270 Failure to address the specific issue with reasonable expedition resulted in the delay of clinical studies and the resultant availability of Z8 for therapy for PUPs by three months.

24.271 Because of policy decisions related to batch dedication the delay of clinical studies did not affect established patients.

Should the PFC have copied BPL's 8Y process?

24.272 Manufacturing technology and process equipment employed by the PFC and the BPL respectively were not compatible in eight distinct technological areas.

24.273 In particular, assay procedures for the monitoring of Factor VIII levels during processing, integral to manufacturing, were incompatible, with the BPL using a unique procedure that could not be accommodated by the PFC.

24.274 Piecemeal adoption of elements from the BPL's integrated manufacturing processes was not a viable option: there was an unavoidable risk of incompatibility.

24.275 Wholesale adoption of the BPL's 8Y process would have been problematical for the reasons given by Dr Smith: idiosyncratic variables 'hidden' within the BPL's process might not be identified with the result that the PFC could not duplicate the process effectively.

24.276 The previous point was validated by events. The discovery of the criticality of the crystal structure of the frozen product in vial in the course of processing, and of the importance of plasma conditioning, factors that had not been identified by the PFL/BPL, brought to light idiosyncratic features of the English process that might not have been discovered in time to avoid delay in Scotland.

24.277 The process of specifying, purchasing and commissioning new equipment would have been time-consuming and expensive and uncertain of success.

24.278 Modification of the PFC's existing technology was the preferable approach.

24.279 It was not demonstrated on the evidence that the PFC should, or could, have attempted to mimic the BPL's 8Y process.

Summary

• There is no basis for adverse criticism of the PFC and its scientists over the period ending with the introduction of Z8 for routine clinical use in April 1987. On the contrary, they achieved outstanding results, as evidenced by the fact that Scotland appears to have been the first country in the world that was able to supply all of its haemophilia patients with a Factor VIII product that did not transmit Hepatitis C.
• After the introduction of Z8, research and development work proceeded on new, purer, products to meet changing demands from clinicians. However, safety from transmission of virus had been achieved, and later developments, while demonstrating the SNBTS's commitment to improving quality of products, did not produce safer products.
• Administrative delays by the SHHD in dealing with the Haemophilia Directors' demands for compensation arrangements for patients adversely affected by new products prior to regulatory approval resulted in delay of about three months in trials and availability of Z8.
• However, the only adverse impact on the safety of patients was the unavailability of Z8 during that period of delay for the treatment of virgin and infrequently treated patients.

25. Screening of Donated Blood for Hepatitis B >