text:
TRENDS IN DEMAND FOR AND USE OF BLOOD PRODUCTS
AND IN PRODUCTION AND SUPPLY OF NHS PRODUCTS
Quantification generally – projection of demand in the 1970s – commissioning of PFC – commercial products – productive capacity, plasma supplies and self sufficiency – importance of yield – SNBTS productive capacity in 1980 to 83 – critical Medicines Inspectorate review in spring 1982 – factors increasing demand for blood products – distribution of PFC products – product selection and its impact on total demand and demand for resources – lack of reporting of actual usage – quantities for 1980 to 83 – SNBTS productive capacity in 1983 to 86 – estimates of demand – distribution of PFC products – usage of commercial products – concern at UK level over lack of co-ordinated policy – PFC production moves into surplus in 1984 – in 1985 research and development and production adversely affected by restriction in FVIII deficient plasma substrate in wake of HIV seroconversion of the Edinburgh cohort – lack of information on commercial purchases persists – introduction of heat treatment and its impact on the pattern of production and distribution – quantities for 1983 to 86 – factors affecting supply and demand in 1986 to 1990 – inconsistent data on commercial purchases – threat posed to production due to possible failure of Z8 to meet clinical trials – April 1988: Chiron announce isolation and cloning of proteins from NANBH virus – additional purchases of commercial products forecast in 1988 – research and development of high purity products proposed and resisted – comparative positions of Scotland and England in production of high temperature heat treatment of FVIII– collaboration with New York Blood Centre on high purity product – Scotland loses self-sufficiency mid-1988 – concern of Haemophilia Society – purchases of commercial products explored – maintenance and development work at PFC restrict productive capacity at end of period – long term production planning in hand – quantities for 1986 to 1990 – productive capacity 1990 to 93 – commercial products were preferred to Z8 – the higher purity S8 fell behind research and development targets – commercial products threaten PFC – growing objections to Z8 on grounds of relative insolubility – PFC turns to CRTS Lille for collaboration on production of high temperature heat treatment of FVIII – data on commercial usage remains unsatisfactory – Collaboration arrangements with Lille finalised in 1991 – strategic stock piling resumed in 1991 – Z8 production ended December 1982 – 'Lille' FVIII substituted – quantities for 1990 to 93.
Quantification of demand generally
10.1 The Inquiry team has not, thus far, identified an evidence-based and structured approach to the assessment of demand for blood and blood products in Scotland as a whole, at least until the appointment, in July 1988, of RRC Stewart, as clinical trials/product surveillance manager at the Scottish National Blood Transfusion Service (SNBTS). On 3 March 1989, he wrote to all regions seeking data on purchases of commercial blood products, and began to assemble more comprehensive data than had previously been disclosed by area boards. SNBTS had requested data previously. However until March 1989, the collection of such data appears to have been incomplete, and the provision of information to have been, at best, of a level of generality that must have limited its usefulness as a basis for estimating the production requirements of the Plasma Fractionation Centre at Liberton.
10.2 As will appear below, attempts to set up a haemophilia register for Scotland that would have informed SNBTS of usage of factor products failed. Scottish haemophilia directors returned data on product usage, and patient counts, to UKHCDO. UKHCDO has provided the Inquiry team with tables of extant data which are set out in the appendices to this report. The data on the use of Factor VIII, Factor IX, Cryoprecipitate, and blood components cover the period 1980–91. Also appended are tables of the data from SNBTS files showing the information available to SNBTS directors about commercial product purchases from year ended 31 March 1981 to year ended 31 March 1992. One would not expect a precise correlation between purchases and usage. Stock levels, wastage and other causes of variation would inevitably have affected the picture. However, the gross discrepancies that are apparent on comparison appear to show that SNBTS were not informed of the actual patterns of purchases or usage. In the case of Glasgow, SNBTS records show purchases of 906,000 international units (IUs) of Factor VIII products in the year ended 31 March 1980. UKHCDO record the use of 938,441 international units. However, in the following three years, use recorded amounted to 868,966, 579,376 and 423,850 units respectively. Purchases intimated to SNBTS were confined to a single purchase of 550,000 units in the year ended 31 March 1983. In proportionate terms the discrepancies between the two sources of data for Edinburgh are even more extreme.
10.3 At certain periods, SNBTS products were in surplus. Self-sufficiency was achieved, in the sense that demand for the domestic products was met by available supplies. However, since commercial purchases never ceased, and the level of those purchases was not known and could not have been taken into account in planning production by the Plasma Fractionation Centre in Edinburgh (PFC Liberton), the demand for SNBTS products could not be taken to have been the measure of domestic demand overall.
10.4 Further, it appears that the factors which limited the ability of SNBTS, and PFC Liberton in particular, to meet actual demand may often have been the supply and quality of the raw material that was dispatched to PFC Liberton for processing, and the quality of the products available, as perceived by haemophilia clinicians.
10.5 As appears from Chapter 3 of this report, NHS Patients At Risk, the population creating demand also increased over the reference period as life expectancy improved; and the clinical approach to therapy changed, notably by the introduction of home therapy and prophylactic regimes and increasingly sophisticated surgery. The range of variables affecting the demand side of the equation changed accordingly. The uncertainties affecting estimates of demand, for the United Kingdom as a whole, in the late 1960s and early 1970s have been commented on in the Introduction and in Chapter 5, The Organisation of Blood Transfusion in Scotland.
10.6 This chapter will necessarily fall short of a comprehensive analysis of supply and demand, on the evidence that has been examined to date. However, it summarises the events and issues which arose throughout the reference period of the Inquiry.
10.7 The Cash and Spencely projection of demand, as at 1976[1], of 15,000 donation units of Factor VIII[2] per patient per year (rising to 20,000 if the only therapeutic material were intermediate purity Factor VIII (IFVIII)) for the south east of Scotland was based on data relating to 75 haemophilia patients. The regional population at the relevant time was
1.2 million. Of the 75 patients, 40 had severe haemophilia, 16 were moderately affected, and 19 had a mild condition. Cash and Spencely note that the proportion of patients with severe haemophilia might vary in other parts of the country. Subject to that, the estimate would point, broadly, to a Scottish demand of 6.3 million units (applying the conversion factor used by the authors of 1:120 for Cryoprecipitate) rising to 8.4 million units per year on the assumption of a total shift to intermediate Factor VIII, equivalent to 52,500 to 70,000 donations. According to SNBTS records, there were 418 known haemophilia patients in Scotland in 1976.[3]
10.8 Internal estimates by SNBTS of requirements at 31 March 1976 were based on an estimated average use of 10,000 units per patient, some 4 million units in total. The quantities of Cryoprecipitate prepared and issued by Scottish RTCs for the whole of Scotland over the second half of the 1970s, and the total volumes of intermediate FVIII products issued by PFC Liberton were:
Cryoprecipitate Issued: donations
Approximate international units x m4
Intermediate FVIII international units x m 5
Approximate Donations for IFVIII production
Table 10.1[4][5][6]
10.9 The conversion factor for IFVIII appears, arithmetically, to have been 240 IUs per donation.[7] The actual use in 1975–76 appears therefore to have exceeded the internal estimate by about 19%. But it fell below the volumes proposed by Cash and Spencely.
10.10 The data in Dr Cash's paper can be compared with data contained in the SNBTS national statistics. There are minor variations between the data reported for Cryoprecipitate issues. The comparative data expressed in donations are:[8]
Dr Cash
Table 10.2
10.11 The differences do not appear to be material for present purposes, and Dr Cash's presentations to the joint meeting are adopted here for discussion purposes.
10.12 However, the overall position remains far from clear. The data on commercial purchases were thought to be unsatisfactory. Dr Cash reported that satisfactory figures were available for 1979 and 1980 alone, that until 1980 commercial purchases were made exclusively in the west of Scotland, and that 1981 figures would show that other regions were currently making commercial purchases. The commercial purchases noted in the report were: 1979–850,000 IUs; and 1980–1 million I.U.s. Dr Prentice had produced figures for Royal Infirmary, Glasgow which showed values for commercial Factor VIII usage for the three years 1978 to 1980 of 273,670, 282,527 and 116,071 units respectively, in addition to FEIBA of 128,500, 97,900 and 144,000 units respectively. The differences have not been resolved.[9] They reflect, in part at least, the unsatisfactory flow of information from the regions to SNBTS nationally and to PFC Liberton in particular that is commented on elsewhere in this report. For present purposes, the data in Dr Cash's reports have been adopted in painting the general picture in terms of quantities.
10.13 Combining the data above with the summary data for Cryoprecipitate issued by the regions, PFC production of Factor VIII and commercial purchases, as presented in Dr Cash's report, and expressed in IUs x million the totals were:
IUs x million 1975
Cryoprecipitate*
PFC Factor VIII
* Assumed each donation gave 100 iu of Factor VIII
Figures in brackets were Dr Cash's 'guesstimates'
10.14 So far as Factor VIII concentrates are concerned, and taking Dr Cash's 'guesstimates' at face value, commercial purchases over the four years from 1977 to 1980 amounted to 27.3%, 31.1%, 33.8% and 33.4% respectively of total usage.
10.15 Public perceptions at the time are reflected in the SNBTS report for the year ended 31 March 1976 which stated:
Of all the blood products available, the only one which has aroused an emotive response in the UK (Scotland is less vociferous) is the supply of Factor VIII and its use in the treatment of haemophilia. Parliamentary questions, newspapers, wireless and television have all been used to publicise the demands of pressure groups, mainly from lay sources. Propaganda has been along two main lines – a demand for immediate implementation of home therapy regimes (the administration of Factor VIII in the home by the patient, relatives or the general practitioner when a bleeding episode occurs) and the philosophy that the haemophilia patient should lead a perfectly normal life.
Home therapy holds out the undoubted advantages of early treatment, hence lessening the risk of sequelae such as ankylosing joints, and the convenience of the patient. Intermediate Factor VIII, being less bulky than cryoprecipitate and remaining potent in a domestic refrigerator as opposed to deep-freeze requirements for the latter, is certainly the product of choice and the BTS must endeavour to meet demands as soon as possible. Cryoprecipitate, however, has proved a most valuable preparation and a gradual changeover to intermediate Factor VIII can be achieved without recourse to commercial preparations.
Haemophilia patients have a permanent disability and, as in all physical handicaps, should live within it. Encouragement to lead a perfectly normal life involving increased hazards of traumatic haemorrhage not only increases the chances of ankylosing complications, but involves considerable additional quantities of a valuable therapeutic agent, human Factor VIII. The importance of this can be gauged by the fact that some 90,000 donations are required to meet Factor VIII requirements for some 400 patients in Scotland annually.
10.16 Total donations in the year ended 31 March 1976 amounted to 262,502. 90,000 would have been 34% of the total. The annual report states that 15% was issued as Cryoprecipitate. 3279 donations were used in the preparation of IFVIII, which amounted to 1.25%. However, the detailed figures in the SNBTS report do not disclose commercial purchases.
10.17 In dealing with future requirements, the SNBTS annual report states:
Future requirements. As supplies of Factor VIII increase, a major factor which requires urgent study is the optimum dose for the average case of spontaneous haemorrhage in a haemophilia patient. The use of cryoprecipitate reveals very wide differences in the amount judged necessary, varying from 6–60 units of cryoprecipitate (in this context a unit is the material from one donation). This problem required concerted study by the directors of haemophilia centres; such an effort was agreed by Directors of Regional Transfusion and Haemophilia Centres and detailed arrangements accepted at an ad hoc meeting between representatives of the major centres, Glasgow and Edinburgh, in December 1975. Until dosage is resolved, future requirements must remain conjectural.
10.18 Though reducing with time, the volumes of Cryoprecipitate issued reflect a high and continuing use of the material over the six years when PFC Liberton was coming into production. Use was to fall after 1979–80, averaging about the equivalent of 12,500 donations over the following decade. However, at the end of the decade, Cryoprecipitate remained the major therapeutic product of Scottish origin in use. In the document prepared by Dr Cash from which the PFC Factor VIII data are taken,[10] it was reported that satisfactory figures for commercial purchases of Factor VIII were available only for 1979 (850,000 IU) and 1980 (1 million IU). In the final year of this period, Cryoprecipitate and Factor VIII from all sources were broadly in balance. But commercial purchases amounted to about one third of total Factor VIII issued or purchased at local level.
10.19 On the documentary material examined thus far, it would appear that there was inadequate information available at this period for reasonably accurate forecasting of demand, and that future requirements for domestic production were indeed conjectural.
10.20 As commissioning of PFC Liberton proceeded and full production capacity was established the production of blood products increased rapidly. But the total production of intermediate Factor VIII concentrate remained relatively low both in absolute terms and as a proportion of the total output of the plant. The annual report of the SNBTS for the year ended 31 March 1976 provided a reasonably clear picture of the scope of the service's operations at the beginning of the reference period, and, in particular, of the operations at the Protein Fractionation Centre, Edinburgh (PFC Liberton), where most of the more sophisticated procedures were developed over the reference period.
10.21 Data recorded for the period spanning 1974 reflected the developing position. The production by PFC of anti-haemophiliac fractions (AHF), anti-Rhesus D Positive cells (Anti D) and stable plasma protein solution (SPPS) shows the following pattern (expressed in units of production):
Anti D
SPPS
10.22 Other relevant data supplied by a comparison of factor production between the pre- and post-1974 positions as provided in the SNBTS report for the year to 31 March 1976:
Coagulation Factor
IFVIII
II, VII, IX, X
(combination)
II, IX, X
10.23 Production was disrupted during the closure of the ERI facility and the commissioning of PFC Liberton. Otherwise total production was increasing. But the production of intermediate anti-haemophilia fractions (IFVIII) formed a small proportion of total production relative to anti-Rhesus D Positive cells and stable plasma protein solution.
10.24 Scotland was self-sufficient in the production of fibrinogen.[11] The demand for Factor IX products for the treatment of Haemophilia B, though increasing, was substantially met in Scotland as throughout the United Kingdom. Total demand for Factor IX was low relative to the demand for Factor VIII, and since the same source plasma was used for both products, production capacity for Factor IX was never a problem at this time. For the UK as a whole, Dr Biggs published information on the period 1969–74,[12] and the haemophilia centre directors supplemented that for 1975.[13] In her report of 1974, she stated:
For Christmas disease patients there is now enough material to give all of the treatment estimated to be required in the form of concentrate. The position is much less satisfactory with regard to haemophilia and factor VIII….The two most valuable materials now made are cryoprecipitate and freeze-dried factor-VIII concentrate. The total amount of these preparations at present available is inadequate….
10.25 That was and remained the position in Scotland at this time. The production of Factor VIII by PFC Liberton made an immediate impact,[14] but it was not sufficient.
10.26 Demand for Factor VIII varied from case to case, making estimates of total demand difficult. There was an immediate background to some of the observations in the 1976 report. In one region, two boys were creating particularly high levels of demand for different reasons.[15] One was likely to be admitted to a remote school with facilities that would have avoided or reduced exposure to risk. Cryoprecipitate could not be stored at the school and that created a high demand for Factor VIII. The other boy, with the encouragement of his parents who were influenced by 'the pressure group from Oxford and elsewhere', had been encouraged to 'lead a normal life' increasing the need for therapy. In 1976 he required 61,990 units of Factor VIII, over 4% of the total concentrate issued by PFC Liberton in the year.[16] Apart from other issues raised, these examples demonstrate some of the factors causing practical difficulties in forecasting demand at the time.
10.27 Looking to the needs of Scotland as a whole, the SNBTS 1976 report envisaged limited continued production of Cryoprecipitate; a major change-over to Factor VIII concentrate; development of a more concentrated form of Factor VIII for certain uses; and agreement with NBTS, England and Wales, on a standard range of products. The main targets set for transfusion directors were:
• increasing use of red cell concentrates instead of whole blood;
• releasing plasma for production of Factor VIII concentrate; and
• increasing supplies of raw materials to PFC Liberton, particularly in the form of fresh frozen plasma, for production.
10.28 The report's conclusions on Factor VIII (Cryoprecipitate and IFVIII) were:
As regards self-sufficiency, Factor VIII is available to treat adequately the known haemophilia population in Scotland. The form in which it is available does not as yet meet the major demand for home therapy. Present policy is to issue intermediate factor to centres, with only a very small national reserve at PFC; directors of haemophilia and regional transfusion centres are expected to maintain their own reserves and patients should be introduced to home therapy only when an adequate reserve–three months' anticipated use–is available for each individual in case PFC meets manufacturing difficulties.
A most important factor in the future requirements of fresh plasma for fractionation of Factor VIII is the loss of activity which occurs at this stage, both in Centres and the PFC….
10.29 Manufacture, supply and self-sufficiency in Factor IX products presented no difficulties. Self-sufficiency in supply of Factor VIII depended, however, on the continuing use of Cryoprecipitate, with gradual change to the use of concentrate as it became available. While the report may reflect the aspirations of SNBTS directors at the time, regional variations in clinical practice were to emerge and influence realisation of these plans.
10.30 As the tables above demonstrate, in terms of volume, production at PFC Liberton was heavily weighted towards the production of anti-Rhesus D Positive cells and stable plasma protein solution. It appears that one reason for the failure to accelerate the production of Factor VIII concentrate may have been the failure of some regions to supply PFC Liberton with plasma.
10.31 Total plasma supplies to Edinburgh over the relevant period, expressed in litres, were recorded as:[17]
10.32 Despite the opening of the facility at Liberton, and the demand for plasma that it created, supplies of fresh frozen plasma from Aberdeen, Dundee, and Glasgow to Edinburgh did not increase significantly until 1976–77. The SNBTS directors had rejected Dr Cash's proposals for servicing PFC Liberton in 1975, promising to 'do their best' to provide material for processing.[18] Edinburgh and Inverness alone made an immediate increase in supplies. Inverness at the time had two major users of Factor VIII, and supplies to them of PFC product were higher than average.[19] There was a particular incentive for Inverness to provide PFC Liberton with the raw material required for production of concentrate. Edinburgh exceeded its target by a comfortable margin.[20] But, overall, as at the beginning of 1976, plasma intake at PFC Liberton had reverted to 1972 levels. Glasgow, at this time and for some time into the future, advocated the use of Cryoprecipitate in the treatment of Haemophilia A. In a memorandum dated 19 January 1977 addressed to regional directors, Mr Watt commented that during most of 1976 the process capacity at PFC Liberton was much larger than the availability of fresh plasma.[21]
10.33 The supply of plasma, and the information required to assess demand, continued to be topics for discussion. Early in 1977 there was a proposal that a haemophilia register for Scotland should be established. A paper was distributed with the agenda[22] for a meeting of the SNBTS and haemophilia directors on 24 January 1977.[23] It emphasised the advantages that would accrue from an appropriate register, including data on the changing age-range of haemophilia patients, consequent changes in demand for therapeutic products, and changes in demand relating to changed therapeutic methods, such as the increase in home treatment. A register had been maintained by the Medical Research Council until 1966. The proposal for the register and its uses (including informing the estimates of use of Factor VIII) was held over for future discussion. The directors met again on 30 May 1977 when the register was again discussed without resolution of the issue.[24] So far as material for present purposes, the result was that there was no ready means of estimating demand from data held centrally by SNBTS.
10.34 At the meeting on 30 May, Mr Watt reported increased supplies of plasma from Glasgow. Dr Wallace replied that this had only been possible because Glasgow had purchased a substantial amount of commercial material to tide them over the initial period of PFC Liberton production.
10.35 At a meeting of SNBTS directors on 12 July 1977, Mr Watt reminded directors that the absolute amount of plasma being collected from the regions was insufficient to meet the demand for SPPS[25] and other products. This seems to have had a beneficial effect: on 12 October 1977 it was reported that there was an increase of almost 40% in the plasma supplied to PFC Liberton compared to the same quarter in 1976.
10.36 On 9 January 1976, Dr Cash, then Director of the Edinburgh and South-East Regional BTS, wrote to General Jeffrey proposing a framework for future operations.[26] The letter was copied to Mr Watt. Mr Watt was pessimistic. [27] He had been disappointed when the regional directors had rejected Dr Cash's proposals for annual estimates of supply to PFC Liberton of fresh frozen plasma. He was concerned inter alia about the 'peregrinations of the plasma supply situation'. He thought that the targets implicit in Dr Cash's framework were unlikely to be achieved. It appears that independence of the regional organisations may have had a materially adverse impact on operations at national level.
10.37 In the mid-1970s, PFC Liberton responded to the shortage of plasma supplies by developing Factor VIII concentrate from supernatant. The Glasgow and West of Scotland Service indicated a distinct preference for Cryoprecipitate.[28] The background to the development is of interest. Mr Watt explained to Dr Wallace that the preparation had been conceived as a stop-gap measure to occupy the time of staff at Liberton who had been employed for making the intermediate Factor VIII but who had become inactive due to the failure of fresh frozen plasma supplies.[29] It appears that while the south east region was providing PFC Liberton with fresh frozen plasma, Glasgow and west of Scotland in particular, but also the other regions already referred to, were not. PFC Liberton's production capacity was not being utilised to best advantage.
10.38 On 5 February 1976, Dr Wallace intimated that Glasgow and west of Scotland would not use Factor VIII produced from cryosupernate.[30] The reason given was that clinicians at Glasgow Royal Infirmary considered it essential to continue to produce large quantities of Cryoprecipitate locally, preferring to rely on Cryoprecipitate rather than any other Factor VIII product. Superficially at least, that would have been a major change of direction from that found by Strathclyde University for the period up to 1974.[31] However, there was a change of attitude in May 1976:[32] one clinician was prepared to use the material, subject to conditions. Mr Watt asked for patience for 'a young organisation stumbling towards a reasonable level of perfection on many fronts at the same time'.[33]
10.39 It appears that Mr Watt failed to get the favourable response he sought. In a letter to Dr Wallace dated 15 June 1976,[34] he acknowledged some production problems, but stated that, despite these, PFC Liberton's production of Factor VIII was using fresh frozen plasma within two weeks of its arrival at Liberton. There were no buffer stocks, and with the approach of the holiday period supplies of plasma were beginning to fall. He expressed his disappointment at the refusal of Glasgow Royal Infirmary to use Factor VIII manufactured from cryosupernatant; and suggested that, unless overall usage had increased, the consultant's use of commercial products 'can only mean that he has a personal preference for the commercial product'. He wrote:
It appears to me that the time has now come when a register of haemophiliacs should be established and the Haemophilia Treatment Centre should be required to show who got what and how often on a monthly basis. Since there are fewer than 500 patients and only 20% of these are regularly important to the overall supply problem it would seem that the compilation of such a register and its maintenance would be a relatively minor operation. One realises that this could be construed as an infringement on the clinical responsibility of the Haemophilia Centre Director but it must also be part of that responsibility to assist the assurance of adequate supply of product. In a situation where the Minister of Health has instituted a policy of national self-sufficiency (which we have all applauded to some extent) it becomes essential to define what we mean by self-sufficiency. Various estimates have been prepared both for Scotland and for the UK as a whole and we have all attended far too many meetings in discussion of the problem to reach, at the present time, what appears to be a point of total confusion.
10.40 The consultant's response, in a letter to Dr Wallace dated 17 June 1976, did not appear to resolve Mr Watt's concerns.[35] Meantime, Factor VIII manufactured by PFC Liberton from cryosupernatant was used in Edinburgh, and by Dr Jones in Newcastle.
10.41 In February 1977, the Royal Hospital for Sick Children, Glasgow, began to administer Factor VIII prophylactically to a few severely affected haemophiliac children.[36] In order to assess the cost-effectiveness of this procedure, they sought information about the NHS cost of Factor VIII and DEFIX. Mr Watt could not provide reliable figures for a number of substantial reasons. He gave data which might be helpful, but warned the RHSC doctors of the dangers of getting this type of accounting exercise wrong.[37] The proposal appears to illustrate the scope for independent research over the country as a whole that might be conducted at this time without reference to its impact on the national supply position.
10.42 Comparative Factor VIII yields, as between PFC Liberton and the English fractionation centres at the PFL and BPL, became an issue in March 1977. Dr Bidwell at PFL wrote to Mr Watt on 16 March proposing a joint study.[38] Mr Watt was not enthusiastic.[39] He thought that because processing at PFC Liberton was undergoing steady review the exercise should be postponed until PFC Liberton was in a stable situation. Dr Bidwell returned to the proposal on 4 April 1977.[40] The exchange duly went ahead.[41] Mr Watt remained concerned about the yields achieved at PFC Liberton. On 30 September 1977 he wrote to Dr Cash with observations on the Factor VIII content of plasma delivered to PFC.[42] The plasma tested was all of a 'stale', eighteen-hour old, variety, with too low a content for easy recovery. He sought Dr Cash's advice on how to tell regional centres that the source material was not good enough. Dr Cash replied on 6 October 1977,[43] criticising Mr Watt's approach. Mr Watt responded by suggesting a policy of returning 'unto the regions that from whence it came'.[44] However, it is significant that the issue of plasma quality was flagged up at this early stage: it was to become a persistent issue.
10.43 PFC Liberton was shut down for a period in 1977. The failure to process during that period had an impact on the Factor VIII supplies available in October 1977.[45] At the same time, supplies of SPPS were restricted.
10.44 In a letter to Dr Davidson at the Royal Infirmary, Glasgow, dated 25 January 1978, Mr Watt commented on PFC output.[46] The limiting factor affecting the production of Factor VIII concentrate was the slow transfer of resources from the production of Cryoprecipitate to intermediate concentrate. The supply of PPSB was entirely dependent on the supply of suitable plasma. At least double the current production was required to meet need. Mr Watt hoped that the information would stimulate regions to respond. He believed that 1978 was well set for the transfusion service to make substantial inroads on the demand problems which clinical practice had created, but he was not optimistic.
10.45 In addition to problems relating to the supply of plasma for processing, research and development work at PFC Liberton was affected by a supply problem. In 1977 the lack of haemophilic plasma substrate left over from routine production to support research activities became critical.[47] Fresh frozen plasma had been stockpiled. Dr Erskine of Glasgow Royal Infirmary made supplies of substrate available. Mr Watt estimated that the quantity of Factor VIII-deficient plasma required was about 250ml per month. Actual supplies between 19 October 1976 and 6 February 1978 had fluctuated between zero and 800 ml.[48] PFC Liberton returned to the question of Factor VIII-deficient plasma[49] required for in-process quality control in March 1978.[50] The continuing supply problem was now affecting routine production.
10.46 A shortage of Factor VIII-deficient plasma in March 1978 led to two developments: an increase in the supply of haemophilia plasma (haemophilic plasma substrate), and an increased interest in the use of artificial substrate.[51] The latter product was considered inappropriate, but had to be used.
10.47 The data available on supplies of units of Factor VIII concentrate to areas in the second quarter of 1978 are:
196,00052
Table 10.7[52]
10.48 Mr Watt's criticisms became focused in a letter to the national administrator dated 8 August 1978:[53]
Once again…we reached parlous straits of supplies of Factor VIII Deficient Plasma to facilitate assay of concentrate. Iain Cook had made a special arrangement whereby Mr X of Wick will travel once a month to Inverness to donate plasma and return to Wick. Dr Cook will pay his transport expenses. X has been consistently one of our best sources of Factor VIII Deficient Plasma and does a great deal to plug the gap left by our less public spirited colleagues in the West of Scotland….
In an attempt to stimulate talk in haemophilia circles I have suggested to Dr Cook that Mr X and his wife be invited to visit Edinburgh and the PFC so that they can see for themselves where this rather special and expensive donation goes….
10.49 Dr Mitchell's response to the criticism was to offer some long-dated donations that were thought to be redundant to Glasgow and west of Scotland needs.[54]
10.50 On 14 March 1979, the DHSS wrote to all regional and local health authorities intimating that the central contracts for the supply of Factor VIII would expire on 30 April and would not be renewed.[55] As from 1 May, arrangements for the purchase of the product would be made by individual authorities. The department identified as possible suppliers: Armour Pharmaceuticals; Immuno Ltd; Travenol Laboratories Ltd; Abbott Laboratories Ltd; and Speywood Laboratories Ltd. Neither of the public sector producers was mentioned in the letter. The policy change increased dependence on information from local centres about levels of commercial purchases.
10.51 In July 1979, the results of a study of the economic and societal aspects of home therapy were said to leave no doubt of the overwhelming advantages of home treatment (using concentrates) as part of the management of severe haemophilia.[56] The study contained explicit criticism of the NHS costing of concentrates. This was immediately controversial in Scotland.[57] Mr Watt prepared a draft letter to The Lancet setting out comprehensive costing data for PFC Liberton.[58] Dr Cash suggested factors to mention.[59] The rebuttal appeared on 11 August 1979.[60] On the face of it, Mr Watt had made a case for the selection of the NHS product on cost grounds.
• By the end of the 1970s, the flow of information to the SNBTS nationally, and to PFC Liberton in particular, relative to demand for Factor VIII was unsystematic, sporadic, and inadequate for the purpose of instructing a rational assessment of demand for the NHS product.
• One potentially effective vehicle for communication, a national haemophilia register, was proposed, but the proposal had not made progress within the haemophilia directorate.
• PFC Liberton's physical production capacity was sufficient to ensure the output of Factor VIII concentrate in volume to match demand for PFC Liberton intermediate Factor VIII, but was not regularly engaged because:
– There were inadequate supplies of plasma from regions for processing;
– Plasma was of variable quality and often less than optimal for Factor VIII production; and
– There were often inadequate supplies of Factor VIII deficient plasma for quality assay of the product with the result that production was disrupted, and research and development work inhibited.
10.52 In the early 1980s there was progress in the production and use of therapeutic materials. Scientific developments in the heat-treatment of factor concentrates together with AIDS infection had an impact on the work of Scottish transfusion centres, and on the work of PFC Liberton in particular. Research and development work on pasteurisation began at PFC in 1981 with a view to reducing hepatitis infectivity. AIDS became an issue after the initial publication of the disease in 1982. Meantime, the production of standard therapeutic products continued, but not without difficulty. Significant up-grading of facilities was required.
10.53 Over the country as a whole, regional transfusion centres continued to collect whole blood: there was a 44% increase in volume between 1974–75 and 1989–90. Apheresis donations increased over the same period from 3312 to 15,542.[61] Over the decade, whole blood transfusion fell to a very low proportion of all uses of blood donations, as already noted. The data collected changed from year ended 31 March 1982. Regional transfusion centres returned quantities of the materials which they had dispatched to PFC Liberton, now distinguishing fresh frozen plasma, outdated plasma, plasma for EDTA, and other materials. The relationship between total blood donations and quantities processed at local centres became less clear. On any view the picture by the end of the decade had become considerably more complex as a result of pressures, internal and external, affecting the functioning of the service.
10.54 The range of products produced, retained locally and placed at issue for local use in regional transfusion centres at the beginning of the period comprised, principally, red cell concentrates, fresh frozen plasma, platelet concentrates, and Cryoprecipitate. By the final year of this period, products produced and placed at issue in regional transfusion centres comprised whole blood, platelet depleted blood, buffy coat depleted blood, red cell and specialised red cell products fresh and frozen, platelet concentrates, white cell products, Cryoprecipitate in three unit sizes, and fresh frozen plasma. Regions produced and sent to PFC fresh frozen plasma, non-fresh frozen plasma, cryosupernatant, anti-D and other hyperimmune products.
10.55 For its part, PFC Liberton, by the end of the 1980s, produced and sent to regional transfusion centres stable plasma protein solution (SPPS), Factor VIII concentrate, Factor IX and a range of immunoglobulin preparations. But it appears that complete coordination of PFC Liberton's production with regional needs had not been achieved by the end of the decade. The production capacity of PFC Liberton fluctuated over the period, partly due to interruptions during the refurbishment programme and partly due to operational changes. The information available is confused, however, largely because the records examined by the Inquiry team are not comprehensive.
10.56 The decade does not break down into self-contained parts. But major events allow some sub-division. Early investigation of heat-treatment in the manufacture of concentrates, and the emergence of the AIDS risk, broadly define the first period.
Productive Capacity
10.57 For a meeting of SNBTS and haemophilia directors in January 1981, Dr Cash prepared figures for fractionation yields which showed considerable improvements in Factor VIII activity recovery over the period from 1975 to 1980 and forecast further improvements.[62] He forecast improvements in Cryoprecipitate yields with improved procedures. Converting the target into raw materials requirements, he produced the following table:
Litres of FFP per annum
Litres per million of population per annum
To produce cryoprecipitate only
To produce intermediate Factor VIII
To produce high purity Factor VIII
10.58 However, in 1980, yields at PFC Liberton were proving to be variable. On 29 August, Mr Watt reported to Dr Cash.[63] Dr Foster thought that, with the development work then in hand, a production yield of >300 IU per litre was achievable. But actual yields, ranging from 177 to 280, indicated that all parameters were not at that stage under control.
10.59 In December 1980, Dr Foster estimated the capacity of PFC Liberton at 975 kg of plasma per week, identifying the limiting factor as freezer capacity.[64] However, working practices affected the actual throughput. In terms of productive capacity, there was a significant increase in 1982–83. In the first two months of 1982, the total processing capacity of PFC Liberton, on existing work practices, was 720 kg of fresh frozen plasma per week, ie about 8500 kg per quarter. Average weekly plasma intake was 700 kg. PFC Liberton were able to process 610 kg only (about 7250 kg per quarter) because there were some short periods of downtime related to plant renovation.[65] Mr Watt hoped to increase throughput by about 100 kg during the next six months. That would have raised throughput to about 8500 kg per quarter, the plant's productive capacity before plant renovation, on the existing staff hours. However, by October, the net process load had exceeded 1300 kg per week, achieved by a combination of increasing plant capacity, amended process scheduling and staff effort. Substantial extension of overtime working had been instructed.[66]
10.60 Even so, at the beginning of the 1980s, there was a perception that the PFC Liberton facility was under-utilised, or alternatively that the productive capacity could be expanded. Within PFC, the first view prevailed, and tended to be expressed in the context of criticism of commercial purchases of products which PFC Liberton could produce. Outwith PFC, the scope for expansion was emphasised. In September 1980, there was a proposal in England that Beechams should take over BPL. This provided a focus for examination of the potential capacity of PFC. In a paper, from X of MED SM4, Room 919 HAN H (who may have been Diana Walford) to Y there is reference to the Scottish position: [67]
3. I have just visited PFC Liberton with colleagues from HS2. Although we have no formal information about its capacity to expand production, it was conveyed to us informally that Liberton had a substantial capacity for expansion, notwithstanding staffing difficulties etc. If Liberton were to take on 1/4–1/3 of the England and Wales fractionation requirements in addition to meeting Scottish needs, UK vulnerability in the event of Beechams pulling out would be reduced and the price of Beechams (or imported) products might be kept down. My impression from that meeting was that the Scots are very willing to consider UK fractionation as a whole and that, having provided the DHSS (through the SHHD) with detailed schedules of their products and performance since commissioning of the plant, anticipate expanding production by an agreed amount for the benefit of England and Wales....
10.61 In April 1980 Dr Cash had obtained information that BPL was commissioning a third freeze-drier, but that on full commissioning the plant's capacity would still fall short of the target for England and Wales.[68] Nothing short of re-building of the plant would do. The option of utilising spare Scottish capacity was not taken up in the event. However, after lengthy negotiations, arrangements were made for the processing of material for Northern Ireland. Arrangements with Northern Ireland were first proposed at a meeting of SNBTS directors on 27 March 1981. The quantity expected for processing was 10,000 litres a year, 2000 of which would be fresh frozen plasma.
10.62 A 'wait and see' decision on the proposal was recorded at that time. At the subsequent meeting of the group on 23 June 1981, it was reported that a formal approach had been made by Northern Ireland, that discussions were under way with CSA, and that PFC staff were to visit Northern Ireland to discuss logistics. On 22 September 1981, the SNBTS directors returned to this issue. It was recorded that the present request from Northern Ireland was for processing of 7000 kg of plasma per annum, which could rise to 12,000 kg. The minute noted:
Taken together with the 'Trends' programme for Scotland, this could mean a combined NBTS/SNBTS requirement for 1750 kg/working week, ie in excess of the existing capacity at PFC operating on a single period of work each day.
Approval was given to the courses of action proposed by Dr Cash, namely a working group from CSA, SNBTS and SHHD who would examine the steps necessary to meet the request of the DHSS, Northern Ireland. The terms of reference were agreed and Dr Cash agreed to approach CS Secretary to establish this Working Group.
10.63 It was decided that Mr Watt would not take in any plasma until a formal agreement had been reached. Agreement was subsequently reached, and the demand from Northern Ireland formed part of the background to the provision of increased production capacity during the refurbishment work.
10.64 The Inquiry team has found no support for some external comments on PFC Liberton's capacity. The perception that PFC Liberton was under-utilised even before the refurbishment seems to have been well founded: working practices appear to have restricted the plant's operating capacity, and the response to Northern Irish interest reflected a belief that increased production was feasible. But the extent of the under-utilisation appears to have been misunderstood. In an article by DO Gordon published in Medical World in September/October 1981, it was claimed that PFC Edinburgh could process blood to serve a population of around 25 million.[69] The claim appears to have been exaggerated: the Inquiry team has not found evidence of such capacity.
10.65 On 29 December 1980, Dr Foster reviewed PFC Liberton's capacity to meet demand in 1981.[70] A new full-scale thawing tank would be ready, removing an existing limiting factor on production. The several operations and procedures currently in use were reviewed to identify the new limiting factor: freeze-drying capacity. His conclusion was that with the existing vial size the capacity of PFC Liberton was limited to 975 kg plasma/week for Factor VIII recovery. Changing the vial size and increasing the number and size of freeze-driers were the preferred options for increased productive capacity. On 13 April 1981, Dr Dickson analysed the limitations in PFC Liberton's system of Factor VIII preparation.[71] He also concluded that the critical limiting factor was the plant's freeze-drying capacity. Failure of the main (Usifroid) drier for any period of time would mean that the plant could not process plasma as it was received. He noted separately that at 40,000 to 48,000 kg of plasma intake per quarter, PFC Liberton's deep freeze capacity was sufficient to handle only three to four weeks' processing.[72]
10.66 On 5 May 1981, Mr Watt wrote to Dr Cash reviewing capacity. PFC Liberton's ability to process plasma was weakened because increased input had come close to freeze-drying capacity. Two heavy bulk driers were obsolescent and had limited uses. One, a Leybold machine, commissioned in 1974 to deal with Factor VIII and Factor IX at then levels of production, had limited capacity. It had recently broken down. Along with the Leybold, the fourth machine (a Unifroid model) had sufficient capacity, subject to shelf modifications, if it could be relied on to work at 90% efficiency on a continuous basis for 40 weeks a year. However, any interruption of production, for example to investigate product failure or because of plant break-down, or closure for major maintenance, would threaten that operation. In addition plasma storage capacity was limited. Further improvements in yield were exacerbating the processing and storage position. He commented:
It is not possible to say precisely when the present delicate balance will collapse completely but I would judge that there is a real possibility of such occurring before April 1982 (the Inspectorate would say June 1981 without being too unreasonable).
10.67 He proposed that a new machine should be installed before April 1982. Mr Watt returned to the subject again on 1 June 1981.[73] Dr Foster had achieved major improvements in yield: the problem was more acute. Further, to increase the freeze-drying capacity would require an upgrade of water-cooling capacity.
10.68 The SNBTS directors met on 23 June 1981.[74] The Medicines Inspectorate had intimated an intention to carry out formal inspections of regional transfusion centres later in the year.[75] In anticipation there was to be a meeting of representatives of the directors and the inspectorate. The SNBTS directors met again on 22 September 1981.[76] Dr Cash thought that the inspection was unlikely to be too rigid during the next five years.[77]
10.69 The up-grading of facilities for bulk freezing of plasma was an issue at regional level, as it was at PFC Liberton. On 11 November 1981, Dr Boulton made proposals for improvement of the freezing process at Edinburgh and South-East Region BTS.[78] Mr Watt responded on 13 November 1981.[79] The problem was affecting almost every regional centre, and he wanted a common solution. Proposals were made for the selection of equipment, the specification of plasma containers, and the process specification required to ensure uniformity. He thought Dr Boulton had raised so many issues that all regions should be consulted on the way forward.
10.70 On 14 December 1981, Dr Mitchell wrote to Dr Cash intimating that the Law Hospital Drying Plant would have to close, despite efforts to upgrade it.[80] The Law facility had been central to the west of Scotland's Cryoprecipitate development and production.
10.71 On 10–11 March and 10–12 May 1982 the Medicines Inspectorate visited the Blood Transfusion Service in Edinburgh. The facility was in the process of being refurbished. The manufacturing licence had expired on 30 June 1981 and no renewal application had been made. The inspectors raised questions relating to the blood transfusion service in Scotland; about the collection of blood; and other operational matters. There was discussion on the need for Cryoprecipitate, including the reduced risk of contracting hepatitis from a small donor pool. The inspectors recommended that the centre investigate the possibility of using accredited donors in an attempt to reduce the risk. The inspectors also recommended a national policy of distribution for PFC Liberton Factor VIII so that supply would go to the centres with the greatest needs. Their overall assessment of the facilities was critical: 'Existing facilities are quite inadequate and must rank amongst the worst seen anywhere.' The facilities at PFC Liberton required extensive refurbishment and development. Three months of down time had to be anticipated.[81]
10.72 The SNBTS directors met on 16 March 1982.[82] Mr Watt explained that PFC Liberton's current freeze-drying capacity allowed him to fractionate 720 kg per week, and that 610 kg per week was processed on average. The directors met on 15 June 1982.[83] The cessation of production of freeze-dried plasma in the Law Hospital plant remained controversial. But it was agreed to recommend that it be suspended.
10.73 One of the criticisms made by the Medical Inspectorate had been that in the SNBTS the acceptance of a donor was 'largely a matter of chance'. Dr Cash considered this a gross exaggeration, but nevertheless acknowledged that consistency between centres had been less than desirable.[84] He asked Dr Ewa Brookes to look into the problem. (Dr Brookes produced a second draft of 'Notes for Transfusion' in January 1983.)[85] The general tenor of the Inspectorate's views was summarised in a letter Dr Cash sent to the Common Services Agency on 21 July 1982 after the inspectors had visited all of the centres:[86]
I think it is important that I put on record, even at this very early stage (the Final Reports have not yet been issued), that the Agency will, in my opinion, have to face up to a major series of building/refurbishment programmes within the foreseeable future.
Briefly, the position is as follows:-
Aberdeen: The Inspectors are wholly dissatisfied with the proposed new facilities we are planning and I believe will insist that we proceed to plan a new Centre. They will be looking for a commissioning date of June 1987.
Dundee: The Inspectors will wish to see the proposed building plans we have expedited and will wish to be closely involved in detailed planning. They will be looking for an assurance that these new facilities will be commissioned in June, 1984.
Edinburgh: The Inspectors are profoundly disturbed by the existing Blood Bank/Issue areas – described as 'dangerously overcrowded'. They are also insistent on a move out of Livingstone House by June 1985. There is, in my view, an urgent need now for the Agency, at the highest level, to grasp the nettle with the Lothian Health Board….In short, there is at the present time no prospect that the serious and legitimate criticisms of the Inspectorate can be resolved and, in my view, the time has come for a clear initiative from the Agency. I would advise that this might start with the Regional Director.
Glasgow: The Inspectorate Reports will indicate that substantial works are required in all areas of storage and blood processing facilities. We are going to need clear and accepted (approved funding) proposals by June 1983.
Inverness: The rebuilding plans, already approved by the BTS Sub-Committee, will, in my view, meet the Inspector's criticisms. However, I should emphasise that the Inspectorate will wish to see these new facilities commissioned by December 1983.
10.74 Time would not be on the agency's side. If Dr Cash's assessment of the position was correct, the facilities in use by the Scottish service were not fit for purpose. Dr Cash wrote to Dr Wagstaff at Sheffield, asking for assistance on procedures. The decision to discontinue production of freeze-dried plasma (with the closure of the Law facility) affected plastic surgeons and burns units, but they were prepared to accept appropriate alternatives.[87] So far as PFC Liberton was concerned, it was anticipated that the change would free plasma for supply to PFC Liberton of the order of 4000 kg per annum, mostly in the form of cryosupernatant. That would involve an additional cost of about £33,000 including some overtime.[88]
10.75 By January 1983, it was expected that the closure of PFC Liberton for up-grading would begin in February, with a shut-down of one month.[89] By March 1983, it was recorded that improvements in recovery had enabled PFC Liberton to issue 6000 to 7000 vials of Factor VIII per quarter, processing 18,500 kg of plasma (against the previous figure of 6000), with an equivalent product of 12,000 kg.[90] The volumes cannot be reconciled precisely. But on any view, the progressive refurbishment of the Liberton facilities by the end of this period significantly increased the plant's productive capacity before the major refurbishment following on the inspectorate's report. Discussion of demand and supply within the period to the end of the financial year 1982–83 must relate to the capacity prior to these improvements.
Other Factors Affecting Demand and Supply 1980–83
Expansion of home treatment in Edinburgh
10.76 Dr Ludlam joined Edinburgh Royal Infirmary in about January 1980 as haematologist.[91] He immediately initiated a home treatment programme. Two brothers were proposed as candidates, with a projected demand of over 400,000 IUs of Factor VIII per annum. He had the support of Dr Boulton, who noted, however, that expansion of home therapy would result in a considerable difference in the pattern of Factor VIII usage in the region, with a move from Cryoprecipitate to concentrate, possibly offset by increased supplies of plasma to PFC Liberton. Mr Watt was not enthusiastic.[92] The proposal would disrupt the established distribution scheme, and special arrangements would be difficult to accommodate. He referred the issue to Dr Cash. Dr Cash wrote to Dr McClelland suggesting that he should intervene: a review of the distribution system was in hand.[93]
Use of Cryoprecipitate in Glasgow and West of Scotland
10.77 The Glasgow Centre's wish for continued operation of the plant at Law Hospital reflected the West of Scotland's stated preference for the use of dried Cryoprecipitate in the treatment of haemophilia patients. In January 1980, Dr Gabra of Glasgow and West of Scotland BTS, (Law Hospital) produced a paper promoting the advantages of Cryoprecipitate in the treatment of haemophilia.[94] He argued that the production of dried Cryoprecipitate was popular outside the UK, and that 'this dried product should have most of the advantages of the dried N.H.S. Factor VIII concentrates; namely the long shelf life, the easy storage and the pre-determined dosage.' The Glasgow team had therefore explored the possibility of producing lyophilised small-pool Factor VIII Cryoprecipitate from five donations and freeze drying these small pools. The experiment and production methods were described.
10.78 The approach had support (dating from March 1979) from the National Institute of Biological Standards and Control [NIBSC]. The proposal won the support of Dr Mitchell,[95] Dr Prowse[96] and Dr Cash[97] but not of Mr Watt.[98] Mr Watt dismissed the product as:
a step back in history…a suitable product for Turkey (perhaps) but not Scotland where we discarded a better product in 1972 as being unsuitable to the state of clinical practice.
10.79 The project was taken up[99] and only abandoned in Glasgow in 1983 following the closure of the facility at Law Hospital.[100] Further development was transferred to Edinburgh. It was a further illustration of the emphasis on yield and process in SNBTS research and development.[101] The project appears to provide one explanation of Glasgow's use of Cryoprecipitate, and may have been reflected in the area's concern at the requirement to service PFC Liberton's demands for plasma.
10.80 Nevertheless, it appears that there may have been an element of controversy relating to practice within the Glasgow and west of Scotland region in the first half of 1980.[102] At the beginning of the year, the emphasis had been on use of Cryoprecipitate. Actual consumption had fluctuated, depending on external factors such as the injury of a haemophilia patient in the aftermath of a football game. The BTS had held buffer stocks against such emergencies. PFC Liberton had, however, increased supplies of Factor VIII concentrate, demand for Cryoprecipitate had fallen, and stocks would be run down. There would be more plasma available for supply to PFC Liberton. Dr Hopkins of BTS at Law Hospital wanted to know whether PFC Liberton could respond to a sudden increase in demand that could not be met in time by increasing Cryoprecipitate production. Mr Watt's response was intended to relieve Dr Hopkins' concerns: PFC Liberton were getting better yields, more plasma was available, and supplies were reasonably secure.[103] Dr Mitchell came home from holiday, and immediately repudiated Dr Hopkins' assessment of the situation.[104] Cryoprecipitate would remain the sheet anchor of treatment in his region. He could not envisage a decline in demand for the product. He acknowledged the information that Mr Watt was hopeful that yields of Factor VIII in concentrate would be maintained.
10.81 On 19 September 1980, Mr Watt wrote to Dr Mitchell.[105] The letter related primarily to Glasgow's continuing use of Cryoprecipitate, but referred to two comments Dr Mitchell had made: that much would depend on the discussion of trends schedules for late in the year, and that 'the spiral keeps weaving in and out and we are in a difficult position in trying to stand still long enough to see just what the particular picture is that is emerging'. Mr Watt said:
The last two paragraphs of your letter create sympathetic harmonics for I have been convinced that the Scottish national policy (or lack of a policy) on factor VIII supply has been basically incorrect since the early sixties and remains in error as we attempt and fail to compensate for previous failures. The seeds of this long drawn disaster were planted more by accident than deliberate intent a long time ago and the sowers are probably no longer with us….I would like to think that the 17 October meeting would be a first stage in this process which should be cemented by 'trends' when it finally happens. Plus la meme chose?
10.82 Dr Cash thought that compromise in demand would be required as between Cryoprecipitate and intermediate purity products, with an experiment in producing freeze-dried Cryoprecipitate as was happening elsewhere.[106]
Surgery increasing demand
10.83 The impact of surgery in creating demand was illustrated in September and October 1980.[107] A relatively mild haemophilia patient had hip replacement surgery in September. After more than four weeks he was consuming 9000 IUs of Factor VIII per day and that was likely to continue for two to three weeks more. A second patient was consuming 2000 units per day, and the third 2500 units per day. Each of them might settle down within a week or so. The total of about 95,000 units per week compares with PFC Liberton's weekly production in 1980–81 of about 68,000 units.[108] A similar episode occurred in April 1981.[109] The patient was admitted for elective surgery without prior warning to the blood transfusion service. The unanticipated demand of 4500 units each day during the patient's recuperation strained local reserves and generated demand on the national reserve stock.
Projections of demand and production requirements
10.84 While there could never be totally reliable projections of demand, discussions in December 1980 led to proposals for a new scheme for distribution of PFC Liberton's Factor VIII concentrate. Mr Watt proposed that the first 15% of total product would be placed in the national reserve; 70 dose units or 4% of the total would be set aside for Inverness; and the remainder would be allocated in the proportions: Aberdeen 10%, Dundee 8%, Edinburgh 23%, and Glasgow 55%.[110]
10.85 During 1981, directors attempted to plan PFC Liberton's forward production requirements. The SNBTS and haemophilia directors had last met in 1977.[111] The Scottish Home and Health Department (SHHD) reconvened the group in January 1981 to discuss matters of mutual interest.[112] For the meeting Dr Cash produced what was to be the first of a series of papers focused on the future availability of products, and in particular Factors VIII and IX, within the NHS in Scotland. The paper,[113] and the discussion at the meeting on 30 January, continue the emphasis at this stage on yield, volume and factor activity. But there was now an increasing interest in virus transmission, and its impact on production. Infectivity was mentioned primarily in terms of the obligation to report untoward patient reactions to the Committee on Safety of Medicines.[114] Viral hepatitis transmission was thought to be a higher risk for Factor IX than VIII concentrates. Continuing efforts were being made to improve matters and a stage had been reached at PFC Liberton when clinical studies would soon be required. Thrombogenicity in Factor IX was also discussed, and Dr Cash recommended further development of Supernine and Factor VII as possible answers. There was no extensive discussion of infectivity in PFC Liberton's Factor VIII product. Otherwise, the report set the context for an examination of the productive capacity of the Scottish service at about the beginning of the decade.
10.86 The units of measurement used by Dr Cash make comparison with data for the previous decade difficult. For example, the conversion of Cryoprecipitate data from donation units to weight in kilograms by multiplying the donations processed by 0.2 (the stated conversion factor) does not produce values consistent with the data set out in the table for regional supplies of plasma to Edinburgh in the period 1972 to 1977. The differences, which may relate to various factors including rejection of plasma for Factor VIII processing purposes, have not been explored by the Inquiry team. The aim of SNBTS was to eliminate the need for commercial purchases. The time was appropriate for the attempt to assess the capacity of SNBTS to meet genuine clinical needs that followed.
10.87 Dr Cash did not attempt an arithmetical extrapolation of the data presented,[115] but discussed future demand on a more general basis. Home therapy was still developing; patients were living longer; disease processes affecting the general population were affecting older members of the haemophilia patient population; and there would be more surgical intervention. He referred to comparative data within and outwith the United Kingdom and produced a table of Factor VIII demand in terms of international units per million of total population per year. These figures were to determine targets for some years to come:
Home therapy 1.75
Moderate/mild patients 0.25
Inhibitor patients 0.50
Elective surgery 0.15
Aging of population 0.10
10.88 He anticipated that the target would rise to 3.75m international units per million of total population per year in ten years. A separate calculation predicted additional demand related to improved survival at an annual increase of 200,000 IU over 25 years.[116]
10.89 Dr Cash remained of the view that compromise would be required in demand as between Cryoprecipitate and intermediate purity products,[117] and with study of the effects of intermediate and high purity products. Factor IX did not present a problem partly because of the low numbers of patients.
10.90 The scene was set for discussion of the requirements of haemophilia therapy over the decade ahead. From the discussion minuted it appears that there was increasing use of commercial products. Some directors referred to an occasional need for high purity products for particular patients. More generally the solubility of the PFC Liberton product was criticised. Individual clinicians were making judgments of patient requirements. But Dr Cash's target was accepted as a suitable basis for planning. In terms of product selection, the haemophilia directors resisted the suggestion that Cryoprecipitate should be used for home therapy, significantly because, in their view, the risks of side effects with Cryoprecipitate were too great. The SHHD officials emphasised the need to match therapeutic needs to the resources available.
10.91 Other issues discussed at this meeting included the system for distribution of PFC Liberton products, European recommendations on treatment, the need for self-sufficiency, and the proposed register of haemophilia patients. In terms of the organisation of haemophilia centres generally, it was noted that Professor Bloom, Dr Forbes and Dr Ludlam had sought approval for the designation of Glasgow and Edinburgh as haemophilia reference centres. The professional members supported the proposition, but Dr Bell of the SHHD thought that wider discussion was necessary.[118] A small working group was set up to ensure regular discussion of issues.
Scheme for distribution of PFC Liberton products–1981
10.92 The scheme for distribution of PFC Liberton products proposed by Mr Watt came under review in February 1981. Dr Cash wrote to him proposing a scheme under which the national reserve would first be built up by appropriating any excess over 200 IUs per kilogram of plasma to build up stock; limiting issues to regions to 200 IUs per kilogram; and allocating issues to regions on the basis of the previous six months' input of plasma to PFC Liberton.[119] The regions would be required to return each month a record of quantities of Factor VIII held in stock, and would be invited to contribute plasma specifically to PFC Liberton research and development. Mr Watt was asked to do the same for stable plasma protein solution.
10.93 Mr Watt replied at some length on 13 February 1981.[120] Many of his observations referred to the practical problems of implementing Dr Cash's proposals. The new continuous thawing tank was just commissioned: it would take time to identify problems with it. National stocks could not be built up beyond PFC Liberton's storage capacity. The calculation of timing of issue of Factor VIII to regions required a shorter reference period, and a gap between the reference period and the issue period intended. Emergency issues were already dealt with in relation to the stock side of the equation, and the regions made returns of the material they held. Supply side problems were more difficult, with continuous reviews of the system, shut-down for equipment changes and maintenance and other reasons. The research and development problem was not related to plasma supplies, but to substrate plasma for assay of product. He re-calculated the likely rates of supply to regions. And he dealt with SPPS supplies. The result of his analysis was that PFC Liberton needed a new clerical establishment position to deal with the activity generated by Dr Cash's proposals, as amended. Copies of the letter went to SNBTS regional directors.
10.94 The North of Scotland BTS did not want the scheme.[121] The supplies proposed were too high; they already had too much stock; and they would prefer a more flexible scheme.
Meetings of SNBTS and haemophilia directors in 1981
10.95 The joint SNBTS and haemophilia directors working group set up at the meeting in January 1981 met on 4 March 1981.[122] Dr Cash's overall production target was discussed and confirmed. There was emphasis on the need for self-sufficiency. The relative merits of intermediate and high purity concentrates were said to be the subject of current investigation at PFC Liberton. Supernine had a licence for clinical trials. Factor VII development was at an early stage. Monitoring of concentrate usage was to be investigated. Proposals affecting clinical practice appeared to cause more difficulty, for example the reporting of adverse reactions: it would be difficult to engage clinicians; there was a lack of information associating products with patients; and user cooperation would be required.
10.96 The SNBTS directors met on 17 March 1981.[123] They discussed a wide range of production and processing issues. Dr Urbaniak reported on the work of the Jenkins Working Party on a code of practice for automated plasmapheresis donors.[124] But there was no discussion of PFC Liberton production.
10.97 As mentioned above, the SNBTS Directors met on 22 September 1981.[125] At this time plasma supplies to PFC Liberton had become a concern in relation to the supply of immunoglobulin preparations. In September, Dr Cash also reminded his colleagues that he awaited from them a note of the resources which they expected they would need to meet the targets of fresh frozen plasma which had been noted at previous meetings. He asked for the additional information by 31 December. The targets were confirmed as 2.75 million IU of Factor VIII per 1 million of the population on the basis that all projections were currently based on intermediate Factor VIII usage. The underlying assumptions were not universally accepted. It was noted at the meeting that the figure for England and Wales was 2 million IU/10 million population, in the proportions of 5% Cryoprecipitate, 95% intermediate Factor VIII. Proposals were made for the issue of PFC Liberton Factor VIII in proportion to plasma supplies.[126]
10.98 The joint working group met on 4 November 1981.[127] All of the topics previously discussed were brought forward, some without additional discussion. The failure to report adverse reactions was a continuing cause of concern. So far as the haemophilia register was concerned, it was thought unwise to commit resources to the project, and Dr Rizza was to be asked whether Oxford could extract the required data for Scotland. And so the opportunity to create a reliable source of data on Scottish demand was lost: at that stage the Oxford data were not explicit enough. A trial of Supernine would take time because there were so few patients available. The Factor VII project was similarly affected by low patient numbers. Dr Cash's Factor VIII target was discussed further, and confirmed, subject to SHHD reservations about the cost implications.
10.99 Between the two Scottish meetings there had been a joint meeting of representatives of BTS and haemophilia centre directors in England, attended by Dr Cash and Dr Macdonald from Scotland. It was explained that ministers had instructed planning for a new blood products laboratory as part of the progress towards national self-sufficiency. Projections of 'UK' demand for Factor VIII and Factor IX were agreed, and the proportionate split between product types agreed. Not more than 10% of total production should be in the form of freeze-dried Cryoprecipitate (including a small amount of frozen Cryoprecipitate); 80% should be in the form of intermediate Factor VIII concentrate; and a maximum of 10% should be in the form of high-purity product for major surgery and other special cases.
10.100 On 20 November 1981, Mr Watt reported to Dr Cash that PFC Liberton held a national stock of Factor VIII concentrate roughly equivalent to one month's issue and an annual rate of issue of 26,844 vials or 6.8 million units of Factor VIII.[128]
10.101 The SNBTS directors next met on 8 December 1981.[129] A table had been circulated on which were shown in each case the actual national stock of PFC Liberton products at 18 November 1981 and the issues for the year to 31 March 1981 plus, in some cases, a target national stock. It was agreed that the concept of self-sufficiency implied uninterrupted supply and that, generally, the national stock should consist of 12 months' usage of products, labelled and ready for use. It was agreed that the evaluation, in February 1981, of the scheme for the pro rata distribution of PFC Liberton products (discussed at para 10.92 and 10.93 above) would be an appropriate time to consider in detail the establishment of national stocks of products. The minutes of meeting of SNBTS directors on 8 December 1981 recorded that the English target had changed to 2 million IU per 10 million population in the proportions 10% Cryoprecipitate, 10% high-purity Factor VIII concentrate and 80% intermediate concentrate.
10.102 Dr Gabra continued to argue that dried Cryoprecipitate stored better, was simpler to handle, was safer because the dose was specified on the bottle, and could be used by patients of any ABO blood group.[130] Clinicians in the west had intended to expand its use, employing the named-patient approach in the case of supplies to both clinics and some home-therapy patients. They intended to look at procedures for early freezing of plasma. Dr Gabra spoke of his hopes that the material produced at Law Hospital might be offered on a named-patient basis to the whole SNBTS. It appears that, as at that stage, concentrating on production at Law Hospital continued to impact on the supply of plasma to PFC Liberton from the west. But these ambitions were frustrated by the decision that was to be taken to close the plant.
Medicines Inspectorate visit to BTS in Edinburgh in 1982
10.103 The visit of the Medicines Inspectorate on 10–11 March and 10–12 May 1982 to the Blood Transfusion Service in Edinburgh resulted in the critical assessment already referred to at para 10.71 above.[131] Dr Cash proposed that PFC Liberton should plan to build up sufficient stocks to tide over an extended period of four months. To achieve that, there would have to be an assessment of stock requirements, the plasma volumes required for production, and production scheduling which would probably create staffing problems. Mr Watt analysed the problems and wrote to Dr Cash on 17 February 1982 with his advice.[132] The work would require phasing, with a major phase held over until April 1983. Throughout the period, plasma supplies and Factor VIII production, reserves and stocks would have to be carefully monitored.
Self-sufficiency in blood products–1983
10.104 Early in 1983 there was renewed emphasis on self-sufficiency in blood products. At a meeting of the directors of the SNBTS and the haemophilia directors (for Scotland) on 21 January 1983, the chairman, Dr Bell, stressed that the purchase of commercial products should be avoided as far as possible. He set out the background to the policy as follows:
[T]he SNBTS had been set up to have the capability to cope with all Scottish requirements, other than those few therapeutic agents the production of which might not be justified on a very small scale, and that in terms of national policy the purchase of commercial products should be avoided so far as possible.
10.105 A table had been produced showing the commercial products purchased in the year ended 31 March 1981. Subsequently, information became available about commercial purchases in the United Kingdom as a whole in 1981–82. Market shares for commercial Factor VIII and total volumes purchased were said to be:[133]
Company Millions of IU
• Abbott 1.9
• Armour 14.6
• Cutter 3.8
• Hyland 3.5
• Immuno 7.3
• Speywood (Cutter) 1.5
Total: 32.6 million i.u
10.106 The Scottish share was not identified separately. Other UK data were not consistent.
10.107 The Blood Products Sub-Committee of the Haemophilia Society reported on
9 January 1984.[134] The report traced the growth in use of Factor VIII from 1975 to 1982:
Factor VIII used (million units)
NHS as % of total
10.108 The figures for Cryoprecipitate were not given, and have been deduced by the inquiry team on an approximate basis from a graph produced. The paper stated:
It can be seen that the trend of increased usage has continued with no signs of levelling off. Extrapolation of the figures in the Graph implies a total Factor VIII requirement for 1985 of 95 million units, and a requirement of 100 million units per year in about 1986.
10.109 As already mentioned, the data provided in Scottish documents tend also to be inconsistent and unsatisfactory. In one source, Factor VIII purchases for 1981–82 were said to be: Edinburgh 725,524 IUs, with no other purchases.[135] In another, attributed to Dr Cash, total commercial purchases were said to be 1.4 million IUs.[136] In another, Edinburgh was said to have purchased 463,868 units, with no purchases recorded elsewhere. These occasional statements underline the lack of information at national level about the activities of local centres at this time, quite apart from the general interest in self sufficiency. An example at the meeting on 21 January 1983 related to immunoglobulin purchases:
It was noted that anti-D IgG had apparently been purchased in W Scotland and Dr Mitchell agreed to investigate this since the Directors were not aware of any commercial anti-D with a UK licence. He agreed also to try to find out who purchased factor IX and why, since there should be no need unless it was in the form of an activated preparation.
10.110 Dr Mitchell represented the west of Scotland, but at this stage appeared to have had no direct knowledge of purchases. The explanation, in time, was that, in his area, purchases were processed by hospitals' pharmacies rather than the BTS. This may underline the lack of a coherent centralised information-gathering system. The concern focused particularly on purchases in Glasgow and Edinburgh. Based on the information produced, concern was expressed 'about the amount of commercially produced Factor VIII which was still being purchased'. Purchases in Glasgow had declined but those in Edinburgh had increased.[137] The comments indicate that at this period there was no system in place, in particular, for regular reporting to transfusion directors of the purchases of commercial products by clinical centres or the reasons for such purchases.
10.111 Dr Ludlam spoke of the position in the Edinburgh area. He had misgivings that Edinburgh perhaps did not receive as much PFC Liberton Factor VIII concentrate as it should on a pro rata basis, and it was remitted to Dr Cash, Dr McClelland and Dr Ludlam to resolve any problems which had arisen in relation to supplies to Edinburgh. Dr Ludlam defended his area's purchases partly on clinical grounds, and partly on the ground that stockpiling was necessary against the suspension of production at PFC Liberton which would occur when a refit required by the Medicines Inspectorate took place. He had started a number of 'new' patients on home therapy in 1982, reaching a projected demand of 500 bottles per month in the course of the year, and by October had to consider commercial purchase if PFC Liberton could not provide the quantities he required.[138]
10.112 Following that meeting, Dr McClelland wrote to Dr Cash on 2 February 1983 a letter which, with enclosures, raises questions whether within the Edinburgh area there were additional issues that may have impacted on efficiency.[139] He challenged Dr Ludlam's repeated contention that he was inadequately informed about the supply position, or that he was forced to buy and stockpile commercial products. He thought that nothing short of a peer review of haemophilia practice would resolve the issue. The background material began with notes of a meeting between Dr Boulton and Dr Ludlam on 13 November 1981. The notes contain a full review of Dr Ludlam's anticipated needs for the following two years.[140] They stated that he would use PFC Liberton material for fairly straightforward major surgical procedures, but would prefer to use higher-purity concentrates, possibly purchased from Armour, if there were possible complications due to the relatively high fibrinogen content of the PFC Liberton product. On 10 May 1982, Dr Boulton wrote to Dr Ludlam noting the relatively high use of Factor VIII in his area due to increased home therapy (now 80% of the area's allocation from PFC Liberton and far in excess of a proportionate return on plasma supplies to PFC Liberton), attempting to moderate usage, and noting that this consumption might require commercial purchases. A letter dated 10 August 1982 repeated the warning.[141] There was a further meeting on 23 August.[142] Dr Ludlam's stock at this stage included 84,000 IU of PFC Liberton Factor VIII; 50,000 IU of Cutter Factor VIII; a quantity of porcine Factor VIII that was due to be returned to the manufacturers; 33,000 IU of Armour factorate; and 11,000 units of FEIBA. Dr Ludlam had already drawn on the September allocation of PFC Liberton Factor VIII. His monthly usage of Factor VIII was between 95,000 and 130,000 units. Dr Ludlam agreed, inter alia, to try to keep within the allocation. Dr Ludlam wrote again on 1 September 1982. He asserted that he had expected more PFC Liberton material, that Dr Cash was looking for production capacity elsewhere, and that he was 'sure that there is some fractionation capacity somewhere for the relatively small amount of plasma in question'. Dr Boulton felt obliged to record formally the guidelines to be followed. In December, Dr Boulton managed to procure additional supplies for Dr Ludlam. Meantime, Mr Watt was beset by industrial action problems, and was apprehensive that PFC Liberton would not be able to increase buffer stocks to carry the plant over its shut-down period.[143] Dr Ludlam moved to increased use of Cryoprecipitate by December.[144] On 7 December 1982, Dr Boulton reported to Mr Watt on events. Dr Ludlam was said to be reducing use of PFC Liberton Factor VIII in favour of Cryoprecipitate. The temporary pressure was relieved by 'donations' from Glasgow and Inverness. By 29 December, Dr Boulton had information of increased usage by two patients, and warned of the risk to stocks.[145] Similar issues arose in January, when, in addition, Dr Ludlam was asked to avoid requesting material by telephone. There are questions at this time about whether the efficient operation of the service was adversely affected by such issues.
10.113 Quite apart from pure issues of quantity, the quality of PFC Liberton's products was questioned. In a letter to Dr Foster dated 10 August 1982, Dr McClelland reported allegations that PFC Liberton Factor VIII preparations were of much lower purity than the commercial intermediate-purity products which were currently available.[146] Dr Foster replied that the comment was probably fair: driven by the aim of maximising yield to meet the philosophy of national self-sufficiency, quality had to suffer.[147] And there was external pressure that related self-sufficiency to commercial supplies.
10.114 The impact of commercial manufacturers' products was a concern in Scotland. On 11 January 1983, Dr Foster wrote to Mr Watt, Dr MacLeod and a range of officials on the market implications of heat-treated Factor VIII:[148]
It is now considered that a number of companies will be making heat treated factor VIII concentrate available to clinicians in the very near future.
This could well have major implications for the NHS users....
10.115 It was clearly perceived that a highly competitive market was likely to emerge throughout the United Kingdom. This was just at a time when Scotland was moving towards self-sufficiency in intermediate-purity Factor VIII concentrate through a combination of extra plasma supplies and increased yield. In marketing as in research and development, the new financial year was about to witness major change.
10.116 The working group met on 22 March 1983.[149] In relation to the need for information to assess demand, it was thought that the Oxford data could be supplemented by annual returns by transfusion directors. But there was no agreed plan of action.
10.117 Overall, the period to March 1983 had been one of complex activity. In addition to domestic problems, the wider environment was changing. The introduction of heat-treated products began. So far as related to supply, commercial developments were identified as posing a threat to the public facilities at the end of the year.
Supply and Demand: Quantities 1980 to 1983
10.118 Overall, Cryoprecipitate issues declined from 95.6% of total Factor VIII usage in 1974–75 to 49.5% of total Factor VIII usage in 1989–90. In the three years of this period, from 1981 to 1983, expressed in International Units per million or population, the following pattern emerged:
Cryoprecipitate
Table 10.10
10.119 Cryoprecipitate issues continued to fall in absolute terms and as a proportion of total usage, amounting to 34.4%, 22.6% and 17.7% respectively. Commercial purchases accounted for a reducing proportion of total concentrate usage at 27.6%, 22.9% and 17.6% respectively.
10.120 Within these national figures, there were wide variations in practice, apparently reflecting varying clinical choices of therapeutic materials in different regions. The balance between regional use of Cryoprecipitate and the dispatch of plasma to PFC (expressed in litres) reflects these variations over the period from 1975 to 1983, which are taken together for convenience:
Litres
Plasma to PFC
10.121 Until the dramatic fall in 1983, Aberdeen maintained a relatively steady use of Cryoprecipitate, but increased progressively the supply of plasma to PFC from a very low starting point. Dundee's pattern was, in broad terms, similar. Inverness (no doubt reflecting the early use of large quantities of Factor VIII concentrate for two seriously affected Haemophilia A patients) always maintained a relatively high rate of supply of plasma to PFC, and soon reduced its local use of Cryoprecipitate to negligible amounts. Edinburgh maintained a relatively high rate of use of Cryoprecipitate, while increasing its contributions to PFC progressively. Glasgow's use of Cryoprecipitate fell after 1979. Its contributions of plasma to PFC increased dramatically over the period from a relatively low level to a relatively high level.
10.122 The increases in absolute quantities, especially from Glasgow and Edinburgh, enabled PFC to increase its output of Factor VIII from 0.11 million IUs to 1 million IUs over this period.
10.123 To some extent, the use of commercial products was controversial. On 24 April 1981, Dr Crawford raised with Mr Watt a problem relating to the home therapy of patients when on holiday.[150] Incidentally, he explained the practice of Dr Davidson at Glasgow of rotating commercial purchases from a number of manufacturers. One reason was to keep commercial contacts open in case of need. He proceeded:
Secondly there have been rumours of relationships between Haematologists and Factor VIII products which an unkind person might think verge upon the corrupt and I suspect that [Dr Davidson's] policy of rotation may be partly designed to ensure that his clinical practice and purchasing policy are not only entirely honest but can be seen to be entirely honest….
Mr Watt did not respond.[151]
• Productive capacity at PFC Liberton increased in this period, both in terms of plant capacity and in terms of working practices.
• However, adverse reports by the Medicine Inspectorate required upgrading of facilities throughout Scotland.
• There were significant changes in practice increasing demand for therapeutic products.
• The flow of information to SNBTS nationally improved in this period, but there remained deficiencies, especially in relation to the purchase and use of commercial products.
• Signs of strain among senior officials appeared that may have affected efficiency of operations.
10.124 The refit of PFC Liberton scheduled for early 1983 was expected to cause disruption. Mr Watt thought that a buffer stock of six months' supply would make fears of a shortage remote, and that cooperation between areas would overcome difficulties. It was known that PFC Liberton would be unable to process plasma for three months during the second phase of refit of the plant, expected to begin in April 1983.[152] The plant was already 'in debt' to regions in terms of return of product in exchange for plasma supplies. Mr Watt thought it necessary to build up a stockpile of Factor VIII over about 15 months to try to minimise commercial purchases.
10.125 There was an encouraging development early in this period. On the initiative of Dr Cash, SNBTS had set up a number of study groups to consider production, among other matters. In a retrospective report in June 1984, Dr Cash reflected on the work of the SNBTS Factor VIII Concentration Study Group[153]. He wrote:
The Group was especially pleased to discover at its first meeting that Dr Foster's PFC team were well advanced in their thinking with regard to improving fractionation yields. It is doubtful whether the Group had much influence on subsequent progress, which has been substantial, but members would like to feel that, at the very least, Dr Foster's team received their active support and perhaps they may have influenced more recent developments.
There can be no doubt that Dr Foster eventually succeeded in convincing colleagues of the need for high quality stable fresh plasma from RTCs and this has had, and should continue to have, a profound influence on subsequent developments.
10.126 The inference appears to be that PFC continued to suffer from inadequate supplies of plasma in 1982, but that the supply position improved over the next two years, largely due to Dr Foster's attempts to persuade the regions that PFC should have the material it required for production, in quantity and in quality. The background to that improvement reflects a number of factors.
10.127 The up-grade of PFC was completed in the summer of 1983. By November 1983, production was in excess of Scottish demand.[154] Current stocks were 7 million units, 35,000 vials, compared with the previous November stock of 5 million, 25,000 vials. This was after a year in which production was disrupted by phase II of the up-grade. It was presumed by PFC that the increase in stockpile represented current excess annual output over and above present demand.
10.128 This raised a concern about the out-dating of stocks. But PFC was thought to be 'genuinely moving near to a national SHS (Scottish Health Service) surplus of factor VIII'.[155] The production model at this time remained that of intermediate-purity Factor VIII concentrate.
10.129 In October 1984, Dr Smith sent Dr Foster a specification for a sterilising oven for manufacturing purposes.[156]
10.130 A report dated November 1984 by Dr Perry contained: 'Proposals for increasing process capacity at the [PFC]' to be submitted to the Medicines Inspectorate. The report was submitted in the first place to the Scottish Health Service, CSA, Blood Transfusion Service Sub-Committee. The aim was to commission an additional processing line at the plant to increase production of SPPS. In summary, it was recommended that:
(a) Urgent consideration be given to the above proposals which result in a substantial and immediate cost saving elsewhere in the SHS.
(b) That for operational purposes, the funds be made available to coincide with major upgrading scheduled for 1985/86.
(c) That urgent formal consideration be given to the creation of additional and permanent warehousing and replacement of existing 4˚C storage areas (phase III). The Project Steering Group may wish to know that there has been no progress since the last PSG meeting in May 1984.[157]
10.131 In April 1985, the Health and Safety Executive agreed that PFC could perform freeze-drying experiments as part of the collaboration with Professor Weiss on inactivation of HTLV III provided that the safety cabinet was up-graded and the ultra-centrifuge fitted with a filter to the exhaust line.[158] Dr Perry sought relaxations of a range of requirements on 7 May 1985.[159]
Strategy in Scotland
10.132 Early in 1983, Dr Cash estimated the Scottish demand for Factor VIII for all moderate and mild Haemophilia A patients (99 and 78 respectively) at one million international units per annum, and the demand for Factor IX at the same level for the country's 90 registered Haemophilia B patients.[160] Prior to the emergence of the AIDS risk, the policy was based on the assumption that, because severe haemophilia patients had already been heavily exposed to untreated products, only mild and moderate patients could benefit from a heat-treated product.[161] Until heat-treated concentrates were ready for production, these patients would continue to receive single donor Cryoprecipitate. AIDS made a review of the strategy necessary.
10.133 The minutes of a meeting between SNBTS directors, haemophilia directors and SHHD on 9 March 1983 under the heading 'Trends in Supply and Demand for Factor VIII Concentrates', gave figures for the five year period 1978 to 1982 (included in Table 10.9 above) showing that
(i) there had been a sustained increase in the total amount of fresh plasma processed, although it was anticipated that the increase would probably level out, unless there was a significant further financial investment at the RTCs,
(ii) there had been a decrease in the amount of Cryoprecipitate issued from the RTCs, and
(iii) there had been a substantial increase in issues of PFC intermediate Factor VIII concentrate. The target figure for the amount of Factor VIII which would be required for the next five years was agreed at 2.75 IU x 10 million.
10.134 In February 1983, there was close scrutiny of draft proposals from England on record keeping and stock control in relation to blood and blood products. SNBTS proposed amendments for Scottish purposes.[162] Subject to those amendments, this was viewed as an important innovation.
10.135 On 18 March 1983, J Watt wrote to J Cash on the subject of the supply of FVIII concentrate.[163] He proposed issuing concentrate in proportion to plasma input which would have resulted in:
Aberdeen 6.2%
Belfast 9.0%
Dundee 6.3%
Edinburgh 21.0%
Glasgow 52.1%
Inverness 5.4%
10.136 SNBTS directors met on 29 March 1983.[164] A change to tear-down plasma pack systems, which had previously been reported on a routine basis without adverse comment, now caused production problems for PFC. Another concern of the Medical Inspectorate was raised.
10.137 Commercial purchases continued to affect assessment of demand. The SNBTS directors met on 14 June 1983.[165] There was dissatisfaction with their inability to compile accurate returns of commercial blood products purchased, largely because not all health boards had their transactions handled by the transfusion centres (a notable example was the west of Scotland where the transfusion centre did not purchase commercial products on behalf of the health board). This gave rise to the suggestion that all commercial products should be purchased through Regional Transfusion Centres. The issue continued to be discussed at the next meeting on 13 September 1983.
10.138 In the wider UK context, on 15 August 1983, the Haemophilia Society wrote to an official at the DHSS in anticipation of a meeting to be held on 8 September 1983, seeking, among other things:
An assurance from HMG that self-sufficiency in blood products within two years will remain a priority with every effort being made to reduce this period.
That there will be no attempt to suspend the importation of US Commercial Products that definite evidence that this would be necessary (sic)
10.139 It appears clear that the Society's interest was to ensure that imports continued to make up the gap until self-sufficiency was established. The source of technical advice to the Society at this time has not been identified by the Inquiry team.
10.140 Dr Cash wrote to J O Wastle at SHHD a letter dated 29 August 1983 enclosing figures for issue of blood products for 1978–82.[166] It showed 'issues' for Cryoprecipitate, PFC and commercial Factor VIII, for each year 1978–82. Over 90% of the commercial products were American in origin.
10.141 On 13 September 1983 at the meeting of the SNBTS directors, the issue of record keeping was discussed.[167] Dr Cash agreed to report when all areas had provided necessary information. In relation to commercial purchases, each region's existing practice was presented:
North: There had been no commercial purchases in recent years.
North East: Commercial products were ordered through the Transfusion Centre apart from FEIBA, on the basis that there was no NHS equivalent. The Directors nevertheless wanted to know about FEIBA purchases and it was suggested that DEFIX was the equivalent product.
East: There was no formal arrangement.
South East: Lothian Health Board had agreed that all commercial blood products should be purchased by the Transfusion Centre.
West: It was not agreed policy in any Health Board that the Transfusion Centre would purchase commercial blood products. Dr Mitchell would have liked to do so. Dr Bell was prepared to help deal with the problem.
10.142 It appears that in these circumstances the persistent lack of reliable data on commercial purchases may suggest that there were continuing problems in achieving centralised administration.
10.143 The issue of commercial purchases was raised again at the meeting of SNBTS on 8 December 1983.[168] There were minor variations in the information previously provided about practice in some regions. In the case of the South East, there was a major change. The 'newly appointed haemophilia director', unnamed,[169] found the practice of purchase by the Transfusion Centre, which had been in use since 1977, unacceptable, and Lothian Health Board would not intervene. Glasgow Western Infirmary/RHSC was reported to be 'the last remaining hospital to use substantial quantities of commercial Factor VIII in the West of Scotland'. Meanwhile, output of SNBTS concentrate from PFC had reached a level sufficient to meet Scottish demand in 1983. Dr Mitchell was to write to the consultants to enquire why they required such purchases, which, unknown to SNBTS, amounted to 550,000 IUs. of Factor VIII in the year to 31 March 1983.
10.144 In 1984, there was further interest at United Kingdom level in self-sufficiency. The Blood Products Sub-Committee of the Haemophilia Society report of 9 January 1984 noted:[170]
Since 1981 the facilities at the Blood Products Laboratory, Elstree, have been upgraded, and this has allowed an increase in production to somewhere near the current target of 30 million units. Further development of BPL, under the supervision of the newly established Central Blood Laboratories Authority, is still intended to make the U.K. self-sufficient in blood products by using present technology (i.e. without allowing for any progress in genetic manipulation techniques). However, the achievement of this target is dependent not only on provision of processing facilities. It also depends, as the last review pointed out, and as X (B.P.L.) concedes, on both increased supplies of plasma to B.P.L. and increased yields in processing. In neither of these respects is there evidence that these requirements will be met. In view of this we must be somewhat doubtful that the NBTS could achieve the requirement, stated by the UK Haemophilia Centre Directors, of 100 million units by the middle of the present decade. To achieve this target would require NHS production to be trebled.
10.145 It is not clear whether the 'UK' referred to included Scotland in either sentence.
10.146 Scottish demand for Factor VIII was re-assessed again in 1984 at a meeting between SNBTS and haemophilia directors and SHHD held on 2 February.[171] A table was produced showing PFC production and stocks of FVIII from 1975–76 to 1982–83, with forward projections.[172] This showed growing stocks. Members were agreed that it was desirable to retain the target production figure of 2.75 million IU per annum per million total population, and that existing stock levels were required to meet sudden demands made on the service, and to bridge the period when the PFC would be converting to a heat-treated product. The possibility of providing surplus production to other parts of the United Kingdom was discussed. It was noted that trends over the last five years indicated that the SNBTS production of Factor VIII concentrates might be exceeding clinical demand: current stocks at RTCs appeared to be increasing. Nevertheless, the practice of making commercial purchases continued. Dr Cash asked members to consider whether, given SNBTS production, it was necessary to purchase commercially unless, exceptionally, a superior product was available. Dr McDonald said that the adult centre in the West was totally satisfied with the NHS product and it was no longer necessary to purchase commercially. Dr Hann found himself in the position of having inherited 30,000 IU of commercial Factor VIII which was rapidly going out of date and which he was prepared to dispose of. Dr Ludlam said that he required to have a small stock of high-purity commercial material for a very few patients. Dr Bell [SHHD] emphasised that the aim of the SNBTS and of national policy was for Scotland to be self-sufficient, and that, although the department would not wish to intervene in what clinicians prescribed, it was not sensible to purchase imported material when suitable NHS product was available. It was also pointed out that an accurate assessment of future need could only be made if commercial purchases were known. (Dr Cash returned to the issue later in the year.)
10.147 SNBTS directors met on 13 March 1984.[173] Record keeping was discussed at some length. It was agreed that there was a need to adopt the standards applied in England and Wales (despite administrative differences that added to the difficulty), and that Scottish practice required review in that light.
10.148 In the wider United Kingdom context, supplies were again an issue. The Central Blood Laboratories Authority met on 23 May 1984.[174] A report on plasma supply was tabled.[175] Each regional transfusion director had been asked for an update on supplies for self-sufficiency. Regional variations in England were noted. It was anticipated that there would be a letter in The Lancet referring to the 'abundance of products available from BPL'. By the end of the year there were government statements on the subject. Lord Glenarthur said in October;[176]
The government has accepted the World Health Organisation's recommendation that countries should become self-sufficient in blood and blood products. Our commitment to the importance of self-sufficiency is shown by our current investment of over £24 million in the redevelopment of the Blood Products Laboratory at Elstree….
10.149 However, on the Haemophilia Society's projections, the prospects of the 'UK' becoming self-sufficient in Factor VIII at this time were poor. Facing that reality, their report discussed the ethical, economic and risk factors bearing on importation. It
re-assessed the relevance to trade between the United Kingdom and USA of the WHO and WFH (World Federation of Haemophilia) policy on self-sufficiency; the operation of the market in containing price inflation; and the hepatitis and AIDS risks inherent in the use of the domestic product, and concluded:
The AIDS scare has given us the opportunity, which we have not yet utilised, to campaign strongly for self-sufficiency in blood products. Given, however, that the original factors in our policy no longer apply or have reduced force, and that AIDS is still a great unknown, I submit that we should not undertake such a campaign. Now is not the time to ask that all our blood-product 'eggs' should be placed in one basket. Indeed, without necessarily abandoning our long-term objectives, we should take Mr Asquith's advice 'Wait and see'. When more facts emerge about AIDS we would then be in a better position to press for whatever action these facts seemed to demand.[177]
10.150 Whatever the society's information and motivation at this period, it was promoting the use of imported products to service what was seen as a growing market. Behind the scenes, advice to the United Kingdom government was not encouraging. What may have been the official position at the time appears from a document dated March 1984, with a heading that refers to the Supraregional Haemophilia Reference Centre, Royal Free Hospital, London. Authorship has been withheld, and there is no indication of the addressee. There are two manuscript annotations. One says: 'Couldn't agree more. Tell RTs', which may indicate that it was an internal government document. It provides a valuable insight into the contemporary position:
The goal of treatment with factor VIII is continuous replacement, as in the treatment of…diabetes with insulin." (Macfarlane, Biggs & Bidwell, 1954).
Over the last 15 years, the amount of factor VIII used in the UK has increased at a rate of almost 20% annually – ie. Usage has doubled every 4 years. It now stands at about 80 million units per year. The reasons for this increased usage are clear: demand has increased because the benefits of more intensive treatment have been obvious, both to doctors and haemophiliacs; supply of factor VIII has been available both to meet and fuel this demand.
Can this 'demand pull/supply push' continue indefinitely, allowing us to achieve the goal of continuous prophylaxis for all haemophiliacs? While we are dependent on human plasma as a source of factor VIII – and this will be for the next few years at least – the answer is unquestionably no, as foreseen by Macfarlane and his colleagues 30 years ago. To provide such prophylaxis would require 5–10 times as much factor VIII as we currently use. The world is short of plasma, we are short of money, and, depending on your viewpoint, the NHS may have more pressing priorities.
In the current difficult climate, in which many sectional interests are competing for limited health care resources, we need to ask ourselves:
'What constitutes an acceptable standard of care for haemophiliacs in the UK in the 1980s?
How should the NHS rank the needs of haemophiliacs against the needs of other patient groups?
Are we living in a fools paradise?
I'm not going to attempt to answer the first two questions here. As regards the third, I would suggest yes. In answer to the last, I believe it would be prudent for us to concentrate our efforts on preservation of what we have, rather than promotion of goals which cannot realistically be met. A major priority must be to reduce our level of dependence on imported plasma products. Not only haemophiliacs needing factor VIII, but also other patients who depend on different plasma products, have become worryingly vulnerable to international political, commercial and economic forces which are outside our control. If high standards of treatment are to be preserved for the future, we need to become masters of our own destiny.
It comes as a surprise to many to learn that the UK, with the notable exception of Scotland, is dependent on imported commercial plasma products. This is despite our long tradition of voluntary blood donation.'
10.151 The document proceeded to discuss levels of importation, US self-sufficiency and capacity to export, the need to learn from industry, and the debt owed by haemophiliacs in particular to industry. It continued:
One major bridge has already been crossed. After years of procrastination by successive Governments of various political shades, the present Government has made a large investment (£25 million) in the construction of a new NHS plasma fractionation factory at Elstree, Hertfordshire. Within two years, this factory should be capable of producing 100 million units of factor VIII annually, and this figure could be increased. All NHS requirements for other plasma products will also be met. However, there remains a problem. To produce these quantities of plasma products, collection of plasma will have to increase three or fourfold. Even with technical advances, this is going to be difficult.
10.152 The document analysed reasons for past failures to coordinate policy and practice, and proposed the creation of a National Blood Authority. It identified as another reason for supply inadequacies: The orientation of the BTS and many clinicians towards the collection and usage of whole blood, rather than its separate components. Traditionally, the BTS had been 'red cell driven' – ie. the need for the red cell component of blood had been the main factor influencing numbers of donations and methods of collection. So, in the view of the document's author, BTS had been slow to respond to increasing demand for plasma and other non-red cell components. Proposals were made, but the view was that they were unlikely to solve the problem. The answer would be to follow industry and adopt plasmapheresis. The process was described. The view was expressed that five new plasmapheresis centres could solve the supply problem. The paper concluded:
The standard of treatment available to people with haemophilia in the UK is widely recognised to be one of the highest in the world, but it has been bought at a price – dependence on a plasma product supply system which is outside our control, and cannot necessarily be relied on in the future. Not only because of our needs for factor VIII, but also because of our increasing requirements for many other plasma products, we must take urgent steps to reduce our vulnerability. The failures of the last decade should not dissuade us from expending maximum efforts to achieve the goal of self-sufficiency in blood products, because the climate has now changed, and the case is stronger than it ever has been.
10.153 The SNBTS directors met on 12 June 1984.[178] Nothing material to production was discussed. A further meeting was held on 11 September 1984.[179] On this occasion there was discussion of a paper drafted by Dr Cash on the release of products to organisations outside the Scottish Health Service.[180] The paper dealt with consent from donors to the release, and procedures generally. It did not deal with quantities available for release, but was clearly relevant only if there were surplus products available. A major new programme was anticipated in Dundee: liver transplantation. There was difficulty in estimating the demand that would create, but it was thought to be significant. More information was sought. Dr Cash wrote to a colleague in Kansas and was told that the cost was phenomenal.[181] The two Kansas transplant patients discussed left hospital but died within a year.
10.154 In November 1984, Dr McClelland developed proposals for batch dedication of Factor VIII concentrate.[182] There had been a decision to limit the batch exposure of haemophilia patients in February.[183] Dr Perry was unhappy about a multiplicity of local arrangements, and preferred a national scheme.[184] Dr Crawford entered the debate on 23 November 1984 in a letter to Dr Cuthbertson.[185] Dr Perry wrote to Dr McClelland on 26 November with proposals for a national scheme for a limited number of haemophilia patients.[186] This was possible because of the high levels of stocks in hand. Dr Crawford made detailed proposals on 3 December 1984.[187]
10.155 A statement was broadcast by John Patten, Parliamentary Secretary for Health on 18 November 1984[188] in which he said that:
• The Government was committed to self-sufficiency;
• This was demonstrated when on 23 March 1984, Norman Fowler laid the foundation stone for re-building of Elstree: the scheduled production date was January 1986.
10.156 The DHSS issued a Press Release, on the same day, repeating the information given to Parliament.[189]
10.157 Scotland at this stage remained in a privileged position in terms of total supplies. A report dated November 1984 by Dr Perry described changes in working practices:
[A] commitment to a high level of overtime working in one section of the production building has produced a significant increase in plasma throughout leading to Scottish self-sufficiency in all major blood products with the exception of albumin solution.
The annual shortfall in plasma throughput (10,000kg) equates to approximately 13,000 bottles SPPS per annum. It is known that significant purchases of SPPS and Human Albumin are made in the West of Scotland which could be eliminated if all existing incoming plasma were converted to product.
10.158 Dr Cash wrote on 22 November 1984 to the Chief Pharmacist to ask whether the SNBTS figures of purchase of commercial blood products in the year to 31 March 1984 were correct. Dr Forrester (SHHD) reported that he could not confirm the figures since the data held by SHHD were incomplete. Dr Forrester offered to undertake a prospective study, with the cooperation of all NHS pharmacists and the SNBTS directors. The results would be reported early in financial year 1986–87.
10.159 An indication of the impact of home treatment in generating demand was given in a letter by Dr Boulton to Dr Perry dated 2 July 1984.[190] Dr Ludlam had 20 patients on home therapy. Dr Boulton did not know the consumption, but assumed the national average of 42,000 units per annum.
10.160 The SNBTS and haemophilia directors met on 29 November 1984.[191] The meeting had been convened to discuss the implications of the recent finding of HTLV antibodies in Scottish haemophilia patients treated exclusively with Factor VIII produced by SNBTS. Dr Perry explained that PFC had commenced heat treatment at 68˚C for two hours as a short-term measure. The subsequent recall of material in issue for this form of treatment followed.
10.161 On 11 December 1984, it was recorded at a meeting of SNBTS directors that a table had been circulated showing purchases of commercial blood products for the financial years 1980–81 to 1983–84.[192] However, the information was still unverified by the Chief Pharmacist. Uncertainty about what was happening in the regions continued. Papers produced included data on haemophilia patients treated between 1978 and 1982, showing quantities of material used.
10.162 PFC's dry heat treated product (68˚C for two hours) was dispatched from December 1984.[193] The immediate intention was to provide approximately one month's supply to each region. Thereafter it was planned to make supplies equivalent to twice existing stock levels. In the New Year, non-heated stocks would be recalled. Batch dedication, to ensure the consistent use of specified batches in regions, would be applied to this second phase of distribution. This proposal led to much debate.
10.163 Dr Hopkins raised a query about the disposal of surplus therapeutic materials. He wrote to Dr Crawford on 4 December 1984:[194]
A UK thought. If you will forget for a moment that Scotland exists, or if you momentarily join those who have not even heard of it, the 'global UK' state is of not enough Hertfordshire factor VIII and that which there is will not be 'heat treated' until some time in 1985. So people are importing foreign material.
In the midst of this, a bunch of uncivilised Picts in the misty marches north of Hadrian's Wall want to sit on a great big pile of their own local home made heat treated factor VIII in order to limit certain batches to certain Pictish patients.
Is this acceptable?
10.164 A meeting took place. Dr Crawford and Dr McClelland attended. On 27 December 1984, Dr Perry reported the outcome to Dr Cash. Three possible batch dedication systems had been devised. The third provided for decanting surplus stocks to England and Wales. Dr Crawford's approach appeared to have had some initial success. Dr McClelland sent a note of his impressions to Dr Perry on 31 December 1984: it differed from Dr Perry's account.[195] On 8 January 1985, Dr McClelland wrote to Dr Cash supporting the first of Dr Perry's three systems: it did not provide for decanting material to England and Wales.[196] Batch dedication generated voluminous correspondence into 1985, but it seems unnecessary to record all of it: the object of the correspondence was to achieve consistency in the selection of materials available at any given centre. Batch dedication was implemented and was in operation in Glasgow in February 1985.[197]
10.165 By the end of 1984 Scotland was in a position to sell surplus blood products. At a meeting of haemophilia directors and representatives of SNBTS held on 11 December 1984, Dr Cash sought an assurance that the proceeds of sale of surplus blood products should be applied towards achieving self-sufficiency.[198] Mr Murray refused to commit the SHHD: the Treasury controlled these matters; they would be asked to take the income into account. That apart, the prospect of disposal was real. The plant at PFC Liberton was in surplus despite the fact that it had to be shut down during October to December 1984, in order to complete a planned upgrade of the facility. Production re-commenced in January 1985. Dr Cash's procedural paper on release of products was finalised and agreed. In the meantime, PFC moved to make available unlimited quantities of its then heat-treated Factor VIII concentrate in later December 1984, and were subject to some criticism.
10.166 The year 1985 began with a statement in Parliament that: 'Scotland is self- sufficient in all normally required blood products.'[199] Given the uncertainty over commercial purchases, it may be necessary to understand this as a reference to capacity rather than actual supply. In England and Wales, the position was less positive. On 19 February 1985 Kenneth Clarke refused to be drawn on the economics of self-sufficiency.[200] In Scotland, Dr Ludlam withdrew cooperation on testing in January, February and March 1985, threatening progress with heat treatment (according to Dr Cash).[201] Dr Cash warned that if the tests were not completed by the end of April, there would be a need to consider immediate dismantling of the batch dedication programme and planning of supplies beyond June/July 1985. In March 1985 it came to Dr Cash's notice that doctors at Glasgow Royal Infirmary were reluctant to undertake studies where blood samples had been taken from haemophilia patients,[202] but their reservations were overcome.[203] Professor Bloom also agreed to cooperate with testing.[204]
10.167 In January 1985, output at PFC was constrained by an eight-hour working day, which limited plasma throughput to 1000 to 2000 litres per day.[205]
10.168 Production was threatened by a new issue raised by Dr Boulton on 15 January 1985.[206] Virtually all of the haemophilia patients who were on the Edinburgh and South-East Scotland BTS donor panel for Factor VIII-deficient substrate plasma had received Factor VIII from batch 023110090, which had been identified as the possible source of transmission of HIV. Edinburgh was therefore most reluctant to use plasma from a donor in this group any longer. He asked about alternative supplies, and about artificial substrate.
10.169 The Factor VIII Study Group met on 7 February 1985.[207] Papers included a proposed specification for fresh frozen plasma. Dr Foster prepared a progress report.[208]
10.170 The SNBTS directors met on 27 February 1985. The papers for the meeting were dominated by discussion of the requirements for training of personnel in transfusion centres, and on AIDS information and in particular leaflets. But, by now, the procedural guidance on release of blood products had become controversial. It emerged that contrary to what BTS directors had understood, SNBTA had not approved the release of blood products. SNBTA had been represented at working group meetings, but that had not had the desired effect of informing the SNBTA executive committee of decisions. Decisions were to be left to regional centres.
10.171 There was a meeting of the SNBTS and haemophilia centre directors on 7 March 1985.[209] In February, Dr Cash produced data on commercial purchases but noted that it had been difficult to collect the data: he had still to receive a reply from the Chief Pharmacist to his letter requesting verification of the data. On the information available, it appeared that only Edinburgh was making commercial purchases at the material time. Dr Ludlam had explained that he had one patient who needed a product not available from PFC. It appears highly unlikely that the data returned were comprehensive. The table shows that there were consistent purchases in the Glasgow area until 1983, but not in 1984 or 1985.[210] But the impression left is of uncertainty about the level of commercial purchases. Nevertheless, the national demand was re-assessed at the meeting on 7 March, and again confirmed at 2.75 million IUs per million of population.[211] That assessment did not reflect Dr Cash's suggestion of a much higher prospective demand. The assessment was based on a view that a severe adult haemophilia patient in Scotland would require about 100,000 IUs[212] using a genetically engineered safe heat treated product.
10.172 Haemophilia directors again agreed to provide the SNBTS with data on the actual usage of Factor VIII in Scotland and Northern Ireland which would supplement the Oxford figures on which Scotland was still heavily dependent.[213] There continued to be uncertainty about the level of usage.
10.173 On 15 May 1985, the haemophilia and blood transfusion directors met.[214] PFC still had stocks of Factor VIII dry heat treated at 68˚C for two hours which were expected to be exhausted in July or August. (Production had stopped in February 1985.)[215] It was expected that it would be replaced by a superior product dry heat treated at 68˚C for 24 hours, but that issues of the latter product would commence only when the existing stocks of two hour material had been exhausted. By now the batch dedication that had been introduced generally was working well and was being monitored.
10.174 Also, the testing of heat-treated Factor IX on dogs was under way at Cambridge. And development of the new Factor VIII was in hand. Preliminary clinical evaluation had been encouraging and PFC had enough data to start heating unheated stocks, and to proceed to production in August.
10.175 SNBTS were engaged in a highly competitive market by 1985, developing and promoting the use of PFC heat-treated Factor VIII in particular. Productive capacity was adequate. And, at least temporarily, the purchase of commercial products was not thought to be controversial. Against the background of an extensive programme of research and development, PFC's range of products changed in the course of 1985. In January, all outstanding stocks of FVIII unheated material were recalled by the SNBTS from RTC and haemophilia centres, for heat treatment at 68˚C for two hours and re-issue on a batch dedication basis.[216] The picture was described by Dr Perry in a report dated 10 January 1986 for a meeting of SNBTS and haemophilia directors and SHHD held on 5 March 1986 (referred to below at paragraph 10.190). It contained a summary of the heat treatment of coagulation factor concentrate production during 1985 which appears to be accurate: (a) because of its contemporary dating; and (b) because it was placed before the meeting and discussed without recorded contradiction:
In January 1985, PFC distributed heat treated FVIII (68˚ /2 hr) to all centres in Scotland and Northern Ireland and this material was used until September/October 1985 when a new formulation product, heated at 68˚ for 24 hrs was issued….
10.176 The SNBTS Directors met on 20 June 1985.[217] A report was prepared on PFC's production for the year ended 29th March 1985. This showed a high throughput of plasma, with a significant increase in plasma stocks in comparison with the previous year end (from 37,878.6 kg to 40,251.1 kg). The data did not distinguish the different products issued (according to heat treatment for example), nor the recall of products in the early part of the year. The minutes do not disclose whether the production data were discussed. Issues that were discussed included the protocol for release of products; AIDS; and record keeping. The unsatisfactory state of information within Scotland about commercial purchases was highlighted. Dr Forrester offered to undertake a prospective study, asking all NHS pharmacies to provide data for the current financial year. It was agreed that the results would be reported early in 1986–87.
10.177 There was a further meeting of the SNBTS directors on 2 October 1985. AIDS, and in particular a prospective study of staff exposure, work in England and Wales, and the commercial interface arrangements for release of blood products, dominated the discussion. However, there was a reported complaint of a shortage of certain plasma products in Aberdeen and Glasgow. In Aberdeen this was thought to relate to plastic surgeons who regretted the abandonment of production of dried plasma. In Glasgow it was thought to relate to an anticipated shortage of albumin. But it was also noted that one purchaser of commercial SPPS in paediatric packs was the Royal Hospital for Sick Children in Glasgow: the product would soon be available from PFC but, by implication, was not available at the time.
10.178 In November 1985, independent information appeared in a paper that supported the PFC view that plasma age was material to the recovery of Factor VIII.[218]
10.179 In the same month, SHHD approved the text of a letter (prepared by Dr Forrester) to be sent to WHO detailing activities in Scotland. It said:
Plasma from Scottish and NI donations is processed at a single central facility, which is among the 25 largest units in the world. Approximately 20 distinct products are generated, and research and development proceed continuously. Nearly all requests for plasma products can currently be met, but a small amount of plasma protein solution is still derived from commercial sources outside Scotland.[219]
10.180 The qualification referred to information that the Royal Hospital for Sick Children, Glasgow was purchasing paediatric packs of commercial SPPS.[220] However, it appears that the actual pattern of commercial purchases was not well understood by SNBTS. The information available was not comprehensive.
10.181 The SNBTS directors' final meeting in 1985 was on 10 December.[221] PFC supplies were discussed in the context of AIDS. Dr Cash had advance information about a report expected from Professor Montagnier in Paris that dry heat treatment at 68˚C for 24 hours might not eliminate HTLV III in Factor VIII. Dr Perry said that experiments were in hand with a view to heat treating blood products at 80˚C for 72 hours. There were stocks of Factor VIII in hand, sufficient for nine months' supply, that had been processed since January 1985 (at 68˚C for two hours) but which might be amenable to re-heating.[222] Dr Perry's report dated 10 January 1986 noted:
More recently unconfirmed reports have emerged which suggest that HTLV III may be less susceptible to heat inactivation than was originally thought. In response to these reports, PFC has recently recalled all residual stocks of 68˚ /2 hr material….
10.182 In January 1986, discussions took place on the possible use of NHS Factor IX to treat Haemophilia A patients with inhibitors. Dr Mayne and Dr Kernoff had outlined strategies for trials.[223] Dr Ludlam wrote to Dr Rizza to enquire whether BPL heat-treated products had been used in this way.[224]
10.183 At a meeting of SNBTS and haemophilia directors and SHHD held on 5 March 1986, the current target for Factor VIII production and data on usage of Factor VIII were discussed.[225] The target for Factor VIII production, previously agreed at 2.75 million IU per million of population per year, was confirmed.
10.184 A threat to donations was discussed when the SNBTS directors met on 25 March 1986.[226] US military authorities had intimated requirements that blood transfusion centres should inform commanding officers of donor service personnel who were AIDS antibody positive. The transfusion service in England and Wales had refused to do so, and the DHSS had similarly intimated that the US requirements were not acceptable. But the discussion disclosed that Dr Mitchell and Dr Brookes had held sessions at US military bases, and the DHSS decision threatened the security of this source of donations.
Supply and Demand Quantities 1983 to 1986
10.185 The summary data for the use of Factor VIII in the three years 1983-4 to 1985-6 is contained in the middle three columns of the following table:[227]
PFC FVIII
10.186 The progressive reduction in the local issue of Cryoprecipitate previously noted as between the years ended 31 March 1981 and 31 March 1982 had not continued: Cryoprecipitate use had more or less stabilised. As before, there were regional variations in the use of Cryoprecipitate and in the quantities sent to PFC for processing. The data recorded (expressed in kilograms) were:
10.187 The data made available on PFC issues of Factor VIII concentrates over this period took account of changes in the specification of the products concerned. But not all practices appear to have been specified clearly, for example sales to England and Wales were not specified in Dr Cash's report.[228]
10.188 In a letter to Dr Perry dated 3 May 1984, Dr Hopkins noted that Glasgow BTS had 4.5 million Factor VIII units in cold store, more than a year's demand taking account of hospital use and home therapy.[229] He pointed to the risk that some stocks would become out-dated, and that: 'the only question is do we use the M74 or the A1'. Dr Perry replied that SNBTS were in the process of initiating formal discussion on the transfer of excess Factor VIII to England and Wales.[230] On 8 June 1984, Dr Perry wrote to BPL noting that agreement had been reached between Dr Cash and Dr Lane for the transfer of excess Factor VIII to England: transfer of 7 – 9 million units within the current financial year was a possibility.[231] The practice appears to have been discontinued 'until the position settled down' when PFC began to introduce heat-treated Factor VIII in January 1985.[232] The extent of transfers to England and Wales has not been identified by the Inquiry team.
10.189 A further factor complicating the supply position at this time arose from the disposal of accumulated stocks of Factor VIII which were in hand when changes in specification were introduced. The summary data on production (in millions of IUs) from Dr Cash's report were:
1983 million IUs
FVIII Intermediate/new formulation
HT-NY FVIII
Z8 FVIII
10.190 In his report for the meeting of SNBTS and haemophilia directors and SHHD held on 5 March 1986,[233] Dr Cash suggested that the data available on intermediate Factor VIII trends at that time were less than reliable because of the interaction of the introduction of batch dedication and the production of heat-treated products. There was no immediately obvious arithmetical trend in the issues of products (at that time up to 1985). The 1985 fall in volume of issues of Factor VIII required explanation. Issues of Cryoprecipitate increased as between 1984 and 1985, but Dr Cash thought that the increase was not due to use in the management of haemophilia patients.
10.191 However, the position may have been more complicated. On 19 June 1984, in a letter to Dr Hopkins, Dr Perry said that the haemophilia directors had agreed to run down stocks of existing product either before or concurrently with using new products: in the early phases using existing product for moderate and severe cases of haemophilia, and using the new product for mild cases and those with minimal prior exposure to blood products.[234]
10.192 There appears to the Inquiry team to be a number of issues that require clarification. The Inquiry has not been able to construct a fully detailed chronology that specifies the production, stocks and distribution of PFC products over this period, including the timing of changes in the heat-treatment regimes applied. The scope for confusion became clear early in 1986.
10.193 At a meeting of the coagulation factor study group on 27 February 1986,[235] Dr Perry outlined the existing stocks and the plans for production current at the end of this period:
Phase I: current 68˚ /24h: 7 months stock
Phase II: improved freezing: 68˚ 72 h: 3 months stock
Phase III: improved freezing + Zn treatment to allow smaller fill volume (0.6iu/mg) and improved freeze-drying: 80˚/72h manufacture from April '86. Issue from Jan '87.
Phase IV: Hi purity PFC product (50 iu/mg). 80˚ /72h early large scale viallings from April '96. (no vWF, this may be available as side product.)
10.194 Dr Foster thought there was scope for confusion, and suggested that the products should be named.[236] On 11 March 1986, Dr Perry agreed, and proposed to write to Regional Directors that the names would be:[237]
FVIII HT – To include 68˚ /2hr, 24 hr, 72hr, since we will not publicly be announcing the 68˚ variant.
Z8 – 80˚/72hr
REAL 8 PFC/NYU
10.195 On this information, it appears that Dr Cash's category 'FVIII Intermediate/new formulation' could have included material heated at 68˚C for two hours, 24 hours, and 72 hours. Production in 1986 would have included material from Phase III, with improved freezing and zinc treatment. The relationship between manufacture and issue of the several categories of product has not been defined on the material studied to date.
10.196 By the end of the financial year 1985-86:
• Production had been disrupted during plant refit work, but productive capacity was increased and there were further proposals for increased production in and after1984.
• The need for high quality fresh plasma to maintain yield of FVIII:C was established.
• AIDS changed the focus for provision of virus safe products towards the protection of severe haemophiliacs.
• National policy remained one of self-sufficiency using domestic products.
• Purchases of commercial products continued to affect assessment of demand for PFC products. Actual levels of purchases remained uncertain.
• At UK level, concerns were expressed about the implications of the cost of haemophilia care for the NHS generally.
• Further surgical procedures for haemophiliacs increased demand.
• Scotland was in surplus by the end of 1984 and SNBTS in position to export FVIII.
• Batch dedication was introduced for heat treated products.
• Supplies of PFC FVIII heat-treated at 68˚ for two hours were distributed from December 1984: 24 hour heating developed.
• In December 1985, Montagnier cast doubt on effectiveness of dry heating at 68˚C for 72 hours.
Factors Affecting Demand and Supply
10.197 In June 1986, it was reported that a young patient of Dr Ludlam's had been treated with 'the current heat-treated' Factor VIII and within a month was showing signs of NANBH.[238] Dr Ludlam was reported to be 'a bit ruthful' with his staff because he felt that this patient should have received English 8Y or an equivalent product. It appears that at this time Dr Ludlam had objections to the use of PFC Factor VIII. However, it is not clear which product was used. PFC had, in issue, material heated at 68˚C for 24 hours and 72 hours. Given Dr Perry's views (11 March 1986 above at para 10.194) the different regimes would not have been disclosed. Dr Perry wrote on 4 August asking for the batch number of the offending product.[239]
10.198 The SNBTS directors met on 25 June 1986. The agenda for the meeting indicates that Dr Forrester's paper on purchase of commercial blood products in 1985–86 was produced, and the minutes of the meeting recorded the discussion.[240] Discussion on the paper noted that, in Aberdeen, all commercial purchases were supplied via the BTS and were re-charged to the health board. It was noted that: 'If a similar system to that which existed in Aberdeen could be operated nationally BTS would immediately be alerted to developing trends in demand and the difficulties of data collection would be overcome.' That was not to happen. It was still a problem that central data were not comprehensive. Dr Forrester commented that his exercise had been difficult. The paper was revised, and re-issued for the October meeting of the directors.
10.199 On 2 July 1986, Dr Perry wrote to Dr Boulton observing that Factor VIII heated at 80˚C for 72 hours would soon become available and that virgin patients would be able to gain access to it before current stocks were exhausted (though that had not become an agreed policy).[241] He wrote again on 7 July, outlining the timetable for supplies and acknowledging that until September 1987 an SNBTS equivalent of the English Factor VIII product, 8Y, would not be available but that 8Y might be obtained for special cases. On
7 July 1986, Dr Boulton again wrote to Dr Perry.[242] Dr Ludlam had asked for 100,000 units of BPL product. Dr Boulton thought the request for 100,000 was unreasonable: 10,000 could be justified; but if even that was difficult to get, he asked whether 4000 units might be obtained.
10.200 However, Dr Perry did approach the NBTS on 10 July 1986[243] and obtained an offer of help[244] with supplies of current 8Y. (The English product was still under development at this time.) He told Dr Boulton on 24 July.[245] On the same day he wrote asking for 50 vials.[246] They were dispatched on 1 August with a trial protocol for use on infusion, reflecting the experimental stage in development that had been reached.[247]
10.201 At the meeting of SNBTS directors on 9 October 1986, Dr Forester's table disclosed purchases of blood products as follows:
Health Board
Units as specified
Estimated Cost per unit
FEIBA
75,000 U
Albumin 20%
212 (50 ml)
PPF 4.3%
20 (400 ml)
Greater Glasgow
1528 (400 ml)
155 (250 ml)
2805 (50 ml)
Porcine FVIII
133 x 1000u
3 x 1000u
74,000u
* corrected later in manuscript to £53,000
10.202 On 3 March 1989, Mr RRC Stewart, who was appointed Clinical Trials/Product Surveillance Manager at SNBTS in July 1988, wrote to all regions seeking data on commercial purchases. Glasgow provided data back to 1985–86:
Greater Glasgow248
FVIII Porcine – Hyate C
133,455u
FEIBA (Activated FIX – Immuno) 249
FIX HT Immuno
FXIII Hoechst250
3,000u
'Factor IX'251
Anti-thrombin III BPL
Albumin 20% Immuno
Albumin 20% Armour
Albumin 4.5% Immuno
'Albumin 20%' 252
-do-
4.3%253 400ml
Table 10.16[248][249][250][251][252][253]
10.203 While most of the data obtained by Mr Stewart coincided with Dr Forrester's table, there was no precise correlation, and significant purchases appear to have been omitted from his analysis. It appears that, at the beginning of this period, PFC production may still have been planned on the basis of inadequate data about total demand, as it had been in previous periods.
10.204 The minutes of the meeting on 9 October 1986 disclose no discussion of PFC production generally.
10.205 A meeting of the SNBTS and haemophilia directors was fixed for 9 February 1987. Dr Cash[254] and Dr Perry[255] each prepared notes for the meeting. Dr Cash provided data on production, all of which has been reflected in the summary tables above. Dr Cash noted that progress in establishing batch dedication in 1984–85 had produced some falsely high issue figures, but that there was reason to believe that there had been a significant true fall probably related to the AIDS problem. Dr Perry's report for the February meeting, dated 15 January 1987, reported that on existing plasma supplies: there would be a comfortable margin in respect of national self-sufficiency.[256]
10.206 However, on 21 January 1987, Dr Perry wrote to Dr Cash identifying problems.[257] There was a risk that PFC would not be able to maintain batch dedication beyond March 1987 'with a total collapse of supply from PFC in March 1987'. His apprehension was that Z8 might not meet its clinical trial tests, and that PFC would be forced to revert to NY, which would involve physically changing process machinery and equipment.
10.207 At the meeting in February, there was considerable discussion of compensation for participants in the trials.[258] Dr Cash presented his report. New products were discussed. PFC had in contemplation a new product, activated Factor IX, but anticipated difficulties in testing. It was thought that such a product would avoid equivalent commercial purchases.
10.208 The minutes of the meeting became controversial, with Dr Ludlam challenging them, accusing the department of reneging on commitments, in another letter complaining about the issue of Z8, and receiving in return to both letters a strongly worded reply from Professor Cash, as he now was.[259] Professor Cash's letter dealt also with Dr Ludlam's lack of knowledge of the impending shortage of PFC product, and the Professor's concern about Dr Ludlam's clinical practice. Dr Ludlam had drafted a letter to patients, inter alia giving them the option of Z8 or the existing product.
10.209 The SNBTS directors met on 3 March 1987. So far as production was concerned, it was noted that an American company had a patent for dry-heat treating concentrates that had not been challenged by commercial manufacturers. It was believed that BPL were being pursued for royalties. Dr Perry undertook to find out what was happening. SNBTS had not been challenged in relation to the patent.
10.210 Dr Forrester produced data on commercial purchases of blood products for the year ended March 1987. Again these required correction, and a revised table was produced for 6 October 1987. The corrected data showed:[260]
Total Commercial Cost
Hyate C
90 (50 ml)
10.211 These data correspond broadly with other SNBTS sources.[261] Dr Forrester had obtained the data through the CSA General Manager. The purchases had cost £348,875 (excluding VAT and excluding Aberdeen purchases), rising to £362,475 following revision, as compared with £308,014 in the previous year. Discussion at the meeting continued to reflect uncertainty about the accuracy and reliability of the data, however. It was acknowledged that PFC required a product for FVIII patients with inhibitors. The proposal for centralised purchasing was not supported by SHHD: it was thought to represent interference with health board activities.
10.212 The SNBTS directors next met on 6 October 1987.[262] Apart from noting amendments to Dr Forrester's table there was no discussion of PFC production. The final meeting of the year was held on 8 December.[263] The principal issue relating to PFC production was the development of a product for patients with inhibitors. There were about 15 such patients in Scotland, and the annual cost of commercial products had been £288,000. Dr Perry thought that an SNBTS inhibitor product could be produced by June 1988, but the small number of patients made clinical trials problematical.
10.213 On 16 February 1988, Dr Cash wrote to SHHD with a list of PFC products and their current licence status.[264] So far as relevant for present purposes, the list indicated that there were licences, but that variation applications were due to be made in April. There was further contact with the Medicines Inspectorate: there was to be a joint session on the current situation and on necessary developments for the future.[265]
10.214 The SNBTS directors met on 12 April 1988.[266] The proposed Factor VIII for patients with inhibitors had encountered problems. Dr Perry would report to the Scottish directors at their 'supply and demand' meeting on 17 May.
10.215 On 14 April 1988, the American journal Blood Bank Week intimated that Chiron Corporation had announced that they had isolated and cloned proteins from the NANBH virus. Both BPL and PFC held plasma stocks and intermediate materials derived from blood donations collected before a screening test was available. On 29 April 1988, SHHD wrote to Professor Cash.[267] Ministerial advice would be required. But disposal of these stocks had to be resolved. The working hypothesis suggested was that they would require to be re-stocked, but that existing stocks should not be disposed of meantime.
10.216 In April 1988, Professor Cash prepared once more a set of 'Notes for Scottish Health Service Haemophilia Centre/Transfusion Service Directors' Meeting' due to be held on 5 May 1988.[268] They contained a similar narrative to Dr Cash's previous notes:
These notes have been produced to facilitate discussion with regard to future SNBTS planning for the production of blood products required for the management of patients with haemostatic or thrombotic disorders within the Scottish Health Service….
10.217 In now common form, the paper set out data on trends in the issue of Factor VIII preparations. The data were up-dated and revised in subsequent reports. (See table 10.20 below) At this stage, the decline in the use of Factor VIII appeared to have been reversed. The trend was seen more clearly in terms of issues to RTCs. The revised figures for PFC Factor VIII products for 1986, 1987 and 1988 were 5.52, 7.44, and 9.51 IUs respectively.[269] In the light of these trends, SNBTS directors decided to review previously shelved plans to increase production at PFC. Professor Cash anticipated the possibility of having to purchase commercial products in 1988–89.
10.218 Over the same period there was increasing usage of DEFIX and related products. Dr Perry reported similar trends in the use of both main concentrates. He expressed the escalation in issues of FVIII as representing an 81% increase in 1988 over 1986 and a 44% increase over 1987: 'a major and unplanned escalation in demand'. There had also been supply difficulties associated with technical problems, and a significant fall in fresh plasma procurement in 1987–88.
10.219 Work continued on the new high purity product. Dr Perry's notes were more extensive:
The PFC has established a two stage development strategy for FVIII products. The basic underlying policy is to concentrate on product virus safety, more appropriate dose size and National self-sufficiency. An emphasis on product purity per se is considered inappropriate at the present time. Directors may wish to note that 'new generation' commercial concentrates (immunopurified, solution heated etc) diminish process yield (approximately 25%–35% of PFC yields) and as a result are substantially more expensive. Moreover there is emerging a major concern that yield penalties of these new processes are leading to product shortages in both the US and Europe.
10.220 The PFC development strategy is:
(a) Development of 'Classical' high purity concentrate utilising 'spin off' technology from the Z8 process. It is planned to manufacture this product in late 1988 for supply in January 1989….
(b) Development of 'High Purity' concentrate…within the next 2–3 years. This product will probably result in a yield penalty of approximately 25% and will require to be phased into routine use over an extended period. This development is being pursued as a collaborative development with New York Blood Centre and Dr Alan Johnson (New York University).
10.221 In relation to Factor IX, he sought advice on whether heat-treated Factor IX was comparable in efficacy to non-heat treated product in the treatment of inhibitor patients.
10.222 Generally, he reported that clinical evidence was accumulating that dry heating (80˚C for 72 hours) was capable of providing non-infective products (ie not infected with HIV, NANBH and HB). The source data mainly related to 8Y, but Z8 had a comparable level of virus inactivation. Subject to necessary clinical and other tests, PFC now had a product that would meet the required standards for virus inactivation.
10.223 The paper presented what appears to have emerged as the standard view of fractionators: purity, with its advantages in solubility and application, was subordinate to the availability of a safe product in sufficient volume to achieve national self-sufficiency. The view was not shared by, and was unlikely to appeal to, haemophilia directors.
10.224 However, at the meeting, Dr Perry commented that the yield of the new Z8 product had not come up to initial expectations, partly because of losses inevitably incurred during heat treatment for virus inactivation. The new Z8 product being developed should be available for trial by the end of 1988–a product of much higher purity was being developed in collaboration with the New York Blood Centre. He said that use of Factor IX (DEFIX) had multiplied 2.5 times since 1983, and possible reasons for the current surge in demand for FVIII were discussed. HIV inactivation studies were being accelerated to meet licensing requirements.
10.225 It appears that there was discussion of the possibility of adopting the processes used in England to accelerate production of an equivalent product in Scotland. Dr Perry commented that to mimic the 8Y product in Scotland would entail substantial changes in equipment, and acceptance of a lower yield.
10.226 SHHD reported on the current arrangements for compensation for participants in clinical trials, but did not convince the directors that enough had been achieved.
10.227 On 16 May 1988 the UK haemophilia reference centre directors prepared a report on the choice of products for non-inhibitor Haemophilia A, B and von Willebrand's patients. It appears to have been circulated by 31 May.[270] The paper discussed manufacturing methods, and classified products. First-generation products were conventionally fractionated and usually dry-heated, according to various protocols. There was clear evidence of NANBH transmission by some of these products. Anecdotal evidence of HIV transmission (always disputed by manufacturers), had led to all of these products except one (Koate HT, Cutter) being withdrawn from the market. Second-generation products responded to the perceived inadequacies of first-generation processes, and had generally been found to have lesser risks of hepatitis transmission. A disadvantage of several methods was low yield, which resulted in the need for larger quantities of source plasma and higher production costs. Third-generation products were prepared by monoclonal immunoabsorption, which resulted in extremely pure final products of high specific activity.
10.228 The report described the specific second-generation products on or soon to come on the market from Cutter, Alpha, Behring, Immuno, Elstree, and Octapharma; and the third-generation products from Armour and Baxter. It was observed that there was a lack of formal reports on products which resulted in 'very poor evidence of product safety', but it was commented that all of the products that were available or soon to be available were considered to have a 'negligible' risk of HIV transmission. In relation to the third-generation products, it stated:
It is claimed that fractionation processes, rather than any viral inactivation steps which may proceed or follow them, are predominantly responsible for freedom from viral contamination. Assuming such 'sterility', the main conceptual advantage of these products lies in their potential to avoid the protein and antigenic loading which is an inevitable consequence of treatment with 1st and 2nd generation concentrates. Possibly, such loading may contribute to immune dysfunction, especially in HIV-infected patients, and it is claimed that therapy with monoclonal-fractionated concentrates may have a favourable influence on immune function. In our view, this claim is at present unsubstantiated.
10.229 The report concluded with recommendations (for Scotland separately from England) which, in general, supported the use of commercial products, by now an established part of the haemophilia doctors' stance. Interestingly, the report criticised the lack of regulatory guidance on therapeutic decisions: 'It has always been the case in the UK such decisions have often had to be made without guidance from the regulatory authorities … this situation is to be deprecated.' It also noted that NHS 8Y was not available in Scotland and Northern Ireland. The analysis was perceived by SNBTS to be partisan in tone and content, but it is instructive in considering the contributions of Dr Ludlam and other haemophilia doctors to wider debate.
10.230 The minutes of the meeting of 5 May 1988 record Dr Ludlam's complaint over the accuracy of the previous minutes, and a general lack of support for his position. Professor Cash requested that the minutes of the current meeting record the disagreement.
10.231 The minutes reflect various points of disagreement and concern.[271] The yield expected from Z8 was not up to expectation; increasing demand for FVIII reflected increasing confidence in its safety, for some; but Dr Lowe and Dr Ludlam found PFC products inferior; and testing of new products on untreated patients was impossible in Scotland because of the low numbers available. Dr Ludlam had issued his explanatory leaflet to patients, despite being asked not to, explaining that it was on advice from the Medical Defence Union. In the absence of a product licence for Z8, he protested against the alternative approval mechanisms that had been put in place. The production target was not changed despite Professor Cash's report.
10.232 Incidentally, it was noted that legal proceedings at the instance of haemophilia patients were anticipated. The minutes did not survive detailed scrutiny in some respects, and detailed changes were made following representations by members of the committee.[272]
10.233 On 16 May 1988, Donald Macquaker, Chairman of the Common Services Agency, wrote to WK Reid, Secretary, SHHD 'in confidence' expressing concern on the subject of NHS management, and the downward trend in donations.[273] He said that the directors of the BTS all stated that they could not find any relationship between the trend and AIDS. There was reference to a Court of Session action raised against a clinician, the SNBTS and the Secretary of State in relation to a haemophiliac who claimed to have been prescribed Factor VIII which was infected with the AIDS virus. He said that the single most worrying position at the moment was that SNBTS were continuing to manufacture Factor VIII as Z8 without a product licence for it. He commented that the Medical Defence Union might instruct their members not to prescribe SNBTS product. That could cost the NHS millions. 'I have asked John Cash to prepare a paper for consideration by myself, Hamish Hamill, Jim Donald and John Cash.'
10.234 Arrangements with England for the supply of 8Y appear to have come under strain in May 1988. Dr Smith's letter dated 4 May has not been located. But in response to it, in a letter to Dr Perry, Dr Boulton anticipated interruptions in the supply of 8Y for a named patient.[274] The purchase of Monoclate was suggested, but that would involve high cost. So far as PFC supplies were concerned, the significant point made by Dr Boulton was that Dr Ludlam would be asking what advances there had been in purer Factor VIII products. In the event, Dr Ludlam resorted to Monoclate.[275]
10.235 On 14 June 1988, WK Reid, wrote to D Macquaker, Chairman, CSA 'I understand that the SNBTS already has a product licence for FVIII–but that a variation is required to cover the Z8 product. Is not the next step for the SNBTS to apply for such a variation?'[276]
10.236 At this time there was further interest in closer cooperation between the two BTS services. On 9 June, Dr Perry responded to a letter from Dr Gunson:[277]
FVIII yield[s] from the Z8 process are significantly lower now compared with yields achieved when the process was originally introduced. Substantial efforts are now being made to bring process yields back into line with our expectations (280 IU/litre) are underway (sic) but we cannot assume that these efforts will be successful.
I believe that the implied option for BPL to implement the Z8 process (or for that matter PFC to implement the 8Y process) is neither viable or sensible as an operational option. FVIII processes are complex and invariably are designed to fit with other processing technologies within individual fractionation centres. Processes are intrinsically vulnerable to significant yield variations and history tells us that the transfer of a process from one centre to another represents a major undertaking with little assurance that the product or process characteristics will be maintained. FVIII process technology is evolving rapidly – it would be unwise (in the short term) to attempt to transplant either the Z8 or 8Y process.
There exists perhaps a more powerful argument for advocating a policy of no change. 8Y has now been substantially validated in naïve patients with very promising results. Such studies have become major factors in the market place and to abandon 8Y in favour of Z8 (which has not been validated in patient studies) at this time would be quite irrational – even if there did exist a significant yield advantage.
8Y is a good product of higher purity than Z8, PFC is planning the imminent introduction of a FVIII product of comparable purity to 8Y and which draws upon features of both 8Y and Z8 processes. Yield data from this process will emerge in due course.
The positive way forward for the UK at a time of considerable turbulence, market vulnerability and technological change is to foster strong collaboration links between BPL and PFC so that each Centre can benefit from the success and failures of the other. Advocating a policy of 'standard processing' between the two Centres is not possible at the present time or desirable. This situation may of course change in the fullness of time but should only be contemplated as part of a structured scientific/strategic development – not on the basis of a snapshot comparison.
10.237 Dr Smith was confronted by the same issue. On 15 June 1988, he wrote to Dr Lane.[278] He analysed the two processes, and reported that there was no evidence that 'at heart' the Z8 process was a higher yielding process than 8Y. PFC did not appear to him to have a significant advantage. It appears that he was no more anxious to take on the Z8 process than Dr Perry was to give it to BPL.
10.238 Dr Perry's view of 8Y was supported by a report of surveillance carried out by a study group of the UK haemophilia centre directors aimed at detecting NANBH transmission by the English product. A very high degree of safety was recorded, comparable with up to date pasteurised products.[279]
10.239 The SNBTS directors met on 14 June 1988.[280] The next meeting was on
27 September 1988.[281] Neither meeting records material relevant to PFC production.
10.240 At a meeting dealing with 'Blood Transfusion Service: Miscellaneous Issues' on 15 June 1988, Professor Cash said that the service was no longer self-sufficient in Factor VIII and albumin.[282] Commercial supplies would be required of the order of 2.5 to
3 million international units of Factor VIII in 1988–89 at a cost of about 15p per unit in the international market. The estimate for the following year, if demand stayed the same, was 3 million IUs. The note stated:
Also in 1989–90 the Service would be moving to a new high purity albumin product which would lead to a 20 per cent drop in yield…He explained that until recently, in common with one major commercial manufacturer (Cutter), the Service had as a matter of policy manufactured a high-yield, low purity product. Following a recent Glasgow University research project which demonstrated the greater efficacy of high yield[283] [sic] albumin, the Service had no option to change, even though Professor Cash had doubts about the conclusive nature of the research.
10.241 On 17 June 1988, D Macquaker, CSA, wrote to WK Reid, SHHD.[284] He had requested that Jim Donald should make all the necessary contacts to apply for a licence variation for the manufacture of Z8. He said:
Beyond the Z8 product there is clearly a problem in PFC with the seemingly endless increase in demand for albumin as well as FVIII …we are being asked to maintain by Dr Perry a throughput at 80,000 litres per year and we are only licensed for 40,000 litres per year. John Cash has in fact written to Jim Donald on this urging that we obtain a manufacturing licence for 90,000 litres per year and has requested that contact be made direct with Mr Calder of SHHD.
10.242 The demand and supply position had deteriorated.
10.243 On 1 July 1988, Dr Perry responded to Dr Boulton's letter of 18 May, agreeing that a meeting with Dr Ludlam would be helpful in light of the supply situation in England and Wales, 'but this should take place in the wider context of PFC developments'.[285]
10.244 On 6 July 1988, David Watters of the Haemophilia Society wrote to Dr Macdonald, CMO, that he was 'concerned to learn from people with haemophilia in Scotland' of the shortage of FVIII.[286] He asked for the official explanation, in view of Scotland's track record of self-sufficiency. He wrote to Malcolm Rifkind.[287] Professor Cash replied on 11 July.[288] Dr Macdonald appears to have replied on 19 July, but the letter has not been traced.[289]
10.245 On 26 July 1988 David Watters again wrote to Dr Macdonald asking for a meeting to discuss the loss of self-sufficiency in Scotland.[290] Manuscript comments on the letter indicate acknowledgement of the inevitability of agreeing to that.
10.246 The outcome appears to have been reflected in an article in The Bulletin in September:[291]
Since the last issue of Update went to press, Scotland has ceased to be self-sufficient in Factor VIII.
We understand that there are a number of reasons for this. Following a visit by government inspectors, the licensed production capacity of the Protein Fractionation Unit at Liberton, Edinburgh has been reduced by 33%. In addition there are production and manufacturing problems. To make the situation worse, there has been an unprecedented rise in demand for concentrate. This will result in a shortfall in supply in Scotland approaching 4 million units of Factor VIII.
While the reason for this shortage in Scotland is unrelated to the world situation, Scotland's problem could not have happened at a worse time. It is not only worrying for people with haemophilia but also a blow for the scientific community. As treatment will be given using commercial products, a unique population of people with haemophilia who have only ever been treated with Scottish NHS concentrate will be lost for research purposes."
10.247 Mr Watters may not have known of Scottish use of commercial products. Alternatively he may have had access to data distinguishing patients who had only ever had PFC concentrates.
10.248 The background to the reduction in capacity appears to have been an adverse report of the Medicine Inspectorate following inspections in May and June 1988.[292] The report concluded that there were deficiencies in staff structure and organisation, and in documentation of procedures and records; and that the premises were unacceptable in a number of respects including inadequate storage areas. It was intimated that an application for a manufacturer's licence would not be supported until the problems had been dealt with. Dr Perry acknowledged the report on 22 August 1988.[293] He corrected a few factual inaccuracies, but generally accepted the report. On 17 November 1988, he wrote to Professor Cash commenting on the report.[294] He was not surprised at the criticisms, which reflected his own views. He commented that the programme had been aimed at increased output: quantity at the expense of quality. There had been 'gross under-management' of PFC. Changes would have to be made. But in the meantime, it appears that productive capacity had had to be reduced.
10.249 On 1 October 1988 the National Directorate of the NBTS was formed and Dr Gunson was appointed National Director.
10.250 The SNBTS directors met on 13 December 1988.[295] A table of commercial purchases was provided. There was discussion of a proposal to swap commercial products held in Scotland with NHS products held in Northern Ireland so that the NHS product could be reserved for patients unaffected by hepatitis. Professor Cash discussed proposals for re-establishing self-sufficiency.
10.251 In anticipation of what a manuscript note on the face of the letter referred to as 'some corporate planning ahead', Dr Cash wrote to Dr Perry on 16 January 1989, asking for a definitive list of PFC products that were likely to require trialling up to about 1995.[296]
10.252 A meeting with the UK Haemophilia Society was arranged for 3 May 1989 to discuss the quantitative and qualitative aspects of SNBTS FVIII production and other matters.[297]
10.253 On 3 March 1989 Mr RRC Stewart, wrote to health boards a letter in which he said:
As you are probably aware, there recently has been a shortfall in the ability of SNBTS to match the demand for certain blood products within the Scottish Health Service, notably Factor VIII concentrate. Thus Health Boards have had to purchase commercial products to meet this immediate problem….
10.254 He asked for data on commercial purchases. Greater Glasgow Health Board provided a print-out for the period from 1985–86. Other boards provided data for the year then ended, and, in due course, for later periods. The data collated by Mr Stewart for the final two years of the current period were:
Y/e 31 March 1989
Argyll & Clyde
Ayrshire & Arran
Dumfries & Galloway
Forth Valley
Profilate
153,200iu
100x100m
Profilate: Armour
£125,000298
Profilate: Alpha
8Y (BPL)
5,500iu
Haemate P
Monoclate Armour
49,000iu
FEIBA (Activated FIX – Immuno)
Albumin Immuno 20%
Albumin Immuno 4.5%
CI Esterase Inhibitor Dutch RC
Total Glasgow cost
FVIII
£11,040299
Albumin Immuno
£392300
Factor VIII
10 vials
266,000 u
HYATE: C
Monoclate
Octa Octapharm
Haemophil M
150 bts
Fibrogammin Hoechst
Total Lothian cost
50 bts
£1,700302
Table 10.18[298][299][300][301][302]
10.255 At the time some of these product types were not available from PFC Liberton at all. Factor XIII and FEIBA fell into that category. Some were purchased in small quantities. But there remained a substantial commitment to the purchase of commercial Factor VIII. For the first year, Mr Stewart prepared charts showing that so far as supplies of albuminoids were considered, SNBTS products accounted for 98.3% of total supplies to regions and commercial products accounted for 1.7%. However, in relation to Factor VIII products, SNBTS products accounted for 86.7% of the total demand, and commercial products for 13.3%. On 26 March 1990, Mr Stewart wrote to boards emphasising the need for data in planning PFC production. However, the raw data tend to indicate that, even at this stage, health boards had considerable autonomy in sourcing therapeutic products. Mr Stewart's letters also underline the dependence of SNBTS on the boards for information about the products they were actually using. Communications were to improve in the early 1990s. But by the end of this decade there appear to have been deficiencies in the organisation of blood product supplies having regard to the interest of Scottish NHS patients as a whole.
10.256 On 29 March 1989, Professor Cash wrote to Tayside Health Board intimating that the need for commercial purchases in 1989–90 was likely to be similar to 1988–89.[303] He explained that the funds required to expand production of FVIII would become available on 1 April, but that it could take a year to realise the investment. On 19 April, Professor Cash wrote to CSA that SNBTS hoped to produce 10.8 million IUs of Factor VIII of which 9.5 million would be issued to RTCs and 1.3 million would be placed in national stocks, always subject to plasma supplies.[304]
10.257 The SNBTS directors met on 13 June 1989.[305] There was no discussion of PFC production.
10.258 Mr Stewart presented a report at the meeting of the SNBTS and haemophilia directors on 21 July 1989.[306] In format it followed Professor Cash's reports for previous joint meetings. Mr Stewart noted that the bulk of the Cryoprecipitate issued was not used for haemophilia care. Use of factor concentrates had recovered to its 1984 level. But plasma supplies were still depressed, and PFC had to draw on national stocks. Increased production was planned. The fears of increased DEFIX usage had not been realised. Dr Perry liked the report, but sounded a word of caution about the production plan.[307] Mr Stewart, for his part, questioned the previous years' reports, and re-calculated some tables.[308]
10.259 On 21 July 1989 Dr Ludlam presented the first report of the Scotland and Northern Ireland Factor VIII Working Party. The report reflected the approach of the haemophilia directors. Thus there was an explanation of commercial usage: 'The amount of commercial product used is not related to patient numbers at any one Haemophilia Centre but to the pattern of previous use of non-NHS products.' Demographic data on the distribution of haemophilia patients was in preparation. There was adverse comment on Z8, and the hope that a new, purer, product would be available. The minutes of the meeting noted the system put in place by Mr Stewart for collecting data on Factor VIII usage and commented that this required a fair amount of work. Dr Ludlam pressed for higher purity products: hoping that the new S8 Factor 8 product would be available. It was responded that purity did not equate with safety. Item 5 of the minute reported that Scotland had the lowest prevalence of HIV infection among haemophiliacs in the world.
10.260 The SNBTS directors met on 29 September 1989.[309] A summary of commercial purchases for 1988–89 was produced.[310] This showed:
Prohilate
100 x 100ml
150 btls
Factor VIII Hyate C + 'Porcine'
Prophilate
50 bots
These data correspond with other SNBTS sources: see data above (Table 10.18)
10.261 On 1 November 1989, Lothian Health Board wrote to SNBTS.[311] The general manager of SNBTS had written on 14 July intimating that SNBTS expected to become self-sufficient in Factor VIII in the financial year 1990–91, and to increase supplies of SPPS. An update was requested to enable the health board to do its planning. The SNBTS directors met on 12 December 1989.[312]
10.262 On 8 November, Dr Pepper prepared an agenda for 'FVIII Improved Stability and Yield'. Internal memoranda indicated that self-sufficiency remained the goal of CSA and the SNBTS. But, with two three-month shut-down periods anticipated in the following year, it was thought that PFC could not supply demand in 1990–91.
10.263 On 8 November 1989, Dr Ludlam wrote to Professor Cash expressing concern about delays in the introduction of 'the new factor VIII formulation (S8)' being developed by PFC.[313] Production had fallen far behind the predicted introduction date. He stated:
As you will be aware the present factor VIII (Z8) being manufactured by PFC is a product of very low purity. It is one of the lowest purity products available in the world. The current factor VIII concentrate (8Y) manufactured by the Blood Products Laboratory at Elstree is a considerably purer product which is proving reasonably acceptable in England and Wales. Furthermore Z8 is inadequate for treating von Willebrand's disease and we are currently having to obtain either 8Y or a commercial equivalent instead of Z8.
There is an increasing trend in the UK and internationally towards the use of concentrates of higher purity, some with good von Willebrand factor activity. My fear is that if SNBTS does not keep up with international developments in the manufacture of such concentrates a time may come when I and my haemophilia director colleagues may have some hesitation in using products produced by PFC.
10.264 The difference of interests between haemophilia clinicians on the one hand, and fractionators on the other appears explicit.
10.265 On 14 November 1989, Mr Stewart began collecting data on projected demand for FVIII in the 1990s to facilitate long-term planning.[314] On 27 November, he wrote to Professor Cash with the results. The haemophilia directors had estimated 1990–91 demand at 11.2 million IUs of Factor VIII. He had proposed production of 12.5 million IUs, requiring 66.5 tonnes of fresh plasma, to allow 11.5 million units for issue to RTCs, and 1 million for addition to the national stock. The regional transfusion directors had reported that they anticipated a national plasma input of 63,160 kg, of which 61,160 kg would produce 11.6 million IUs. PFC had to shut down for two three-month periods. He did not believe that PFC could supply SHS needs in 1990–91. On his amended proposals, if PFC were to hold minimal stocks, 9 million units would be available for distribution, and health boards would have to purchase 2 million units on the commercial market. On 14 December 1989, Professor Cash wrote to Dr Ludlam intimating that SNBTS took the view that for 1990–91 directors should plan on the basis of issues of 8 million IUs of PFC product.[315]
10.266 On 28 November 1989 (following a meeting of the Factor VIII Working Party the previous week) Dr Mayne wrote to Professor Cash.[316] She had raised the possibility of sending Scottish plasma to Elstree for processing to avoid commercial purchases. She said:
I would reiterate my disappointment at the delays in producing the new S8 and my periodic dissatisfaction with the present Z8 product. However, regardless of delays, etc. I would prefer using such material rather than commercial concentrate….
10.267 The immediate background was a bad experience with a previously untreated patient who had suffered a severe reaction to excess fibrinogen in Z8 and had to be switched to 8Y for further therapy.[317] She had told Professor Cash that Z8 was no longer suitable for all patients.
10.268 On 19 December 1989, SNBTS sent a memorandum to CSA commenting on Factor VIII stocks.[318] Stocks of Z8 Factor VIII were under pressure.[319] All production was focused on Z8. Processing of S8 for clinical trials could not be accommodated without putting Z8 at risk of 'stock out'. S8 development was already behind schedule. The key issue was artificially restricted capacity: the plant at PFC Liberton was currently working a thirty-hour week out of 168 hours available. A variation order was required from SHHD to work shifts in order to increase output.
10.269 PFC research and development work at the end of the year appears to have been under challenge. Z8 was an increasingly unpopular product among haemophilia doctors. It was acknowledged to be very safe but, in comparison with commercial products, and BPL 8Y, it was lacking in purity with consequential disadvantages in its administration. S8 was not making the progress hoped for. A lack of confidence in PFC scientists was reflected in Dr Mayne's suggestion that Scottish plasma should be sent to England for processing as 8Y.
10.270 On 5 January 1990, Mr Stewart reported problems with the production of FVIII.[320] As a result there could be no production related to the 'new' product (S8) until the problems with the current product were solved. Forecasts of production depended on the selection of one of four scenarios, all of which appeared to be problematic to some degree.[321] The scenario planning was discussed on 16 January 1990.[322] Phase iii/iv of the planned works would create disruption in the spring/summer of 1992 lasting for a minimum of 18 months.
10.271 On 18 January 1990, Mr Stewart wrote to Dr Ludlam and others seeking guidance (on a 'best guess' basis) on future demands for FVIII.[323]
10.272 A conference was held in Rome on 18 and 19 January 1990 with the title 'Factor VIII Concentrates and Treatment of Haemophilia: State of the Art in 1990'. The record of the proceedings available[324] was prepared by Dr Smith, who worked originally at PFC and later at BPL and at PFL during the material period, and reflected some of the tensions that existed between the fractionators on the one hand and the haemophilia doctors on the other. Dr Smith records that before the meeting he had expected 'another benefit match for the League of Purity', but that the meeting turned out to be more open-minded. There was tension between fractionators and haemophilia clinicians. Based on his experience, Dr Smith appears to have regarded the pressure for increased purity as inappropriate.
10.273 On 29 January 1990, Mr Stewart wrote a memorandum on the up-to-date position.[325] PFC stocks of Z8 had fallen to about 1.25 million units. This was because there had been a problem with the heating unit which resulted in a build-up of material at that stage in production. The problem had been resolved and stocks would increase again. There were no problems with RTC stock levels. Production planning remained on the agenda. On 25 January 1990, John Francis provided an update on scenario planning.[326]
10.274 Dr McClelland wrote to Mr McIntosh about factors affecting supply on
30 January 1990.[327] In Edinburgh and the south east, the policy was to maintain individual patients on PFC Factor VIII or on commercial products. Patients would only be transferred to PFC Factor VIII 'if there was a reasonable expectation of a sustained supply at an increased level'. He also noted that Lothian Health Board anticipated spending £350,000 on commercial Factor VIII in the current year, less than the £500,000 asked for. The Royal Infirmary Edinburgh Pharmacy was already £200,000 over budget.
10.275 The SNBTS directors met on 13 February 1990.[328] Virus safety of blood was discussed in terms of HTLV I and Hepatitis C virus. Testing was the focus. In relation to HCV, a decision on testing had been deferred pending further advice from Professor Zuckerman and Dr Tedder. Counselling was discussed. There was also reference to testing for HIV 1 and HIV 2.
10.276 On 15 February 1990, there was a meeting of the 'SNBTS Service'.[329] The final version of the SNBTS 'Mission' statement was tabled.[330] Otherwise the meeting was mainly concerned with bids for funding, product licences and manufacturing licences. There was minuted a decision on production:
SNBTS would require a business plan delineating those products to be manufactured, those to be contract fractionated and those to be purchased. If the Service failed to meet its production targets and was obliged to buy more this would affect the budget adversely. Conversely, if the Service exceeded its manufacturing targets, the allocations made for commercial products could be saved and vired (sic) appropriately.
It is not clear whether this was regarded as innovative.
10.277 Prepared by Mr Stewart for the meeting on 11 May 1990 was in a different format from that used for the meeting on 21 July 1989. The following summary data have been derived by the Inquiry team from the two reports.
10.278 The summary of Factor VIII usage in International Units was:
PFC Factor VIII intermediate
HT NY
* It was agreed at a meeting in July 1989, that Cryoprecipitate would be taken out of the calculations of the amount of FVIII used for haemophilia care.
Table 10.20[331][332]
10.279 Total plasma sent to PFC was recorded, in kilograms, as:
10.280 The data recorded of plasma sent to PFC for processing (expressed in kilograms) were:
To PFC
* As above.
• In this period there were increased efforts to identify and quantify commercial purchases.
• Data recovered appeared inconsistent and unconfirmed.
• PFC's improved Factor VIII product, Z8 was delayed in trials and threatened production. By 1988 its yield in production was disappointing
• Chiron's isolation and cloning of NANBH was announced in April 1988 with an impact on the use or disposal of donations collected before testing became available.
• Increased demand for higher purity factor products continued to be anticipated.
• Some commercial products were associated with HIV transmission.
• Litigation based on alleged infection by SNBTS products began.
• Attempts to align Scottish and English production methods were proposed and resisted.
• In the wake of an adverse inspection report by the Medicines Inspectorate, PFC's capacity was restricted.
• By June 1988, Scotland was no longer self-sufficient in blood products.
• The Haemophilia Society published its concern at the situation.
• There was increased management effort to restore the position in the light of increased knowledge of the extent of commercial purchases.
• SNBTS research and development increasingly focused on the production of a high purity product with collaborative projects with Dr Johnson in New York as Z8 became increasingly unpopular and research and development of SNBTS's alternative, S8 failed to progress.
10.281 Additional plant was required for routine production in January 1991.[333] Upgrading of the Usifroid freeze-drier and associated equipment was undertaken.[334]
Other Factors Affecting Demand and Supply 1990–1993
10.282 The delay in producing a clinical trial batch of S8 became critical in February 1990. Dr Perry wrote to Dr Foster:[335]
We simply do not have the time to accommodate further delays to this development programme. It is now substantially delayed and there is clear evidence of patients being transferred to commercial product in preference to Z8. Z8 is now obsolete!...
Supply for Z8 is now secure and thus scheduling is not a problem – can be done any time from a production point of view.
Please arrange for S8 batch S8 (007) to be run as early as possible in March and advise me of the selected date.
10.283 On 28 February 1990, Dr Stewart and John Francis produced a specification of the information required for PFC's purposes on receipt of plasma at PFC and on yields.[336] Dr Perry sought more data.[337] It appears that a more rigorous reporting regime was anticipated.
10.284 On 11 March 1990, Dr Ludlam intimated to Dr Cash that the haemophilia directors in Scotland had agreed to request distribution of the 1990–91 production of the 8 million IUs of Factor VIII as follows:
Aberdeen 600,000 IU
Dundee 600,000 IU
Edinburgh 2,100,000 IU
Glasgow 4,300,000 IU
Inverness 400,000 IU
10.285 That was agreed.[338] At this time there were informal transfers between centres to accommodate problem situations.[339] However, Dr Urbaniak wanted the direct link to PFC to be reinforced.[340] Dr Stewart replied on 12 April 1990.[341] The informal arrangement had been agreed by the haemophilia directors. As background he said:
As you are aware, for the last two years the SNBTS has been unable to supply sufficient Z8 to satisfy the demand for Factor VIII in the Scottish Health Service, and commercial products have been purchased to make up the difference.
10.286 On 19 April 1990, Dr Perry added his views to the same effect.[342]
10.287 On 13 March 1990, Professor Cash wrote to Dr Foster about FVIII yield and plasma quality. The letter asked for data, enclosing an Australian paper that Professor Cash thought relevant. On 30 March 1990, Dr Foster wrote to Professor Cash about yield from eight and 18 hour plasma.[343] It appears that it had now been accepted that the yield differences between the two types of plasma was not significant except in relation to the final 80˚C heating step. The critical comment, however was:
[W]e now know (from the Z8 crisis investigation) that a key parameter of the Z8 process was not being correctly controlled throughout the period. This has been rectified and I understand that we are now seeing a much lower loss of VIIIC over 80˚ C heating. Hence last years data may be misleading for planning purposes.
10.288 It appears that Lothian Health Board complained to SHHD that SNBTS were building up stocks of FVIII and supplying the board with reduced quantities. SHHD wrote to Mr McIntosh on 4 April 1990 to enquire.[344] The response was forceful, repudiating the suggestion, pointing to the arrangements with the haemophilia directors, and Dr Ludlam's central role, and observing that stocks were the absolute minimum for safety.[345]
10.289 On 19 April 1990, Dr Cash gave tentative support to a paper by Mr Stewart on product development.[346] The paper set out a number of matters affecting demand, which was thought likely to grow at 10% per annum. The number of haemophilia patients was growing; more were on home therapy; and HIV-infected patients were living longer than expected due to treatment such as AZT. The general factors affecting the likely demand were:
• FVIII: the haemophilia directors considered it 'a poorly acceptable product'. If S8 did not come within two years, it was likely that the 'market' would demand such products and they would be purchased; and
• FIX: there was no evidence of change in demand, and the product caused less concern.
10.290 Provision for inhibitor patients was discussed. PFC Liberton did not intend to produce an activated Factor IX, but did plan a Factor VIIa product. Anti-thrombins were also discussed.
10.291 Dr Prowse wrote a paper in April.[347] He conceded that a virally inactivated high-purity product had to be produced within two years.
10.292 On 26 April, Dr Perry distributed a memorandum proposing a review of operational procedures associated with conditioning, crushing and thawing, and asked for data to discuss current plasma preparation protocols.
10.293 On the same day, 26 April 1990, Dr Stewart produced fresh proposals for Factor VIII distribution.[348] He referred to the problems that had arisen at smaller centres. He proposed a combination of annual issues and maximum stock levels as a means of controlling distribution. Discussion followed.[349]
10.294 On 7 May 1990, the first steps were taken towards revision of the management structures of the SNBTS.[350] An SNBTS Management Board was proposed, through which all key policy and strategic decisions were to be channelled as from 5 June 1990 (in the event the first meeting was on 19 June). There were detailed provisions for medical and scientific coordination; financial management; operational management; quality assurance and research and development. These changes were reflected in the flow of information within the service, and in its presentation, as compared with previous periods.
10.295 On 11 May 1990, the SNBTS and haemophilia directors met.[351] The meeting of 9 May does not appear to have been reported. Dr Stewart wrote a report to provide background for discussion of future production by SNBTS of products for the management of patients with haemostatic or thrombotic disorders.[352] Dr Stewart acknowledged the help received from directors and commented that the regular returns of the haemophilia directors 'have allowed inclusion of more up-to date data than previously has been possible'. Dr Stewart's data in relation to FVIII activity was the last to be expressed according to the 7th British Working Standard. Future reports would use revised units as stipulated in the 8th standard, making direct comparison with earlier returns impossible: values would require adjusting by a factor of 88 new units: 100 old units for direct comparison. The summary data provided to March 1990 are set out above.
10.296 Dr Stewart estimated current FVIII demand at 9 million IU per annum, with an increase to 10 million IU likely. Stocks of Z8 held nationally had been reduced in October and November 1989 to maintain supplies to the health service. It was planned to rebuild strategic stocks to ensure that there would be sufficient to cover a planned shut-down in the two years ending in 1992 and 1993. Dr Stewart set out plainly the critical points on which the plan was dependent. He also reported on product development. Section 3.14 of the minutes recorded that the processes for production of S8 had been completed up to the freeze-drying stage, and testing was now at the end of the heat-treatment process. However, due to production difficulties with Z8, production of higher-purity S8 had been temporarily postponed. Clinical trials of S8 were expected to commence in August 1990. There were no plans for an activated Factor IX. SNBTS had plans for a non-thrombogenetic product. This was a clear, professional, report focused on future requirements which Dr Stewart outlined. On his hypotheses, it was considered that SNBTS would be able to meet demand. But there would require to be changes in working practices at PFC, for example shift working, and these were in hand.
10.297 Commercial purchases were analysed in detail, and explanations were sought and given of particular transactions.
10.298 Dr Ludlam presented the second annual report of the Factor VIII Working Party. The report repeated the haemophilia directors' views that Z8 was not an ideal product.[353] Quality was low due to the presence of large amounts of plasma proteins other than FVIII.C. The BPL product was approximately ten times more pure. Z8 was relatively less soluble. The unitage per vial varied. The conclusion was that: 'unlicensed Z(8) is an unsatisfactory product by any standard and must be superseded by a more acceptable therapeutic material in the near future'. The report was written and presented by Dr Ludlam. SNBTS made its reply:
In defence it was countered that Z8 was a very safe product and, because of the manufacturing processes involved, higher purity products may be less safe. The SNBTS are committed to a high purity product but are interested in safety first and convenience second. Co-operation with the French to produce a high purity product was under consideration. Due to the quality problem Northern Ireland had not been taking up its full allocation.
10.299 The safety surveillance exercise under Dr Ludlam, involving previously un-transfused patients, had shown that, to date, PFC heat-treated Factors VIII and IX did not appear to transmit either hepatitis or HIV.
10.300 There is a second minute of the haemophilia and SNBTS directors' meeting on
11 May 1990.[354] The defence of Z8 presents it as a 'relatively safe' product. The change left the issue of safety of the product obscured.
10.301 The choice of product, reflected to some extent in Dr Ludlam's report, had a broader background. In early 1990, the third edition of the UK Regional Haemophilia Centre Directors Committee's 'Recommendations on the choice of therapeutic products for non-inhibitor Haemophilia A; Haemophilia B and von Willebrand's disease patients' was in circulation in draft.[355] Professor Cash was exercised by the statement that:
[T]hird generation high purity concentrates are advocated by their proponents both because of their presumed lack of viral contamination, and because of possible beneficial effects on the immune system. While we do not consider current scientific evidence sufficiently strong to justify general adoption of such products for routine therapy, we recognise the difficulties of obtaining such evidence and the 'common sense' argument….
10.302 On 9 March, Professor Cash sent a copy of the draft to the general manager of SNBTS pointing out that the authors represented a powerful influence on transfusion services throughout the United Kingdom, had a Scottish component, but no BTS component, and were hostile to BTS.
10.303 Professor Cash wrote to Dr Kernoff at the Royal Free Hospital on 20 February 1990:[356]
You will not be surprised, after our chats in Rome last month, that I raise my eyebrows at the last para on page 7 and ponder on what is the 'common sense' argument? I did not, I must confess to my great disappointment, in Rome hear any evidence from which I concluded that intermediate purity products were in any way 'bad' for HIV-I seropositive patients whereas higher purity products were 'good'. I had hoped that this clear message would have emerged from Dr Brettle's studies: it did not–and almost 80% of their patients are HIV +ve. Nor did Louis Aledort help us–his 'common sense' approach was quite the reverse of the Levine group's and Carol Casper did not seem particularly interested in this debate.
I agree the difficulties in demonstrating an advantage of higher purity products in an HIV –ve population are formidable–and logistically almost impossible in some countries (notably the USA), but it should not be as difficult in an HIV +ve population, not least because you and your colleagues can measure different end-points. It seems to me that this study should be set up before we resort to 'common sense argument'….
10.304 In a separate letter dated 9 March 1990, Professor Cash raised with Dr Kernoff another issue, relating to the lack of licensing of the NHS products.[357] He agreed with the need for licensing (a traditional SNBTS view), but pointed out that the position of the prescribing clinician was not unclear, as suggested: SHHD had offered indemnity pending up-dated licences.
10.305 The need for a high-purity product was discussed by Professor Cash in a memorandum dated 22 May 1990.[358] He agreed it would be necessary, and set out specific criteria for the product. His target date for clinical trials was September 1991. He thought that PFC would have to abandon precipitation technology in favour of chromatography. Immunopurification would not be acceptable. In the circumstances, he thought it would be unwise and unreasonable to pursue the introduction of the 'Johnson option',[359] and best to pick up an offer from CRTS, Lille. He was equivocal on pursuit of S8, and thought it should await the outcome of the Lille reports. Major changes of direction were in hand.
10.306 On 31 May 1990, Dr Stewart produced revised plans for distribution to the health service.[360] The discussion continued, and the documents became longer.[361] When agreed, Aberdeen wrote to amend it, to reduce their stock levels.[362]
10.307 On 6 June 1990, the issue of solubility arose again. Mr McIntosh wrote to Lothian Health Board.[363] He gave details of Z8 batches with poor solubility and commented that they met all product specification requirements other than solubility. He hoped for agreement that the material could be used rather than disposed of 'because of a problem which can be readily overcome with a waterbath'. It should not be discarded in favour of expensive commercial products. The conflict between safety criteria and convenience continued.
10.308 The SNBTS directors met on 12 June 1990,[364] the last meeting of the group in its existing form. The directors' meeting would be replaced by a medical and scientific committee, with a remit to advise the management board. HTLV1 was off the agenda. The study of HCV tests was under way. A small group was asked to develop a standard SNBTS approach to counselling.
10.309 Record-keeping was also discussed at the meeting on 12 June 1990. It was recommended that records to identify donor and donation would be retained for 15 years. A document was prepared dealing with medical audit within the blood transfusion service.[365]
10.310 On 12 June 1990, Mr McIntosh wrote to Dr Stewart discussing tactics for a forthcoming meeting.[366] SNBTS must not promise anything they were not absolutely sure they could deliver, and 'stocks must not be compromised just for the joy of self-sufficiency (which would only be short lived in that case anyway)'.
10.311 On 14 June 1990, DB McIntosh produced a broad definition of self sufficiency reflecting current European understanding: the satisfaction of the appropriate clinical demands of a population for human blood and blood products, by the provision of sufficient quantities of suitable products derived from within that population.[367] Mr McIntosh recognised that this was not a 'steady state' definition. Along with the mission statement, it set the context for the SNBTS strategy for 1990–93.[368] This envisaged a sufficient number of appropriate donors, with a target of 281,000 donations; sufficient plasma supplies to PFC, with a target of 73,900 kgs; Factor VIII production of 10 million IUs in 1990–91; and appropriate levels of Factor IX and other specified products all with appropriate financial targets.
10.312 The first meeting of the SNBTS management board was held on 19 June 1990.[369] The meeting was largely devoted to housekeeping matters.
10.313 The third edition of the UKHCDO's guidelines on the choice of products for the treatment of patients with haemophilia and vWD was issued on 1 August 1990.[370] The passages Professor Cash had drawn to Dr Kernoff's attention were radically amended. The pending applications for licences were acknowledged, and the paragraphs quoted became:
We acknowledge the paucity of evidence concerning the additional benefits of HP concentrates. However, it appears self-evident to us that the presence of contaminants and impurities in therapeutic products is undesirable, and therefore should be minimised. Our consensus view is that if it were not for their current high cost, and provided that further experience confirms that there is no increased risk of inhibitor development, HP products would be preferred for the routine treatment of haemophilia for reasons of possible superior safety, particularly if manufactured from donor plasma….
10.314 On 19 July 1990, Glasgow and West of Scotland returned to the question of Factor VIII distribution after discussions with Dr Stewart.[371] The focus was on providing satisfactory arrangements for Glasgow, (which was, by implication at least, the place where need was greatest), and providing a clear picture of the scheme. SNBTS headquarters unit sounded a note of caution: it was a first stab at a system, and monitoring would be necessary.[372] Correspondence on meeting the needs of the hospitals continued between Glasgow and West of Scotland BTS on the one hand and RHSC, Yorkhill and Glasgow Royal Infirmary on the other.[373] Meantime, North of Scotland BTS put in a bid for additional stocks to cover demand from the Spey Valley, where haemophiliac patients went for holidays.[374]
10.315 A report prepared in August 1990 for the four months to July 1990 indicated that plasma input to PFC was below target, but that plasma processed and stock progression were ahead of target.[375] Factor VIII production was below target. The new arrangements for product distribution were working well.
10.316 However, a report by Dr Stewart to Mr McIntosh dated 6 August 1990 indicated that data on Factor VIII usage in the year ended June 1990 were still not entirely reliable.[376] The caveats highlighted by Dr Stewart were that (a) usage figures for Glasgow Royal Infirmary for May and June 1990 were estimates; and (b) it was assumed that the products were used for the purposes indicated, but that could not be guaranteed. Subject to that, the picture painted was:
COAGULATION FACTORS IN SCOTLAND – YEAR TO END OF JUNE 1990
Annual Usage
(x 100,000 IU)
Estimated cost to Health Boards
Normal FVIII
Haemophilia A
Z8 (PFC)
Profilate (Alpha)
High Purity FVIII
Haemophilia A who 'react' to normal products
Monoclate-P (Armour)
Activated FVIII
Haemophilia A with inhibitors of FVIII
FEIBA (Immuno)
Acquired Haemophilia
Hyate – C
FVIII with vW Factor
Von Willebrand's disease
Haemophilia B
DEFIX (PFC)
10.317 In purely quantitative terms, PFC products amounted to over 78.5% of total coagulation factor consumption in Scotland in this period. Relevant research and development undertaken by SNBTS covered: a high purity Factor VIII product; a Factor VII concentrate; and S8 which was expected to have a similar vW Factor content to 8Y. The total cost of the commercial purchases was £832,500. The cost of the two commercial products likely to be supplanted by new PFC developments, FEIBA and BPL 8Y, was £312,500.
10.318 Dr Stewart continued to press for information on the levels of stock held.[377]
10.319 The medical and scientific committee met on 14 August 1990.[378] The committee discussed target definition and achievement in the context of self-sufficiency; the assessment of market requirements; and some aspects of product development. The scope of medical audit was discussed.
10.320 On 31 August 1990, Dr Stewart was asked by the Factor VIII working party to review the system for Factor VIII distribution.[379] He wrote to Glasgow Royal Infirmary and West of Scotland BTS on 3 September.[380] West of Scotland BTS, Glasgow Royal Infirmary,[381] and RHSC, Yorkhill[382] exchanged letters on the topic. And West of Scotland BTS wrote to Dr Stewart.[383] Dr Stewart appears to have made considerable efforts to accommodate Glasgow.[384]
10.321 On 9 October 1990, Dr Ludlam wrote to Professor Cash, having canvassed the views of the haemophilia directors in Scotland and Northern Ireland.[385] Their views were:
• Arrangements for the production of S8 should be shelved and Cryoprecipitate or fresh frozen plasma should be shipped to BPL for the manufacture of 8Y;
• A 'technology transfer' agreement should be made with Baxter or Armour for the manufacture of a monoclonally fractionated Factor VIII concentrate.
10.322 A two-day conference was arranged for 11–12 October 1990. Various papers were prepared for the meetings. Professor Cash prepared a discussion paper on total quality management.[386] The wider environment was changing. Consumer protection legislation, and the removal of Crown immunity demanded a change in quality assurance practice. Further capital and revenue expenditure would be required to achieve total quality assurance. Other documents focused on plasma quality monitoring;[387] service strategy, including a mission statement and key targets;[388] self sufficiency;[389] and a detailed production and plasma procurement plan prepared by Dr Stewart.[390]
10.323 Professor Cash's paper on self-sufficiency set out some historical background. In the early 1980s SHHD had refused to make a policy statement on self-sufficiency in blood and blood products. On 5 July 1989 that stance changed in the light of European Council Directives. In the light of what had transpired, it was necessary to define the market place and the relationship of SNBTS to its NHS customers: if SNBTS produced an appropriate product, would clinicians be obliged to use it? SHHD would have to abandon its sustained negative approach to production targets and participate in developing strategy. England and Wales had adopted the European notion of self-sufficiency, which applied a community-wide source area. Scottish managers had to know what standard they had to achieve. In relation to PFC, the environment had changed: what should the range of products be? Cross-charging and price required attention. Product development was an important area in which policy direction was required.
10.324 Dr Stewart's report analysed current performance, examined targets, and proposed solutions. The scene was set for a major review. In an exchange of correspondence between Mr McIntosh and Dr Stewart dated 4 and 5 October, 1990, Dr Stewart reported that lack of data made it difficult to comment on stock trends.[391]
10.325 The minutes of the board meeting on 11 and 12 October were bland narratives of issues and decisions, many of which involved remits for further study.[392]
10.326 On 16 October 1990, at a meeting convened to discuss the relative ineffectiveness of S8 in virus inactivation compared with Z8, it was agreed that no S8 should be released for routine clinical use until available data had been thoroughly evaluated and it could be concluded that S8 was as safe as Z8.[393]
10.327 On 16 October 1990, Dr Stewart estimated the cost of commercial products for 1990–91 at £330,200, compared with £284,200 in the previous year.[394] His estimate was supported by detailed figures. On 23 October, Dr Stewart sent a memorandum to Mr McIntosh:[395]
According to data which I recently have received from the Haemophilia directors no Prophilate (sic) was used in Scotland in September. Thus, allowing for the 'specialised use' of Monoclate in 'allergics' and 8Y in vWD, it can be regarded that self sufficiency in normal Factor VIII was achieved in this month.[396]
10.328 On 24 October 1990, Dr Mayne reported an adverse reaction in a PUP (previously untreated patient) who had received Z8. The patient had reacted badly to fibrinogen in the product, and his therapy was changed to 8Y.[397]
10.329 The board next met on 30 and 31 October.[398] Discussion took place on the scope of the SNBTS business. Provisional conclusions recorded were that the core range of products should be:
Whole blood and blood and plasma products;
Direct substitutes, such as recombinant FVIII;
Other human tissues;
together with other therapeutic products for which there was demand, and associated services.
10.330 A formal contract for collaboration with CRTS Lille was drafted in November 1990.[399] Dr Ludlam was concerned: Scotland should not be isolated from England; there were doubts and fears and worries over delivery; there was a low level of confidence in PFC; and there were qualifications about regulatory consent.[400]
10.331 On 9 November 1990, SNBTS entered into a confidentiality agreement with Cutter Biological Miles Inc relative to a possible licence for the manufacture of Koate HP Factor VIII.[401] Dr Prowse made contact with New York Blood Centre on 13 November raising the possibility of reconsideration of the use of solvent/detergent technology.[402] On
12 November Dr Prowse wrote to Mr McIntosh pointing out the need for a decision on the choice of process to follow, and the factors relevant to solvent detergent as against the Lille option.[403] Dr Cash also wrote to Mr McIntosh commenting on aspects of the choice to be made.[404] After a visit to Lille, Mr McIntosh wrote to CRTS on 16 November.[405] A draft agreement was in preparation. Discussions with Scottish colleagues pointed to a successful arrangement.[406] Government approval would be required. But, 'Vive le Club'. Substantial agreement had been reached. Detailed drafting followed. Lille confirmed ownership of the necessary intellectual property rights on 29 November, and their commitment to entering into a formal agreement.[407]
10.332 A full option appraisal was carried out in December 1990.[408] The need for a high purity product was set out: without it there would be 'desertion' to costly commercial products. Z8 had been declared unacceptable in October 1990. Eight options were discussed. Collaboration with Lille was the preferred option.
10.333 The board met again on 4 December 1990.[409] There were reports on plasma 'performance' (96% of target for SNBTS as a whole); use of albumin; demand for platelets; and Factor VIII concentrate options. Collaboration with Lille was the preferred route for the appraisal of Factor VIII options. Quality assurance was discussed. Performance monitoring was reported in some detail, measuring output against the targets contained in the service strategy. PFC's Factor VIII production was 110% of target. The facility was on course for the target of 10 million IU by 31 March 1991.
10.334 On 19 December 1990, Dr Ludlam wrote to Professor Cash inter alia expressing his delight at the progress being made, and the hope that the Lille proposal would receive ministerial approval in the near future.[410]
10.335 Overall, the impression from the papers available is that in terms of management structure, SNBTS had made advances in management in 1990, with the possible exception of the management of supplies to Glasgow and West of Scotland BTS, and Dr Foster's concerns.
10.336 Transitional arrangements for production of HPFVIII Factor VIII, referred to as 'The Bridge', were outlined in January 1991.[411] Clinical trials were programmed for February 1991, with exclusive supply of the product by January 1993 with a view to a product licence in mid 1994. The terminology for the product was to follow development in three stages:
• 'Lille VIII' to be produced in France from French plasma;
• 'Semi-tartan VIII' to be manufactured in Lille from Scottish plasma; and
• 'Tartan VIII' to be a wholly Scottish product put into general distribution when Z8 was exhausted.
10.337 But at this stage the phased programme was described less colourfully. The programme was:
(i) Immediate supply of HPFVIII (high purity Factor VIII) from Lille CRTS.
(ii) Contract manufacture of HPFVIII at Lille from PFC intermediate material from
(iii) Routine manufacture of HPFVIII at PFC from January 1992.
(iv) Discontinue manufacturing Z8 from March 1992
(v) Accumulation of Z8 stocks prior to Phase IV building programme.
(vi) Accumulation of Z8 for the development programme.
10.338 Details of the proposals were developed. A second paper set out arithmetical data with planning targets for a three year period.[412] It described the future issues of Z8 until phased out by December 1992. Quantification was further detailed on 28 January 1991.[413] Dr Perry outlined an agenda for the transitional arrangements at that time, with a paper for discussion at a meeting of the Factor VIII working party on 25 January. A business plan was prepared for these arrangements covering the period January 1991 to March 1993.[414] This document consolidated the planning data for Z8 production, the introduction of high-purity Factor VIII, and cash flow.[415] Critical success factors were detailed, including: acquisition of a quantity of Lille high-purity Factor VIII, development of technology to ensure supplies of Lille product from SNBTS plasma in accordance with the programme; on-time PFC production; and requisite funding. Details of the action required were set out, including obtaining health ministry approval. Dr Foster prepared a report summarising the development plans for the new product, the transitional arrangements, and further trials on 11 February 1991. The paper described the development stages, with comments on what had been achieved and scheduling of further steps needed; and provided schedules for production and other trials. The aim was to produce pilot batches for trial in June, July and August 1991, and production batches in September and October 1991.
10.339 It appears that, in the event, a meeting to discuss the arrangements took place on 30 January 1991.[416] Agreements were reached on refinements of the programme model, which was generally agreed. It was agreed that the formal contract with Lille should be finalised before 13 February 1991. A detailed action list was prepared following the meeting. On 13 February the transitional arrangements were discussed further.[417]
10.340 Ministerial approval was obtained on 15 February 1991.[418] SNBTS envisaged no difficulty in satisfying the conditions set as to cost, the introduction and licensing of the product and completion of the formal agreement. The programme for regulatory approval was fully detailed. On 22 February, the Medicines Control Agency intimated exemption from importation licensing requirements for 28 days.[419] This allowed the programme to proceed.
10.341 However, on 15 February 1991, Mr McIntosh introduced a word of caution.[420] He had been examining PFC production and stock data, and was apprehensive that available stocks would fall far below target.[421] On 19 February 1991, Dr Ludlam wrote to Mr McIntosh representing the views of the haemophilia directors.[422] They wanted the results of the PUP studies in France, assurances about the absence of HIV seroconversions in French patients, indemnities for individual clinicians, delays in half life and recovery tests until PFC were producing the material at Liberton, and adoption of a distribution schedule in terms proposed. On 7 March, Dr Ludlam wrote again proposing a scheme of allocation of Z8 and high-purity concentrate.[423]
10.342 On 22 February 1991, Dr Prowse wrote to Mr McIntosh asking about progress in obtaining the NYBC licence, the final agreement with CRTS Lille, and arrangements for shift working at PFC.[424] On 28 February, Mr McIntosh wrote to CRTS asking for comments on the draft agreement, and possible alternative forms of agreement.[425]
10.343 On 1 March 1991, Dr Prowse reported that the project was on schedule, and outlined the practical steps taken to pursue the stages of the product.[426] The Haemophilia Society approved of the Scottish proposals as a step in the right direction.[427] An article comparing England and Wales unfavourably appeared in the Independent on 9 April 1991.[428] MEDISPA officials were not amused,[429] and became less so.[430] They had to be reassured that SNBTS had nothing to do with the article. The public discussion and political interest led to an analysis by Dr Stewart of the legal position of Factor VIII use in Scotland.[431]
10.344 On 20 March 1991, Dr Perry wrote to Dr Prowse proposing a meeting to 'revive and agree' development strategy, and ensure that the associated manufacturing programme was viable.[432] The first trial run of the new product had been completed, and the objective was to establish the status and revised delivery date of a validated technology to support the transitional programme.
10.345 On 2 April 1991, Dr Ludlam wrote to Dr Perry.[433] He intimated that it was unlikely that there would be any uptake of the high-purity product in April because of the delay in obtaining indemnities from SNBTS and the fact that haemophilia directors would not be able to review data from France until the end of March.[434] Meantime they would use Z8.
10.346 It appears to the Inquiry team that this raises a question of the ground on which the pressure for a high-purity product was justified by haemophilia directors. It appears that it would have been difficult to have justified the pressure on grounds of safety: election to use Z8 would not have been justified if there had been any residual doubt about its safety. Having regard to the importance of the interaction of commercial usage and use of PFC products, this may be an issue for the inquiry.
10.347 On 10 April 1991, Dr Perry wrote to Mr McIntosh with Factor VIII stock figures at the year end, 31 March 1991. The short-term supply problems had all been overcome, and strategic stock-piling was back on course. Dr Stewart commented on 22 April 1991.[435] It appears that sufficiency of stocks depended on the plan one used as a reference point. Mr McIntosh responded with a plea to Dr Perry and Dr Stewart for a final resolution of the uncertainties over stock levels.[436]
10.348 On 26 April 1991, Dr Mayne, Northern Ireland, wrote to Professor Cash.[437] A meeting was to be held on 31 May to consider the nature and quantity of Factor VIII needed for the United Kingdom in the future, reporting of adverse reactions, and the future use of genetically engineered Factor VIII.
10.349 Early in May a draft was prepared of information for patients on the trials of the new high-purity product.[438]
10.350 The SNBTS and haemophilia directors met on 10 May 1991.[439] There were comprehensive reports on plasma procurement and FVIII production. There was a reduction in use of commercial products. Following discussions with Lille, the S8 project had been abandoned, and Lille technology was to be adopted to produce HP Factor VIII. It was thought unnecessary to maintain stocks of Z8 once HP Factor VIII was completely phased in. Future plasma supply requirements were dependent on studies that had not been completed. In particular, haemophilia directors wanted to conduct a survey of all adult patients in Scotland to estimate demand for the next five to seven years, and it was expected that the outcome would be crucial for SNBTS resource planning. SNBTS were now planning a single Factor IX product. The third annual report of the Factor VIII working party was presented. It was reported that Z8 distribution was working well, and that solubility had improved. Dr Ludlam spoke of the high safety record of the product. There had been one adverse reaction to DEFIX. SNBTS had in hand plans for a high-purity Factor IX product.
10.351 Among the papers accompanying the minutes was a report of the proceedings of the UK regional haemophilia directors committee meeting on 4 February 1991.[440] This document indicated widely differing, and in some respects confusing, views among the directors from England and Wales. The Scottish project with Lille was explained. Dr Kernoff explained that the intention of the UK services generally to produce what would initially be un-licensed products had been caused by the haemophilia directors 'pushing' for high-purity products, while there was no scientific evidence for their benefit, but he suggested that their contribution to improved haemophilia care would be considerable. Dr Jones said that he would require a reasoned scientific argument to convince the Northern Region to pay for high-purity products, and that 'god-like' pronouncements were not enough. On the invitation of Dr Mayne, each director declared his or her preferred product. Among the ten there were four different choices, adding to the impression of a fragmented approach to providing the service. BPL had not been allowed to attend, and the PFC representative was asked to leave before the end and told he would not be asked back. (In light of a letter sent by Dr Mayne to Professor Cash on 1 February, but stamped 12 February 1991, he would not have been allowed to attend at all on a consistent application of the committee's policies.[441])
10.352 On 13 May 1991, the progress of the transitional arrangements came under review at a meeting at SNBTS headquarters.[442] The production plan remained realistic, but the model would be tested on a range of hypotheses. The development programme was on course. The arrangements with Lille were reviewed.[443] In the case of plasma sent to Lille, there was a risk of stability problems in the product returned to Scotland which, if it persisted, would have to be investigated. CTX applications[444] were to be harmonised between France and the United Kingdom. It was noted that issues of the new material to regional centres awaited ethical committee approval.
10.353 On 28 May 1991 Dr Stewart wrote to Mr McIntosh.[445] The allocation of material to stock designations had been agreed. Stock targets would have to be reviewed having regard to a decision to send plasma to Lille, but Dr Stewart would report when the position had clarified. It appears that agreement had been reached on an acceptable approach to stock control accounting. The change of arrangements with Lille was explained in a letter from Dr Perry to Mr McIntosh dated 31 May 1991.[446] Integration of PFC's S8 technology with standard procedures at Lille had proved more difficult than anticipated. Access to proven and validated technology by 1 April 1991 had not been achieved as planned. As a contingency plan, Scottish plasma was being sent to Lille for processing. There were said to be significant advantages in this route in respect of an assured outcome and yield,[447] simplification of CTX arrangements, and financial outcome. Mr McIntosh acknowledged the arrangements on 18 June 1991.[448] He asked for information on procedures, and Dr Stewart provided this on 20 June 1991.[449]
10.354 Final protocols for clinical trials of HPVIII were distributed on 31 May 1991.[450] On 7 June 1991, Dr Perry announced that supplies of Lille High Potency Factor VIII would begin in June, with Glasgow and Edinburgh being allocated the first quantities.[451] A further meeting of the group monitoring the transitional arrangements took place on 10 June 1991.[452] The manufacturing and supply programmes were brought up to date. Contractual discussions continued. Transport arrangements were discussed. There was apparent disagreement over Dr Ludlam's insistence on use of Scottish plasma.
10.355 On 24 and 25 July 1991, a technical audit of the HP VIII process was carried out during the second production trial.[453] A number of areas of concern were identified, and the overall good manufacturing practice rating of the process was 'poor'. This was a detailed analysis of plant, operating systems, and controls and recording of data. It appears that two of the points noted were of sufficient seriousness to justify a 'report of incident with potential implications for product quality'.
10.356 On 27 August 1991, Dr Crawford, Glasgow, reported that HP Factor VIII had been found effective in practice, and that Yorkhill haemophilia patients were delighted with it. The only adverse reaction was attributed to features of the patient's condition other than the infusion.[454] In September 1991, additional supplies were made to Glasgow where Dr Stewart had understood that stocks had been threatened by use.[455] Dr Crawford corrected the error: supply arrangements were satisfactory.[456]
10.357 On 10 September 1991, Dr Perry reported on the transitional arrangements, and sought firm data on demand to the end of 1992.[457] The transitional arrangements had progressed. Lille-manufactured Factor VIII was expected to run out by November 1991. PFC were manufacturing the products, and PFC supplies from SNBTS plasma would be available thereafter. It was anticipated that manufacture of Z8 would be discontinued at the end of September 1991. On 18 September, Dr Perry wrote to Dr Ludlam explaining the programme and the assumptions on which it was based.[458] He also commented on the scope for continuing Z8 production if necessary, 'particularly if there is a requirement to stretch the supply of Z8 until the grant of the HP8 product licence'. In contrast to Dr Ludlam's concerns, Dr Crawford asked for the supply of Z8 to Glasgow to be reduced due to the introduction of HP Factor VIII.[459]
10.358 In the event, there was delay in Dr Perry's programme. The need (arising from regulatory controls) to segregate the processing of Scottish plasma from the processing of domestic plasma in Lille, together with down-stream scheduling implications, would delay the availability of a wholly Scottish product until December 1991.[460] Current CRTS supplies would continue to be available, but the delay would affect those waiting for HP VIII manufactured from Scottish or Northern Irish plasma. Dr Perry confirmed the supply date for 'Semi Tartan' as 16 December 1991.[461]
10.359 On 25 September 1991, Dr Prowse circulated CRTS data (from 14 December 1990) on the safety of the Lille product.[462] No cases of elevation in transaminase levels were noted; and all PUPs remained HBsAg, HIV-1-ab, and HCV-ab negative. The letter enclosed a considerable volume of additional material on the French and comparative experience of HIV infection.
10.360 Towards the end of the year there was confusion about the availability of treatment for vWD patients.[463] A paper reflecting the situation was prepared in January to brief Professor Cash.[464] Conflicting information about the immediate availability of French Factor VIII may have developed into a crisis reflecting poor relationships. There may have been strain in working relationships among officials and haemophilia clinicians at this time.
10.361 At the end of December 1991, high levels of Z8 stocks were reported.[465] A complete set of coagulation factor usage graphs to December 1991 for individual units and for Scotland as a whole was produced on 23 January 1992.[466] The data showed that cumulatively over the year 1991 Z8 remained the major therapeutic product used. From July, HP VIII usage, the second highest in volume terms, also grew steadily, as did commercial usage, though commercial usage was by far the lowest in volume. Provision of papers in the same format became part of the monthly routine, ensuring up-to-date information about stocks and usage.
10.362 On 3 February 1992, Dr Perry set out details of the supply of material from Lille, and proposed that arrangements for regulating issue should be established as soon as possible.[467] The arrangements in place were changed on 18 February 1992 to incorporate the provision of buffer stocks at Edinburgh, Glasgow and PFC.[468]
10.363 On 4 March 1992, Dr Perry circulated a letter intimating that SNBTS would not supply Factor VIII 8Y; High Purity vWF or Factor IX. Health boards would require to purchase these direct from BPL or CRTS.[469] SNBTS had made arrangements with CRTS to have supplies manufactured and held for draw-down.
10.364 On 6 March 1992, Dr Ludlam wrote to Dr Stewart confirming arrangements for therapy.[470] Patients receiving Lille products would progress to Semi-Tartan and then Tartan VIII. Patients on Z8 would continue until stocks were almost exhausted. They would then change to Tartan VIII. A small stock of Z8 would be retained. Dr Ludlam stated that there was a small demand for the product as a source of fibrinogen. Dr Perry saw the letter, but responded to it through Dr Stewart 'in order to keep lines of communication clear'.[471] He was content that Z8 should be kept in stock–but at haemophilia centres.
10.365 On 22 April 1992, Dr Stewart estimated the growth in demand for Factor VIII, and forecast a demand for 25 million IUs by 1996, using data provided by Dr Aledort.[472] Dr Ludlam disagreed, forecasting only a small additional increase in demand for Factor VIII.[473] Dr Stewart returned to the issue in August 1992.[474] He now estimated maximum demand at 42.1 million IU per annum.
10.366 The SNBTS haemophilia directors met on 15 May 1992.[475] The report of the former Factor VIII working party, now the coagulation factor working party, was presented by Dr Ludlam.[476] The report explained the recent history of Factor VIII development:
• On 15 November 1990 the working party agreed that it would be reasonable for SNBTS to plan for production of a high purity Factor VIII at PFC[477].
• Following an SNBTS assessment of technology available, and consultation, the minister of state for health approved a technology transfer with CRTS Lille.
• A phased programme of 'high potency' VIII was introduced
– Lille VIII was produced in France from French plasma;
– Semi-Tartan VIII was manufactured in Lille from Scottish plasma; and
– Tartan VIII would be a wholly Scottish product put into general distribution when Z8 was exhausted.
10.367 Production of Z8 was to terminate in December 1992. Meantime, PUP data on Z8 trials had indicated that heat treatment at 80˚C for 72 hours 'was most efficacious'. Haemophilia directors were said to be more comfortable with that regime than the solvent detergent method.
10.368 Long-term usage demands were thought likely to continue to rise. The general assumption was 10% per annum. But new factors had to be allowed for. There was a move towards prophylactic treatment of children which would potentially allow them to grow up without developing haemophilic arthropathy; and there was a possibility in the other direction that in adult life there would be fewer haemarthroses. It was now clear that combination Factor IX concentrates including Factor II and Factor X should not be used in large doses, and therefore there was in development a high-potency single Factor IX concentrate similar to the Lille product.
10.369 Dr Mayne attended the meeting and presented a special report of the UK regional haemophilia centre directors committee on the choice of therapeutic products. There had been a material change in the regulatory environment. The National Health Service and Community Care Act 1990 was thought to have thrown haemophilia care open to market forces, with very little provision and protection offered for patient groups. District health authorities (in England and Wales) were cash-limited. Crown immunity had been withdrawn. Recommendations concerned: Hepatitis B vaccination; use of DDAVP; and the discontinuance of use of Cryoprecipitate in view of the potential for virus transmission. Specific recommendations were:
• HIV antibody positive patients should receive high purity Factor VIII/IX products;
• HIV negative patients should be transferred from intermediate-purity to high-purity products;
• Patients with Factor IX deficiencies should receive high-purity Factor IX as soon as practicable; and
• Patients with von Willebrand's disease should also be moved from intermediate to high-purity products.
10.370 The minutes of the meeting record Dr Mayne's presentation, and the chairman's comment that there was a need for effective communication, especially in the area of resource management. In a letter dated 19 May 1992, Dr Prowse challenged the accuracy of the Scottish data in the special report; the accuracy of the representation of parvovirus removal by Octapharma procedures; statements about a series of studies referred to; and concluded with an implied criticism of recommendations of products that could only be provided on a named-patient basis. It appears that criticisms of Dr Mayne's material may not have been fully ventilated at the meeting. She responded to Dr Prowse on 29 June 1992, gave a lot of background information, and promised that inaccuracies would be corrected.[478]
10.371 There was a paper on the provision of haemophilia treatment and care, prepared in response to requests from directors and the Haemophilia Society.[479] It contained a description of haemophilia, and the evolvement of patient care, with centres established in and after 1968 to provide treatment and care. The pattern of demand was influenced by the practice of self-referral (without the intervention of a general practitioner). This could lead to surprise demands. There was detailed discussion of the options available for providing the care required, including contracting out to other authorities. The paper did not refer to Scotland, and Dr Mayne and Dr Keel agreed to follow up on the Scottish position.
10.372 Finally, there was a report on a pilot external audit of the Scottish haemophilia centres involving patient questionnaires in addition to discussions with clinicians and others. This was seen as a stimulating and valuable exercise and it was agreed that it should be continued annually.
10.373 The minutes were amended in numerous respects.
10.374 In July 1992, Dr Prowse attended the 38th annual meeting of the International Society on Thrombosis and Haemostasis in Munich.[480] There was emphasis on inhibitor prevalence and treatment. In terms of general science, there was a recognised need to replace current Mega and British working standards, and certain international standards. Virus safety was also discussed.
10.375 On 24 September 1992, an example of insolubility in HPVIII, batch 013, was reported.[481]
10.376 There was concern about the naming of HPVIII as a 'high purity' product. 'High potency' was preferred. In a letter to Dr Ludlam dated 15 December 1992, Mr McIntosh explained that 'high potency' reflected the anxiety of SNBTS to disassociate themselves from the 'largely unsubstantiated market claims for the benefits of purity as such'.[482] The new product had about four times the potency of Z8.
10.377 The 1993 annual meeting of SNBTS and haemophilia directors was held on 30 April 1993.[483] Dr Ludlam spoke to the annual report of the coagulation factor working party for Scotland and Northern Ireland.[484] It contained an account of the transition from intermediate-purity Z8 to HPVIII. Background correspondence set the scene. On 8 February 1993, Mr McIntosh wrote to Dr Ludlam confirming that the view of the then Factor VIII working party was on record as having intimated that it had been agreed on 15 November 1990 that an ion exchange chromatographically purified product from volunteer plasma, similar to that manufactured at Lille and by Octapharma, would be acceptable; that it would be a high-purity, high-potency product, soluble and sterilised.[485] It also noted that the working party would be interested in further discussions to consider the possibility of terminal heat sterilisation. The letter also contained Professor Cash's comments:
Whilst we favour a terminal virucidal step in any process and have been well satisfied with our dry super heat procedure, we believe that there is currently no bar to considering the introduction of upstream pasteurisation of the solvent detergent procedure. Our colleagues will wish to know that we regard a terminal virucidal step to be of considerable importance in the context of product safety and believe that this option should be available in the future.
10.380 Against that background, Mr McIntosh assured Dr Ludlam that the overall policy remained the same, and anticipated the introduction of terminal virus inactivation at an early date. The letter proceeded to discuss the programme in detail more appropriate to the discussion of viral inactivation. For present purposes, it explains Dr Ludlam's report that:
At PFC a manufacturing process has therefore been established for the production of HPVIII from HBsAG, HCV and HIV I/II antibody negative plasma….During the past year the distribution of Z8 has ceased and the new high potency VIII has become the sole factor VIII concentrate manufactured by PFC for use in Scotland and Northern Ireland. It is issued on a clinical trial basis under a CTX with indemnity being provided by SOHHD and endorsed by DoH NI.
10.381 Factor VIII use ('issues' in the case of PFC products) was summarised by Dr Stewart in a paper prepared for the meeting dealing with PFC production, commercial usage and planned production.[486] Dr Ludlam's report also spoke of the need for improved reporting of blood product use, information which was essential for monitoring the use of concentrates and for SNBTS planning purposes.
10.382 The SNBTS medical and scientific committee met on 9 and 10 November 1993.[487]
Supply and Demand: Quantities 1990–1993
10.383 For the 1993 annual meeting of SNBTS and haemophilia directors held on 30 April 1993, Factor VIII use ('issues' in the case of PFC products) was summarised by Dr Stewart in a paper dealing with PFC production, and commercial usage as follows:[488]
HPVIII
Commercial*
* Including BPL 8
** Detailed figures for the three years to 31 March 1992 were set out in tables prepared on 1 June 1992,[489] and duplicated in December.[490] The totals in this table square with the June data. However, another table[491] for these three years, detailing Scottish, other NHS, American and European imports produces different results: total Factor VIII of 8.05; 8.44; and 10.11 units respectively.
10.384 The acceleration in use in 1991-92 at 15%, in keeping with a similar increase in England and Wales, as against the annual increase of about 10% over the previous twenty years, might have been due to the increase in prophylactic therapy.
10.386 Detailed data on plasma sent to PFC for processing was not provided in a form comparable with previous years.
10.387 In the case of Factor IX, PFC continued to produce a complex containing Factors II and X. The report commented that PFC were at an advanced stage in development of high-potency single Factor IX product. Meantime commercial purchases of high-potency Factor IX continued.
• Delays in developing S8 became critical. Commercial purchases increased.
• It was anticipated that demand for Factor products would continue to grow.
• Z8 continued to attract unfavourable comment despite its acknowledged safety.
• Collaboration with CRTS Lille was progressed to agreement and production of a purer product.
• Data on commercial usage improved, but remained unreliable.
• Arrangements for the distribution of SNBTS products continued to be revised.
• S8 development was shelved.
• Practical arrangements for the introduction of products based on CRTS technology were developed and implemented.
• Ministerial approval was granted for technology exchange.
• Final protocols for clinical trials were distributed in May 1991.
• Following some unscheduled delays, the products were introduced and production of Z8 was terminated.
• Further research and development to refine the processes continued.
[1] Haemophilia A and the blood transfusion service: a Scottish study BMJ 18 September 1976. See: The Organisation Of Blood Transfusion In Scotland
[2] Cryoprecipitate and concentrate
[3] [SNB.010.3921] Annual Report of the SNBTS for the year ended 31 March 1976. The UKHCDO DATA, corrected for duplications, indicated that at 1975 there were 323 patients registered with Scottish Haemophilia Centres.
[4] [SNB.001.5076]
[5] [SNB.010.3921] The Annual Report of the SNBTS for the year ended 31 March 1976 gives an average conversion factor of 250.
[6] [SNB.010.3921] The Annual Report of the SNBTS for the year ended 31 March 1976 gives the actual value as 3279 donation equivalent.
[8] [SNB.010.1548] [SNB.010.1550] [SNB.010.1551] [SNB.010.1553] [SNB.010.1554] [SNB.010.1555]
[9] The appendices contain data provided by UKHCDO which appears to be reliable, but to differ from the sources available at the time.
[11] [SNB.010.3921] SNBTS Report for y/e 31 March 1976
[12][DHF.002.6338] 'Haemophilia Treatment in the United Kingdom from 1969 to 1974' British Journal of Haematology, 1977, 35, 487. Data was collected and published on the basis of units of factor VIII. A 'unit' is defined relative to the material involved. A 'unit' of factor VIII is arbitrarily defined as the amount of AHF activity present in 1 ml of normal male plasma: [LIT.001.0141] Buchholz 'Blood Transfusion: Merits of Component Therapy' The Journal of Pediatrics, February 1974 Vol 84 Number 2 page 165
[13] [DHF.002.6335] 'Haemophilia Centre Directors' Annual Statistics for 1975' British Journal of Haematology, 1977, 36, 447
[14] There was also greatly increased production of immunoglobulins, as noted in the table above.
[17]There are two sources of information on supplies which differ in detail. The differences do not affect the overall picture.
[18][SNB.007.0769]
[25] Stable plasma protein solution
[31] 'Cost or Management of Patients with Haemophilia' Cater and others, BMJ, 21 August 1976, page 465: see Chapter 5: Blood Organisation
[41] Partial results at [SNB.007.1234] [SNB.007.1235] [SNB.007.1236] [SNB.007.1237] [SNB.007.1238] [SNB.007.1239] [SNB.007.1240] [SNB.007.1241] [SNB.007.1242]
[48] [SNB.007.1343] [SNB.007.1344]
[49] [SNB.007.1549] [SNB.007.1550]: the function of assay of FVIII content was discussed in papers sent by Dr Smith to Dr Foster in August 1978 in anticipation of a visit to PFC
[51] [SNB.007.1495] [SNB.007.1497] [SNB.007.1499] [SNB.007.1501] [SNB.007.1502] [SNB.007.1507]
[52] [SNB.007.2478] The increased supply to Inverness created an embarrassing surplus in July.
[54] [SNB.007.1561], and Mr Watt's reply [SNB.007.1559]. Mr Watt was not alone in concern about the West of Scotland: see Dr Cook's letter dated 28 August 1978: [SNB.007.1564]
[56] [SNB.007.2476] Lancet, July 14 1979. page 77, 'Haemophilia and Home Therapy'
[60] [SNB.007.2490] Lancet, 11 August 1979, page 301: Watt, 'The Price of Factor VIII'
[61] [SNF.001.0210] At the SNBTS Directors' meeting on 27 March 1981, it was noted that the quantity of plasma required to meet the need for factor VIII merited a study of the possibility of procurement of normal plasma by plasmapheresis. A group of SNBTS staff were to visit Belgium, where there was an extensive programme of plasmapheresis for source plasma
[66] [SNB.007.3230] letter by Mr Watt to Dr Cash dated 11 October 1982.
[69] [SNF.001.4034] HIV group litigation, Statement of Claim, para 37(b)
[75] [SNB.002.2843] letter dated 18 May 1981.
[76] [SNB.002.2889] [SGF.001.0316]
[77] In the event this forecast was wrong: see below
[90] [SNB.007.3535] Letter J Watt to J Cash dated 18 March 1983
[99] But this was not a new stance for Dr Cash: Cash et al 'Haemophilia A and the blood transfusion service: a Scottish study'. BMJ, 1976 (682-684) [LIT.001.0255] had suggested a possible re-think of freeze-dried Cryoprecipitate. See also [SNB.007.1622] for progress with the project.
[101] See discussion in the minutes of the meeting of SNBTS and Haemophilia Directors working group on
4 March 1981: [SNB.001.5064] and on 4 November 1981:[SNB.001.5069]
[106] Compare Mr Watt's views above: there were clear divisions of opinion between BTS Regions and PFC. But this was not a new stance for Dr Cash: See note 99 above
[111] [SNB.001.5055] Minutes of meeting of 30 January 1981. The previous minutes were of a meeting on 30 May 1977 [SNB.001.5006].
[114] [SNB.001.5055], para 8
[115] See paras 10.118 - 10.122
[117] See comments above.
[118] The proposal was later approved
[123] [SNB.002.2623] [SNB.002.2629]
[130] [SNB.007.2887] para 4. 28 January 1982
[134] [DHF.001.5151]
[136] [SGF.001.0952] and [SGF.001.0953] cover the period 1978 to 1982
[137] [SNB.007.2976] In a letter to Mr Watt dated 3 March 1982, Dr Mitchell said that Glasgow Royal Infirmary had abandoned their old policy of making up deficits from commercial purchases.
[138] [SNB.007.3264] Letter John Cash to J Watt 28 October 1982.
[143] [SNB.007.3270] Letter J Watt to John Cash 4 November 1982.
[154] [SNB.007.3984] Memorandum Dr Perry to J Watt & Others
[156] [SNB.007.4543] [SNB.007.4544] [SNB.007.4549] [SNB.007.4550]
[157] [SNB.003.2186], page 10
[163] [SNB.007.3535].
[165] [SNB.002.6354] [SNF.001.0085]
[169] Dr Ludlam?
[174] [DHF.003.0181] The report was identified as CBLA 84/30
[176] [SGF.001.0928] News & Appointments Review of 17 – 24 October
[183] [SNB.007.4586] letter Dr Cash to Dr Perry 20 November 1984
[184] [SNB.007.4587] letter to Dr Ludlam 21 November 1984.
[187] [SNB.007.4648] letter to Dr Perry
[189][SGH.002.6540]
[199] [SGH.001.2274] Parliamentary Answer on 5 February 1985 by John MacKay.
[207] [SNB.007.4809] [SNB.007.4811] [SNB.007.4815] [SNB.007.4816] [SNB.007.4817] [SNB.007.4818] [SNB.007.4819] [SNB.007.4820] [SNB.007.4821] [SNB.007.4822] [SNB.007.4823] [SNB.007.4824] [SNB.007.4825] [SNB.007.4826] [SNB.007.4827] [SNB.007.4828] [SNB.007.4830] [SNB.007.4835] [SNB.007.4911] [SNB.007.4843] [SNB.007.4846] [SNB.007.4847] [SNB.007.4848] [SNB.007.4849] [SNB.007.4850] [SNB.007.4851] [SNB.007.4852] [SNB.007.4853] [SNB.007.4854] [SNB.007.4855] [SNB.007.4856] [SNB.007.4857] [SNB.007.4858] [SNB.007.4859]
[209] [SNB.001.5357] [SNB.001.5370] [SNB.001.5372] [SNB.001.5373] [SNB.001.5374] [SNB.001.5375] [SNF.001.0415] [SGF.001.0932] [SNB.001.5384] [SNB.001.5386] [SNF.001.3176]
[210] Information collected later by Mr Stewart in 1989 would indicate that there were purchases in 1984, but that 1985 was an exceptional year when, apparently, there were no commercial purchases anywhere in Scotland. However, compare the UKHCDO data in the appendix 1.
[211] [SNF.001.0241] Minutes of meeting held on 7 March 1985, between SNBTS Directors, Haemophilia Centre Directors and SHHD, item 6
[212] [SNB.001.5448] Later corrected to 150,000
[213] [SNB.001.5443] Dr Perry to Transfusion Directors asking for estimates of usage of FVIII and FIX in 84/85 and projections for 85/86 since data was required for production purposes.
[214] [SNB.001.5352] this was Dr Bell's last meeting of this group as representative of SHHD. He was moving to Fife Health Board
[220] [SGH.001.6412] Minutes of meeting of SNBTS Directors, 2 October 1985: item 12
[222] The minute is not clear, but it appears that the standard suggested was the only one available: PFC did not expect to proceed to a more intensely tested product until February 1986.
[225] [SNB.001.5446] [SNB.001.5448] Minutes.
[228] [SNB.007.6865] In October 1989 it was confirmed that the supplies to England and Wales were not heat treated.
[232] [SNB.007.4752] Letter Dr Cash to Dr Perry 9 January 1985.
[233] [SNB.001.5454] [SNB.001.5446] Minutes: [SNB.001.5448]
[244] [SNB.007.5980] letter dated 24 July
[247] [SNB.007.5990] [SNB.007.5991] [SNB.007.5992]
[248] For 1986 to 1989 Glasgow submitted data for the Royal Infirmary only
[249] [SNB.002.4297] FEIBA for 1985-86 squares
[250] [SNB.002.4297] squares for 1985 – 86
[257] [SNB.001.5505] , pages 2 and 3 of the document
[261] But compare the appendices: UKHCDO figures do not correlate well.
[264] [SNB.002.4397] [SGH.002.6450]
[269] The comparative figures reported in 1988 were 5.83, 7.32 and 10.56.
[271] [SGF.001.2283] Dr Ludlam had given notice of some of his concerns in a letter to Dr Forrester dated 21 April 1988.
[272] [SNB.001.5560] letter dated 24 August 1988.
[279] [SNB.007.6745] See also [LIT.001.1085],Pasi et al, 'Safety trial of heated factor VIII concentrate (8Y)', Archives of Disease in Childhood, 1989; 64: 1463-1467. The BPL factor 8Y product, introduced in 1985, appeared to have prevented transmission of HCV and HIV.
[283] The third last line should perhaps refer to 'purity'
[285] [SNB.007.6749], replying to [SNB.007.6729]
[298] For 1989-90 Glasgow did not submit costs: the amounts were estimated by SNBTS: This year, the Board submitted data for Yorkhill, Western/Gartnavel; Southern General; Victoria Infirmary; Glasgow Royal; Sick Kids.
[299] Cost estimated by SNBTS
[300] Cost estimated by SNBTS: Hairmyres Hospital only
[307] [SNB.001.5649] letter dated 13 March 1989
[308] Second draft of report and appendices [SNB.001.5650] [SNB.001.5651] [SNB.001.5659] [SNB.001.5660] [SNB.001.5661] [SNB.001.5662] [SNB.001.5663] [SNB.001.5664] [SNB.001.5666] [SNB.001.5667]
[309] [SNB.002.4509] Minutes: [SNB.002.4517]
[311][SNB.007.6911]
[326] [SNB.007.7016] [SNB.007.7017] [SNB.007.7018] [SNB.007.7019] [SNB.007.7020]
[331] Corrected for error in report: 1989 data incorrectly carried forward. The 1989 figure for Z8 included 1 m I.U. reallocated from Northern Ireland supplies to Scotland as part of an exchange deal. The values reported by Directors were PFC VIII 7,823,764 and commercial 1,197,400, a total of 9,021,164 I.U.
[332] Corrected for error in report: 1989 data incorrectly carried forward. The 1990 figure was derived from usage, extrapolated from three quarters' data, and did not necessarily equate to purchases. In light of planned orthopaedic surgery in Glasgow the value might have been underestimated.
[346] [SNB.007.7064] [SNB.007.7065] ,pp 1-7
[347] [SNB.007.7074] – pp 1-3
[359] The collaboration with Dr Johnson of New York discussed in chapter 11, Viral Inactivation
[369] [SNB.002.4724], [SNB.002.4726]
[396] [SNB.007.7585] On 27 November, Dr Stewart confirmed that this level of self sufficiency had been sustained for three months.
[397] [SNB.007.6954] Unless there is a problem with dating, this is generally the same complaint as she had made in November 1989
[400] Manuscript notes appended to [SNB.007.7488]
[403] [SNB.007.7509] (a draft)
[406] [SNB.007.7597] On 30 November, Dr Cash wrote to Dr Ludlam thanking him and his colleagues for their cooperation.
[413] [SNB.007.7678] [SNB.007.7679] [SNB.007.7680] [SNB.007.7682] [SNB.007.7686] [SNB.007.7690]
[415] [SNB.007.7717] Page 6 sets out the critical success factors and action required.
[418] [SNB.007.7735] [SNB.007.7736] [SGH.004.2641]
[421] However, see [SNB.007.7790], where he appears to confirm that recovery to target stock was on schedule, with improvements in quality and yield. See also [SNB.007.7798] [SNB.007.7799] [SNB.007.7800] [SNB.007.7801] [SNB.007.7802] [SNB.007.7803] [SNB.007.7804] [SNB.007.7805] [SNB.007.7806] [SNB.007.7807], where stock levels were said to be satisfactory.
[434] [SNB.007.7827]: it was on 30 April that SHHD intimated that normal compensation arrangements would apply to evaluation and clinical trials stages of the exercise.
[438] [SNB.007.7836] pp 1-2
[443] See [SNB.007.7849] for an account of the change.
[444] See chapter 12: Licensing
[447] A review of PFC vial content in 1991 indicated that the average FVIII content was 236 IU, an apparently high value, supporting the use of Scottish plasma.
[461] It is not clear that this is consistent with other descriptions of the product at this stage in development. CRTS were already processing Scottish plasma under the revised 'contingency' arrangements.
[463] [SNB.007.7942] [SNB.007.7945] [SNB.007.7946] [SNB.007.7955] [SNB.007.7956]. Inevitably it involved Dr Ludlam, but Glasgow were also involved.
[464] [SNB.007.7980]: see also [SNB.005.1924] (copy with manuscript annotations)
[465] [SNB.007.7970] [SNB.007.7971] [SNB.007.7972] [SNB.007.7973] [SNB.007.7974] [SNB.007.7975] [SNB.007.7976] [SNB.007.7977] [SNB.007.7978]
[466] [SNB.007.7982] [SNB.007.7983] [SNB.007.7984] [SNB.007.7985] [SNB.007.7986] [SNB.007.7987] [SNB.007.7988] [SNB.007.7989] [SNB.007.7990] [SNB.007.7991] [SNB.007.7992] [SNB.007.7993] [SNB.007.7994]: the provision of these papers became a monthly event.
[487] [SNB.009.9176]: minutes of previous meetings have not been inspected.