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Chapter 21

Haemophilia Therapy - Use of Blood Products


21.1 Aspects of two of the Terms of Reference set the general context for discussion of the topics dealt with in this and the 10 chapters:

1. To investigate the systems in place in Scotland for the ... preparation for supply and supply for use by the NHS of blood and blood products with particular reference to the risks of transmission of the Hepatitis C virus ... to patients treated by the NHS in Scotland ....


8. To investigate the steps taken by those involved in, and those responsible for, the NHS in Scotland including NHS boards and SNBTS, their officers and employees and associated agencies, to prevent the provision of infected blood and blood products.

21.2 Reports of AIDS in haemophilia patients treated with blood products, and with no other risk factors for AIDS, brought about a major change in the approach to factor concentrate therapy in the treatment of coagulation disorders in 1983-84. Up to that point, the focus was on the risk of transmission of hepatitis arising from the use of coagulation therapy and on the risk of other adverse effects of therapy such as the development of inhibitors. The history of developing knowledge of hepatitis is discussed in Chapter 14, Knowledge of Viral Hepatitis 1, and Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985. It will be appropriate to rehearse some of that history in this chapter to provide context for the decisions taken by haemophilia clinicians in selecting products for therapy.

21.3 It is necessary to disentangle a number of interrelated strands of history to provide a reasoned response to the Terms of Reference. It is clear, however, that in reality the developing position over this period was 'multifactorial', an expression used frequently in the course of the evidence.

21.4 The arrival of commercial concentrates in 1973 changed market conditions, and had an impact on the public sector producers in the UK as a whole. Coincidentally, plasma fractionation facilities in Scotland and in England were in the course of or about to undergo major structural changes at the Protein Fractionation Centre (PFC) and the Blood Products Laboratory (BPL) respectively.[1]

21.5 The first use of commercial concentrates from 1972 coincided with the identification of the Hepatitis B virus (HBV), an agent responsible for blood-borne hepatitis, and development of a test to indicate exposure to HBV by presence in the blood of its surface antigen, subsequently referred to as HBsAg. For a brief period it was hoped that using the HBsAg test to identify all blood donors previously exposed to, and possibly still infected by, HBV would eliminate post-transfusion hepatitis and hepatitis among people with haemophilia. By 1975, studies (mainly in the USA) were indicating that there were one or more other infective agents responsible for a significant proportion of post-transfusion hepatitis, the so-called non-A, non-B Hepatitis (NANBH) virus(es). Producers of Factor VIII products and haemophilia clinicians prescribing their use were faced with a dilemma: whether, on the one hand, to manufacture and use products to relieve real and known risks to the patient and accept the relatively unknown or partially understood risks associated with developing therapy, or, on the other hand, avoid treatment altogether. No form of therapy was without risk to the patient. As commented in Chapter 2, Patients at Risk, some risks are inherent in the use of human blood and its components and are always present. Whole blood, fresh and fresh frozen plasma and cryoprecipitate were all associated with risk of transmission of virus infections such as hepatitis.

21.6 AIDS became the most significant consideration for patients and for medical and scientific staff in the period from about 1982 to about 1985. There are no precise dates that define the period more particularly. After about 1985, transmission of NANBH (later the Hepatitis C virus) and its natural history emerged as the main focal points affecting the management of patients. This chapter will deal with developments before the AIDS period. However, it will be convenient to deal with statistical data for the period to 1991 as a whole.

21.7 It has been necessary to deal with some aspects of the relevant history separately. The evolution and manufacture of blood products before and during the period was dealt with in Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s. This chapter deals with the availability and use of human blood products in haemophilia therapy.

Treatment of haemophilia: Overview

21.8 Until well into the twentieth century, treatment of haemophilia and other coagulation deficiencies and the complications associated with the diseases was rudimentary. Whole blood or fresh plasma might be transfused in an attempt to replace missing or deficient levels of clotting factors. A major risk associated with those forms of treatment was overload of the recipient's circulatory system which could result in heart failure. From about 1941, human plasma was freeze-dried (lyophilised).[2] The preparation of frozen plasma from whole blood was the first step towards developing therapeutic plasma products. In freeze-dried form, plasma had a substantial shelf-life. It could be stored for up to three months without perceptible change.[3] That removed the need for immediately available supplies of fresh plasma. But it did not solve the problem of circulatory overload.

21.9 Professor Christopher Ludlam explained the treatments that were available before concentrates were developed.[4] If bleeding into a joint occurred, the patient was advised to take bed rest. He might spend up to several weeks resting until the painful swelling gradually subsided. Fresh frozen plasma was administered on occasion but, because of the risk of overloading the circulation, it was not given in quantities large enough to raise the patient's Factor VIII level sufficiently to stop the bleeding. A bleed was a significant event, often requiring a stay in hospital.

21.10 A major advance in therapy came in the 1950s with the development of methods of plasma fractionation. This enabled the production of early forms of coagulation factor concentrates. From the 1960s, a simpler process of partitioning of whole blood led to the production of cryoprecipitate.[5] Subject to availability of supplies, by the very early 1970s, haemophilia clinicians had at their disposal, in addition to fresh frozen plasma, early concentrates of Factor VIII and Factor IX, and cryoprecipitate.

21.11 As set out in Chapter 19, Production of Blood Products - Facilities, there was considerable uncertainty about the levels of demand for haemophilia therapy in the UK as a whole in the late 1960s and early 1970s. That affected the planning of production facilities in England and in Scotland. It also affected perceptions of developments in the market for blood products. When development of the NHS plasma fractionation facilities was planned, there was a poor understanding of the likely drivers of domestic demand for haemophilia therapy. The history of reactive, and often in-patient, treatment of bleeds, with a limited range of therapeutic materials, did not prepare policy-makers or the public sector manufacturers of blood products for changes in clinical practice that generated ever-increasing demand for concentrates, and for improvements in their effectiveness and ease of use.

21.12 In general terms it was understood that demand would rise. In Self-Sufficiency in Blood Products in England and Wales: a Chronology from 1973 to 1991, the Department of Health (DoH) commented:

It became apparent in early 1973 that production of factor VIII concentrate in the UK was insufficient to meet the stated needs of clinicians. There was a body of evidence suggesting that considerably more concentrate would be used if it were available.[6]

However, the general understanding reflected in the statement did not inform planners of the enormous scope for use of coagulation products that was to emerge.

21.13 As a result, there was a deficiency in planning. It is, however, relevant to note that by 1973 forms of concentrate had been produced in the UK for nearly 20 years, and cryoprecipitate had been readily available for about 15 years. Actual demand for therapeutic materials had been limited by the supplies available. Clinicians could not prescribe what they could not procure, and there was to prove to be very substantial unmet demand. But it had also taken a considerable time for the potential of coagulation products to be understood, and growing knowledge aggravated the problems of supply as clinicians explored treatment options. Furthermore, by no means all patients with haemophilia who might require treatment had been identified by 1973 in the UK.

21.14 In 1973, Scotland was preparing to move production to a new PFC facility that would change the supply position in this country, but not because of a more accurate assessment of domestic Scottish needs in response to changing demand. In that respect the Scottish position was similar to that in England and Wales ('UK' in DoH terms): the potential demand was underestimated. Commercial pharmaceutical companies had already identified the market for increased supplies of concentrates. On 3 December 1972 Baxter applied for a UK licence for Hemofil, which was granted on 19 February 1973. On 8 December Immuno applied for a UK licence for Kryobulin, which was granted on 22 March 1973.[7] Early release of their products stimulated demand.

Treatment policy in England and Wales: The early 1970s

21.15 During 1972, the majority of Haemophilia Centre Directors in England and Wales had expressed a preference for freeze-dried concentrate therapy.[8] Dr Brian Colvin said that he and his colleagues at the London Hospital began to use them in 1970.[9] It seems likely that, at such an early date, the materials would have been used in clinical trials. Commercial products were more generally available and in use on a named patient basis in 1972.

21.16 On 6 March 1973 a letter was sent by the Chief Medical Officer (CMO) for England and Wales to all senior administrative medical officers (SAMOs) advising them that two product licences referred to had recently been granted to Baxter and Immuno which enabled the licensees to supply foreign human Anti-haemophiliac Globulin (AHG) concentrate to hospitals and haemophilia centres in the UK. Hemofil and Kryobulin could now be prescribed as licensed products.[10] The CMO noted that AHG concentrate was in many instances the therapeutic agent of choice in the treatment of haemophilia patients, and that at the time production of concentrate in the UK was insufficient to meet the stated needs of clinicians who cared for patients requiring surgical, including dental, treatment or who had episodes of severe bleeding. The letter noted that one of the two firms had indicated that it could supply large quantities of AHG. The dynamics of the market place were obvious: if the UK (and more specifically England and Wales) had the demand, the pharmaceutical companies could supply it.

21.17 But there were serious concerns about the very high cost of the foreign AHG. An expert group was set up by the Medical Division of the Department of Health to assess need and arrangements for the purchase of the product and also the possibility of producing sufficient material in the UK, and to advise the Department.[11] The expert group included representatives from Scotland, and policy recommendations reflected the view held at that time that it was essential that the production and distribution of the therapeutic agents for haemophilia care should be considered as a UK exercise. However, the data on demand and supply discussed by the group related mainly to England and Wales.

21.18 So far as they related to planning of domestic production, the expert group's views are discussed in Chapter 19, Production of Blood Products - Facilities.[12] It was recognised by the group that the number of registered patients with haemophilia underestimated the scale of demand.[13] It was thought that 3000 was a reasonable estimate of the number of individuals affected with haemophilia. The discussion covered the grounds for preference of cryoprecipitate and freeze-dried concentrate over other products and their relative advantages and disadvantages.

21.19 The reported discussion of the group provides insight into the view of risk associated with therapeutic products that was prevalent at the time. As a practical matter, transmission of Hepatitis B was the central issue.

The present policy of rejecting donations which give a positive test for hepatitis B antigen will reduce the incidence of virus in the blood used to make plasma pools. In practice, studies in several centres have shown that the incidence of hepatitis among severely affected patients who have been treated with the freeze-dried preparation is not very much higher than that at centres not using freeze-dried concentrate and this suggests that the development of hepatitis in these multitransfused patients may be dose-related. It was agreed that the theoretically increased risk of acquiring hepatitis (which does not seem to be borne out in practice) should not be a deterrent to using the freeze-dried preparation and in any case this complication will decrease with universal screening of donors for hepatitis antigen.[14]

It was agreed within the group that products from 400,000 donations would be required to treat UK sufferers from haemophilia of all degrees of severity. More would be required if strenuous efforts were made to clear surgical waiting lists and if home treatment, or eventually prophylactic treatment, became accepted ways of dealing with the needs of haemophilia patients. Demand exceeded NHS production capacity, but it was agreed that:

Since more freeze-dried AHG concentrate has become available from two foreign sources the prospects of improved management of day-to-day bleeding episodes using this therapeutic agent has become realistic.[15]

21.20 It was accepted at that stage, as a reality, that the NHS production facilities in England could not cope with the anticipated demand and that commercial purchases would be necessary. NHS concentrate from 30,000 blood donations had been issued in England, Wales and Northern Ireland in 1972, as against the estimated future requirement of 400,000 donations.

21.21 Recommendations of the group included:

  • DHSS should give early consideration to central purchase of freeze-dried AHG concentrate from the firms who had recently been granted product licences.
  • Distribution to haemophilia centres and hospitals in Scotland should be through the regional centres (either Edinburgh or Glasgow).
  • Discussions were to take place between DHSS and the Regional Transfusion Directors about the problems of decreasing production of cryoprecipitate, increasing production of fresh-frozen plasma for fractionation and the possibility of increased collection of plasma by plasmapheresis.
  • Home treatment and, in due course, prophylactic treatment were subjects that needed to be discussed further at future meetings.

21.22 These recommendations, concentrating on practical implementation of policy, reflect the group's assessment of related risk. The general understanding of risk is discussed in Chapter 14, Knowledge of Viral Hepatitis 1. When the expert group met in 1973 the Maycock report for the MRC had not been published,[16] but when it did appear in 1974 the Maycock report would underestimate the true incidence of post-transfusion hepatitis, largely because of the requirements stipulated for a diagnosis of the disease.[17] Dr William

Maycock was a member of the expert group, and knowledge of the report's findings can reasonably be assumed. At this stage it is sufficient to note that the expert group's discussions in 1973 did not reflect any perception that there was a relatively high risk of transmission of infection associated with commercial products, or that such increased risk as was recognised was significant.


21.23 During the early and mid-1970s there was emphasis in UK Government policy on achieving self-sufficiency in blood and blood products, reflecting views expressed by the World Health Organization (WHO). The reasons advanced for self-sufficiency are again significant.

21.24 In May 1975, a WHO resolution was passed by delegates conscious of the increasing use of blood and blood products. It urged Member States:

  • To promote the development of national blood services based on voluntary non-remunerated donation of blood.
  • To enact effective legislation governing the operation of blood services and to take other actions necessary to protect and promote the health of blood donors and of recipients of blood and blood products.

21.25 In making its recommendations the WHO had considered:

[T]he extensive and increasing activities of private firms in trying to establish commercial blood collection and plasmapheresis projects in developing countries.

[C]oncern that such activities might interfere with efforts to establish efficient national blood transfusion services based on voluntary non remunerated donations.

[A]wareness of the higher risk of transmitting diseases when blood products have been obtained from paid rather than voluntary donors, and of the harmful consequences to the health of donors of too frequent blood donations (one of the causes being remuneration) ....[18]

Relative risk had been identified as an issue, focused on the dangers associated with paid donors.

21.26 On 24 December 1974 the DHSS wrote to all regional administrators about the problems of blood product production and in particular the inability of the Blood Transfusion Service to meet the demands of clinicians for certain preparations of human blood. There was an immediate need to provide more AHG (Factor VIII) concentrate. The memorandum stated:

At present part of the demand ... is being met by expensive imported material which is now marketed in this country, and as the demand increases commercial firms may consider it worth their while to establish panels of paid donors in this country in order to obtain their supplies of human blood. Such a development would constitute a most serious threat to the voluntary donor system upon which the NBTS is founded. The Department therefore regards it as of the greatest importance, quite apart from the question of cost, that the NHS should become self-sufficient as soon as practicable in the production of PPF [plasma protein fraction] and other blood products ....[19]

21.27 There was a proposal to invite estimates of requirements in regional transfusion centres for the increased production of plasma, with the primary aim of making the NHS self-sufficient in AHG concentrate in two to three years.[20] The concern expressed in the circular letter reflected the second WHO point in paragraph 21.25: it did not express concern about relative infectivity.

21.28 On one level that is hardly surprising. Following the CMO letters of March 1973, the DHSS had notified relevant parties in England and Wales in October 1973 that the supply division of DHSS had negotiated with Travenol Laboratories Ltd and Serological Products Ltd to enable haemophilia centres to purchase AHG concentrate.[21] This letter advised parties that the department was in close cooperation with the SHHD in considering ways of increasing NHS production. In November 1973 a circular letter was sent to Scottish administrative medical officers in very similar terms.[22] Adverse comment on commercial products generally would have been inconsistent with this approach to meeting need, and comment on specific products would have offered a hostage to fortune. But, perhaps more pertinent to this discussion, it reflected a common understanding in government that distinctions related to transmission of infection were not significant.

21.29 In January and February 1975 Dr David Owen told the House of Commons that the amount of Factor VIII materials, including cryoprecipitate, produced within the NHS was not sufficient to meet demand at that time. In particular, there was an immediate need for AHG concentrate (acknowledged as the preferred treatment for haemophilia). Dr Owen stressed that it was of vital importance that the NHS should become self-sufficient as soon as practicable in the production of Factor VIII, including AHG concentrate. He announced that special finance of up to £500,000 had been allocated with the objective of the NHS becoming self-sufficient over the next few years, and expected that this would stop the dependence on commercial imports and make the best known treatment more readily available to people suffering from haemophilia.[23] There was no separate policy statement relating to self-sufficiency in Scotland at this time.[24] There was awareness in Scotland among all those working in the field that self-sufficiency was what was being sought: Dr Robert Perry referred to self-sufficiency as 'the only game in town'.[25]

21.30 However, across the UK as a whole, the reality of burgeoning demand for Factor VIII replacement therapy posed a serious challenge to the government's commitment to self-sufficiency. Data are available for the amounts of Factor VIII concentrates used in the whole of the UK. Equivalent information is not available for the use of Factor IX or cryoprecipitate, both of which were largely produced locally and met local demand for NHS products. The discussion which follows does not present a comprehensive picture of total haemophilia, but it was the demand for Factor VIII that was the critical consideration in aiming at self-sufficiency.

21.31 Total annual consumption of Factor VIII concentrates in the UK between 1970 and 1990 is shown in Figure 21.1. The data are set out in Table 21.1 in the Appendix to this chapter.

Figure 21.1: Total annual consumption of Factor VIII concentrates in the UK, 1970-1990

Figure 21.1: Total annual consumption of Factor VIII concentrates in the UK, 1970-1990

21.32 These data for the UK as a whole show sustained growth in use of Factor VIII concentrates from 1975 onwards, with a dip in 1983 that was reversed thereafter. The dip in 1983 probably related to the switch to cryoprecipitate in response to the threat of AIDS.

21.33 The trend shown in Figure 21.1 suggests planning for the provision of NHS Factor VIII based on experience up to the mid-1970s was unlikely to be remotely accurate. It would have required a high degree of imaginative foresight rather than statistical projection to forecast and provide for demand.

21.34 Although all parts of the UK were subject to the same growing demand throughout this period, the circumstances in which the different parts of the UK found themselves towards the end of the 1970s led to the demand for Factor VIII concentrates being met in different ways.

21.35 As events happened, and despite WHO encouragement, the target of self-sufficiency in England, Wales and Northern Ireland was most unlikely to have been achieved with the level of expenditure granted by Parliament while demand was left free to grow without restriction.

21.36 Figure 21.2 shows, for England, Wales and Northern Ireland, the annual consumption of NHS and imported commercial Factor VIII concentrates between 1970 and 1990. The data are set out in Table 21.1 in the Appendix to this Chapter.

Figure 21.2: Annual consumption of NHS and commercial Factor VIII concentrates in the UK, excluding Scotland, 1970-1990

Figure 21.2: Annual consumption of NHS and commercial Factor VIII concentrates in the UK, excluding Scotland, 1970-1990

21.37 Figure 21.2 illustrates the extent of the use by clinicians of imported commercial Factor VIII concentrate and, in respect of that product, shows the deficiencies in domestic supplies. The source data do not distinguish use related to clinical preference from use dictated by available supplies. Total use of commercial products cannot be explained exclusively on the basis of clinical choice in the circumstances, but it may have been a contributory factor. Subject to that, the overall impression is of rapidly increasing demand for Factor VIII concentrate, met substantially by imported product.

21.38 Figure 21.3 shows, for the UK excluding Scotland, the percentage of total Factor VIII concentrate consumption from NHS and from commercial supplies in each year from 1970 to 1990. The data are contained in Table 21.1 in the Appendix to this chapter.

Figure 21.3: Percentage of total Factor VIII concentrate consumption from NHS and commercial sources for the UK, excluding Scotland, 1970-1990

Figure 21.3: Percentage of total Factor VIII concentrate consumption from NHS and commercial sources for the UK, excluding Scotland, 1970-1990

21.39 On the evidence before the Inquiry, there was some scepticism whether self-sufficiency was possible. In relation to England and Wales, Professor Cash said that he did not consider self-sufficiency was a realistic goal as there were insufficient resources. In his opinion, Scotland was already ahead of England and Wales in the mid-1970s in achieving this aim.[26]

21.40 Professor Cash described the reaction to a talk he gave on the notion of self-sufficiency at a World Federation of Hemophilia congress in New York in 1977. His talk was interrupted by the then Chief Executive of Immuno, Dr Eibl, who, as Professor Cash recalled it, told the audience that he, John Cash, was talking nonsense and that the UK government did not accept that the WHO commitment to self-sufficiency was achievable. A member of the UK Haemophilia Society who was present, told Professor Cash that the Society agreed with Dr Eibl. Moreover, the Society did not think that the NHS would get anywhere near self-sufficiency in England and Wales.[27] Professor Cash thought that, despite the talk in England and Wales about self-sufficiency, 'they just weren't in the hunt' and had been told so.

21.41 It is unnecessary, and would be inappropriate, to express any view on these observations. The steep increase in demand from 1975 would have challenged the ability of policy-makers to respond. Comparison with Scotland (so far as concerns the capacity to respond to increasing demand) is particularly inappropriate. It is necessary to bear in mind that, as discussed in Chapter 19, Production of Blood Products - Facilities, Scotland's favourable position in relation to meeting growing demand was due to the government providing resources to build a new centre - the PFC - at which it was originally aimed to process about a third of English plasma in addition to all Scottish plasma. Making use of the Scottish facility for processing output of plasma produced in England and Wales was proposed in the Department of Health's letter to regional administrators on 24 December 1974, for example.[28] The failure to achieve a practical means of realising that policy objective made a significant contribution to Scotland's relative lack of dependence on imports, and aggravated the problem in the rest of the UK, in the 1980s.

Demand and supply in Scotland

21.42 In Scotland, as in the rest of the UK, there was interest in the impending arrival of commercial concentrates in the early 1970s. A Working Party was set up by the Central Consultative Committee on Blood Transfusion (CCC): 'To consider the production, laboratory and clinical evaluation of the various factor VIII and IX products in relation to the overall production capacity of the Blood Transfusion Service and to report.'[29] The group met on 21 September 1972 and the minutes of the meeting were circulated for discussion. It was estimated that 30,000 donations a year would be required for the production of Factor VIII concentrate.

21.43 It was recorded that consideration must be given to how much Factor VIII should be provided in the form of cryoglobulin precipitate (cryoprecipitate) and how much in the form of an AHF (Factor VIII) concentrate prepared by the fractionation unit (then still a small-scale operation at the Royal Infirmary of Edinburgh (RIE)). The recent appearance of commercially prepared concentrate was also discussed, although licences had not been granted at that point. It was agreed that treatment in the form of cryoprecipitate would continue for most patients for the foreseeable future but the desire was to replace this treatment and Cohn Fraction I with a potent AHF concentrate. Such a concentrate was liable to be subjected to more rigorous quality control. However it was conceded that estimating demand for a new product was difficult and was on a 'guess at best' basis.

21.44 Availability of a 'super-concentrate' (the commercial concentrate) was discussed in Scotland when the CCC itself met on 15 March 1973.[30] The general feeling was that Scotland should be able to manufacture enough of its own product from Scottish blood donations and would only require commercial material in very small quantities. By this time the estimated requirement of 30,000 donations a year for production of Factor VIII concentrate for Scottish patients was thought likely to be an underestimate, and the more realistic figure would be 50,000 donations.[31]

21.45 On 28 March 1973, the SHHD issued a letter to the SAMOs (copied to the Directors of Haemophilia Centres, Regional Directors of the Blood Transfusion Service (BTS) and the Scientific Director of PFC) on 'Trends in the Treatment of Haemophilia', in terms almost identical to the English CMO letter of 6 March 1973.[32]

21.46 Total annual consumption of Factor VIII concentrates in Scotland between 1970 and 1990 is shown in Figure 21.4. The data are set out in Table 21.1 in the Appendix to this chapter.

Figure 21.4: Annual consumption of Factor VIII concentrates in Scotland, 1970-1990

Figure 21.4: Annual consumption of Factor VIII concentrates in Scotland, 1970-1990

21.47 Information provided to the Inquiry by the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) for this period is not complete.[33] There are gaps in some early years which affect the reliability of the data until the mid-1970s. But the trend in consumption of Factor VIII concentrates is sufficiently well defined for comparison with the rest of the UK.

21.48 As in the rest of the UK, the data show sustained growth in use of Factor VIII concentrates from about 1975 onwards. Figure 21.4 shows a significant spike in consumption in 1988. This is accounted for by a major rise in demand at the Royal Hospital for Sick Children (Yorkhill) in Glasgow, and is discussed further at paragraph 21.292 below.

21.49 There is no obvious explanation for the dip in consumption of Factor VIII concentrates in 1985 and 1986. It cannot be related to a switch to cryoprecipitate in response to the threat of AIDS, as was the position in 1983 in the rest of the UK. Effective viral inactivation had been introduced at the beginning of 1985. Nor do SNBTS figures for the amount of frozen plasma collected through this period suggest any supply constraints.[34]

21.50 Scotland, in common with the UK as a whole, experienced a rise in demand for Factor VIII concentrates from the beginning of the Inquiry's reference period until the late 1980s that was far in excess of what those involved in planning at the beginning of the 1970s could have expected. The inability of NHS sources to supply demand inevitably led to the importation of commercially prepared products from North America from 1972. Nevertheless, in comparison with the rest of the UK, Scottish production met a substantial proportion of the demand for Factor VIII concentrates.

21.51 Figure 21.5 shows the percentage of total Scottish Factor VIII concentrate consumption met from NHS and from commercial supplies in each year from 1970 to 1990. The data are contained in Table 21.1 in the Appendix to this chapter.

Figure 21.5: Percentage of Scottish Factor VIII concentrate consumption from commercial and NHS sources, 1970-1990

Figure 21.5: Percentage of Scottish Factor VIII concentrate consumption from commercial and NHS sources, 1970-1990

21.52 As is apparent from Figure 21.5, total use of NHS concentrates far exceeded use of commercial Factor VIII products throughout the period, even in 1974 when the PFC's production was disrupted by the move to Liberton. In Figure 21.5, NHS data include some material sourced from the BPL for Scottish use. But the amounts were relatively small, in total, and do not materially affect the position. As already indicated in paragraph 21.41, production facilities in Scotland had considerably more capacity relative to total domestic demand than was available in England and Wales.

Choice of therapeutic products

21.53 The comparative exercise discussed above, as between Scotland on the one hand and the rest of the UK on the other, does not take account of all therapeutic materials used for Haemophilia A therapy over the period 1969-91, and it is necessary to turn to that topic at this stage in order to describe fully what happened in Scotland. As already indicated, for all of the period there was some use of cryoprecipitate, very small amounts of fresh frozen plasma, and FEIBA in addition to Factor VIII concentrates. Cryoprecipitate and fresh frozen plasma were prepared from single donations (though usually administered in pools or in succession in larger numbers) and, for present purposes, can conveniently be grouped. FEIBA was not used exclusively in treatment of patients with Haemophilia A, but had a significant place in the treatment of Factor VIII deficient patients with inhibitors. There are no data to enable the allocation of total FEIBA between Haemophilia A, Haemophilia B and other blood coagulation disorders. From 1979 onwards there was some limited use of DDAVP, but the quantities were insignificant in relation to total use and have not been noted at this stage.

21.54 Figure 21.6 shows the use of Factor VIII replacement products in Scotland between 1969 and 1991. The data are set out in Table 21.2 of the Appendix to this chapter.

Figure 21.6: Scottish use of Factor VIII replacement products in Millions of International Units (Miu) - 1969-1991

Figure 21.6: Scottish use of Factor VIII replacement products in Millions of International Units (Miu) - 1969-1991

21.55 As noted above, some caution must be used when looking at the data for the early part of the period. At that time, cryoprecipitate and fresh frozen plasma were the principal therapeutic products in use. NHS Factor VIII concentrate then grew in significance, and remained the principal product in use throughout the period. Commercial Factor VIII concentrate remained a small proportion of the total, as did FEIBA.

21.56 In practice, individual haemophilia clinicians exercised a degree of autonomy in the selection and prescription of products, if they had independent funds or if the relevant health authority supported the choice. Within Scotland there were significant variations between regions, which will be discussed later in this chapter. There were, however, a number of general factors that had an influence on product choice.

21.57 The PFC's move to Liberton interrupted production in the early part of this period. Bulk stocks of intermediate Factor VIII were prepared at the RIE to carry over the transitional period. In addition, to effect a smooth changeover from cryoprecipitate to intermediate Factor VIII in the treatment of haemophilia an initial stockpile of about one million units was required, and stocks were built up in anticipation of that change.[35]

21.58 Two observations are appropriate. First, the total issues of Factor VIII concentrates before the PFC was commissioned were relatively small: there was not much AHG available for issue to regions until the PFC was fully in operation, when there was a rapid build-up of output. Secondly, although there was a major increase in use of cryoprecipitate and fresh frozen plasma in 1974 and 1975, coinciding with the transitional period at the PFC, use of cryoprecipitate continued to be significant for the rest of the decade until falling away after 1980.

21.59 Some clinicians, however, were beginning to express views, as early as 1974, on the future availability of products to meet changes in clinical practice. On 18 December 1974, Dr Howard Davies, then Director of the haemophilia centre of the RIE wrote to Professor Cash (copying in John Watt of the PFC) stating that he hoped that sufficient supplies of human intermediate Factor VIII concentrate would be available in Edinburgh in January 1975 to cover the operative needs of his haemophilia patients and enable him to start some of them on home therapy.[36] In response, John Watt sent a telex to Professor Cash on 23 December 1974 suggesting that Dr Davies needed to be a little patient a little longer. He explained that production of Interate[37] had not yet started and he envisaged that volume problems would continue until supplies of fresh frozen plasma increased to a reasonably stable figure above 500 donations per week. He estimated that regular output would not be available until April.[38] However, timetable apart, it appears clear that clinicians' choice of product would become a more significant issue once the PFC was in full production.

21.60 Scottish clinical practice was entering a period when clinicians' choice would be made against a background of more ample supplies of therapeutic products than had previously been available. Already, however, Dr Davies had pointed to two aspects of practice that were to increase pressure on supplies: elective surgery and the move to home treatment.

21.61 Whether Scotland achieved self-sufficiency in the events that happened is, to some extent, dependent on the definition of demand. In an environment in which individual clinicians were free to select commercial products, given appropriate funding by local health authorities, by industry or by charities, actual demand for NHS products cannot be a reliable measure of total demand. Where available supplies are known to be limited, clinicians may have accepted the reality and avoided making demands on the NHS facilities that could not be met. Dr Peter Foster commented:

I think if you go back into the 1970s, when PFC was really still getting going and usually doctors were moving forward with home therapy, there is clearly correspondence where SNBTS is really saying, 'Look, we can't provide more at the moment, and the choice is for you', and they decide to buy commercial product because they want to do home therapy. So there is a period when clearly there is a discontinuity between the aspirations of the clinicians and what we can provide.[39]

21.62 In the mid-1970s the Scottish internal market had not settled, and choice may not have been real. However, Dr Foster prepared a report on 'Self Sufficiency and the Supply of Blood Products in Scotland', with particular reference to the treatment of Haemophilia A which is helpful.[40] He tabulated the amounts of Factor VIII available from the SNBTS compared with the amounts used clinically (as understood from UKHCDO data available before revision for the purposes of the Inquiry) in the period 1975-88. The data, expressed in terms of million units per head of population at each year, are reproduced below.[41]

Year Total SNBTS FVIII Available (Miu per pop.) Proportion of Clinical Use Matched by Available FVIII from SNBTS
(% average UK use per pop.)
Incl. Cryo Excl. Cryo Incl. Cryo Excl. Cryo
1975/76 0.97 0.21 202 111
1976/77 0.86 0.33 134 103
1977/78 0.99 0.39 129 100
1978/79 1.11 0.44 134 70
1979/80 1.27 0.69 136 89
1980/81 1.49 0.99 141 109
1981/82 1.48 1.14 123 105
1982/83 1.80 1.55 138 129
1983/84 1.94 1.71 149 142
1984/85 2.85 2.60 204 197
1985/86 2.56 2.23 180 163
1986/87 2.75 2.50 177 166
1987/88 2.20 1.93 138 125

21.63 Dr Foster's data and the UKHCDO data were prepared on different bases, with reference to overlapping periods: they cannot be correlated precisely. However presented, the data paint a very different picture from that shown for England, Wales and Northern Ireland so far as concerns the balance between use of NHS product and commercial product. It is necessary to bear this in mind when considering comments on the supply position in the 'United Kingdom', particularly in documents recovered from UK departments. Throughout the UK (including Scotland), however, there was a similar increase in demand overall. In the early 1980s, annual consumption of Factor VIII concentrate in Scotland, as registered by the UKHCDO, more than doubled in comparison with the late 1970s.

21.64 In relation to his data, Dr Foster concluded:

The data in Table 18 [reproduced at paragraph 21.62 above] indicate that at any point in time the SNBTS had available sufficient Factor VIII to meet average UK clinical practice, if cryoprecipitate was considered to be suitable to supplement Factor VIII concentrate. If cryoprecipitate is excluded then, with exception of the two year period 1978/9 - 1979/80, the availability of Factor VIII concentrate from the SNBTS was sufficient to meet average UK clinical use throughout this period.[42]

21.65 It was suggested to Dr Foster that the figures in his table for the years 1978-79 and 1979-80 indicated that clinical demand was ahead of the Factor VIII concentrate available from the SNBTS at that time. Figures for the following years did not indicate difficulties of supply. Dr Foster agreed, and said that they were quite clear that they were not able to produce enough concentrate. He told the Inquiry: 'We couldn't meet the aspirations and we were always chasing this moving target'.[43] Dr Foster's assessment of the practical position is accepted: however one presents the available data, he was intimately involved in the production process, and his opinion is reliable.

21.66 However, it does not present the whole picture. There remains the necessary caveat in relation to any assessment of the balance of supply and demand for products: individual choice was an aspect of practice, and would have differed not only within Scotland but as between Scottish centres and centres in England and Wales. Averaging of UK demand patterns necessarily concealed such differences. 'Self-sufficiency' might imply a capacity to satisfy the demand for NHS products as distinct from the total demand for concentrates where there was a preference for the commercial product that existed independently of whether NHS products were available.

21.67 It was the view of some witnesses, for example Dr Frank Boulton, that Scotland had become largely self-sufficient by the early 1980s notwithstanding that some commercial product was still being used in Edinburgh and possibly more so in Glasgow.[44] However, Dr Boulton thought that, without there being an actual ban on importation of commercial material, self-sufficiency was a lovely ideal and one to which transfusion services should aspire at all times, but that 'absolute' self-sufficiency was not achievable. There would always be special needs that could not be serviced from local materials.[45] It became a matter of definition. For him, the expression 'absolute self-sufficiency' meant that the community would be able to supply every single vestige of blood or blood products from within that community, with no dependence on outside agencies at all. A more realistic definition, short of perfection, would be that the NHS could service with local products that part of total demand for which clinicians sought NHS products, subject to such regulatory constraints on freedom of prescription as might be in force.

Increasing demand for Factor VIII products

21.68 At the beginning of the reference period two closely related matters drove increasing demand: the inherent attractiveness of Factor VIII concentrates in haemophilia therapy generally, and, shortly thereafter, a change in clinical practice towards home therapy. As discussed in Chapter 14, Knowledge of Viral Hepatitis 1, the late 1960s and early 1970s saw increasing emphasis on blood component use in surgery, and, arising from that, promotion of a policy of total fractionation as the ideal towards which the transfusion services should aim.[46] Best use of the available scarce resource of whole blood was the driver of the SNBTS's research and development of fractionation. A wider range of more effective therapeutic products became available to haemophilia clinicians.

21.69 A lively debate began on the best approach to clinical practice. As noted above, in the UK as a whole the use of imported Factor VIII concentrate began before products were first licensed for use and quickly became established. At a joint meeting of the UKHCDO and Blood Transfusion Directors on 31 January 1974, there was a wide-ranging discussion about the relative merits of cryoprecipitate and freeze-dried concentrates. With the exception of Inverness, every Scottish region was represented. Mr Watt represented the PFC. Factors taken into consideration were: ease of manufacture, recovery from the original plasma, ease of administration, and recovery of activity in patients. Those present at the meeting expressed a clear preference for freeze-dried concentrate if it was available.[47]

21.70 The question of how much material was likely to be needed led to discussion, with different data and methods being employed by different contributors. A consensus was reached, to the satisfaction of the chairman, Professor Blackburn of Sheffield, on a recommendation to the DHSS as a basis for planning future requirements for Factor VIII in the UK. It was felt that once the new fractionation laboratories in Edinburgh and the Lister Institute were in full production, the needs of the country should be met provided sufficient plasma was available. This view was soon to be confounded in relation to England and Wales, as Figures 21.2 and 21.3 above show. But it appears to be clear that, at this stage, the consensus among the Haemophilia Centre Directors as a group was that the UK was on the brink of self-sufficiency. The rapid increase in demand that was to come about was not anticipated.

21.71 There were, however, already indications that increasing demand might develop. Several contributors stressed that home therapy was becoming more accepted and widespread, improving the quality of patients' lives. It was recognised that cryoprecipitate was not ideal for that use. Some directors were already buying commercial AHG for home therapy.[48] The minute does not reflect any appreciation that this might affect total demand or demand for NHS products.

21.72 A paper entitled 'Optimum Use of Available Factor VIII' was considered by the Expert Group on Treatment of Haemophilia at a meeting on 11 October 1974. This paper acknowledged that those present at the last meeting of the Haemophilia Centre Directors were unanimous in preferring freeze-dried concentrate to cryoprecipitate.[49]

21.73 The disadvantages of cryoprecipitate were again stated: the material must be stored at minus 30°C or below[50] and its potency could not be known before use; it was tedious and time-consuming to make up for use; and to prepare clinical doses, packs or bottles could only be pooled after each had been handled individually. Advantages of the concentrates were known potency and no requirement for freezing. However, there was not sufficient NHS freeze-dried material for wide distribution. Commercial concentrates could be readily purchased but were expensive.

21.74 Cryoprecipitate was widely available at this time and its use was recommended for the routine treatment of early bleeding in joints and muscles. It was generally thought not to be suitable for home treatment, for which there was a growing requirement. NHS freeze-dried concentrate was recommended for routine surgery and cover for dental extraction, and for home treatment when more material could be made available.

21.75 Until NHS supplies of concentrate became adequate, commercial material was recommended for use in three areas:

  • For heroic surgery and major trauma; also in the management of serious bleeding in the face of anti-VIII antibodies.
  • As back-up when NHS materials temporarily ran out. It was stressed that commercial Factor VIII should only be ordered after all reasonable attempts had been made to obtain NHS materials.
  • For the immediate provision of home treatment (in the absence of NHS concentrate) in suitable cases who lived too far from a haemophilia centre to be adequately treated there.[51]

21.76 As in other areas, control was in the hands of haemophilia clinicians. If the last recommendation might have restricted growth in demand, it failed. When giving oral evidence, Professor Charles Forbes commented that it was not carried out in practice. The advantage of home treatment was that it could be given immediately by the person who had a bleed or their family. He did not think it would have been a good idea that only people who lived a long way from a haemophilia centre should be eligible for home treatment.[52]

21.77 Professor Ludlam agreed that the last recommendation did not reflect practice in the early 1970s. In his experience, each patient was considered individually, and he did try to help some patients who had severe haemophilia and who travelled very long distances by putting them on to home treatment.[53] However, he did not think that the recommendation had ever operated as a way of rationing treatment.

21.78 These views reflected a movement in thought towards wider use of home therapy, irrespective of distance to the patient's home. But it was dependent on the availability of concentrate. Efficacy and ease of use of concentrates, coupled with the change to home therapy became closely related aspects of growing demand, both for concentrates generally, and for particular products.

21.79 Among matters that influenced choice, Professor Ludlam noted that early concentrates (Factor VIII and Factor IX), whether NHS or commercial, were relatively impure and contained large amounts of plasma proteins other than those required for therapy. They were also difficult to dissolve. He told the Inquiry:

[T]he volume of reconstitution was relatively large. The early concentrates were only slightly more purified than freeze-dried cryoprecipitate. The volume of a single infusion might be 200-300mls of concentrate, as compared to 1-5mls with recombinant clotting factors today.[54]

21.80 For particular patients, this could affect the choice of therapeutic material. In the course of this period the PFC continued to produce Factor VIII and IX concentrates of what was termed 'intermediate purity' while commercial companies began to produce more highly purified products. For some patients, the commercial products were preferable to NHS products on clinical grounds. At a meeting of Directors of the SNBTS and Haemophilia Directors on 30 January 1981 held in Edinburgh, reasons for the continued use of commercial products in Scotland were discussed.[55] Haemophilia directors stated that sometimes only a commercial product was available. On other occasions, a high purity product was required and some directors said that the slower solubility of the PFC intermediate Factor VIII was a disadvantage. Some patients experienced more side-effects with the PFC products than with the commercial products. Mr Watt from the PFC acknowledged that there was a solubility problem and expressed hope that an improved product would be available soon.

21.81 On the other hand, some clinicians were clearly influenced by the view that American concentrates were prepared from blood that was more likely to be contaminated. When asked what the prevailing view was in Edinburgh regarding the difference between US concentrates and NHS concentrates, Dr Boulton referred the Inquiry to Richard Titmuss' book The Gift Relationship which was published in 1970. He said:

[I]t very clearly describes the risk of using blood from donors who are paid, that is the profit-making donor centres and the blood from the non-profit-making donor centres, who used volunteer donors in America .... The book very clearly established the greater risk from using blood - this is not fractionated products but just straight blood - from donors who are paid compared with donors who are not paid, and although there has been more than one magnitude of difference drop in the risk of paid and non-paid blood donors, that debate is still going on to this day, as far as I know.[56]

21.82 By 1980, Dr Boulton thought that one would be very aware of the problems of using blood and fractionating plasma from donors who were paid. For him, the 1975 World in Action programme described later highlighted a known problem:

[I] think that one was certainly aware that there were risks associated with using commercially obtained plasma from companies who were bleeding their donors and paying them in America or indeed, on reflection, in Austria.[57]

21.83 The data on use of products overall have to be understood as subject to these, and other factors, affecting individual clinical choice. The selection of products for home therapy reflected a complicated mixture of influences: it was not necessarily straightforward, and individual clinicians might reasonably differ in their views and preferences.

The development of home treatment

Early to mid-1970s

21.84 As matters developed, the move towards home treatment accelerated throughout the UK because haemophilia clinicians thought it to be in the best interests of individuals who would benefit from it. In oral evidence Dr Mark Winter outlined a typical example of a patient's experience of treatment in hospital with cryoprecipitate.[58] The problem would arise out of hours. There would be a good chance that the haemophilia centre would be closed so that the patient would have to attend a hospital casualty department. It would be extremely unlikely that the doctor seeing him would know anything about haemophilia so there would be a delay while the doctor found out. After consulting the on-call consultant haematologist, the blood transfusion department would be contacted and asked for cryoprecipitate to be prepared. So the patient could be in the hospital for 6-8 hours before the doctor tried to inject the cryoprecipitate with a very large needle rather than the small butterfly needle which was perfectly suitable. Dr Winter said:

[I] have laboured this point because it was a very harrowing experience. I have never, in all my years of haemophilia, ever heard a patient say, 'I went to casualty with a bleed and everything went well'. It never does, for pretty obvious reasons. These departments are very busy. The doctors know nothing about the condition, and haemophilia is rare.

So not only was cryoprecipitate not a very good medical treatment, for the patients it was a pretty dreadful experience having to go to hospital to have the treatment. So that was why, when one spoke to patients or you went to residential Haemophilia Society weekends, there was a very strong, very strongly expressed view from the patients of, 'We want concentrate, not cryoprecipitate and we want it to be British concentrate, not American'.[59]

21.85 Some haemophilia patients could react to protein impurities in the cryoprecipitate resulting in quite an unpleasant experience for the patient. Dr Winter said: 'Over the period of an hour they might shake and shiver and run a fever and have muscle aches and feel generally unwell'.[60]

21.86 He said that it was a major revolution when concentrates became available: they were so much easier to use than cryoprecipitate and unlike cryoprecipitate did not need to be deep frozen. At this early period, nobody had a freezer in their homes. Factor VIII and IX concentrates could be kept in small volumes in a domestic refrigerator so home therapy became possible.

21.87 Home therapy could start from the age of about three, depending on the state of the child's veins and the competence of the parents, who were taught how to inject the patient with concentrate. The patient would then go on home therapy for the rest of his life with a comprehensive clinical review every two to three months, depending on the severity of the disorder. Dr Winter said:

Prior to that, schooling in particular had been so variable an experience for children with haemophilia that there was actually a dedicated boarding school in Hampshire for patients with haemophilia, called the Lord Mayor Treloar School, where many of my patients went. When the concentrate came in, the boarding aspect of that school was no longer deemed to be necessary.

So this was a very major breakthrough. It enabled patients to get control back over their lives, to be on home therapy, and in retrospect we now call this period 'the golden interval'. This would be sort of 1973 until we entered the years of viral contamination problems, say five or six years later.

In retrospect it seems like a golden time where there was a disease which for 2000 years had had no treatment and then suddenly there had been this enormous quantum leap forward. People were getting decent jobs, having a decent amount of time at school, getting early treatment at home for their bleeds. That was causing less joint problems.

21.88 Parents were taught how to recognise an episode of bleeding. For joint bleeding, heat was a good indicator that there was bleeding. Parents were taught to compare, for example, knees - the knee with a joint bleed would be a lot hotter than the other one. A child would not want to move the joint if there was a joint bleed so it should be pretty obvious that the child had a bleed.

First assessments of consequences of home treatment

21.89 By 1975 home treatment programmes were being run by several haemophilia centres. Over 1975 and 1976, Drs Jones,[61] Forbes, Fearns and Stuart compiled data on home treatment for patients with haemophilia, including information about access to treatment. Questionnaires were completed by Haemophilia Directors throughout the UK. The number of patients on or in training for home treatment increased from 267 to 488 in the two years, and a further 241 haemophiliacs were considered suitable for home therapy by the end of 1976. About 60% of patients with Haemophilia A were receiving or being considered for home treatment in 1976. Home treatment had become a major part of the programme of therapy. In 1978, they published a paper in which they noted that:

  • The related demand was more than half the estimated total national requirement.
  • There were many variables requiring research.[62]

21.90 It was also noted that there was a rise in prophylaxis, expected to be sustained in 1977. There was a continued shortfall in the production of NHS concentrate from the voluntary donor system of the blood transfusion service. In 1976 there were still some areas in the UK where home treatment had not been implemented.

21.91 The paper proceeded:

Home treatment for many of the haemophiliacs in the United Kingdom would have been impossible without recourse to factor VIII concentrates prepared by pharmaceutical companies. About 55% of the blood product used for home treatment in 1976 was imported, importation being necessary because of continued shortfall in the production of NHS concentrate from the voluntary donor system of the Blood Transfusion Service .... In 1976 the Department of Health announced that the UK requirement for factor VIII concentrate would be met from NHS sources by mid-1977 after the grant of an additional £0.5m to the Blood Transfusion Service.[63] This target has clearly not been met, nor could it have been in the absence of the necessary financial aid to increase fractionation capacity .... The difficulty of implementing home treatment in some areas is reflected in the continued use of cryoprecipitate, which, despite its disadvantages, remained the only product available for 15% of haemophiliacs in 1976.[64]

21.92 Professor Forbes advised the Inquiry that he and his co-authors wanted to document the enormous long-term advantage to individual patients who had been on home therapy.[65] Home therapy reduced complications and bleeds. In relation to the high number of patients on or awaiting home therapy at the end of 1976, Professor Forbes commented:

Yes, it was a very popular move and this, of course, is before all the horrendous complications came on stream. So this was the golden age, in which we actually seemed to be doing something valuable for these patients.[66]

21.93 In the Discussion section of the article it was commented that: 'Perhaps the most disturbing aspect of the 1976 inquiry was the lack of adequate follow-up in some centres'.[67] Professor Forbes said that they were looking at follow-up of the number of joint bleeds and joint deterioration and so on but of more concern trying to ascertain whether all these plasma products had a downside. It was to become clear that they did, but that was for the future. Liver function tests were among the follow-up tests carried out. Professor Forbes thought that these tests would have been part of good follow-up. He said:

I'm pleased that we had put that in. We had no idea what would happen. And that was major concern for hepatitis, and for perhaps other infections that we didn't know about.[68]

21.94 The paper reflected clearly that so far as haemophilia clinicians were concerned, the expectation was of continued and increasing use of factor products, including use in home therapy, with a significant dependence on imported products. Cryoprecipitate was not expected to meet the demand. Commentators, such as Professor Forbes, were sufficiently concerned about risk to recommend follow-up of concentrate therapy by liver function tests, but they had no means of knowing at that stage what the risks were.

Home therapy mid-1970s to 1982

21.95 Support for home therapy strengthened in the remainder of this period. Home treatment was discussed in Dr Michael Willoughby's textbook on paediatric haematology written in 1976 and published in 1977. Dr Brian McClelland advised the Inquiry that he knew Dr Willoughby's book very well. He said that, although out of date, it was an extremely good book where you could still find the information that you wanted when you wanted it.[69] The textbook offered the Inquiry a useful perspective on the treatment of children with haemophilia in the 1970s.

21.96 In his book Dr Willoughby commented that commercial and NHS concentrates had advantages over cryoprecipitate in respect that that they could be stored at 4°C and could be carried by the patient when travelling - extending the meaning of 'home', but giving emphasis to the flexibility of the product.[70] In respect of home treatment, he referred to programmes of home transfusion in the early 1970s in the UK and the USA. In a 1970 study carried out in the USA, patients' preliminary experience showed a reduction in the number of school or work days lost as the patients were spared frequent 'time-consuming and psychologically undesirable' visits to hospital.[71] A pilot study was carried out in 1972 in the UK for patients suffering very frequent haemorrhage (at least once every two weeks). Dr Willoughby wrote:

Le Quesne et al (1974) in the UK and Levine (1974) in the US have similarly come to the conclusion that home treatment is highly efficacious in reducing the morbidity of haemophilia and improving the quality of life. No increase in utilization occurred except in patients previously undertreated.[72]

21.97 Professor Forbes agreed with the suggestion that in the late 1970s home treatment was thought to be the way ahead. Most people who were on home treatment programmes eventually had better joints and were less crippled. Patients who had a bleed could get their treatment instantly rather than wait for an ambulance, be taken to an inappropriate casualty department, wait to be assessed and many hours later get treatment.[73]

21.98 Home treatment also improved patients' experience of life. Expectations of haemophilia patients were discussed at the meeting of the UKHCDO in January 1977.[74] Mr John Prothero from the Haemophilia Society said that the society aimed to encourage those with haemophilia to lead a full life within a reasonable range of activities. As treatment improved, the patients' expectations widened. Mr Prothero said that home therapy had helped a great deal, permitting patients to go on holiday away from their centre and to travel on business. Education was discussed and it was noted that some local education authorities and headmasters had not allowed a boy with haemophilia to go to an ordinary school. Mr Prothero thought that by early 1977 the majority of haemophilia patients were not barred from attending ordinary schools.

21.99 Dr Charles Rizza talked about 13 severely affected Christmas disease patients who had received prophylactic treatment with Factor IX concentrate and commenced home treatment.[75] He said the treatment had been very effective enabling two of his patients, young twin brothers, to never miss school.

21.100 Several publications were available or in preparation at this point providing guidance to patients and clinicians on home therapy, including a handbook by Dr Jones, Newcastle, and a Haemophilia Society handbook.[76]

The early 1980s: An Edinburgh insight

21.101 As the figures earlier in this chapter show, there was increasing demand for Factor VIII concentrate in 1979-82 (rest of the UK) and 1980-82 (Scotland). As more fully discussed below from paragraph 21.260 onwards, there were variations in practice across Scotland. A practical illustration of what was happening in Edinburgh and south east Scotland at the time was given by Professor Ludlam and Dr Boulton. Dr Davies, Professor Ludlam's predecessor, had consistently used cryoprecipitate and PFC Factor VIII, predominantly cryoprecipitate.

21.102 When Professor Ludlam and Dr Boulton arrived in Edinburgh in 1980, increasing demand for concentrates for home therapy became a significant issue. Professor Ludlam told the Inquiry that in Edinburgh, in contrast to Glasgow under Drs Forbes and Willoughby, there was no particular policy in relation to home treatment. When there was a plentiful supply of Factor VIII, home treatment was for anyone who was competent to give it to themselves and bled sufficiently frequently that they needed it.[77] However, it was clear that home treatment was in demand, and it was increasingly provided over time.

21.103 In a written statement, Professor Ludlam noted that at the beginning of 1980 there were only six patients on home treatment out of a population of 187 patients registered with Haemophilia A. He said: 'There was a lot of enthusiasm for home treatment and I was continually being asked about it'.[78] The number on home treatment in Edinburgh increased from six in 1980 to 47 in 1989.

21.104 Professor Ludlam and Dr Boulton did not favour cryoprecipitate for home treatment. Dr Boulton agreed with the view expressed by other clinicians that cryoprecipitate was very difficult for home therapy. He said:

It was not totally unsuitable. It could be used. But the patients, and if they were a young boy, the patient's family, the parents, would need quite careful and specific training and monitoring so to do. And so it was only really practical in families (a), who were relatively well trained and (b), probably in fairly close proximity to the hospital in case things went wrong.[79]

21.105 Professor Ludlam said that he was not prepared to take the risk of giving patients cryoprecipitate at home.[80] Storage requirements and the inconvenience of administration made it an unsuitable material, in his view. The patient would have to have a deep-freeze and a water bath that could be heated to 37°C to melt the individual frozen units of cryoprecipitate. Professor Ludlam emphasised the need for a clean, if possible sterile, environment, and careful control of temperature for optimal results.[81] If the water was too hot the proteins in the frozen plasma would congeal, a bit like egg white. Professor Ludlam described to the Inquiry what the patient at home would have to do:

They ... would take out of the deep freeze 15 packs of cryoprecipitate, put them in the water bath. They take about a quarter of an hour to melt. And then each of those packs has to have a tube put into it and the melted cryoprecipitate rolled out. Because they are polythene bags, you can roll them up and squeeze the cryoprecipitate out. You do that repeatedly 15 times, squeezed out into a bigger bag. You would then have to hang that up, connect it to a drip set, like giving a conventional blood transfusion, the patient would then have to put the needle into their vein and connect up the transfusion set to the tubing on the needle. And it would take about half an hour/40 minutes to run in.[82]

21.106 He said that treatment with cryoprecipitate was straightforward in hospital:

But in a home setting, well - I wasn't prepared to let patients have treatment at home with cryoprecipitate for all these reasons. But perhaps the most important reason ... is the reactions. A lot of patients getting cryoprecipitate had reactions. Often these were mild and they would take an antihistamine beforehand, but I was looking at some information a day or two ago, suggesting that actually cryoprecipitate should only be given where adrenaline is available, and adrenaline is when you get an acute life-threatening allergic reaction, what's called an anaphylactic reaction. So for these reasons I wasn't keen and I did not have a home therapy programme based on a cryoprecipitate. I concede other places did and it seemed to work for them, but it was logistically difficult.[83]

21.107 In a paper provided to the Inquiry after the Oral Hearings,[84] Professor Ludlam stated that home therapy critically depended on a ready and reliable supply of concentrate. If there was a reduction in the availability of concentrate, hospitals could adapt by substituting cryoprecipitate for treatment. This was not an option for those on home therapy. If there was a lack of concentrate, home therapy had to be discontinued. Professor Ludlam noted that this was very disturbing and disruptive for patients (and their families) and was to be avoided if at all possible. Many of his patients could not get home therapy because there was not an adequate supply of concentrate. In England the majority of patients were treated with both NHS and commercial products. He preferred not to expose patients who had only received NHS concentrate to commercial product.

21.108 Professor Ludlam said that home treatment could start from the age of four or later, depending on the child. He explained the difficulties of treating babies:

A child with severe haemophilia usually starts to bleed around the age of nine months when they start to crawl around and walk and fall over. And so to begin with, they only get occasional bleeds, perhaps every month or so, and so they need treatment and the baby is distressed from the pain of the bleed and that makes their veins constrict a bit. They have very small veins, they may have chubby arms, and it is not easy to treat small babies, give them an intravenous infusion of anything. The clotting factor concentrate is of some volume and therefore it can be very traumatic for everybody, treating very small babies.[85]

21.109 He maintained Dr Davies' policy of using NHS material for the treatment of children.[86] He commented on his predecessor's preference for NHS concentrates:

[Dr] Davies had a policy of not using commercial concentrates because of the uncertainty about hepatitis viruses in the concentrates derived from plasma collected in the United States and elsewhere .... The disadvantage of this policy was that there was relatively little factor VIII concentrates available and this [was] significantly delaying the introduction of home treatment for many eligible patients. I impressed upon SNBTS my desire to have more factor VIII concentrate.[87]

21.110 But Professor Ludlam pressed ahead with home treatment. His policy in commencing home treatment at age four or later was different from Dr Winter's, but not materially.

21.111 Jones and colleagues expressed a similar view about the wider picture.[88] Concentrate was needed to support home treatment: it was not until freeze-dried concentrates were more freely available that large-scale home treatment programmes became possible, in their view. Given the limited supplies of NHS product, Dr Jones thought that home treatment for many of the haemophilia patients in the UK would have been impossible without recourse to commercial Factor VIII. In Scotland, that was the position for a short time in the early 1980s.

Prophylactic treatment of haemophilia

21.112 The practice of prophylaxis was also initiated in the 1970s although Dr Winter thought that the prophylactic programme did not really get going until the 1980s.[89]

21.113 In his textbook on paediatric haematology, Dr Willoughby discussed prophylactic treatment.[90] He wrote:

Prophylactic administration of Factor VIII or IX in severely affected patients has met with greater success. Clearly this is reserved for patients with quite exceptionally severe and frequent haemorrhages ....

The rationale for intermittent prophylactic replacement therapy is that spontaneous haemorrhage is only seen in patients with Factor VIII levels below 1-2 per cent and infusions of concentrates at 36 to 48-hour intervals can keep the concentration above this level for most of the time ....

21.114 At the UKHCDO meeting on 13 January 1977 there was a discussion about a trial of prophylactic treatment of severely affected haemophilic boys at Lord Mayor Treloar School, Hampshire.[91] The boys were treated with cryoprecipitate, Kryobulin and Hemofil. All but one of the boys had a fairly substantial reduction in the number of bleeds. Not all of them preferred prophylaxis to 'on demand' treatment but it was suggested that the two boys with good results who wanted to stop prophylaxis might have forgotten what a bad bleed was like. Professor Stewart from the Middlesex Hospital in London commented that prophylactic treatment for haemophilia patients should not be entered into on a large scale until there was sufficient evidence that it was beneficial to the patients. The trial was said to be aimed at providing information for future discussion, and not with the intention of immediate implementation. It was, in the event, the beginning of a new form of demand for therapeutic products that was heavily dependent on factor concentrates.

21.115 When Professor Forbes was asked why he thought some people appeared to have reservations about prophylaxis, he replied: 'I think the concern was that it was the huge amount of exposure to plasma products that it would entail'.[92]

21.116 At a meeting of the UKHCDO on 20 and 21 November 1979, Dr Jones presented a report from the Home Therapy Working Party. Professor Stewart asked whether there had been any move to find out if prophylactic treatment really did any good. Dr Jones responded by saying: '[F]or haemophilia A patients, limited prophylaxis was very effective indeed but it must be for a very good reason. One could spend less on prophylactic treatment than on on demand treatment in some instances'.[93]

21.117 Professor Forbes commented on Dr Jones' remarks:

This was a very interesting concept because people thought it would be very expensive giving routine treatment but in fact it reduced the amount of bleeding so that over a period of time the number of units of factor VIII given reduced, and of course, the joint damage and the other things reduced as well. So it seemed to be a very efficient and effective way of proceeding.[94]

21.118 Professor Ian Hann, who took up the position of Consultant Paediatric Haematologist and Oncologist at the Royal Hospital for Sick Children, Yorkhill, Glasgow in January 1983, told the Inquiry that he thought that his predecessor Dr Willoughby was well ahead of his time with regard to his belief that prophylaxis was the way forward. There was a great deal of scepticism over whether it was efficacious or practical, a view shared at that time by Professor Hann. He now considered that Dr Willoughby was right.[95]

21.119 At Yorkhill, Professor Hann carried out short-term prophylaxis in patients who had bursts of bleeding problems or a very severe bleed which did not settle down. He said:

So we carried out short-term prophylaxis, usually for several months or a little longer, during which we could verify a supply and then, in almost all of these cases, we had to discontinue prophylaxis.[96]

21.120 They never had enough product to carry out long-term prophylaxis. There was also doubt at the time whether long-term prophylaxis would work.

21.121 When Professor Hann was working at the Royal Free Hospital in London (prior to taking up the post in Glasgow)[97] his colleagues were worried initially that early prophylaxis might increase the risk of developing inhibitors, the antibodies to factor proteins which make a patient resistant to treatment. It took years, probably until nearly 1990 or thereafter, for people to accept that prophylaxis worked. Professor Hann moved to Great Ormond Street Hospital in London in 1987 and his unit was the first to get all patients onto recombinant prophylaxis in about 1990.

21.122 The evidence indicates that the emergence of prophylactic treatment had begun to influence demand at this period in some cases, but there is insufficient evidence to suggest that it had made a huge impact on total demand by 1982.

21.123 The discussion so far shows that there was persistent and significant growth in the use of Factor VIII products throughout the period to 1988, and points to some of the factors driving that growth:

  • Meeting the hidden demand related to patients' needs for treatment with coagulation factor products that had not previously been available, or available in sufficient quantity, to provide for the treatment of all haemophilia patients.
  • Changing patterns of provision as new products became available.
  • The ability to develop therapy regimes, and in particular home treatment, as concentrates became more readily available.
  • To some extent, the start of prophylactic therapy.

21.124 In parallel with these developments, there was growing understanding that there was a price to pay. In Professor Cash's colourful expression, there were no therapeutic roses without thorns.

Transmission of hepatitis

21.125 The first part of that price was exposure to risk of transmission of homologous serum jaundice or serum hepatitis.[98] The risk was widely recognised, but little understood by haemophilia clinicians and commentators on therapy in the early part of the period.[99] The second part of the price was exposure to the risk of developing inhibitors. By the end of the 1960s both risks were the subject of comment. At this stage, before the licensing and general importation of commercial concentrates, Factor VIII concentrate therapy was provided by cryoprecipitate and early forms of AHG.

21.126 In 1967, the Haemophilia Centre Directors decided at a meeting of representatives of all 36 of the haemophilia centres that then existed to set up a study of the incidence of transfusion hepatitis and the incidence of inhibitors[100] - 'two most alarming, but unrelated, complications of treatment of patients with coagulation defects' - in patients treated for Haemophilia A and B.[101] The study appears to have been taken forward by the Cryoprecipitate Working Party of the MRC Blood Transfusion Research Committee.[102] A progress report, most likely prepared by Dr Rosemary Biggs, was presented to the Haemophilia Centre Directors on 5 April 1971.[103] The study represented a significant initiative in the late 1960s and early 1970s in hepatitis research.

21.127 The progress report presented data for 1969 (and therefore before imported commercial concentrates had arrived in the UK). So far as disclosed in the report, prior structured research into hepatitis in haemophilia appears to have been very limited. The narrative provides an insight into contemporary thinking:

Transfusion hepatitis is thought to be a virus infection transmitted to the recipient by the donor plasma. There is every reason to suppose that the virus is contained in the various protein fractions used to treat haemophilia and Christmas disease (cryoprecipitate, human antihaemophilic globulin ... and factor-IX concentrate). The incidence of the virus in the donor population may be of the order of 1 per 1000 ....[104]

21.128 By this stage, a number of preparations had been introduced, and there are difficulties with the terminology used to identify them. In the late 1960s, AHG (in Scotland largely Cohn Fraction I) was a low potency product sometimes called 'concentrate'. In the early 1970s, commercial pharmaceutical companies introduced a true concentrate, of variable but increasing potency, sometimes referred to as AHG. Where possible, the distinctions will be noted.

21.129 Clinicians were asked to record the varieties and amounts of therapeutic materials used and 'the incidence of inhibitors and jaundice'.[105] Progress with the study is discussed in Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.16 to 14.19. The focus was on 'clinical jaundice'. No attempt was made to record sub-clinical hepatitis since it was thought that the important feature from the point of view of the patients was clinical illness. For 1969, it was reported that 29 patients (2.8%) were jaundiced.[106] Three patients had died. Two of the three had been treated with cryoprecipitate only. The third had been treated with cryoprecipitate and 'concentrate' (in this case AHG, the low potency product).[107] A more detailed examination of the records of haemophilia patients in Oxford showed that seven had developed jaundice.[108] Other data, derived from 60 patients treated at the Oxford centre, indicated the incidence of Hepatitis B associated antigen and antibody. It was reported that, of the sample of 60 patients, 11 had a positive test for Hepatitis B antigen or antibody and that of these only one developed 'clinical hepatitis'.[109] In retrospect, it is very likely that the vast majority of these jaundiced patients had been infected with the Hepatitis B virus (HBV). During the period covered by the data reported (1969 and 1970), the first, insensitive, tests for the so-called 'Australia antigen', later to be identified as the Hepatitis B antigen (HBsAg), were available. The antigen had been identified in 1967 as associated with serum hepatitis virus.[110]

21.130 The reports identified a fundamental dilemma for clinicians that was to persist, in one form or another, for decades:

The clinical value of free and early treatment of haemophilic patients in the saving of life and the prevention of crippling is now well established. This treatment is known to carry two main hazards: (1) the transmission of viral hepatitis; (2) the development of specific antibodies against coagulation factors.[111]

21.131 At this early stage, the risks were thought to be low. On the basis of the data from the 60 Oxford patients, it was reported that whereas about 18% of individuals had evidence of infection with HBV at this time, only 2.8% had overt illness. The view expressed was that:

Although the surveys do not involve large numbers it is likely that the prevalence of hepatitis virus in the materials used to treat haemophiliac patients is approximately as expected. The overall low incidence of clinical illness is presumably due to the fact that the patients became immunized in childhood.[112]

21.132 The research findings led to the incorrect conclusion that patients with coagulation defects were very resistant to clinical infection with the HBV. For haemophilia clinicians, concerned to balance the advantages of therapy with the materials available against the risks of transmission of infection, the emphasis on what they could observe in treating patients is clear. As in cases of post-transfusion hepatitis, the focus in discussing hepatitis in haemophilia patients treated with blood products (cryoprecipitate or concentrate of any generation) was on acute, clinically observed, hepatitis, and in 1971 it was thought that this was largely due to HBV infection.[113] A low number of diagnosed cases was taken to indicate a low risk overall. However, an infection that escaped identification on the screening tests available could not be taken into account. The possibility of any form of chronic disease was ill understood and little appreciated.[114] At this time (up to the early 1970s) it was thought and hoped that development of good (screening) tests for HBV would lead to a very great reduction in post-transfusion hepatitis or its equivalent in haemophilia patients.

21.133 So far as concerns the second hazard, the author, Dr Biggs, had reservations about data on the development of specific antibodies against coagulation factors (inhibitors): it was thought to be fragmentary and inconclusive. There was, to that date, no evidence of a steady increase in patients with antibodies. Of the patients seen at the centres in 1968, 5.47% had antibodies, and in 1969 the figure was 6.1%, but those were the only two years for which there were data.[115]

21.134 The progress report stated:

Hepatitis transmission must be related to the number of 'donor exposures' of the patients. This number will increase with the use of dried concentrates made from large pools of donors. These concentrates have advantages in treatment in that the potency is known and they are convenient to make up and administer. The problem in recommending an increased manufacture of these lies in the possible increase in hepatitis and antibodies. From the point of view of clinical hepatitis this danger seems to be small though the high incidence of Australian antigen and antibody in haemophiliacs suggests that they do become infected. We feel that the increased risk of clinical illness is not so great as to overbalance the advantages of the use of concentrates.[116]

21.135 In practice, haemophilia therapy had come to be dependent on blood products. Before the discovery of cryoprecipitate (in the mid-1960s) fraction concentrates (introduced in the late 1950s) were in short supply and usually reserved for surgery and the treatment of major complications in hospital. Most haemophilia patients had received fresh frozen plasma for the routine management of haemorrhage. The introduction of cryoprecipitate allowed outpatient treatment for all but the most severe bleeding episodes.[117]

21.136 Changes in clinical practice inevitably increased the numbers of patients exposed to blood products at a time when knowledge of the risks had not developed. The discovery of the Australia antigen, in Professor Cash's words in 1972, heralded an explosive research effort in which clinicians, biochemists, geneticists, microbiologists and immunohaematologists all made important contributions to developing knowledge.[118] At the same time, the ready availability of large-pool concentrates heralded an explosion in their use.

21.137 The WHO scientific group's report 'Viral Hepatitis' reflected progress in the understanding of the clinical, epidemiological and immunological behaviour of Hepatitis B.[119] One aspect of that progress was developing understanding that not all cases of post-transfusion hepatitis were caused by Hepatitis B infection, and that, as more Hepatitis B carriers[120] were eliminated from serving as blood donors, the proportion of cases due to other types of hepatitis would increase.[121] The report noted that some carriers had been found to have liver abnormalities ranging in severity from minor changes in the nucleus of the cell to severe hepatitis and cirrhosis. There was also a changing picture of the prevalence of HBsAg in apparently healthy blood donors. Prevalence was said to vary with such factors as the socio-economic status and sex of the donor, whether he was a volunteer or paid, and whether he lived privately or in an institution. Antigen had been detected most frequently in males in the younger age-groups. And the association between a history of clinical jaundice and a chronic HBsAg carrier state was breaking down.[122]

21.138 In Scotland, the report of the joint symposium held by the Royal College of Physicians of Edinburgh and the Royal Society of Edinburgh in 1972 indicated the state of knowledge among transfusion specialists at that time. The risks of transmitting serum hepatitis and of inducing antibodies (inhibitors) associated with Factor VIII products were recognised as established.[123] Other BTS studies in the early 1970s, in England and Scotland, sought to determine the prevalence of Hepatitis B infection in the general population, and in specific cohorts such as prisoners, in connection with blood collection policy.[124] In transfusion circles, there was increasing interest in the relationship between transfusion and hepatitis infection.

21.139 The second published report of Dr Biggs' study, in 1974, again related to the incidence of jaundice in patients treated for Haemophilia A and B (Christmas disease). The period covered was 1969 to 1971.[125] By the date of publication, with the benefit of improved testing and screening for HBV, it was thought that more than one blood-borne virus might be responsible for post-transfusion hepatitis. But the focus for haemophilia doctors, exemplified in Dr Biggs' report, remained on clinically apparent disease and on Hepatitis B.[126] The diagnostic features of clinical jaundice identified were identical to those reported at the Haemophilia Centre Directors' meeting on 5 April 1971, and related to the acute illness. The possibility of chronic liver disease arising from one or more of the post-transfusion hepatitis viruses was barely recognised by haemophilia doctors in the early 1970s, even as late as 1974.

21.140 The paper recognised the clinical value of treatment of haemophilia patients, and the known hazard of transmission of serum hepatitis. It stated:

The data on hepatitis suggest that severely affected and multi-transfused patients with coagulation defects do not have a high incidence of clinical illness associated with jaundice. Present calculations suggest that if all of the patients were exposed to virus contained in pools of plasma 4-5% of them might develop clinical illness. The proportion of patients exposed to virus is likely to decrease in future rather than to increase since donations grossly infected with Hepatitis B antigen will be excluded by universal donor screening.[127]

21.141 It was still thought that patients developed some immunity to the virus from multiple transfusions.[128] The paper also suggested that large donor pools might be a positive advantage because the virus would be diluted and would also contain Hepatitis B antibodies (conferring passive immunity to HBV infection with these antibodies).[129]

21.142 The incidence of anti-HBs found by Dr Biggs in haemophilia patients treated with blood products showed that a proportion did become infected by HBV. Dr Biggs' 1974 paper recognised that factor concentrates generally were associated with a risk of transmitting hepatitis. It was the nature and the scale of the problem that were not captured. The publication of the MRC study (chaired by Dr Maycock) in 1974 helped to continue the erroneous perception among haemophilia clinicians that post-transfusion hepatitis was rare in the UK.[130] Others took a different view,[131] but the balance of opinion in the UK seems clearly to have been reflected in these major studies.

21.143 Generally, however, in the early 1970s the increased risk of clinical illness was thought by clinicians to be insufficient to overbalance the advantages of the use of cryoprecipitate and concentrates in clinical treatment of haemophilia.[132] By 1974 many haemophilia patients receiving cryoprecipitate or Factor VIII concentrate had already become infected with the HBV but subsequent studies were to show that the vast majority of these individuals did not sustain long-term liver damage from that source of infection.

21.144 However, the focus on Hepatitis B which had largely characterised the approach to assessing transfusion-associated transmission of infection until this time was about to shift. The Hepatitis A virus (HAV) was identified in 1973 and it became apparent that this was a water-borne, not blood-borne virus.[133] From 1974, research began to indicate that HBV accounted for a relatively small proportion of cases of post-transfusion hepatitis. On epidemiological and, subsequently, serological grounds, it became clear that HBV and, now, HAV could not account for the majority of cases of post-transfusion hepatitis as had been implied in earlier discussion. In 1974 Prince and others postulated the existence of an additional hepatitis virus or viruses, distinct from HAV and HBV.[134] The putative existence of non-A, non-B (NANB) Hepatitis was suggested by serological analysis published in 1975.[135]

1975 and growing understanding of risk of transmission

21.145 Developing knowledge of hepatitis thereafter is discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985. In Europe, Dr Mannucci and colleagues at Milan were among the leading commentators. In February 1975, they published a paper on the incidence of asymptomatic liver disease in haemophilia patients treated with cryoprecipitate, commercial factor concentrates, and, in the case of the older patients, fresh frozen plasma.[136] The authors reported asymptomatic liver abnormalities, and suggested that there was a need for long-term prospective evaluation of any possible relationship between these abnormalities in haemophilia patients and the development of overt hepatic dysfunction. It was a suggestion that the condition occurring in haemophilia patients (which came to be recognised as NANB Hepatitis) might be more than just a benign condition.

21.146 Dr Garrott Allen, Stanford, a campaigner for volunteer donation in the USA, wrote to Dr Maycock on 6 January 1975. He commented on the ineffectiveness of screening for the HBV antigen and said that at least half of the cases of post-transfusion hepatitis were caused by an unknown agent other than Hepatitis A or B.[137] He remarked that this unknown agent still seemed to be more frequently encountered in the lower socio-economic groups of paid and prison donors. Dr Allen had raised an issue over the selection of donors that was to become significant in relation to the choice of therapeutic product as the period progressed.

21.147 From 27 July to 1 August 1975, a symposium, organised by the World Federation of Hemophilia and the International Society of Blood Transfusion, took place in Helsinki. Topics included problems related to adverse effects of coagulation concentrates. The reports of proceedings at the symposium showed that concentrates were frequently associated with adverse effects which might include liver disease, thromboembolism and hepatitis. It was agreed, however, that the occurrence of these adverse effects, albeit of clinical relevance, did not justify withdrawal or reduction of the very effective and life-changing use of concentrates.[138] For a period this became the prevailing view among clinicians, and total consumption of Factor VIII concentrates continued to grow in the UK, as shown in Figure 21.1 above.

21.148 In his evidence to the Inquiry Professor Forbes agreed that this was a view he shared around this time. Although aware of these risks, he advised that the risk of dying of bleeding was always much greater and that was what drove him and his colleagues to use these products despite the possible downside.[139] It appears, however, that there was now growing acceptance at international level that clinically relevant liver disease could be associated with the use of human blood products. The risk/benefit balance was about to become more problematical.

21.149 There were two publications concerning concentrates and hepatitis in The Lancet of August 1975. The first, by Dr John Craske et al, reported an outbreak of jaundice associated with three out of four batches of a commercial brand of freeze-dried Factor VIII concentrate (Hemofil) at the Bournemouth Haemophilia Centre the previous year.[140] Dr Craske was then based at the Public Health Laboratory in Poole, Dorset.[141]

21.150 Out of the 18 patients who had received the commercial concentrate nine became ill. Five patients had 'non-B hepatitis', two had Hepatitis B and two had both. In the introduction, Dr Craske commented on the huge improvement brought by concentrate treatment: concentrates were not associated with pyrexia and urticaria which occasionally occurred with cryoprecipitate, and they had made home treatment more practicable and major operations on haemophilia patients much easier.[142] But, on the authors' findings, the risk of transfusion-associated hepatitis was greatly increased over single donor preparations. When blood for transfusion was prepared from commercial donations the risk increased the frequency of jaundice between three and nine times. In respect of concentrates, the article said:

There seems to be a pronounced increase in the risk of post-transfusion hepatitis when some batches of commercial freeze-dried factor-VIII concentrates are used. This must be balanced against the undoubted advantage that the freeze-dried product has over cryoprecipitate.[143]

21.151 The article noted that the pool size might be critical in Factor VIII concentrates since transfusion hepatitis was a known hazard with large-pool products prepared from volunteer donors in the UK.

21.152 Measures to reduce the frequency of jaundice were suggested:

  • The first recommendation was that commercial Factor VIII concentrates should be reserved for the treatment of life-threatening bleeds in all haemophilia patients and for covering major operations.
  • The second recommendation was to reserve commercial concentrates for severely affected haemophilia patients '[S]ince they are more likely to be immune to hepatitis A and B'.[144]

21.153 When giving evidence, Dr Winter commented that the first recommendation was not feasible in England at that time because there was not enough NHS concentrate to sustain the haemophilia population. In relation to the second recommendation he said that as the major hepatitis risk was transmission of Hepatitis C (NANB Hepatitis), the fact that the more severely treated patients might be immune to Hepatitis A or B would not actually be relevant.

21.154 But Dr Winter thought that the paper generally stated exactly what would be expected: if haemophilia patients were given Factor VIII concentrate at that time, they would nearly all get abnormal liver function tests, yet only a minority of them would get clinical symptoms.[145]

21.155 The second publication in The Lancet of August 1975, a letter by Dr Dane and Dr Cameron from the Middlesex Hospital Medical School in London, reported the testing of batches of commercial Factor VIII concentrate (including one of the batches referred to by Dr Craske in the first article) using the authors' own solid phase radioimmunoassay (RIA) test.[146] All three batches were found to be HBsAg positive (and therefore infectious for Hepatitis B). The authors believed that if donations were screened by RIA (a more sensitive test than employed by the manufacturers of the concentrates for routine screening) the final product would be much more likely to be safe. The letter from Drs Dane and Cameron did not refer to 'non B hepatitis' - the expression adopted in the Craske letter to distinguish unidentified cases from cases of HBsAg positivity.

21.156 It was suggested to Dr Winter that the test used by Drs Dane and Cameron might be leading people in the wrong direction because it was creating a kind of reassurance: if there was better screening for Hepatitis B, the problem would be solved. He agreed, as Hepatitis C (HCV) was to become a much greater problem than Hepatitis B.[147]

21.157 The papers by Drs Mannucci, Craske, Dane and Cameron in The Lancet of August 1975 marked a transition point in the information available to haemophilia clinicians that had a bearing on the selection of therapeutic products. While screening of donated blood for HBsAg had already substantially reduced the risk of post-transfusion Hepatitis B, the tests for screening each donor for HBsAg were, until the late 1970s, relatively insensitive. Many commercial Factor VIII concentrates contained contributions from thousands of donors, and were still infectious for Hepatitis B (as demonstrated by these studies). From 1975, as tests for Hepatitis B became increasingly sensitive, the realisation grew that one or more other infectious agents were responsible for a very high prevalence of liver blood test abnormalities in recipients of concentrates since evidence for past exposure to Hepatitis B was becoming less common. Biopsy results were to become an important factor in the debate.

21.158 Awareness of NANB Hepatitis grew in the second half of the 1970s and particularly in association with blood product concentrates. Dr Winter said:

I think it was very well established by 1975, the group in Milan of Professor Mannucci had actually done liver biopsy studies which had demonstrated histological hepatitis in these patients as well, and it was for that reason by, you know, the mid 1970s that UKHCDO were starting to approach DOH with a view to persuading them to initiate moves toward self-sufficiency. It was the hepatitis argument that was obviously driving this initiative.[148]

21.159 As noted above (paragraph 21.84), Dr Winter said that haemophilia patients expressed a very strong preference for concentrates. Compared with cryoprecipitate, concentrate offered very significant improvements in their quality of life. But they would also state that they did not want to have any concentrate of US origin. They wanted concentrate of British origin because of the perception that British donors were voluntary donors and were therefore acting out of altruistic motives whereas the commercial donors were donating for financial reasons and were more likely to be infected with viruses. This simplistic argument was very strong within the haemophilia community. Because of this perception, it took a lot of work in Dr Winter's clinic to persuade patients in some cases to continue to receive commercial concentrate.

21.160 Dr Winter said there was a 'Tarzanoid' philosophy in relation to concentrates around this time: UK product good, US product bad.[149] The whole issue was about to move into the glare of media publicity.

'World in Action' television programmes

21.161 'World in Action', a television programme in two parts shown in 1975, investigated the manufacture of blood products in the USA and the concept of self-sufficiency in the UK. A DVD of the programme was shown to the Inquiry and sent to several clinicians for their comments.[150]

21.162 Part one, broadcast on 1 December 1975, featured three haemophilia patients whose lives had improved significantly since using commercial concentrates. One of these patients had experienced severe hepatitis, associated with Hemofil manufactured by Hyland, then a US drug company. Professor Arie Zuckerman, then recognised as an authority on hepatitis, was interviewed, as was Dr Craske. The documentary included footage of Hyland Donor Centres including centres in San Jose and downtown Los Angeles. The 'World in Action' team found that Hyland's paid donors included alcoholics and down-and-outs. It was suggested that, because of their lifestyles, many of these donors from 'Skid Row' areas were likely to be carriers of hepatitis viruses.

21.163 Dr J Garrott Allen, the campaigner against the paid donor system in the USA already mentioned, was interviewed on the programme and he said that a number of studies carried out in the previous decade had indicated that the risk of hepatitis was 60-70 times greater from paid donors than from a volunteer source such as friends and relatives.

21.164 Dr Richard Wilbur, the senior Vice President for Medical Affairs at Baxter Laboratories (then owner of Hyland), was also interviewed. Dr Wilbur's reaction to hepatitis infection in England following use of Hemofil was that the reported cases occurred from earlier batches made before their new techniques for screening donors for hepatitis were in place.[151] He considered that the risk-benefit ratio of taking Factor VIII concentrate compared with 'this relatively mild' disease was a good one for the patient.[152] When asked about the type of donors who sold their plasma to Hyland, Dr Wilbur said:

[W]e would prefer that all of the plasma were available from better sources and we do not deliberately seek out as a source of plasma the unfortunate people in the country. As I said before, we would vastly prefer to have it from voluntary donors just as everyone would like to have blood transfusions from voluntary donors.[153]

21.165 This part of the programme ended with the investigation team commenting that Hemofil carried a high risk for three reasons: the use of paid donors, its production from large plasma pools, and the inadequacy of hepatitis tests.[154]

29.166 Part two, broadcast on 8 December 1975 focused more strongly on the supply of concentrates in the UK. Patients and the Haemophilia Society both indicated their preference for UK material. Dr Maycock, then senior advisor to the Department of Health on blood transfusion policy, was interviewed, as was Mr John Watt, of the PFC.[155]

29.167 Dr Maycock was asked about the decision to import concentrates in 1973, given the known hepatitis risk of paid donors. It was suggested that the Department of Health had been somewhat complacent about these risks. Dr Maycock did not agree: he thought the quality of the material was controlled, both in the UK and the USA. His view was not shared by Professor Zuckerman who believed that it was well recognised that the commercial donor carried a considerably greater risk of transmitting hepatitis than the volunteer donor. But it was reported that British-made concentrates were not entirely free of risk either. Since the previous year, Professor Zuckerman had also detected a surprising number of infected batches of English concentrate.

29.168 Dr Maycock said he hoped that self-sufficiency would be achieved by mid-1977. He rejected the suggestion that there might not be sufficient production capacity or enough donors. He stressed that there was certainly no lack of donors.

29.169 Mr Watt told the presenter that the new plant in Edinburgh, the PFC, should be able at capacity, to produce more than the need for all plasma fractions for Scotland by the spring of the following year (1976). After that it would depend on government policy. Mr Watt agreed with the presenter that making concentrates in the UK should be very much cheaper than importing foreign concentrates. As well as cost, Mr Watt talked about the ethics of importing Factor VIII concentrates from impoverished countries. He said:

I know of one Middle Eastern country where a haemophiliac patient may travel 300 miles and wait for several days outside the clinic looking for treatment and it's not because the clinic doesn't want to take them in, it's because they don't have enough beds and they don't have enough material. The Factor VIII isn't there. It's all gone to the more affluent parts of the world.[156]

29.170 Dr David Owen, then Secretary of State for Health, also appeared on the programme and was asked how long it would take before Britain could stop being dependent on imported concentrate. He replied: '[A]s fast as buildings can be set up and equipment purchased .... We've brought it down to two years and maybe we can improve even on that'.[157] He agreed with the journalist interviewing him that paid donors were a greater health risk than volunteer British donors. But he said there was always some risk from any use of blood from donors.

29.171 In relation to the world trade in plasma Dr Owen said: 'I think there's a very strong moral case for once you are self-sufficient, ensuring that you use only your own national sources and freeing up those resources in other nations for their needs'.[158]

29.172 Dr Winter viewed the documentary and provided the Inquiry with a statement in which he commented:

The opening scenes, with various British teenage haemophiliacs and their families, are especially important since they underscore the very great improvement in quality of life afforded by the new concentrates, as compared with the use of cryoprecipitate, which was clumsy, time consuming, associated with side effects and in particular had to be administrated in hospital.[159]

The programme had looked at the case of one boy who, before home therapy, had made 98 visits to hospital in one year and had three months off school.[160]

29.173 Dr Winter noted in his statement that the programme set out visually what was already clear at the time: blood products derived from commercial donations were significantly more likely to be associated with viral infections.[161] Near the beginning of the programme it was revealed that paid donors had six to 13 times the risk of having hepatitis.

29.174 The programme showed people waiting to give blood with bottles of alcohol sticking out of their pockets, but Dr Winter advised the Inquiry that the major consideration to prevent a batch being infected was the viral status of a donor: whether the donor was underweight or drank alcohol would be of less significance to the risk of virus infection of the donation.[162]

29.175 Dr Winter said that it was his understanding that the pool size in commercial manufacture would be at least 20,000 and sometimes higher by the mid-1970s. Haemophilia doctors thought at the time that if the patient received Factor VIII concentrate in the 1970s, particularly from US donor plasma, it was inevitable that he was getting a number of different hepatitis infections.[163]

29.176 In Dr Winter's opinion, Professor Zuckerman and the others were really talking about Hepatitis B in the programme. In the mid-1970s after two or three years of concentrate use, many patients with haemophilia were displaying blood tests suggestive of a hepatitis-like pattern in their liver function blood tests. They were by and large very well. Maybe 5% or perhaps higher had circulating levels of Hepatitis B and about 20% could be shown to have antibodies against Hepatitis B; a small percentage could be demonstrated to have Hepatitis A but for the majority of these other patients, who clearly had a hepatitis-like picture on their liver function blood tests, all the standard Hepatitis A and B markers were negative. So it was for this reason that haemophilia doctors came to think that there was a third type of hepatitis which was called 'non-A, non-B Hepatitis'.

29.177 Dr Winter advised that a patient who got NANB Hepatitis could become clinically unwell, but that was not necessarily a very common event and not as common as clinical illness in Hepatitis A or B. In case of infection with either of those viruses, the patient normally felt thoroughly unwell at the time of the infection. NANB Hepatitis was more likely to get into the blood stream and inflame the liver. The focus for discussion in the documentary should have been NANB Hepatitis, because it was (in retrospect) by far the most relevant type of hepatitis for these patients.[164]

29.178 It has to be noted that while, in retrospect, Dr Winter was correct in his comment about the incidence of NANB Hepatitis it was only in 1975 that the first suggestions of the existence of NANB Hepatitis (first postulated in 1974) were beginning to be accepted. And, beyond the observation that many individuals with haemophilia were beginning to have persistent, usually mild, blood test abnormalities, nothing was known about NANB Hepatitis/HCV-related chronic liver disease, still less about its impact on infected haemophilia patients 10 or more years later. The documentary could not have dealt with NANBH/HCV at the time: it was really concerned with Hepatitis B.

29.179 In the programme Professor Zuckerman said:

[H]epatitis, or jaundice, is a particularly interesting infection because the severity of the illness ranges from a very mild form of infection, perhaps with trivial symptoms, to an attack of jaundice with quite a lot of disability which may last for some weeks or perhaps even months, and it is associated with a significant death rate. In addition, in a number of cases it may progress to chronic liver damage and may end up in a condition such as chronic active hepatitis or cirrhosis of the liver.[165]

29.180 A professor of medicine at the University of Southern California, Dr Mosley, was asked in the programme to quantify the risk of getting hepatitis from a clotting factor concentrate and his response was: 'probably 100 per cent if the individual is susceptible'.[166] Dr Winter suggested that 'susceptible' in this context probably meant that the individual did not already have antibodies to HBV.[167]

29.181 One of the committee members from the Haemophilia Society interviewed in the programme said that people with haemophilia were not too bothered about where the blood came from as long as they had blood concentrate to keep them going, and in some cases to keep them alive; of course they would prefer that blood was donated voluntarily and not from people who were undernourished and alcoholic.[168] Dr Winter recognised that sentiment. In his centre the supply of NHS concentrate was very limited and at least 90% of the concentrate was commercial in origin. This was due to the capacity of the plant at Elstree to produce the concentrate, and a policy of preferential supply to certain hospitals.[169]

29.182 One of the patients featured on the programme who had contracted hepatitis while using Hemofil talked about how he was vomiting really badly and wondered whether it was worth using the concentrate. Two days later, he had a bleed in his elbow and said he had no hesitation in going to the fridge and injecting the Hemofil because he knew it would stop the bleeding and the pain from the bleed was going to be so much worse than any of the pain he had suffered with hepatitis.[170]

29.183 Dr Winter was not surprised by what this patient had said and commented:

That's a mirror of, as I have been trying to reflect in my comments, the quite extraordinary change of quality of life for these people whose existence had really been pretty miserable, regular bleeding into joints and muscles, poor schooling, lifelong pain, no sport, limited ability to get jobs because of poor education, and suddenly there was this white powder they could give at home and it had an enormous difference. So for all these reasons, when faced with this variable data with variable opinions by doctors, their view was 'Well, we are extremely reluctant to consider not using this product any more because of the quality of life it has given us'.[171]

29.184 Professor Forbes said that he had not watched the programme when it was shown in 1975 but had seen it twice since then. He remembered when it was broadcast that it was the talk of the haemophilia part of the hospital. He thought that there was a gasp of disbelief when they showed the types of donors that were being used to give plasma in commercial centres. Professor Forbes was appalled when he watched the programme recently; there was no monitoring at all of these paid donors and even if they were asked questions, they denied they had any problems whatsoever but clearly they did have. He thought it was incredible to see the donors drinking alcohol immediately before they gave blood.[172]

29.185 Although Professor Forbes could not remember any specific details in relation to practitioners' reactions to the programme, he stated that people felt this was not the way to go. Commercial concentrates of all kinds, probably not just Hemofil (featured in the programme) but the other ones too, were all 'tarred with the same brush'.[173]

29.186 Having watched the 'World in Action' programme, Professor Cash wrote to The Lancet at the beginning of January 1976 stating:

There is no doubt that the import into the United Kingdom of factor VIII concentrates derived from external sources, however well screened for hepatitis viruses, represents an unequivocal pathway by which the level of a potentially lethal virus into the whole community is being deliberately increased. Although the absolute magnitude of this problem was exaggerated and over-dramatised by the television programmes, nobody with direct or indirect responsibilities for this phenomenon would wish to belittle the serious nature of the moral and practical dilemmas which face us all.

Perhaps the most misleading feature of the second television programme was the impression given that the recent and specific injection of £500,000 by the DHSS into the blood transfusion services will have worked its way through by mid-1977 and by that time the necessity to purchase further supplies of factor VIII concentrates will be eliminated. Our own experience indicates that this will not occur, not least because the present NHS production target for factor VIII concentrates is too low.[174]

29.187 Professor Cash was asked about the letter when he appeared at the Inquiry and it was suggested to him that he had been something of a prophet, in commenting on risk of a 'potentially lethal virus' in the early 1980s. His response was:

[B]ut I wouldn't see myself as some prophet, a prophet of doom ... in 1969 I did my own World in Action. I had a WHO travel fellowship and spent three and a half months in the States looking very carefully at all aspects of their transfusion service, made a lot of hugely important friends over there that were immensely important in the later years. And one of the things I did when I was in California was to go into the Cutter - it was Cutter, not Hyland - skid row area, and this is San Francisco, as I recall, and - I mean, I thought the film was pretty gentle on that. What I saw was obscene. It was just obscene.[175]

29.188 Professor Cash went on to say that he thought the film had exaggerated the situation because not all plasma that was used in commercial concentrates was coming from 'Skid Row'. There were some companies who claimed (and Professor Cash said he believed them at this time) that they did not use these sorts of donors at all but used 'university campus people'. He pointed out that PCR Hepatitis C studies were carried out many years later on old batches of commercial concentrate and some of them were negative.[176]

29.189 Dr Boulton who was working as a Director of the Liverpool Haemophilia Centre at this time told the Inquiry that he did not see the programme but he remembered conversations after it was broadcast.[177] He felt at the time that the programme had exaggerated the problem but he admitted that he was then a young and inexperienced doctor. A year or so before the programme, in 1973 or 1974, Dr Boulton was working at the London Hospital and had seen a haemophilic patient who needed Factor VIII over Christmas for a fairly major dental problem. There was not enough NHS cryoprecipitate or NHS Factor VIII in stock to cover the surgery safely so Dr Boulton ordered in a small amount of commercial Factor VIII and this mild haemophilic man in his 50s received some. The man got both Hepatitis B and NANB Hepatitis. Dr Boulton said that he had a rather rude awakening into the dangers of hepatitis from commercial (in this case US) Factor VIII.

29.190 Dr Boulton said that when he was working in Liverpool (after October 1975), commercial Factor VIII was bought from Austria not the USA. There was clearly a concern then that US products were to be avoided and he believes that this was a legitimate or at least understandable reaction to his experience of treating and giving a patient NANB Hepatitis. Dr Boulton was asked if the plasma used for the Austrian commercial product was Austrian. He replied that it was quite possible that some of the plasma came from the USA but he did not know that at the time; he was under the impression, and had been told by Immuno's director, that the material was Austrian in origin. But it was clearly from paid donors.[178]

Commercial concentrate production in the mid- to late-1970s

29.191 As the 'World in Action' programme revealed, one of the first concentrates used in the UK was Hemofil, manufactured by Hyland. It was not the only product on the market. By the late 1970s four major companies controlled most of the world's plasma. Based in the USA they were:

  • Cutter Laboratories of Berkeley, California.
  • Alpha Therapeutic Corporation of Los Angeles.
  • Armour Laboratories of Chicago.
  • Hyland in a suburb of Los Angeles.

29.192 International pressure against exploiting developing countries had restricted the supply of plasma from 'the Third World plasma mills',[179] and foreign firms were keen to have access to the lucrative American drug market. By the end of the 1970s only Hyland remained in American hands; it belonged to Baxter Travenol Laboratories, based in Chicago. Alpha Therapeutic had been bought by a Japanese company (Dr Naito's Green Cross Company); the German pharmaceutical company, Bayer AG, had taken over Cutter Laboratories; and Armour was in the hands of the French multinational Rhone-Poulenc.[180]

29.193 Concentrates available at or about the time of the programme were:[181]

Factor VIII products

Manufacturer Trade name FDA licence granted Last release
Armour Pharmaceutical Company Factorate 1973 1985
Factorate Generation II 1977 1985
Alpha Therapeutic Corporation Profilate Licence transferred in August 1978 from Abbott Laboratories Not available
Hyland Division, Baxter Anti-haemophilic Factor (Human) May 1966 Not available
Hemofil January 1968 Not available
Cutter Biological (later Miles, Inc.) Koate January 1974 October 1984

Factor IX Products

Manufacturer Trade name FDA licence granted Last release
Hyland Division, Baxter Proplex July 1970 Not available
Cutter Biological (later Miles, Inc.) Konyne December 1968 May 1985

Increasing evidence of the risk of hepatitis in the late 1970s

29.194 Notwithstanding Professor Cash's reservations about their accuracy, the 'World in Action' programmes could have left no interested observer in doubt that at least some clinical specialists believed that commercial factor products carried an unacceptable risk of transmitting hepatitis virus infection in comparison with the NHS products in manufacture at the time. The accounts of reactions among hospital staff, for example by Professor Forbes, indicate that these were extreme. Some experts, in addition to Professor Cash, could draw on personal observation and experience.

29.195 Dr McClelland was appointed to the SNBTS in 1977. Sometime after his appointment, he visited the Cutter Company in San Francisco. In his statement provided to the Inquiry, he wrote:

I also remember very clearly an experience that has coloured my thinking about the use of blood from commercial donors throughout my career, and I cannot think of any reason why this would not have influenced my own views about commercial Factor VIII during the early 1980s. Shortly after my appointment to the SNBTS in 1977 (I do not have a record of the dates) I visited the Cutter Company in San Francisco. During this trip I visited their Oakland plasma centre. I have a very clear recollection of being amazed to find that there were no donors in the centre and that I asked one of the two staff in evidence why the centre was empty. I recall her response, which was that this was typical for that day of the week, because it was the day for collection of social security cheques. I also recall that I took away a copy of a notice displayed in the centre [reproduced at Figure 21.7 below]. This stated the fees for a plasma collection - $US 16.

This visit left me in no doubt that even in this relatively favoured part of the USA, the company depended very heavily on the provision of plasma by people of low income. One implication of this that was clear to me at that time was that plasma was being collected from individuals who might be dependent on the payments from the plasma centre and who would therefore have an incentive to conceal any aspects of their health that might make them unsuitable as donors.[182]

Figure 21.7

Figure 21.7

21.196 Dr McClelland referred to the 'World in Action' programme when giving evidence about haemophilia patients keeping abreast of developments in therapy. He was very impressed with the common sense knowledge that a lot of the patients and some of the parents featured on the programme expressed about the infection risks and the safety and effectiveness of the products.[183]

21.197 Dr McClelland told the Inquiry that when he was on-call for the BTS, professionals who happened to be haemophilia patients would visit and they would very often have their own specific personal views about which product they had chosen to be treated with.[184] He said:

There were some individuals who would only accept to be treated with cryoprecipitate, even accepting all the inconvenience. There were some who would not accept treatment with imported Factor VIII. There are some who had a very strong preference for particular products and it would be quite wrong, I think, to say that these were idiosyncratic preferences. These patients almost certainly had extremely good reasons, which they could probably explain very articulately in many cases, why they chose a particular approach to their own treatment, and my recollection is that that was evident among some, not all, but some of the haemophilia patients early on in my career.[185]

21.198 When asked if the patients' expertise related to their perception of the effectiveness of the different products, Dr McClelland replied:

In the broad sense - well it depends how you define 'effectiveness'. Strictly speaking, I would define clinical effectiveness as essentially describing the balance of benefit and disbenefit. So safety is actually, in that sense, part of effectiveness, but it may be easier to separate them out and say were they concerned about the safety, which, if you think might be: what will this do to me in the long term? Will I get something nasty in two, five, ten years' time? As opposed to: will this stop my bleed and control my pain now, better than other products?

And of course, the third factor that to some patients mattered a lot, is inconvenience. Will it take me an hour fiddling around with syringes and needles and jars of salt water and other things to get my dose, or can I go to the fridge, take it out, stick a syringe in and that's it? All those factors and many others would have influenced their choices.[186]

21.199 In the Inquiry's view Dr McClelland's impressions reflected a realistic assessment of the position. In the meantime, more structured investigations continued.

21.200 At the meeting of the UKHCDO held on 13 January 1977 (referred to above), Dr Craske presented a report on his continuing study of hepatitis in haemophilia patients treated with Hemofil.[187] Three hundred and seventy one patients had been followed up. One had died with cause of death possibly attributable to Hepatitis B. Dr Craske proposed an extension of his study over two years. He suggested that:

This continued study would include a follow up of patients who had had Hemofil associated hepatitis to study the incidence of chronic sequelae, and a comparison of jaundice associated with NHS Factor VIII and commercial products.[188]

21.201 The discussion reflects a degree of scepticism among the haemophilia clinicians. As minuted:

Prof Stewart said that jaundice would always occur and there were difficulties in specific identification of the causal agents. Dr Dane [a virologist] said there were problems with the sub-typing. This was possible with samples from patients but was difficult with the concentrates because of the very small amounts of virus present in the samples. Tests for HBsAg could not pick up trace amounts of antigen. Hepatitis B was uncommon in the general population in patients under 14 years of age.[189]

21.202 Dr Craske was challenged on how he distinguished between Hepatitis B and non-B types. At the same meeting, Dr Biggs reported data returned from haemophilia centres on the incidence of jaundice. There was no action proposed in response to Dr Craske's study, which continued in any event, and his Working Party reported in due course.

21.203 The meeting discussed the supply of Factor VIII. At earlier meetings of the Reference Centre Directors it had been established that the BTS could supply sufficient plasma for fractionation to provide a minimum of 40 million units of Factor VIII per year. However there was a hold-up in the expansion of the fractionation process in the UK.

21.204 Dr Macdonald (Glasgow Royal Infirmary) talked about supplies of Factor VIII concentrate in the west of Scotland. He said that the PFC at Liberton had the capacity to make 60 million units of Factor VIII per year but to reach this figure, the centre would need about £25,000 for new equipment and extra running costs including payment for staff to operate a 24-hour shift system of working. He advised that, in 1976, 14% of all Factor VIII used in the west of Scotland was commercial and 46% of Factor VIII used was freeze-dried NHS intermediate potency concentrate (from the PFC at Liberton).[190]

21.205 The meeting was informed of a joint plan by the DHSS and the SHHD to divert plasma from south of the border to Liberton for fractionation and return to England and Wales once the Liberton PFC was fully operational: it was not known at this time when that would be.[191]

21.206 Once more, it was Professor Mannucci and his colleagues who moved the debate forward in an editorial published in 1977 on the work of the Helsinki Symposium, 27 July-1 August 1975, as noted above at paragraph 21.147.[192] The work of this team, as published in 1975, on the natural history of NANB Hepatitis is discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985, at paragraph 15.37. The 1977 editorial contained an important analysis of papers discussing the known side-effects of the use of concentrates and an assessment of their significance. It pointed to the advent of home therapy as a factor that might be significant, especially in the light of the observations by Jones et al which emphasised the possibility that complications might develop far from the control of specialised centres. But the editorial did not expand on it. The material part of the paper carried forward the group's analysis of the consequence for haemophilia patients of long-term exposure to 'the agent(s) implicated in post-transfusion hepatitis'. They noted that the incidence of clinical illness associated with jaundice was surprisingly low in people with haemophilia. But they commented:

[T]he research of Hasiba et al and Yannitsiotis et al suggests that the observed abnormalities are likely to be related to the frequent and repeated exposure to the agent contaminating the blood derivatives. The observation of Hasiba et al that abnormal liver function was more frequent in patients treated with commercial concentrates than in those treated with blood-bank cryoprecipitate is rewarding, because it clearly shows a way in which prevention can be attempted.[193]

21.207 The position remained, however, that the clinical and prognostic significance of the observed anomalies in patients was unknown, and that the great majority of the patients were asymptomatic and free of physical signs of liver involvement. It was concluded that until an answer could be provided by long-term prospective evaluation, it appeared unjustified to withdraw or reduce the very effective and life-changing use of concentrates. The same view was emphasised in the discussion:

[A]nti-hemophilic concentrates are frequently associated with side effects which may be of clinical relevance. However, they do not justify withdrawal or limitation of replacement therapy, which would be accompanied by a consistent deterioration of the present pattern of life of hemophiliacs.[194]

21.208 In April 1977, Mannucci and colleagues reported on the use of 1-Deamino-8-D-Arginine Vasopressin (DDAVP) to promote Factor VIII properties in patients with moderate and mild haemophilia and von Willebrand's disease undergoing surgery, without use of plasma concentrates.[195] In his review of this period in the paper 'AIDS, hepatitis and hemophilia in the 1980s: memoirs from an insider', Professor Mannucci stated that the advantages of DDAVP in reducing the risk of blood-borne infection in mild haemophilia were immediately appreciated in Italy, where the early use of DDAVP led to a significantly lower rate of infection in Italian patients with mild Haemophilia A when compared to patients with mild Haemophilia B which was unresponsive to DDAVP.[196]

21.209 SNBTS researchers were aware that there was a rise in Factor VIII activity after infusion of DDAVP. The effect had first been described by SNBTS staff using peptides synthesised in Czechoslovakia.[197] However, there was reluctance to trial the preparation in UK patients, and the intelligence was shared with Italian colleagues who published the 1977 paper referred to. In the circumstances, Mannucci's confirmation of the effectiveness of DDAVP might have been expected to lead to increased use of DDAVP in the UK and Scotland in particular. There was no reference to DDAVP therapy in the minutes of the UKHCDO for 1977, after Mannucci had published, as bearing on the treatment of haemophilia patients. Scotland was well represented at the meetings, but the representatives do not appear to have raised the subject.

21.210 Towards the end of the 1970s there was an increasing awareness that use of concentrates carried a high risk of hepatitis, particularly in previously untreated patients or in patients who had been treated infrequently.

21.211 Papers in late 1977 and 1978 by Lesesne,[198] Spero,[199] Mannucci[200] and Preston added significantly to the debate about the relationship between concentrate use and hepatitis. All of these papers were based on the results of liver biopsies which was new evidence. Developing thought is discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985.

21.212 What was to prove in time a significant development in the UK was reported on 16 September 1978. Preston and colleagues (Sheffield) published 'Percutaneous liver biopsy and chronic liver disease in haemophiliacs'.[201] Having dealt with HBV, the paper commented:

In addition, non-A, non-B hepatitis may well be an important factor and observations in four of our eight patients support this possibility.

21.213 Among other conclusions, the paper stated:

A wide spectrum of chronic liver disease was demonstrated, including chronic aggressive hepatitis and cirrhosis. The liver pathology bore no relation to clinical history or to biochemical findings .... The high incidence of chronic liver disease seems to be a recent development and is probably related to factor-concentrate replacement therapy.

21.214 The immediate impact of this research in the UK, and in particular of the Preston publication, was not great. At the time, Sheffield was not a noted centre of excellence in research in this field, and the significance of the findings of Preston et al was not appreciated. Lesesne, Spero and Manucci had not recommended an immediate change in therapeutic practice. Nor had Preston. As Table 21.1 in the Appendix to this chapter shows, growth in concentrate usage accelerated after 1978.

21.215 After the initial outbreak of hepatitis following infusion of Hemofil Factor VIII concentrate in 1975, Dr Craske and his colleagues had been charged by the Haemophilia Centre Directors with forming a working party to survey more closely the overall incidence of hepatitis following the use of Hemofil and all other Factor VIII products used in the UK. In addition, the survey was originally aimed at analysing the different types of hepatitis that occurred, whether due to Hepatitis B virus or non-B (subsequently non-A non-B) virus or viruses. It was also to begin to assess the possibility that some attacks of hepatitis could lead to chronic liver disease.

21.216 Although the survey was far from perfect, partly because knowledge of the putative NANB Hepatitis virus became progressively more definite during the two years of the survey period, the results and the conclusions drawn by Dr Craske and his colleagues were important. The full results of the incidence of hepatitis following use of all Factor VIII products were disclosed to the Haemophilia Centre Directors in August 1978. The report was published in November 1978.[202]

21.217 There were returns from 24 haemophilia centres. Overall 207 overt episodes of hepatitis (symptoms of hepatitis and abnormal liver test results) were reported. All Factor VIII products were implicated. One hundred and thirty five cases (65.2% of the total) were thought to be non-B and 72 (34.8% of the total) were thought to be Hepatitis B related. Hepatitis was again defined by symptoms. There was no systematic measurement of liver function tests carried out on all recipients. From these studies Craske and colleagues concluded that there were probably two different organisms responsible for 'non-B' Hepatitis, based upon incubation times and the occurrence of apparent multiple attacks in some patients.

21.218 Although no evidence was produced by the survey as to the likelihood of development of chronic liver disease following an acute attack, the report also referred to a visit by Dr Craske to Dr Roberts and his colleagues at the Department of Medicine at the University of North Carolina. One hundred liver biopsies had been carried out on patients there who had been treated for up to 10 years with Factor VIII concentrates. Chronically elevated serum transaminases were recorded, and nearly 50% had histological changes compatible with cirrhosis, chronic active or chronic persistent hepatitis. The report noted:

There is controversy as to whether these changes are the sequel to acute virus hepatitis, or are due to some other cause, but Dr Roberts and many other physicians are of opinion that virus hepatitis is the main factor. The elucidation of this problem, therefore, remains the most urgent one from the patient's point of view.[203]

21.219 Unlike post-transfusion hepatitis, in respect of which different views were held at this time as between the USA and the UK/Europe, in the case of chronic hepatitis in haemophilia patients there was a consensus among US and European investigators. Despite cautious reports, the general view remained in 1978 that the disease in people with haemophilia, while inevitable in a high proportion of patients, was, to a great extent, probably benign. This view was to change very gradually over the next 10 years, as discussed later.

21.220 The possibility that further work might show whether more than one agent was involved, canvassed by Dr Craske and his colleagues, was taken up in a letter to The Lancet of 11 November 1978: 'Evidence for existence of at least two types of Factor-VIII-associated non-B transfusion hepatitis'.[204] Comparison of observations following infusion of a number of commercial products suggested that at least two agents might be involved. The finding was said to emphasise the need for further work to attempt to isolate the infective agents involved.

21.221 Discussions about the risk of transmission of hepatitis continued throughout 1979. Only now, more attention came to be focused on NANB Hepatitis. The issue was raised in a meeting at the MRC on 12 February 1979.[205] At this meeting it was decided that a major UK study of post-transfusion hepatitis should not be supported by the MRC.[206]

21.222 The decision that a survey of post-transfusion hepatitis was not warranted was to have longer-term consequences. In the US studies had contributed to the understanding that the prevalence of infection in a given community was an important factor in assessing risk. Lack of similar research contributed to the perpetuation of error about the prevalence of infection in the UK.

21.223 On 10 March 1979, Wyke and others (including Zuckerman), published 'Transmission of NANBH to chimpanzees by Factor IX concentrates after fatal complications in patients with chronic liver disease'.[207] Seventeen patients at the liver unit, King's College Hospital, received concentrate from four different batches of commercial and non-commercial concentrate. Six cases of NANB Hepatitis resulted. The chimpanzees were infused with batches of Factor IX (from commercial and non-commercial sources) which were associated with the transmission of NANB Hepatitis to the infected patients, and with blood from implicated donors. All the chimpanzees had developed hepatitis. It was suggested that, until there was a screening test for the NANB Hepatitis agent, concentrates should be restricted:

Until blood-donors can be screened for the non-A non-B hepatitis agent, it would seem wise to restrict the use of both commercial and non-commercial concentrates to life-threatening situations. In particular, their use in patients with chronic liver disease should be avoided, as the risk of a serious illness resulting appears to be increased.

21.224 That advice was not followed. The Haemophilia Reference Centre Directors met again on 15 October 1979.[208] The Hepatitis Working Party had produced a report in relation to liver disease in patients with haemophilia which had been circulated to all the Reference Centre Directors in advance of the meeting. One hundred and seventy nine patients with severe Haemophilia A were studied. Following physical examination of the patients and analysis of their liver function tests, results showed that in spite of multiple transfusions and very large numbers of grossly abnormal liver function tests, very few patients showed any stigmata of chronic liver disease. Patients treated with different types of Factor VIII (NHS and commercial) showed no significant difference in either their liver function tests or viral hepatitis markers.[209] There was discussion regarding the details in the report but this was not recorded in the minutes. Dr Craske invited the Centre Directors to let him have their comments on a draft form (Form C3) asking for information on patients thought to have developed chronic hepatitis.

21.225 At the 10th meeting of the UKHCDO on 20-21 November 1979, an updated version of Dr Craske's Hepatitis Working Party report was presented.[210] There was much discussion on the contents of the report including (apparently for the first time at a UKHCDO meeting) the prevalence of chronic hepatitis in haemophilia patients. Age appeared to be a very relevant factor. The average attack rate of hepatitis in patients over 40 was six times that for those aged up to 40. Dr Craske commented that most patients thought to have developed chronic hepatitis had not previously had an overt attack of hepatitis. Professor Stewart of the Middlesex Hospital suggested that samples of liver should be obtained from all haemophilia patients who went to post-mortem. Causes of hepatitis were said to be uncertain: the meeting was reminded to keep an open mind. The directors were again asked to report cases of chronic hepatitis by completing the working party's approved version of the new Form C3.[211] Dr Craske stated that there were two types of non-A, non-B Hepatitis, a more confident assertion than previously. In a wide-ranging discussion over two days, including a scientific session, there was, so far as recorded, no discussion of change in practice relating to the prescription of Factor VIII.

21.226 On 30 April 1980, the Council of Europe, Committee of Ministers, made a number of recommendations including No R(80) 'concerning blood products for the treatment of haemophiliacs'.[212] The recommendations stated that Member States should pursue the goal of self-sufficiency in anti-haemophilia products and in blood plasma for their preparation. The appendix set out recommendations the Council considered desirable for each Member State including:

[T]o give the necessary information to all concerned in haemophilia therapy regarding the problems arising from the procurement and rational use of products; it must be realised that a balance should be achieved between the available resources and the justified needs of haemophiliacs.[213]

21.227 On 30 September 1980, the UK Haemophilia Centre Directors met in Glasgow.[214] Dr Craske presented the report of the Hepatitis Working Party for 1979. The report set out the results of surveillance for 1978 and 1979. It narrated:

This year has seen the completion of the first year of the surveillance programme financed by a grant from the Department of Health and Social Security. This is part of a three year programme. The second part of the project consists of an investigation for evidence of chronic liver disease in haemophiliacs on long term factor VIII therapy.[215]

21.228 The report stated:

The prevalence of hepatitis in 1978 and 1979 has had about the same level as that observed in 1976-77. There has been an increase in the proportion of cases of N/A, N/B hepatitis reported in patients with mild coagulation defects receiving concentrate for the first time to cover operations .... The observed increase in mild haemophiliacs contracting hepatitis is probably due to the fact that most severe haemophiliacs have already been exposed to viruses present in all brands of concentrate and are therefore immune to re-infection. Patients with mild haemophilia have not so been exposed; therefore there is no evidence to suggest that the contamination rate of different brands or batches of concentrate with N/A, N/B viruses has diminished.[216]

21.229 The main conclusions of the working party were that:

1. Transaminitis is unrelated to current factor VIII therapy and the level of anti HBs antibody.

2. Transaminitis is unrelated to a previous history of overt hepatitis.

This is supported by the observation that in 6 out of 7 cases of jaundiced patients observed at Oxford in the past year, the liver function tests quickly returned to normal after the acute attack ....

These results suggest that if transaminitis is related to viral hepatitis, the patients who become carriers and develop chronic liver disease will only contract mild or symptomless acute hepatitis, and the most overtly jaundiced patients will fully recover. This is supported by our observations of hepatitis B infections in haemophiliacs ....[217]

21.230 'Transaminitis' was emerging as a descriptive condition identified by biometric abnormalities. At this time it seems that there was some ambiguity in the use of the expression. It is not clear whether those who used the term associated 'transaminitis' with ongoing liver inflammation (hepatitis) or with more established liver damage. However, these conclusions show that among haemophilia doctors, as among hepatologists, there was increasing realisation that chronic liver disease might be associated with persistent mild liver test abnormalities - 'transaminitis' - and possibly a carrier state. Furthermore, it was now realised that liver damage and disease might arise in the absence of symptoms.

21.231 The minute of the UKHCDO meeting on 30 September 1980 stated:

Large pool concentrates appeared to give a higher risk of hepatitis than small pooled concentrates and Dr Craske felt that increased usage of small pooled concentrates would help to reduce the incidence of hepatitis in the haemophilic population. First-time exposure to large pooled factor VIII concentrate resulted in many cases of hepatitis, especially in von Willebrand's disease patients. Professor Bloom wondered whether cryoprecipitate would be a better product to use for mild haemophiliacs and von Willebrand's disease but pointed out that there was a problem over the amount of factor VIII in these materials. Dr Craske agreed and he said that the NHS product was certainly better than the Commercial products because of the screening of the blood donors and the regular donor panels which were used in the U.K. The screening procedures for donors of plasma used to make Commercial factor VIII is radioimmunoassay but because of the unstable population and the poor social background, it is likely that there will be a higher incidence of carriers of the hepatitis virus than in the U.K. volunteer blood donors.[218]

21.232 There was no reported discussion, in the Hepatitis Working Party Report, or at the meeting on 30 September 1980, of the need or desirability for a fundamental reassessment of, or change in, the Haemophilia Directors' approach to product selection. In Scotland, over the next six months there were discussions relating to the use of cryoprecipitate, but records do not disclose serious concern among haemophilia clinicians of adverse consequences from the use of the PFC concentrates.

21.233 At a meeting of Directors of the SNBTS and Haemophilia Directors on 30 January 1981 held in Edinburgh, Professor Cash spoke about cryoprecipitate and emphasised that it should be seriously considered for home therapy.[219] Home therapy was increasing and would place such a strain on resources that all options had to be included. The Haemophilia Directors were generally not in favour of using cryoprecipitate for home therapy as they considered the risks of side-effects were too great. They were prepared to use cryoprecipitate in hospitals.

21.234 When Professor Cash appeared at the Inquiry he explained his reason for recommending cryoprecipitate to meet the therapeutic needs of haemophilia patients. He said:

As a person responsible for self-sufficiency, so I thought, I was drawing attention to my colleagues, not just saying, 'Keep going with cryoprecipitate chaps', but cryoprecipitate was much higher yielding than John Watt's PFC's concentrates, and that applies across the world. So if you switched fast from cryoprecipitate to concentrate, from the point of view of self-sufficiency, you were going to need a lot more plasma to stay still. And I actually suggested we gave just a thought before we rushed down that track, and that's all that that was really about.[220]

His advocacy of cryoprecipitate was not based on apprehension of risk related to Factor VIII concentrate.

21.235 At the joint meeting on 30 January 1981, Dr Albert Bell of SHHD introduced paper 81/2, regarding the Council of Europe recommendation concerning blood products for the treatment of haemophilia.[221] The Directors agreed that policy and practice in Scotland were consistent with the recommendations urging Member States to become self-sufficient and to follow guidelines for the preparation and use of blood products. Professor Forbes told the Inquiry that he was not aware of this recommendation and admitted he knew nothing about the Council of Europe and their role in relation to blood products at that time.[222]

21.236 Concern was expressed again at a meeting of the Scottish Haemophilia and Blood Transfusion Working Group held on 4 March 1981 about the level of commercial material being purchased.[223] It was agreed that the aim must be for the NHS in Scotland to be self-sufficient. This could be achieved with good planning and steps had been taken to improve the input of plasma. Professor Cash again spoke in favour of cryoprecipitate highlighting two factors:

  • The increased yield.
  • The increased pool size (although acknowledging that there was a school of thought in the UK that the larger pool size may increase the risk of hepatitis).

21.237 Professor Cash urged members to bear in mind the allergic reactions and side-effects which could arise. He commented that the majority of home therapy patients had no problems when using cryoprecipitate and in Belgium it was used extensively. Professor Cash did not develop the argument, and the context indicates that his primary concern at this stage was still related to supply.

21.238 The meeting then agreed that Professor Cash and Dr Foster would monitor ongoing studies in relation to the improvement of the yield of intermediate Factor VIII and the development of a product of higher potency. Dr Foster also drew attention to the importance of reporting adverse reactions to the PFC products. This was necessary to meet the requirements of the product licence but also gave the PFC the opportunity to withdraw other material of the batch giving rise to suspicion pending investigation. The discussion reported gave no indication that the Haemophilia Directors present considered that there were serious risks of adverse reactions: the discussions related to procedural difficulties in devising a reporting system.

21.239 On 4 July 1981, an editorial in the BMJ set out the risk to haemophilia patients in rather more stark terms. It narrated:

Despite advances in screening donors and in blood fractionation, post-transfusion hepatitis remains the major complication of the modern treatment of haemophilia. The diagnosis is usually inferred from abnormalities in the results of hepatic biochemical tests rather than from clinical evidence. Surveys in haemophiliacs have shown changes in the liver architecture consistent with previous viral assault, including those of chronic persistent and chronic active hepatitis and of cirrhosis. Indeed, in some cases early death from liver disease might prove to be the price paid by haemophiliacs for the improved quality of life afforded by the easy availability of clotting-factor concentrates.

So while no one doubts that the only way to treat haemorrhage in severe haemophilia is by rapid replacement of the relevant clotting factor, considerable thought is being given to reducing the risks. Attention has focused on three practices: the risks of collecting plasma from paid as opposed to volunteer donors; the optimum size of the plasma pool; and attempts at removing the several viruses of hepatitis from blood products.

The risks of viral contamination are certainly increased if plasma is obtained by plasmapheresis of paid donors. True, the sensitivity of testing for hepatitis B has been improved so that its incidence in patients given multiple transfusions is about the same from either paid or volunteer sources, but hepatitis B is a relatively minor problem.[224]

21.240 The article went on to identify NANB viruses (at least two) as the main cause of chronic liver disease in patients with haemophilia. In relation to the volunteer/paid donor issue, the editorial provided relevant evidence of a material reduction in risk when a hospital changed from commercial to volunteer blood. In relation to the second factor, there was again relevant evidence. The final paragraph stated:

Thirdly, is it likely that the recipients of multiple transfusions can be immunised, or that the threat of hepatitis can be removed from donated blood entirely? Immunisation against hepatitis B is certainly a possibility, but, in the absence of specific markers for non-A, non-B hepatitis, overall protection against hepatitis appears remote. A more likely possibility is that hepatitis-free blood products will become available ....[225]

21.241 The editorial referred to three recent reports dealing with heat-inactivation, β-propriolactone, and wet-heat treatment processes as more likely to achieve the removal of viral contamination.

21.242 The third and final Annual Report of the three-year retrospective study financed by the DHSS (project no J/S240/78/7) was produced by the Oxford Haemophilia Centre on behalf of the UK Haemophilia Centre Directors for the year 1980-81.[226] The report, written by Dr Craske and dated 24 September 1981, covered a series of cases of Factor VIII and IX related hepatitis in the UK. Haemophilia Centre Directors had reported 283 episodes of hepatitis relating to 253 patients. Of those, 197 episodes were non-B Hepatitis and were therefore thought probably to be non-A, non-B incidents. There were 86 incidents of Hepatitis B. The incidence of Hepatitis B continued to decline as the sensitivity of screening tests for infectious HBV improved. As published, the report was little different in its terms from the report presented to the UKHCDO Hepatitis Working Party at Glasgow on 30 September 1980. The final report stated:

The question of the significance of chronic hepatitis observed by several groups of workers in liver biopsies of patients with chronically elevated transaminases is still unanswered. Current investigations are attempting to relate the results in different groups of patients to their transfusion history, and there is strong evidence that different types of non-A, non-B hepatitis are related to different products .... Most patients in this group are still entirely symptomless. The natural history of the disease in non-haemophiliacs is still not known ....[227]

21.243 The incidence of overt NANB Hepatitis infection associated with US commercial concentrates was 4-20 times higher than that associated with the NHS product. There had been no further deaths directly or indirectly attributable to liver disease in the past year. This report was very significant because it implied that, by 1981, the vast majority of severe and moderately severe haemophilia patients already had NANB Hepatitis. It stated:

The chief finding is that 70-80% of cases of non-A, non-B hepatitis were associated with the first dose of concentrate that the patient received.[228]

21.244 This was subsequently shown to be the case. The corollary was thought at the time to be that:

Most of the patients treated with any batch of concentrate will be immune to non-A, non-B hepatitis, since batches of concentrate of any brand are contaminated with one (or more) serotypes of these agents.[229]

21.245 Dr Craske presented this report at the 12th meeting of the Haemophilia Centre Directors on 9 October 1981.[230] He recommended continued surveillance; a study of sub-clinical hepatitis; collection of data on batch numbers; need for post-mortem liver samples; and hepatitis-free concentrates.

21.246 This report summarised the findings of the survey. Dr Craske had several recommendations to make including:

  • Surveillance should continue.
  • A multi-centre prospective study of hepatitis in first time/seldom treated patients was planned. This group seemed to have a higher risk of contracting NANB Hepatitis whatever type of material was used for their treatment.
  • The working party to continue to collect data on the batch numbers of materials received by patients who developed hepatitis.
  • Some commercial firms had claimed that a hepatitis-free Factor IX concentrate was available. Dr Craske thought this may well be true but there were problems in proving the safety of each batch of concentrate as only a limited number of laboratory animals were available for testing the materials.

21.247 There was some critical comment on Dr Craske's methodology. He had still not overcome the scepticism of some members of the group. Nevertheless, this report shows that enormous progress in understanding the size and nature of the problems of hepatitis in haemophilia patients had occurred in the three years since the initial survey report of 1978.

21.248 Paragraph 6.79 of the Preliminary Report commented:

Throughout this period there was a debate taking place in the medical community. On one side the view was held (mainly by virologists and public health doctors) that haemophilia patients should not be given concentrates because it was not known what viruses were being transmitted to them. The contrary view (mainly held by the Haemophilia Society and haemophilia doctors) was that concentrates should continue to be given because they transformed the lives of haemophilia patients and hepatitis appeared to be a relatively benign condition.

21.249 When Professor Forbes appeared at the Inquiry he was asked whether he thought this summarised the points of view at the time. He replied:

All these papers were highlighting something that we did know and understand, that hepatitis was a problem. How much of a problem we didn't really grasp initially, and it's only as these papers came out - the first was Eric Preston, and I think it was liver biopsy he used, and we were appalled that so many of the patients clearly had liver disease and that was then confirmed by the Mannucci paper and so on. So we were gradually becoming aware that the use of all these blood products was not as benign as we thought it was.


We started to feel anxious about the use of the products that we gave, which were so wonderfully life-changing for the patients, and that's why, of course, the Haemophilia Society didn't want to change anything. They wanted to go on and give as much product as possible. Because it was thought that the hepatitis that clearly was there was a pretty benign disease, not so eventually, but there we are. That was the state of play.[231]

21.250 By 1981, a more cautious use of Factor VIII concentrates made from large plasma pools was beginning to be supported, by haemophilia centre clinicians among others. Professor Mannucci's recommendation of DDAVP has already been noted. A similar point was made in 1981 in a study from the University of Gothenburg, Sweden, reported by Norkrans and colleagues.[232]

21.251 The search for alternative therapeutic materials reflected a degree of growing concern about the use of large-pool factor concentrates. However, there was as yet no change in practice: as the growing use reflected in Figures 1 and 4 indicates, despite the concern about transmission of hepatitis, haemophilia practice throughout the UK continued to depend largely on the use of concentrates.

Choice of products

21.252 As noted at the beginning of this chapter, there were good reasons for the selection of specific products to meet specific needs in some cases. However, the Inquiry was aware of comment that individual haemophilia doctors may have been influenced in their selection of commercial products by factors other than the clinical needs of the patient. The origin of this view, for the most part, appears to have been Douglas Starr's book Blood. It is possible to comment only in relation to practice in Scotland.

21.253 In Blood, the relationship between the commercial companies and treatment providers was described as 'cosy'. Douglas Starr was talking specifically about Germany where almost all of the therapeutic material had been bought from the USA. It cost only a quarter to a third as much as the German-made product. But the suggestion was that this type of relationship appeared to be commonplace throughout the advanced world. Douglas Starr wrote: 'Most of the World Haemophilia Federation's budget was paid for by the fractionation companies, who picked up the tab for its lavish annual meetings ...'.[233]

21.254 Douglas Starr also commented that the National Hemophilia Foundation in the USA received anywhere from 15-25% of its operating budget from the industry as well as special grants for educational projects. He said:

The doctors and the hemophilia organizations argued that the relationship was appropriate and collegial, not coercive. They saw it as a mutual exchange of medicine, money, and information to help their patients get as much clotting factor as they needed at the best prices. Yet patients would later claim that the financial links between the drug companies and the doctors influenced the treatment providers to be complacent about safety.[234]

21.255 When giving evidence to the Inquiry, Professor Forbes was asked whether he was aware of a cosy relationship of the kind described. He replied: 'I have never been at any meetings that were lavish. So I must have missed out on that'.[235] In the UK, a Symposium on Haemophilia held in Glasgow on 19 September 1975 was sponsored by Travenol.[236] When asked about sponsorship of this symposium, Professor Forbes replied that he did not remember the detail but must have been there. He thought that the sponsors would support the travel of some of the speakers and they may even have paid for accommodation, if required.[237]

21.256 The evidence set out at paragraphs 21.301 to 21.306 below, relating to the succession from Dr Willoughby to Dr Hann at Yorkhill shows how, in the exercise of their clinical judgement, haemophilia doctors differed in the selection of therapeutic products. Individual clinicians had their preferences, and, objectively, some preferences may have been based on grounds of varying substance.

21.257 There was, however, no evidence before the Inquiry that would support a finding that Scottish practitioners were influenced in their choice of therapeutic products by benefits provided by pharmaceutical companies in the way hinted at by Starr.

21.258 The DoH scheme for England and Wales provided for the distribution of NHS products to regions pro rata to the contributions of plasma made for fractionation. At all material times, NHS output was insufficient to meet total demand. The unmet balance of demand was provided by commercial purchases funded by regional health authorities. That allowed for variations within regions. The arrangements for procuring therapeutic products in England, and particularly in London and the south east of England, including Canterbury and Thanet, were described by Dr Winter. In some respects, they were very different from arrangements in Scotland. Dr Winter said that individual Haemophilia Directors exercised autonomy in the selection of therapeutic products.[238] It was for the individual to form a view of NHS and commercial concentrates. They would ascertain how much NHS product was likely to be available for the year, and then enter into negotiations, along with procurement colleagues, with a commercial company for purchase of the concentrate of their choosing.[239] In London and the south east, the position was different. Two major centres, St Thomas' Hospital and Kent and Canterbury, had budgets for commercial purchases while others, perhaps 15 small centres, had little or none. It was agreed to allocate NHS material preferentially to them. As a result, Dr Winter used a relatively small proportion of NHS concentrates in his practice.[240]

21.259 Dr Winter's evidence indicates that national government policy on distribution of available NHS concentrates might have, at best, an indirect bearing on clinical practice and the risks to which patients were exposed. It also indicates clearly that haemophilia clinicians were closely involved in decisions about the procurement and use of commercial products.

Edinburgh and south east Scotland

21.260 UKHCDO data on therapeutic products used in managing patients with Haemophilia A in Edinburgh and south east Scotland are summarised in Table 21.3 in the Appendix to this chapter, and shown graphically in Figure 21.8. In the Figure, cryoprecipitate and fresh frozen plasma quantities have been aggregated. DDAVP values have been omitted since they are insignificant in quantity. The picture that emerges is for the period from 1969-91. It provides a quantified historical account as background to the written and oral evidence available to the Inquiry.

Figure 21.8: Edinburgh Haemophilia A Therapy in Million International Units (Miu) - 1969-91

Figure 21.8: Edinburgh Haemophilia A Therapy in Million International Units (Miu) - 1969-91

21.261 When Dr Davies was in charge, up until 1980, locally produced cryoprecipitate and PFC's concentrates were preferred in the region. As Figure 21.8 demonstrates, Dr Davies clearly made extensive use of cryoprecipitate. He also made not insignificant use of PFC concentrates but took the precautionary view that cryoprecipitate involved fewer donors and was less likely to transmit infections known and unknown. Edinburgh used almost no commercial product under Dr Davies' stewardship.[241] Until 1975, the PFC concentrates were small pool AHF Cohn Fraction I concentrates and for the last three or four years of Dr Davies' period, PFC concentrates made from relatively large pools. Dr Davies used 500 units of commercial Factor VIII in 1974, a unique departure from his general practice, and otherwise prescribed SNBTS products. Professor Ludlam told the Inquiry that Dr Davies had a cautious attitude towards the use of imported commercial Factor VIII concentrate policy. He did not use commercial concentrates because of the uncertainty about hepatitis viruses, in part because he considered the domestic product to be generally safer than concentrates derived from plasma collected in the USA and elsewhere, and in part because he did not want to expose his patients to viruses that might be novel to the local community.[242]

21.262 Professor Ludlam said that he had tried to follow Dr Davies' policies when he came to Edinburgh in 1980. However, he was interested in introducing home treatment, and was not enthusiastic about home treatment with cryoprecipitate, as discussed earlier at paragraphs 21.101 to 21.106.

21.263 However, in the early 1980s demand for home treatment put pressure on the available supplies of PFC Factor VIII concentrate, and Professor Ludlam said that during 1981 and 1982 a small amount of commercial concentrate was purchased to treat a small number of patients with specific haemostatic therapeutic difficulties, or, in one case, to provide home treatment to one of two patients who lived at some distance. The other was on home treatment for other reasons.[243] In 1980, Professor Ludlam had six patients on home therapy out of 187 registered with his centre. Five per cent of the product used was commercial.[244] By 1983, when Professor Ludlam had transferred most of his patients to concentrates, he had managed to maintain most of them on Scottish product.

21.264 Following Professor Ludlam's appointment, there was a significant increase in the use of therapeutic materials generally, met in part by commercial purchases. As compared with Dr Davies' practice, use of cryoprecipitate, initially at a peak in 1980, began to fall, reaching a low point in 1987 before rising again in 1989 when there was a major readjustment of the balance between SNBTS and commercial products, and, within the SNBTS range, between cryoprecipitate and PFC Factor VIII. There was an immediate and significant increase in demand for concentrates in 1980 and following years. The shortages of PFC Factor VIII at the beginning of the 1980s described by Dr Foster were reflected in an increase in commercial purchases.

21.265 So far as commercial products are concerned, use began in 1980 and grew in 1981 as Professor Ludlam's approach to therapy took effect, and then fell until 1988 when there began a significant and sustained increase. There was also a change in the commercial products used after the initial unsettled period, when Factorate was used to make good the limitations in NHS production. From 1982 until 1987 the main products from commercial sources contributing to the total were FEIBA and porcine Factor VIII. From 1988 a wider range of Factor VIII products were purchased including Monoclate, Profilate, Octapharma Factor VIII and Hemofil-M in addition to FEIBA and porcine Factor VIII.

21.266 Professor Ludlam said that for patients with severe Haemophilia A there were two treatment options: cryoprecipitate and NHS Factor VIII concentrate. Patients were very keen to get onto Factor VIII concentrate and home treatment. Initially, concentrate was in 'desperately short supply'.[245] At that stage he had to delay introducing patients to home treatment because of the lack of NHS concentrates and patients were unhappy about it.[246] A large-scale effort had gone into scaling back cryoprecipitate production and scaling up the manufacture of concentrate to enable patients to be treated at home.[247] Over the period, the SNBTS succeeded in increasing production and meeting demand for Factor VIII concentrate, with commercial purchases reducing as a result until 1988.

21.267 The graph in Figure 21.8 suggests a more complex picture. The initial surge in use in 1980 to meet Professor Ludlam's new approach to therapy clearly stretched the PFC's capacity. The reduction in use of cryoprecipitate in 1981 was balanced by increasing supplies of the PFC Factor VIII in and after 1982. Dr Foster's evidence indicated that the switch to commercial products in 1980 and 1981 was driven by the need to make good, shortages in the domestic product in order to meet Professor Ludlam's requirements. The first year or two of the 1980s saw a radical change in clinical policy.

21.268 Overall, the data tabulated for Edinburgh reflect broadly the balance Professor Ludlam was aiming for, though the proportions differ. About 9% of Edinburgh's Factor VIII supplies in 1980 were commercial. That rose to over 34% in the following year before falling back to about 8% by 1983. Commercial purchases were significant as Professor Ludlam introduced home therapy, but fell rapidly at the same time as the risk of AIDS was becoming more firmly associated with a transmissible agent or, on his analysis, progressive immune compromise caused by reaction to antigen overload.

21.269 Over the same period, from the 1970s to the mid-1980s, therapy for Haemophilia B had progressed from treatment with fresh frozen plasma to Factor IX concentrate, which itself developed over time from a combination product, including several factors, to a concentrate composed of Factor IX alone.[248] Professor Ludlam was able to use Scottish products for most patients.

21.270 So long as the PFC supplies continued to meet the demand for concentrates among Professor Ludlam's patients, the position in Edinburgh and south east Scotland, as presented by Professor Ludlam, was close to the ideal. Products produced locally from blood donated in Scotland were used more or less exclusively in haemophilia therapy. The Council of Europe Committee of Ministers 'Recommendation No R(80) of 30 April 1980: Concerning Blood Products for the Treatment of Haemophiliacs', stated that Member States should pursue the goal of self-sufficiency in antihaemophilia products and blood plasma for their preparation. The Recommendation acknowledged the fact that both the geographical origin and type of donor population had a significant effect on the risks of infectious diseases.[249] Professor Ludlam's arrangements would have satisfied that recommendation if his area of operation had been a state.

21.271 Dr McClelland joined the service in Dr Davies' period. He said of his early experience:

As a first year junior house officer in 1969, I was privileged to work for the late Dr Howard Davies, an Edinburgh Royal Infirmary consultant physician who cared for patients with haemophilia. Dr Davies was a strong proponent of cryoprecipitate rather than factor VIII concentrate. I remember clearly that his rationale for this struck me as being eminently sensible. It was that by avoiding the use of products made from the blood of thousands of donors, especially those from other corners of the world, one was almost bound to reduce the risks of passing on infections, known or unknown, to the patients.[250]

21.272 The observation does not quite fit the pattern of use demonstrated in the graph at Figure 21.8, though the contrast was with concentrates prepared from 'thousands' of donations, the position in commercial production rather than at the PFC. Subject to that, Dr McClelland's comments reflect the picture in Figure 21.8.

21.273 Dr McClelland commented specifically on Dr Davies' preference for local products, rather than imported products, as a way of minimising infection. He told the Inquiry:

[I] think his view was as a sort of matter of fairly elementary biology: the more, as it were, different donors' blood samples contributed to the dose that one received as a patient, arithmetically the risk of getting something nasty was increased, and the further afield the blood came from, there was a certainly incalculable but reasonable grounds to expect that something new and different and unfamiliar to the indigenous population might be in that blood.[251]

21.274 As described by Dr McClelland, the reasoning was not complicated, but it explained clearly the pattern of use of materials in Edinburgh during Dr Davies' period. Professor Ludlam was prepared to use commercial products, in particular Armour's Factorate Factor VIII, which was not heat-treated to any extent until 1984.[252] There is no basis in evidence, however, to doubt that the early use of Factorate was a response to shortage of the SNBTS product rather than a matter of choice.

21.275 Apart from putting pressure on the SNBTS by changing clinical practice, the Edinburgh Centre took steps to protect individual patients when they were away from home. A national system in use since the 1970s provided every patient diagnosed with haemophilia with a card stating what their condition was, the level of severity, which haemophilia centre they were registered with and where to phone in an emergency. Professor Ludlam said:

Patients were individually told to request either cryoprecipitate or an NHS concentrate and to avoid a commercial concentrate if possible. To emphasise the importance of this each patient was supplied with a small statement to this effect, which was placed in their haemophilia card, which they could then show to get treatment at another Centre.[253]

21.276 This step was initiated because patients might travel to England and if they required treatment there was a possibility they might get an injection of commercial concentrate.[254] It gave added emphasis to the continuing preference for NHS products, where possible, after Professor Ludlam took over from Dr Davies in 1980. Professor Ludlam had a research interest in monitoring a group of his patients treated solely with NHS product. The card system supported monitoring.[255] But there is no reason to treat this as other than an incidental aspect of treatment policy.

21.277 Dr Boulton took up his post in Edinburgh in 1980. In his oral evidence, he talked about the different forms of therapy available for the patients at that time, comparing perceptions of the SNBTS product then and later:

[A]s time went by, I did become aware of views that there were problems with fractionated product, even from NHS volunteer donors. But I think it was not unreasonable for the newer generation to advocate an increase in usage of Factor VIII.

The problem was that if one were to restrict the use to what, at that time, was felt on good grounds but not on established grounds, to be a safer product, ie a cryoprecipitate that was more difficult to use, less potent, the patients would not have so much protection from joint damage, whereas one would be able, with higher doses of smaller volume infusion lyophilised from the freeze-dried fractionated product, be able to embark on a programme of prophylactics for preventing the damage to joints, particularly in boys as they were approaching their teens.[256]

21.278 The dilemma for clinicians could only be resolved by the exercise of judgement. Dr Boulton pointed out that Professor Ludlam was anxious to increase the use of Factor VIII for the haemophilic patients, particularly the young ones.[257] In Dr Boulton's view, Professor Ludlam was right to move away from cryoprecipitate treatment and towards the use of more Factor VIII for treatment of haemophilia patients. At that time they had no inkling of HIV/AIDS but did of course know about hepatitis.

21.279 Dr Boulton and his colleagues thought that the process of blood donor selection and testing and ever better hepatitis screenings would result in a quality of plasma sent for fractionation that would be as risk-free as possible.[258] He considered the PFC product to be as good a quality product as could be obtained anywhere in the world and on a par with commercial firms. But the commercial firms developed a very good marketing strategy. The packaging, the literature with attractive pictures etc were of a standard way beyond the budget of the PFC.

21.280 The change of practice in Edinburgh, including the use of commercial products during the early part of Professor Ludlam's tenure, reflected the state of knowledge at the time. No single factor explains the whole picture, however. There were specific cases where commercial product was preferable for the particular patient. Some patients did not tolerate the PFC intermediate concentrate, for example, and for them a commercial alternative was prescribed. That apart, Professor Ludlam promoted home treatment to a greater extent than Dr Davies and that explains his resort to commercial concentrates in 1980 and the next few years.[259] The PFC had to gear up production to meet increasing demand generated by changes in treatment policy, increasingly towards home treatment.

21.281 But the picture is complicated by other factors. By the end of the 1970s there were growing and widespread concerns about the use of concentrates related to risk of transmission of NANB Hepatitis. However, there was no evidence of a shift to cryoprecipitate at that stage. Later, in 1982-83, some clinicians in the USA, in particular Dr Oscar Ratnoff, attempted to move patients back to cryoprecipitate, but this was resisted by patients who wished to continue taking concentrates.[260] Figure 21.8 shows use of cryoprecipitate increasing in 1979, peaking in 1980 and then beginning to fall, but on Professor Ludlam's evidence this could not be said to relate to a policy decision relating to transmission risk. He told the Inquiry that he did consider switching his patients from factor concentrates to cryoprecipitate in 1982-83 (as happened in some parts of England and Wales). He discussed the possibility with his colleagues in the SNBTS and they did not look at all favourably upon being able to achieve it within the timescale. He thought the possibility was discussed informally with Dr McClelland and Dr Boulton. He said that all three had offices close together and used to talk about these sorts of things. It may also have been discussed in a more formal context but he could not recall this happening.[261]

21.282 The wider picture at the time was of increasing emphasis on scaling up concentrate production at the PFC, not least to meet Professor Ludlam's requirements. The SNBTS was putting all its effort into improving the PFC's plant for concentrate production.[262] The logistics of making the switch to cryoprecipitate would have been huge, and, in treatment terms, it seemed a retrograde step.[263] A large effort had gone into scaling up the manufacture of factor concentrates, which enabled patients to be treated at home.[264] Professor Ludlam would have had enough cryoprecipitate to switch one or two patients back to it but if there was to be a wholesale move back to cryoprecipitate his understanding was that it would have taken some time for the SNBTS to change course in manufacture. It would have required huge changes to the manufacturing practices.[265] It would have taken time to acquire the necessary production equipment, train staff and obtain the required consumables.[266]

21.283 As Figure 21.8 shows, from 1982-87, use of cryoprecipitate decreased, the SNBTS Factor VIII concentrate was the principal product used, and use of commercial products fell to a very small percentage of total Factor VIII usage. Professor Ludlam was asked about alternatives to the standard treatment options for patients with severe Haemophilia A. The alternatives discussed were:

i. No treatment (although this was not an option if the patient was bleeding).

ii. Reducing the amount of factor concentrate (including switching from prophylactic treatment to on-demand treatment).

iii. Treatment with cryoprecipitate.

iv. From 1984 onwards, the use of commercial heat-treated Factor VIII concentrate.

21.284 In Professor Ludlam's view, the first course proposed was not appropriate. He explained that the risks that arose from not treating patients greatly outweighed the risk of transmission of infection, a view generally shared by other haemophilia clinicians. In addition to the practical difficulties already mentioned, switching to cryoprecipitate would not eliminate the risk of transmission of infection entirely.[267]

21.285 The second option raised a more technical issue. In the period 1982-84, Professor Ludlam had studied abnormalities in the immune systems of patients.[268] When he received the results of immune function tests showing reductions in CD4 counts, he considered whether the results were related to the amount of concentrate the patient had received over the past two or three years. He was very quickly able to go back over several years' worth of transfusion records and there seemed to be no correlation between the immune abnormalities, and the amount of factor concentrate the patient had received. There was nothing to suggest that if patients used less concentrate this would result in fewer immune abnormalities.[269]

21.286 Professor Ludlam accepted that it was possible that certain patients might not have seroconverted if the amount of factor concentrate they received had been reduced at an earlier stage. However, the issue was not straightforward. At this period (in the mid-1980s), all treatment at the Edinburgh Haemophilia Centre was on demand, that is in response to the patient suffering a bleed, and usually at home. If patients used less Factor VIII or chose not to treat bleeds as intensively as they might have normally, they might actually require a lot more treatment to settle the bleed. Professor Ludlam explained that bleeds into joints (particularly elbows and knees) can be extremely painful and can last for several days. An untreated knee bleed, for example, will last about a week to 10 days. If not treated from the outset the pain becomes so great that patients may require large amounts of morphine or pethidine. At that point, the patient might opt for treatment and would then require a lot more treatment to settle the bleed than if he had commenced treatment from the beginning. If a bleed was treated very early on then usually a single injection was enough, whereas if the bleed was left to develop over several days, the patient needed an awful lot of treatment and therefore a lot of Factor VIII.[270]

21.287 Professor Ludlam said that occasionally patients presented with recurrent bleeds into a joint (typically where they had received a short course of treatment in response to a bleed and then had re-bled). One possible course of treatment under those circumstances was to treat the patient for two or three months, often every day, to try and keep the factor level up to stop the recurring bleeding.[271] Circumstances varied. Professor Ludlam's evidence was that he considered carefully all of the treatment options in selecting the appropriate course before deciding what was in his patients' best interests. The second option, of reducing the amount of concentrate infused, did not provide a generally acceptable approach. The third option, increased use of cryoprecipitate, was subject to the limitations on supply already discussed. More generally, on Professor Ludlam's approach it was one of the range of treatment options to be considered on an individual basis.

21.288 So far as use of commercial products is concerned, Figure 21.8 reflects a shift in policy in and after 1988, implicit in the pattern of usage. Views were developing at that time about the ease of use of commercial Factor VIII products because of their high purity; relative to the SNBTS product. Professor Ludlam had also observed immune abnormalities in some of his patients that were not associated with viral infection, but were hypothesised to be associated with protein impurities in the PFC products. Until late 1984 there was confidence in the relative safety of the SNBTS product. Steps taken at the end of that year to inactivate HIV in the PFC's intermediate Factor VIII product proved to be successful. The question whether any products were 'safe' from transmission of NANB Hepatitis/HCV is discussed in other parts of this Report.

21.289 Having regard to the evidence as a whole, there is no basis for a view that Professor Ludlam's general practice was other than as described by him: decisions on therapy were made on an individual basis, with a clear bias towards the use of SNBTS products in most cases, consistently with the policy of his predecessor. Decisions were made on professional grounds. There was no suggestion that he was influenced by any considerations other than his patients' welfare, and there is no basis for inferring that he was. Professor Ludlam's research interests are considered later, in the context of information and advice tendered to patients. However, in the Inquiry's view, these interests did not influence his choice of therapeutic product for the treatment of his patients.

Glasgow and west of Scotland

21.290 When looking at the picture that emerges in Glasgow and the west of Scotland it is important to take account of the division of clinical responsibility between two treatment centres. Until their teens, children received specialist management of their blood coagulation disorders at West of Scotland Children's Comprehensive Care Haemophilia Centre at Yorkhill Hospital. Thereafter they were transferred to the GRI. A patient diagnosed with HCV infection while in adult care might have received the infective agent at either hospital, and under very different clinical regimes.

Royal Hospital for Sick Children, Yorkhill

21.291 Data on Haemophilia A therapy at Yorkhill are summarised in the Appendix to this chapter at Table 21.4, and shown graphically in Figure 21.9. The Figure has been prepared on the same basis as that for Edinburgh and south east Scotland.

Figure 21.9: Glasgow Yorkhill Haemophilia A Therapy in Million International Units (Miu) - 1977-91

Figure 21.9: Glasgow Yorkhill Haemophilia A Therapy in Million International Units (Miu) - 1977-91

21.292 Data are available for Yorkhill from 1977 onwards. The UKHCDO has not reported any use of products up to 1976. Within the period for which data are available, there are variations that reflect changing policy. Cryoprecipitate use varied considerably until 1982, annual quantities ranging from 60 to 41,930 units without discernible pattern. Use of commercial products, already administered in 1977, rose steeply to 1981, fell back in 1982, and from 1983 dwindled to almost zero. 31,000 units of FEIBA were used, exceptionally, in 1991, but made no impression on Figure 21.9 in light of the high value for NHS products. The spike in 1988 reflects an exceptionally heavy use of NHS Factor VIII concentrates, probably related to one or two unusual clinical events creating exceptional demand. There was no evidence that it reflected a change of policy.[272]

21.293 Dr Willoughby, who was a haematologist at Yorkhill until the end of 1982, provided the Inquiry with two written statements.[273] He explained that commercial Factor VIII was used in order to make home therapy as easy as possible for the parents of his young patients. He wrote:

It was much easier to reconstitute with its diluent, taking only a few minutes of gentle handling, as I remember it. The volume for a normal dose could be comfortably drawn up into a 10 or 30ml syringe, which could then be easily attached to a slender scalp-vein IV needle for injection (rather than a drip-stand etc.).

Commercial factor products were typically supplied boxed with all the necessary components for immediate and easy use. The material was ordered through the hospital pharmacy and was relatively expensive, but it was considered that the advantages justified the expense.

21.294 Dr Willoughby explained in his second statement that his prime concern was to treat haemorrhagic events as expeditiously as possible and home therapy avoided the need to travel, often some distance, to hospital. Dr Willoughby was an advocate of prophylactic therapy (see paragraph 21.113). In his statement he said that the aim of prophylactic home treatment was to prevent serious joint and muscle pathology, and to transform the children's quality of life and that of their families. Cryoprecipitate was unsuitable for home therapy due to the 'slow thawing out process in a 37 degree water bath, drip type infusion and somewhat uncertain dosage'.

21.295 Although the risks of NANB Hepatitis were well known, Dr Willoughby's perception was that all concentrates carried a high risk of transmission, whether NHS or commercial. Pool size was less of a concern than using a product that permitted the establishment of a home therapy programme. Dr Willoughby thought that much more attention was paid to pool size following the discovery of HIV.

21.296 Though scarcely discernible from Figure 21.9, cryoprecipitate was used at Yorkhill, but, both in absolute and relative terms, in very small quantities.

21.297 As already indicated Dr Willoughby was a strong supporter of home therapy and of prophylaxis.[274] However, at Yorkhill, very young (and newly diagnosed) patients were usually managed as hospital-based patients (as opposed to home-therapy-based patients).[275] In general, Dr Willoughby considered that commercial and NHS concentrates had advantages over cryoprecipitate in that they could be stored at 4°C and could be carried by the patient when travelling.[276]

21.298 In his book on paediatric haematology, Dr Willoughby discussed the different products used to treat coagulation deficiencies. He noted that plasma and cryoprecipitate had an advantage over human concentrates in carrying a low risk of transmitting serum hepatitis since each bag was prepared from a single donor, rather than a pool. He noted that commercial Factor VIII and Factor IX concentrates were available as well as similar concentrates being available from many of the UK blood transfusion centres. He commented on the high cost of commercial concentrates. There was nothing to suggest bias in favour of the commercial product.[277]

21.299 At the UKHCDO meeting held in Glasgow on 30 September 1980, Dr Willoughby said that from his experience of working with children it was clear that using Factor VIII concentrates would give the possibility of non-crippled adults.[278] He clearly favoured use of concentrates. According to Professor Hann, in a statement provided to the Inquiry, Dr Willoughby '[H]ad what appeared to be a preference for commercially (as opposed to NHS-produced) products ....'[279]

21.300 That preference is reflected in the data for the early years covered by Figure 21.9. In a discussion with Professor Hann just prior to his departure from Yorkhill, Dr Willoughby said that he was generally disillusioned with the health service throughout the UK and felt he had been let down with regard to supplies.[280] He said that commercial concentrate was a better option as it was available, and enabled doctors to treat patients with very severe or life-threatening bleeding without having to rely on cryoprecipitate which was extremely difficult to use in children. He felt that the Scottish concentrate suffered from being of very low purity, difficult to draw up, with significant wastage, and there were also other problems such as infusion-related reactions.

21.301 Professor Hann became Director of the West of Scotland Children's Comprehensive Care Haemophilia Centre in January 1983, in succession to Dr Willoughby.[281] There was an immediate, and significant, change in treatment policy. So far as recorded, Dr Willoughby had used Travenol Hemofil Factor VIII in 1977 and 1978. Armour Factorate was used in each year from 1977 to 1984, with usage in 1983 falling to 7.6% of the level in 1982, and to just over 1% of the 1982 level in 1984. Professor Hann effectively withdrew commercial concentrates from use on taking up his appointment.

21.302 Professor Hann did not share Dr Willoughby's preference. He explained that the NHS product was cheaper, and that the risk of transmitting viruses was perceived to be smaller because of the better donor pool. But, he added, there were several caveats to that. One of these was the desire not to 'chop and change' products too much because of the small risk of inhibitor development which could be devastating as it made the patient untreatable in that era. For Professor Hann, the prime reason for choosing NHS product was the lower risk of infectivity.[282] However, he considered that, having discussed the issue with Dr Willoughby, his predecessor made the choice for what he regarded as good reasons. His evidence to that effect is accepted. Dr Willoughby justified his position in discussion with Professor Hann, and there is no evidence that undermines his position. Similarly, Professor Hann did not at that time share Dr Willoughby's belief that prophylaxis was the way ahead. When he took over, he shared the scepticism, common at the time, as to the efficacy and practicality of prophylaxis. He now considered that Dr Willoughby was right.[283]

21.303 Professor Hann said that he and Dr Willoughby discussed the question of supplies from the USA, which had been affected by Hepatitis B.[284] Dr Willoughby's view was that the problem of Hepatitis B had largely been overcome. It was also Professor Hann's experience at that time that they were not seeing new cases. Dr Willoughby felt that in the very early 1980s NANB Hepatitis was a minor disorder, and that all products were susceptible to it. The evidence rehearsed in this chapter indicates that there was a body of professional opinion supporting that position. Professor Hann commented that the Royal Free Hospital in London (a major hepatitis centre) also thought NANB Hepatitis was a minor disorder at that time.[285]

21.304 Professor Hann said that he and Dr Willoughby agreed that there needed to be a move within the NHS to self-sufficiency. Professor Hann would have preferred to be able to use NHS concentrate, but it was not possible then to use Scottish product exclusively: there were periods when they had to call in extra commercial products.[286] Whether that was a sustainable position is less easy to determine. When asked whether a clinician could have felt that there was not a reliable enough supply of Factor VIII coming through around 1979-80, Dr Foster of the PFC replied that he did not know how well informed clinicians were about the stock situation. From his own analysis there was not a sustained problem.[287]

21.305 When Professor Hann took over, treatment policy was reassessed, and in some respects took a new direction. Very young and new patients were still treated in hospital. They would be offered cryoprecipitate treatment in the first instance if it was possible logistically to give it to them (that is, if their veins were adequate and they did not have any reactions). As a result there was a sustained but relatively low level use of cryoprecipitate in the period 1983-87, as shown in the Appendix at Table 21.4.

21.306 Professor Hann said that cryoprecipitate treatment may have even been recommended as the first option for his patients in the difficult interim period in 1984 when the HTLV-III virus had been isolated, and some of the patients were found to have antibody to the virus upon testing.[288] When asked whether he would have offered a child who was already receiving Factor VIII concentrate in late 1983 the possibility of ceasing concentrate therapy and returning to cryoprecipitate, he said that he believed that was what they had in fact done at Yorkhill.[289] He was almost certain that in late 1983, when 'people like Peter Jones and others' were suggesting that children could be treated with cryoprecipitate, he did change some patients over to cryoprecipitate and continued others for longer than he would have done previously.[290] Some patients returned to cryoprecipitate treatment in 1984 for a period of time.[291] His oral evidence is supported by the numerical data. However, he stressed that it was not a matter of automatically switching every child over to cryoprecipitate. The decision had to be tailored to each individual patient.[292]

Glasgow Royal Infirmary

21.307 Following the same approach as above, data on Haemophilia A therapy at the GRI are summarised in the Appendix to this chapter at Table 21.5, and shown graphically in Figure 21.10. The Figure has been prepared on the same basis as in the case of Edinburgh and south east Scotland and Yorkhill.

Figure 21.10: Glasgow Royal Infirmary Haemophilia A Therapy in Million International Units (Miu) - 1969-91

Figure 21.10: Glasgow Royal Infirmary Haemophilia A Therapy in Million International Units (Miu) - 1969-91

21.308 There are gaps in the data for 1971, 1972 and 1973, but these do not appear to be material to a general understanding of trends in product selection over the material part of the period covered.

21.309 So far as it is possible to draw inferences about the early years, it appears that cryoprecipitate use peaked in 1975 and then fell progressively until 1982. There followed a slow upward trend until 1985, and thereafter a reduction in use until 1989. No cryoprecipitate was used in 1990 and 1991. Use of SNBTS Factor VIII concentrates began in 1975, more or less coinciding with the commissioning of the PFC at Liberton, and thereafter increased progressively until 1988. In the final three years of the period use fell and commercial products became a more significant factor. In this last respect there is a close parallel with Edinburgh and south east Scotland. Purity had become an issue and the commercial product had an added attraction.

21.310 In contrast to Edinburgh and south east Scotland, the data show measurable usage of commercial products before 1980, reaching a peak of just over 28% of Factor VIII concentrate use in 1979. Between then and 1987 there is no discernible pattern in the use of commercial products, either in absolute terms or in relation to total concentrate use.

21.311 The commercial products used varied. Human Factor VIII plasma products in the period to 1980 included Kryobulin, Hemofil, Profilate, Factorate and Humanate. Koate entered the picture in 1981 and 1982. Otherwise, from 1981 until 1984, Factorate, Humanate, and Hemofil appeared without discernible pattern. From 1985 onwards, Porcine Factor VIII was prescribed. Use of commercial human plasma products began again in 1988, and included Profilate, Kryobulin, Monoclate, and Haemate P. The detailed data in Table 21.5 include limited use of DDAVP in 1978, 1980, 1981 and more consistent use from 1985 to 1991.

21.312 In view of the somewhat confused picture painted by the numerical data, it would have been helpful to have had a clear explanation of policy from the senior consultants in charge of patient care. Professor Forbes started to work with haemophilia patients in the GRI in 1965, initially under Professor Douglas, and then as Haemophilia Director. However, he candidly told the Inquiry that after forty years he found it quite difficult to remember the details of what he thought at any one time and that his memory was 'not as good now as it was all those years ago'.[293] According to his recollection, the policy for treating bleeding, from an early date, was the use of pooled cryoprecipitate. Cryoprecipitate was preferred because, being locally harvested, it carried a lower risk of transmitting hepatitis than 'concentrates which were made with indeterminate but huge numbers of patients' plasma being pooled together'.[294] The policy continued for many years. Patients with mild disease received DDAVP, but with caution because of its long-term side-effects.

21.313 Professor Forbes' evidence on product choice was that he continued to use cryoprecipitate for both routine treatment in the centre and for distribution to people on home therapy. He said:

[I]n reality, we had to give them what we could and they had to accept that that was what was available. They had to be pretty intelligent to use it correctly and effectively and make it up themselves, and I think that that was a limiting factor.[295]

21.314 Professor Forbes had reservations about the use of DDAVP.[296] It caused changes in blood pressure and fluid retention.[297] For patients at the GRI, he had made efforts to provide cryoprecipitate from small pools for mildly affected patients and those on home therapy.[298] However, he repeated that cryoprecipitate was used because it was available from the SNBTS. But, there was concern about the efficacy and safety of concentrates made in Scotland and so the preference was still for cryoprecipitate.[299]

21.315 The supply position caused Professor Forbes concern. As described by him, SNBTS's ability to service demand was in stark contrast to the picture painted by Mr Watt and Professor Ronald Girdwood. Professor Forbes thought that any suggestion that Scotland was virtually self-sufficient in Factor VIII was 'cloud-cuckoo land': he did not think Scotland was ever self-sufficient in quality Factor VIII at that time.[300] In his view self-sufficiency meant that:

[A]t the drop of a hat, at any moment of time, if a patient required treatment, you could go to your people and say, 'We need to treat this patient, we need X, Y and Z,' that it would be available ....[301]

21.316 However, it became clear that his requirement related to a combination of volume of supplies and quality. He said of the Factor VIII he wanted:

I mean stuff that you could rely on as to what it said on the bottle was actually in the bottle. So potent, effective therapy was the difficulty because there was such variation. So every time we gave a material, we measured it in the blood of the patient to ensure that there was enough to make them safe for whatever the procedure was. So if they were having major surgery, we would work out the dose required, we would give it and then we would check by a blood test after 20 minutes or so that we had achieved a haemostatic level of the Factor VIII or IX .... [If not] we would give another dose.[302]

21.317 Professor Forbes confirmed that it was not a case of saying: 'The NHS Factor VIII isn't working, we had better get some commercial stuff'. Treatment would be continued with the NHS product.[303] He appeared to accept, subject to his reservations about consistency of Factor VIII efficiency, that there was enough product for routine treatment of patients in 1983. However, there was apprehension that there might be shortages if there had been a major car accident or major trauma, or a bleed into the brain.[304]

21.318 Understandably, given the procurement role of the SNBTS at the GRI, Professor Forbes was not familiar with the supply position for Scotland as a whole. When he was shown Dr Donald Hopkins' letter to Dr Robert Crawford dated 4 December 1984[305] concerning the disposal of surplus SNBTS stock, he said he did not remember Dr Hopkins.[306] He did not know what the overall supply position was in Scotland relative to demand.

21.319 In relation to the period discussed in this chapter, he said that he was not involved in procuring concentrates.[307] His department had no funds, and they 'used what was available'.[308] The system in Glasgow, as he described it, was that when clinicians 'wanted something to give', they had to approach Blood Transfusion, which then ordered it, and then it would depend on what deal they could make with the various companies.[309] The SNBTS had a unit embedded in the GRI, and it was the responsibility of the doctor in charge of that unit to decide whether to acquire commercial materials. Professor Forbes said that he had no idea how decisions on the purchase of commercial material were made.[310] As a clinician, he only knew whether he had commercial or NHS material available when it arrived in the ward and he was about to administer it.[311] On his evidence, if it is accepted as accurate, the SNBTS had, at least, a significant influence on the use of therapeutic materials. The prescribing clinician had no role in product choice. As Professor Forbes himself frankly admitted, it is unlikely that his recollection is completely reliable. In any event, it is reasonably clear from UKHCDO data that use of commercial material in the GRI up to about 1984 involved a wide range of products from different manufacturers, at least consistent with sourcing according to market conditions rather than clinical assessment of the relative qualities of the products and the risks to patients.

21.320 Due to the dimming of recollection with the passage of time, Professor Forbes' evidence cannot be accepted as a comprehensive, or sufficient, explanation of the position. It is clear that following the commissioning of the PFC at Liberton, the most significant therapeutic product prescribed was not cryoprecipitate but SNBTS Factor VIII concentrate. And his evidence does not explain the use of commercial concentrate, nor does it provide an explanation of the recorded use of DDAVP.

21.321 Professor Lowe's evidence reflected more clearly the position in Figure 21.10. He told the Inquiry that factor concentrates had been introduced to the Glasgow Haemophilia Centre and increasingly used from the 1970s. However, there was a small amount of cryoprecipitate prescribed for patients with moderate severity Haemophilia A and von Willebrand's disease throughout the 1980s. This was because of the smaller blood donor pool and hence lower risk of hepatitis and HIV infection. The policy of the Directors at the time, as with many other haemophilia centres, was to keep cryoprecipitate and use it preferentially in patients who less frequently required treatment.[312]

21.322 This policy continued until the UK Haemophilia Centre Directors guidelines on choice of blood products in May 1988 recommended that cryoprecipitate no longer be used for such treatment, unless the haemostatic efficacy of factor concentrates for treatment of von Willebrand's disease was in doubt.[313]

21.323 Professor Lowe's recollection was that from about 1980 the Directors' policy was to treat patients with mild Haemophilia A preferentially with desmopressin (DDAVP), where appropriate and tolerated, or cryoprecipitate. Patients with mild Haemophilia B were treated preferentially with fresh frozen plasma.[314]


21.324 Numerical data for Aberdeen are set out in the Appendix to this chapter at Table 21.6. Graphically, the picture that emerges is shown in Figure 21.11.

Figure 21.11: Aberdeen Haemophilia A Therapy in Million International Units (Miu) - 1969-91

Figure 21.11: Aberdeen Haemophilia A Therapy in Million International Units (Miu) - 1969-91

21.325 The most noticeable feature of Figure 21.11 is the use of FEIBA for patients with inhibitors to Factor VIII concentrate, which provides a clear example of the adaptation of clinical practice to the perceived needs of specific patients. Otherwise, commercial product use was minimal and sporadic. In 1988 a relatively small quantity of Profilate was used, but there was no shift to greater use of commercial products generally such as occurred in Edinburgh and Glasgow. Cryoprecipitate use was inconsistent. It was initially displaced by use of SNBTS Factor VIII in 1976 after the PFC came on stream, but regained ground from then until 1980, after which use fell away until about 1985. For the next three years there was a small increase in cryoprecipitate use, but the PFC Factor VIII remained the dominant product throughout the period from 1981. Leaving aside the specific use of FEIBA, treatment policy at Aberdeen was clearly to use SNBTS products.


21.326 Numerical data for Dundee are set out in the Appendix to this chapter at Table 21.7. Graphically, the picture that emerges is shown in Figure 21.12.

Figure 21.12: Dundee Haemophilia A Therapy in Million International Units (Miu) - 1969-91

Figure 21.12: Dundee Haemophilia A Therapy in Million International Units (Miu) - 1969-91

21.327 Two small quantities of commercial material were purchased in 1982 (Porcine Factor VIII) and 1988 (Profilate). The 1988 transaction was a close parallel to Aberdeen's use of commercial human plasma Factor VIII in that year. A very small quantity of the BPL 8Y was used in 1991. Otherwise, treatment policy was consistently to use SNBTS products, predominantly Factor VIII concentrate after the PFC came on stream.


21.328 Numerical data for Inverness are set out in the Appendix to this chapter at Table 21.8. Graphically, the picture that emerges is shown in Figure 21.13.

Figure 21.13: Inverness Haemophilia A Therapy in Million International Units (Miu) - 1969-91

Figure 21.13: Inverness Haemophilia A Therapy in Million International Units (Miu) - 1969-91

21.329 Inverness used a tiny quantity of Hemofil in 1974. It is irrelevant to the pattern of use in the centre. The same comment can be made in relation to DDAVP. Small quantities were used from 1986 to 1991, but do not impact on the picture overall. From the commissioning of the PFC, Inverness used SNBTS Factor VIII almost exclusively.

21.330 In relation to product choice and use, there is a clear distinction between the Glasgow and Edinburgh centres on the one hand and Aberdeen, Dundee and Inverness on the other. Practice in the three smaller centres involved far less use of commercial materials, and perhaps reflected most clearly the implementation of government, and SNBTS, policy that haemophilia treatment should be on a self-sufficient basis using domestic products other than in exceptional cases.

21.331 Since various commercial products have been mentioned, it is perhaps worth noting their relative impacts on the UK market, as illustrated for 1980 and 1981:[315]

International Units
Manufacturer Trade Name 1980 1981
Abbott Profilate 1,649,000 1,909,000
Armour Factorate 16,576,000 14,646,000
Cutter Koate 4,935,000 3,823,000
Hyland Hemofil 5,095,000 *5,554,000
Immuno Kryobulin 5,377,000 7,377,000
Speywood Humanate 615,000 1,561,000
Hyland Interhem 502,000
TOTAL 34,749,000 34,870,000

*Includes Interhem

21.332 Armour's Factorate was the most used product, with Hemofil, Kryobulin and Koate following. Relative to Scottish use, Abbott's Profilate might have been expected to have had a higher profile.

21.333 The Inquiry has not investigated the issue of choice of product in England and Wales. That was not required by the Terms of Reference.


21.334 Turning to the wider issues raised in respect of this period, it is clear that considerable advances had been made in the treatment of haemophilia. Patients' lives had been transformed by the new products which became widely available in the 1970s. In particular, the arrival of concentrates led to an overwhelming improvement in quality of life, especially for those with severe haemophilia.

21.335 Although there was awareness that there were risks associated with concentrates, primarily the risk of contracting hepatitis, the natural history of hepatic disease was not well understood by 1981. As discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985, there remained substantial deficits in knowledge of NANB Hepatitis and its natural history well into 1985. The seventh edition of Professor Sheila Sherlock's book Diseases of the Liver and Biliary System dated October 1985 noted that there was increasing concern 'in some quarters' about the potential seriousness of NANB Hepatitis. As at 1981, both clinicians and the haemophilia population in general considered that the life-enhancing benefits of concentrates far outweighed any perceived risks. As the 1970s progressed, more and more evidence had emerged reinforcing the risk of acquiring hepatitis, but with the exception of a few reported cases of serious illness and a very few fatal cases, hepatitis was not reported to be associated with serious outcomes.

21.336 With the publications of Mannucci et al, and of the proceedings at the World Federation of Hemophilia and the International Society of Blood Transfusion symposium in Helsinki, the dilemma facing clinicians over the use of concentrates became more pronounced. Professor Forbes' evidence that the 'possible downside' of concentrate use was known, but the risk of death from bleeding was greater and drove clinicians to use the products is accepted. It was to the same effect as Dr Craske's views, reported in The Lancet of August 1975, relating to the balance of risk and benefit in the use of Hemofil.

21.337 From the point of view of Dr Craske and his colleagues in public health, reducing risk was a factor examined in their recommendations: use of commercial concentrates should be restricted to life-threatening situations and to major surgery. Until the end of the period of Dr Craske's surveys for the UKHCDO in 1982-83, their reports acknowledged the possibility of a non-B Hepatitis that was not Hepatitis A, but did not attempt to attribute specific risk to NANB Hepatitis, and as a result, Dr Winter noted, the recommendation to reserve commercial concentrates for severely affected haemophiliacs was based on irrelevant reasoning. A more cogent reason would have been that regularly treated patients with severe haemophilia would almost certainly have already acquired NANB Hepatitis, distinguishing them from new and infrequently treated patients. But that had not yet been realised. It was at the very end of this period that an association with NANB Hepatitis was specifically acknowledged. It would not be appropriate to conclude that Dr Craske's views would, or should, have carried particular weight at this point. Rather, they illustrate continuing confusion over the nature of the hepatitis risk that was only gradually being resolved.

21.338 That confusion was apparent in the comments made in the 'World in Action' programme of 8 December 1975. The differences between Dr Maycock and Professor Zuckerman showed that professional opinion in the UK had not resolved a common position on the risks associated with large-pool factor concentrates. The ambition to remove risk by increasing manufacturing capacity in the public sector to self-sufficiency, in retrospect, illustrated the depth of misunderstanding of the risk of NANB Hepatitis transmission. Dr Winter's interpretation of the discussion in the programme is accepted: in retrospect it was about Hepatitis B. Although NANB Hepatitis had been postulated in 1974, it had not made the impact on professional thinking that would begin to be seen in the early 1980s.

21.339 It is not appropriate to accept Dr Winter's evidence that the discussion 'should' have been about NANB Hepatitis in the circumstances, except in the sense that, with the benefit of hindsight, that was the real issue for patients. But it was not known to be the issue at the time. Professor Zuckerman could still talk of 'hepatitis or jaundice' being a particularly interesting infection as if the terms were synonymous. What is clear from the programme is that the clinical dilemma continued to be whether to accept the risk of serious morbidity and mortality associated with bleeding, or accept the risks associated with hepatitis, as they were understood at the time. Dr Winter's observations on the contribution of the patient who was on the point of discontinuing the use of Hemofil when he had a bleed in his elbow and sought immediate relief by using the preparation was eloquent of the problem. There was no settled view from haemophilia experts about the risk of hepatitis: the effects of haemophilia were only too clear to the patient.

21.340 The 1975 programmes would have made an impression on any interested viewer. They clearly did affect the perception of clinicians. Professor Forbes' evidence of the reaction of haemophilia clinicians demonstrated that clearly. But it was the sensational aspect of the television programmes that struck home: the lines of people with alcohol, and other disadvantaged people, queuing to give blood. As Dr Winter noted, that was fundamentally irrelevant. The fact that they took alcohol did not prove their viral status. The technical discussion, for example the difference between Dr Maycock's and Professor Zuckerman's views, would not have added materially to the general understanding among clinicians of the fundamental nature of the problem of transmission of infection.

21.341 Dr Craske's ongoing study of infection following infusion of commercial products is instructive. His report to the UKHCDO on 13 January 1977, comparing NHS and commercial Factor VIII, continued to focus on jaundice. Dr Biggs reported data returned from haemophilia centres on the incidence of jaundice. Professor Stewart's somewhat dismissive comments indicated that, for some haemophilia specialists, the risk of jaundice was something one simply had to live with.

21.342 It was not until the early 1980s that there was a growing realisation that, while the risk of Hepatitis B was declining markedly due to constant improvements in screening blood donors for evidence of Hepatitis B infectivity, there was a new form of hepatitis (NANB Hepatitis). Little was known about the likely progression of this new illness, but by 1981 it was known to be very common among haemophilia patients treated with concentrates. As discussed in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985, it was not until 1984-85 that the natural history of NANB Hepatitis was beginning to be understood to involve a risk of serious long-term progressive liver disease with significant morbidity and mortality.

21.343 Despite these acknowledged risks, there was no desire in the haemophilia community to revert to the pre-concentrate era. While cryoprecipitate was seen as less risky in terms of hepatitis transmission, there were too many disadvantages associated with its use. It was hoped that improved screening methods would lead to the eradication of hepatitis and other impurities in blood products. However, at the end of this period, about 1982-83, an unidentified virus was beginning to emerge that would transform the lives of the haemophilia population once again. This new virus, later identified as HIV, and the link with concentrates (particularly commercial in origin) was to have a devastating impact on the haemophilia population in the 1980s.

21.344 Until that happened, haemophilia therapy continued to depend largely on concentrates, and the demand for the products increased.

21.345 This chapter has touched on the preparation and supply of NHS blood and blood products, but has been concerned mainly with the second of the two relevant Terms of Reference noted at the beginning of the chapter:

8. To investigate the steps taken by those involved in, and those responsible for, the NHS in Scotland including NHS boards and SNBTS, their officers and employees and associated agencies, to prevent the provision of infected blood and blood products.

21.346 There was considerable work done in the 1970s and early 1980s to identify and defer blood donations that were found to be infected with HBV and other viral conditions on routine testing with the best assays available from time to time. This is discussed in Chapter 25, Screening of Donated Blood for Hepatitis B. Steps taken to treat therapeutic products to eliminate or reduce the risk of transmission of viral infection are discussed in Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985. The technology developed and applied was targeted at the pathogens that were either known or postulated, with a degree of confidence, to be likely to be found in components of, and in products produced from, human blood. Nothing was done to prevent the provision of blood and blood products infected with the viruses that are of central importance in this Inquiry: NANB Hepatitis/HCV in the 1970s and early 1980s or, when it emerged, HTLV-III/HIV.

21.347 Incidentally, technology developed to deal with known pathogens came to have significance in relation to identification of materials infected by one or other of these viruses or to inactivation of infection in blood products. However, there was nothing that could have been done to prevent the provision of blood and blood products infected with NANB Hepatitis in the period covered by this chapter. Firstly, and most importantly, there was no possibility of detection of the virus until it (or they) had been identified. Until HCV was partially isolated and characterised in 1988, it was speculated that there might be more than one pathogen causing hepatitis that was neither Hepatitis A nor Hepatitis B. HTLV-III/HIV was not know at all until 1982. Whole blood and the cellular components of blood for transfusion benefited from screening, but could not be treated to activate any virus in the materials.

21.348 Moreover, both before and after the licensing of commercial Factor VIII for general prescription, the choice of therapeutic material was a matter of judgement for individual clinicians in relation to the needs of particular patients. Commercial products were administered in 1972, necessarily on a named patient basis, since they were not then licensed. After they were licensed, from 1983 onwards, clinicians were free to prescribe and use them more generally. Interference with clinical judgement at the point of treatment of the patient would have been considered to be a breach of the clinical autonomy of the practitioner.

21.349 The NHS in Scotland could not have restricted the import and use of commercial products once they were licensed. Licensing was a function of the UK Government. NHS Boards were not in a position to make any contribution in this area.

21.350 From 1974, the operational responsibility for the provision of human blood for transfusion and for the production of blood products had been delegated by the Secretary of State for Scotland to the CSA, subject always to such directions as the Secretary of State might give. As discussed in Chapter 17, Blood and Blood Products Management, the CSA did not exercise operational control over the delivery of the blood transfusion service, and regional and national managers had largely autonomous control of their respective operations. Blood transfusion directors asserted and were allowed a degree of operational autonomy comparable to that of clinicians.

21.351 Scotland was in a particularly favourable position in respect that production capacity was sufficient in general to meet demand for NHS product. In the late 1970s, into early 1980s, demand outstripped supply briefly. But the continuing increase in demand for NHS products over the period was dramatic.

21.352 In this period, all human plasma products, including cryoprecipitate, exposed haemophilia patients to the risk of transmission of NANB Hepatitis/Hepatitis C.

21.353 So far as NHS products are concerned, they were perceived by most practitioners to be preferable to imported products, being prepared from local blood donations, and less likely to transmit infection. Promotion of their use was the obvious policy position to adopt over this period. That they turned out to be infective, though, at least in relation to HCV, less so than imported products, would only have been a basis for intervention if those responsible for the decision had been prepared to prohibit their use, and expose patients to the known risks of morbidity and mortality associated with haemophilia that had existed prior to 1973. That was never likely to happen, and would in any event have been strenuously resisted by patients and patient groups. The inexorable increase in demand over this period shows the commitment of clinicians and patients alike to concentrate therapy.

21.354 Looking to the factors that generated increasing demand for concentrates, home treatment and prophylaxis were clearly contributory factors, especially the first. Home treatment enabled people with haemophilia to lead a more normal life, but exposed patients to a greater amount of product than would have been used in purely reactive therapy. Exposure to commercial concentrate, where there was a lack of NHS product, led to greater exposure to transmission of viruses. The evidence as a whole demonstrated that home treatment was to the overwhelming advantage of the haemophilia population. It enabled the speedy and effective treatment of bleeds by the patients or their families who were trained in recognition of the symptoms of a bleed, and in the administration of therapy. That was preferable to the risks of inappropriate treatment in a hospital accident and emergency department with all the associated problems that involved, as described in the evidence.

21.355 Could the NHS have intervened to prevent the introduction and expansion of home treatment? Again it would have involved an interference with clinical autonomy at the doctor-patient interface. It would not have been acceptable, and given the state of knowledge of the long-term risks associated with factor therapy at this time, it would have been wrong.

21.356 Where prophylaxis was introduced, it might have exposed patients to substantially more product than on-demand treatment. But it prevented spontaneous bleeds, for example cerebral bleeds which used to be the most common cause of death for people with haemophilia, and it reduced joint damage and crippling, resulting in less pain in later life and a better quality of life for the patient.

21.357 In this, as in most areas, it is superficially easy to ask, with the benefit of hindsight, whether all developments should have been held up until research had established that products and procedures were 'safe' in some absolute sense. However, safety is never absolute: it is always relative to some reference point in current knowledge. The manufacturers who promoted the use of early concentrates did not do so in the knowledge that they were 'unsafe'. They were conscious of the risks of 'hepatitis', as the risks were understood from time to time. But those risks were thought to be acceptable given the benefits of therapy. These subjects were discussed, researched and reported. In the final analysis, all concerned; manufacturers, haemophilia clinicians, patients, and the Haemophilia Society, wanted to carry on treatment with concentrate despite the risks rather than reverting to cryoprecipitate, because of the benefits they saw and experienced.


  • There was no evidence before the Inquiry that would support a finding that Scottish practitioners were influenced in their choice of therapeutic products by benefits provided by pharmaceutical companies.
  • There was considerable work done in the 1970s and early 1980s to identify and defer blood infected with HBV and other viral conditions.
  • Nothing could have been done to prevent the provision of blood and blood products infected with NANB Hepatitis in the 1970s and early 1980s or, when it emerged, HTLV-III/HIV. There was no possibility of detection of either virus until each had been identified (HIV in 1983-84 and HCV in 1988-89).
  • Both before and after the licensing of commercial Factor VIII for general prescription, the choice of therapeutic material was a matter of clinical judgement. Commercial products were administered in 1972, necessarily on a named patient basis, since they were not licensed. After they were licensed, clinicians were free to prescribe and use them more generally. Interference with clinical judgement at the point of treatment of the patient would have been considered to be a breach of the clinical autonomy of the practitioner.
  • The NHS in Scotland could not have restricted the import and use of commercial products once they were licensed. That was a function of the UK Government.
  • There is no criticism that can legitimately be made of practice in relation to the use of factor concentrates over this period. Change was beginning. DDAVP had been recommended for mild haemophilia. Biopsy investigations had indicated a risk of more severe liver damage than had been anticipated. But the general body of medical opinion remained favourable to the continued use of concentrates. It would have been quite unrealistic for the NHS in Scotland to have promoted a different approach by the end of 1982.

Appendix to Chapter 21

Table 21.1: Consumption of Factor VIII concentrates, 1970-1990 (Millions of International Units)

All UK[1] Scotland[2] UK excl. Scotland[3]
NHS Commercial Total NHS Commercial Total NHS Commercial Total
1970 0.9 0.0 0.9 0.1 0.0 0.1 0.8 0.0 0.8
1971 3.1 0.0 3.1 0.1 0.0 0.1 3.0 0.0 3.0
1972 1.9 0.7 2.6 0.2 0.0 0.2 1.7 0.7 2.4
1973 2.5 0.8 3.3 0.2 0.0 0.2 2.3 0.8 3.1
1974 2.7 2.7 5.4 0.1 0.1 0.1 2.6 2.6 5.3
1975 3.1 5.1 8.2 0.4 0.1 0.5 2.7 5.0 7.7
1976 6.9 11.1 18.0 1.4 0.2 1.6 5.5 10.9 16.4
1977 12.9 15.0 27.9 1.7 0.3 2.0 11.2 14.7 25.9
1978 14.6 19.3 33.9 1.5 0.2 1.7 13.1 19.1 32.2
1979 15.1 26.2 41.3 1.8 0.8 2.5 13.3 25.4 38.8
1980 14.4 34.7 49.1 3.9 1.0 4.8 10.5 33.7 44.3
1981 22.5 35.5 58.0 3.5 1.2 4.7 19.0 34.3 53.3
1982 22.9 45.6 68.5 4.8 0.5 5.3 18.1 45.1 63.2
1983 30.0 36.2 66.2 5.9 0.4 6.3 24.1 35.8 59.9
1984 40.2 34.0 74.2 6.9 0.1 7.0 33.3 33.9 67.2
1985 23.1 50.9 74.0 5.7 0.4 6.1 17.4 50.5 67.9
1986 31.5 53.7 85.2 6.2 0.2 6.4 25.3 53.5 78.8
1987 26.0 59.2 85.2 8.5 0.1 8.6 17.5 59.1 76.6
1988 41.0 55.0 96.0 12.4 0.9 13.3 28.6 54.1 82.7
1989 65.5 36.5 102.0 7.1 1.2 8.3 58.4 35.3 93.7
1990 85.0 23.0 108.0 7.4 0.7 8.1 77.6 22.3 99.9

Note 1: UK data taken from Table 1 in the SNBTS paper Self-sufficiency and the Supply of Blood Products in Scotland [PEN.013.1125] at 1148. The paper states that the UKHCDO is the source of the data.

Note 2: Scottish data consolidated from Table 1 in the UKHCDO report National Haemophilia Database: Bleeding disorder statistics for the Penrose Inquiry, 2012 [PEN.019.0927] at 0935-55

Note 3: Data for the UK excluding Scotland were calculated by subtracting the Scottish figures from the UK figures.

Table 21.2: Scottish use of Factor VIII replacement products 1969-1991 (International Units)

Year Cryoprecipitate and FFP NHS Factor VIII concentrates Commercial Factor VIII FEIBA
1969 296,417 197,800 - -
1970 348,074 115,810 - -
1971 116,250 131,250 - -
1972 253,476 222,350 - -
1973 428,450 162,408 - -
1974 1,601,797 83,148 54,012 -
1975 1,690,380 412,459 84,250 -
1976 1,267,125 1,432,107 174,774 -
1977 1,294,620 1,731,719 300,244 61,000
1978 1,403,280 1,475,578 224,269 128,500
1979 1,259,670 1,760,837 751,788 135,900
1980 1,538,725 3,867,751 958,441 171,000
1981 941,296 3,488,171 1,224,684 141,000
1982 681,880 4,754,658 541,426 188,000
1983 526,040 5,925,670 389,130 495,000
1984 304,046 6,889,163 138,010 100,000
1985 402,800 5,662,241 426,795 361,335
1986 293,228 6,153,435 207,390 489,600
1987 264,977 8,479,160 111,095 902,000
1988 202,549 12,442,246 868,665 424,650
1989 259,408 7,054,175 1,204,060 484,000
1990 11,184 7,429,473 717,093 585,000
1991 3599 7,289,270 461,731 529,000

Note 1: Data consolidated from Table 1 in the UKHCDO report National Haemophilia Database: Bleeding disorder statistics for the Penrose Inquiry, 2012 [PEN.019.0927] at 0935-55

Table 21.3: Edinburgh Haemophilia A Therapy (International Units)

Year Cryo FFP Cryo + FFP PFC VIII[1] English VIII PFC + Eng VIII Comm FEIBA Comm + FEIBA DDAVP
1969 108,150 108,150 158,200 158,200
1970 6350 121,666 128,016 73,850 73,850
1971 76,800 13,020 89,820 131,250 131,250
1972 179,050 4410 183,460 221,550 221,550
1973 361,250 1120 362,370 162,400 162,400
1974 608,700 608,700 83,070 83,070 500 500
1975 604,380 604,380 111,840 111,840
1976 697,760 697,760 439,344 439,344
1977 640,640 640,640 355,976 355,976
1978 647,325 647,325 272,589 272,589
1979 694,190 694,190 201,486 201,486
1980 1,212,470 650 1,213,120 1,644,750 1,644,750 164,000 164,000
1981 720,160 720,160 840,130 840,130 442,018 442,018
1982 612,000 612,000 1,612,800 1,612,800 7300 110,000 117,300
1983 341,700 341,700 1,756,000 1,756,000 151,000 37,000 188,000
1984 139,000 139,000 2,506,880 2,506,880 127,050 8000 135,050 6
1985 127,680 127,680 1,947,420 1,947,420 45,720 47,000 92,720 1
1986 44,930 6000 50,930 2,073,710 2,073,710 15,840 193,600 209,440 7
1987 42,560 42,560 2,842,810 2,842,810 87,000 87,000 11
1988 54,730 54,730 2,610,300 26,980 2,637,280 299,485 169,650 469,135
1989 157,080 157,080 1,919,650 1,919,650 610,790 353,000 963,790
1990 2,383,690 118,665 2,502,355 345,593 425,000 770,593
1991 2,010,760 131,735 2,142,495 117,165 267,000 384,165

Note 1: Includes 'French' product.

Table 21.4: Glasgow Yorkhill Haemophilia Therapy (International Units)

Year Cryo FFP Cryo + FFP PFC VIII[1] English VIII PFC + Eng VIII Comm FEIBA Comm + FEIBA DDAVP
1977 41,930 460 42,390 99,625 99,625 105,682 105,682
1978 565 565 22,144 22,144 22,809 22,809
1979 60 60 137,465 137,465 354,276 354,276
1980 1305 1305 161,242 161,242 682,732 682,732
1981 29,200 29,200 457,126 457,126 632,497 632,497
1982 7050 7050 516,300 516,300 485,880 485,880
1983 30,500 30,500 1,121,075 1,121,075 36,850 36,850
1984 32,340 32,340 1,035,396 1,035,396 5460 5460
1985 27,930 800 28,730 739,094 739,094
1986 38,780 38,780 600,360 600,360 2720 2720
1987 27,860 900 28,760 922,700 922,700
1988 11,900 2 11,902 5,288,770 5,288,770
1989 15,650 2 15,652 1,498,830 1,498,830 20
1990 7560 3 7563 1,133,610 25,840 1,159,450
1991 10 564 574 1,161,330 27,100 1,188,430 31,000 31,000

Note 1: Includes 'French' product.

Table 21.5: Glasgow Royal Infirmary Haemophilia A Therapy (International Units)

Year Cryo FFP Cryo + FFP PFC VIII1 English VIII PFC + Eng VIII Comm FEIBA Comm + FEIBA DDAVP
1969 101,350 62,500 163,850 25,200 25,200
1970 151,190 20,100 171,290 41,960 41,960
1974 860,000 860,000 53,500 53,500
1975 947,200 202 947,402 288,945 288,945 84,250 84,250
1976 493,555 493,555 576,013 576,013 174,774 174,774
1977 443,350 443,350 913,608 913,608 178,562 61,000 239,652
1978 626,910 626,910 829,609 829,609 196,870 128,500 325,370
1979 395,740 395,740 994,776 994,776 392,652 97,900 490,552 229
1980 147,750 1300 149,050 1,491,349 1,491,349 111,709 144,000 255,709
1981 56,650 6 56,656 1,246,155 1,246,155 150,169 90,000 240,169 348
1982 40,950 40,950 1,978,658 1,978,658 25,496 68,000 93,496 538
1983 136,550 136,550 1,954,490 1,954,490 200,000 187,000 387,000
1984 121,100 4 121,104 2,258,674 2,258,674 5500 69,000 74,500
1985 223,990 8800 232,790 1,891,567 1,891,567 381,075 53,335 434,410 735
1986 175,800 5280 181,080 2,359,155 2,359,155 188,830 261,000 449,830 978
1987 142,439 3080 145,519 3,327,720 3,327,720 111,095 742,000 742,000 745
1988 103,640 1684 105,324 3,256,061 3,256,061 523,180 226,000 749,180 1400
1989 39,800 32,018 71,818 2,474,140 2,474,140 593,270 9000 602,270 1548
1990 1924 1924 2,880,750 40,961 2,921,711 371,500 107,000 478,500 1590
1991 22 22 2,722,085 50,900 2,772,985 344,566 144,000 488,566 1120

Note 1: Includes 'French' product.

Table 21.6: Aberdeen Haemophilia A Therapy (International Units)

Year Cryo FFP Cryo + FFP PFC VIII[1] English VIII PFC + Eng VIII Comm FEIBA Comm + FEIBA DDAVP
1969 4657 10,240 14,897 14,200 14,200
1970 32,293 6600 38,893
1971 15,540 2 15,542
1972 50,750 9800 60,550 800 800
1973 63,490 800 64,290
1974 71,890 1820 73,710
1975 134,750 1250 136,000
1976 55,230 55,230 121,800 121,800
1977 89,600 89,600 92,660 92,660 16,000 16,000
1978 81,040 81,040 99,546 99,546 4590 4590
1979 133,840 133,840 129,540 129,540 4860 38,000 42,860
1980 140,130 140,130 111,050 111,050 27,000 27,000
1981 86,480 86,480 185,320 185,320 51,000 51,000
1982 20,510 20,510 298,180 298,180 10,000 10,000
1983 10,710 10,710 356,085 356,085 1280 271,000 272,280
1984 9030 12 9042 347,223 347,223 23,000 23,000
1985 10,300 3300 13,600 378,920 378,920 261,000 261,000
1986 17,080 8 17,088 286,760 286,760 35,000 35,000
1987 42,210 8 42,218 459,600 459,600 73,000 73,000
1988 30,590 3 30,593 371,600 371,600 25,300 29,000 54,300
1989 14,840 18 14,858 400,130 400,130 122,000 122,000
1990 1680 17 1697 353,120 353,120 53,000 53,000
1991 2030 13 2043 434,280 434,280 87,000 87,000

Note 1: Includes 'French' product.

Table 21.7: Dundee Haemophilia Therapy (International Units)

1969 3700 1000 4700 200 200
1970 2385 2300 4685
1971 114 4 118
1972 263 8 271
1973 551 22 573
1974 50,400 7600 58,000
1975 1086 38 1124 200
1976 9860 9860 112,000 112,000
1977 78,640 78,640 89,800 89,800
1978 47,440 47,440 86,000 86,000
1979 35,840 35,840 146,360 146,360
1980 35,120 35,120 188,940 188,940
1981 48,800 48,800 512,900 512,900
1982 1370 1370 215,000 215,000 22,750 22,750
1983 4240 800 5040 359,040 359,040
1984 2560 2560 403,920 403,920
1985 346,000 346,000
1986 5280 5280 530,000 530,000
1987 5920 5920 556,600 556,600
1988 502,820 502,820 20,700 20,700
1989 462,700 462,700
1990 210,817 210,817
1991 960 960 478,310 9,900 488,210

Table 21.8: Inverness Haemophilia A Therapy (International Units)

1969 4820 4820
1970 5190 5190
1971 10,770 10,770
1972 9195 9195
1973 1217 1217 8 8
1974 1387 1387 78 78 12 12
1975 1474 1474 11,674 11,674
1976 10,720 10,720 182,950 182,950
1977 180,050 180,050
1978 165,690 165,690
1979 151,210 151,210
1980 270,420 270,420
1981 246,540 246,540
1982 133,720 133,720
1983 1540 1540 378,980 378,980
1984 337,070 337,070
1985 359,240 359,240
1986 70 70 303,450 303,450 4
1987 369,730 369,730 24
1988 385,715 385,715 41
1989 298,725 298,725 108
1990 282,020 282,020 56
1991 262,870 262,870 24

Note 1: Includes 'French' product.

1 See Chapter 19, Production of Blood Products - Facilities

2 Foster, 'Plasma Fractionation in Scotland', Blood Letter, Spring 2008; 21-25 [PEN.017.2468]

3 Newman et al, 'Methods for the Production of Clinically Effective Intermediate- and High-Purity Factor VIII Concentrates', British Journal of Haematology, 1971; 21:1 [SGF.001.1913]

4 Professor Ludlam's draft, Expert Report Human Immunodeficiency Virus Infection in Haemophiliacs, 1990 [PEN.015.0385]

5 See Chapter 20, Haemophilia Therapy - The Period up to the Early 1980s, paragraphs 20.21-20.24

6 Self-Sufficiency in Blood Products in England and Wales: a Chronology from 1973 to 1991, Department of Health, 2006 [DHF.003.0931] at 0947

7 Chronology of events with relevance to 'self-sufficiency', Hepatitis C transmission and the establishment of terminal dry heat treatment for UK coagulation factor concentrates, Department of Health [SGH.002.1313]

8 Note of meeting of Expert Group on the Treatment of Haemophilia, 20 March 1973 [SNB.006.7631] at 7633

9 Dr Colvin - Day 2, page 119

10 CMO's letter of 6 March 1973 [DHF.001.2122]

11 Ibid [DHF.001.2122] at 2124

12 Paragraphs 19.26-19.30

13 Note of meeting of Expert Group on the Treatment of Haemophilia, 20 March 1973 [SNB.006.7631]

14 Ibid [SNB.006.7631] at 7633

15 Ibid

16 Chapter 14, Knowledge of Viral Hepatitis 1, paragraph 14.20

17 Ibid paragraph 14.22

18 WHO, World Health Assembly Resolution 28.72 of May 1975: Utilization and Supply of Human Blood & Blood Products [DHF.003.0764]

19 DHSS letter of 24 December 1974 to Regional Administrators [DHF.002.9393]

20 Ibid [DHF.002.9393] at 9394

21 Letter from CMO to English Senior Administrative Medical Officers, 23 October 1973 [SGH.002.9308]

22 Letter from CMO to Scottish Senior Administrative Medical Officers, 6 November 1973 [SGH.002.9306]

23 HC Hansard, Vol 884, cols 392-3, 22 January 1975 [PEN.012.0185]; HC Hansard, Vol 887, cols 262-264, 25 February 1975 [PEN.012.0186]; HC Hansard, Vol 887, cols 144-146, 26 February 1975 [PEN.012.0183]

24 Professor Cash - Day 25, pages 83-85

25 Dr Perry - Day 25, page 5

26 Professor Cash - Day 25, pages 83-85

27 Ibid pages 87-88

28 DHSS letter of 24 December 1974 to Regional Administrators [DHF.002.9393] at 9393-94

29 Note of meeting of Working Party on Products Containing Factor VIII and IX, 21 September 1972 [SNB.007.2128]

30 Minutes of Central Consultative Committee on Blood Transfusion, 15 March 1975 [SNB.010.2011]

31 Ibid [SNB.010.2011] at 2013

32 Letter from CMO to Scottish Senior Administrative Medical Officers, 28 March 1973 [SGH.002.9309]; see paragraph 21.17 for the English letter of 6 March 1973

33 National Haemophilia Database: Bleeding disorder statistics for the Penrose Inquiry, UKHCDO, April 2012 [PEN.019.0927] at 0933-34

34 SNBTS paper, Self-Sufficiency and the Supply of Blood Products in Scotland, February 2011 [PEN.013.1125] at 1158-59

35 Minutes of SNBTS Directors Meeting, 15 October 1974 [SNB.002.4952]

36 Dr Davies' letter of 18 December 1974 to Dr Cash [SNB.007.2254]

37 Interate was the new PFC Factor VIII product.

38 Mr Watt's telex of 23 December 1974 to Dr Cash [SNB.007.2255]

39 Dr Foster - Day 22, pages 129-130

40 SNBTS paper, Self-Sufficiency and the Supply of Blood Products in Scotland, February 2011 [PEN.013.1125]

41 Ibid [PEN.013.1125] at 1184. The expression of production and use data in terms of units per head of population was common at this period. In this table the unit of measurement of available supply is relevant only to the comparison with demand for coagulation therapy, expressed on a consistent basis. The final two columns show the percentage relationship of available SNBTS supplies to average demand, as assessed on a UK basis.

42 SNBTS paper, Self-Sufficiency and the Supply of Blood Products in Scotland, February 2011 [PEN.013.1125] at 1184

43 Dr Foster - Day 22, page 130

44 Dr Boulton's statement on the use of blood product concentrates [PEN.015.0054]

45 Dr Boulton - Day 24, pages 77-79

46 Paragraph 14.53

47 Minutes of Joint Meeting of Haemophilia Centre and Blood Transfusion Directors, 31 January 1974 [SNB.007.2190] at 2194-95

48 Ibid [SNB.007.2190] at 2196-97

49 Minutes of Expert Group on the Treatment of Haemophilia, 11 October 1974 [DHF.002.3161]; 'Optimum Use of Available Factor VIII' [DHF.002.3406]

50 In a hospital setting cryoprecipitate might be stored at minus 70°C: Forbes et al, 'Cryoprecipitate Therapy in Haemophilia', Scottish Medical Journal, 1969; 14/1: 1-9 [LIT.001.4018]. For home therapy, Jones et al, 'Haemophilia A Home Therapy in the United Kingdom 1975-6', British Medical Journal, 3 June 1978, 1447-50 [LIT.001.0258] required only domestic deep-freeze facilities. See also: Jones P. Haemophilia Home Therapy, Pitman Medical 1980, page 78. Other recommendations included minus 18°C. There was no consistency in specifying a maximum temperature for safe storage of cryoprecipitate at this stage.

51 Optimum Use of Available Factor VIII [DHF.002.3406]; and Minutes of Expert Group on the Treatment of Haemophilia, 11 October 1974 [DHF.002.3161]

52 Professor Forbes - Day 17, pages 38-39

53 Professor Ludlam - Day 18, page 65

54 Professor Ludlam's report Edinburgh Haemophilia Treatment Policy [PEN.015.0375] at 0378; and Professor Ludlam - Day 18, pages 42-44

55 Minutes of meeting of SNBTS Directors and Haemophilia Directors, 30 January 1981 [SNB.001.5055] at 5055-56

56 Dr Boulton - Day 24, pages 17-18

57 Ibid page 18

58 Dr Winter - Day 15, pages 79-80

59 Ibid page 80

60 Ibid pages 80-81

61 Peter Jones was then a consultant paediatrician working at the Newcastle Haemophilia Reference Centre, Royal Victoria Infirmary, Newcastle upon Tyne; he was also Chairman of the UKHCDO's working party on Home Therapy. His handbook for haemophilia patients entitled Haemophilia Home Therapy was published in 1980.

62 Jones et al, 'Haemophilia A home therapy in the United Kingdom 1975-6', British Medical Journal, 3 June 1978; 1447-50 [LIT.001.0258]

63 HC Hansard, Vol 884, col 392, 26 February 1975 [PEN.012.0183]

64 Jones et al, 'Haemophilia A home therapy in the United Kingdom 1975-6', British Medical Journal, 3 June 1978; 1447-50 [LIT.001.0258] at 0260

65 Professor Forbes - Day 17, page 57

66 Ibid page 58

67 Jones et al, 'Haemophilia A home therapy in the United Kingdom 1975-6', British Medical Journal, 3 June 1978; 1447-50 [LIT.001.0258] at 0260-61

68 Professor Forbes - Day 17, page 60

69 Dr Brian McClelland - Day 21, page 124; for excerpts from Dr Willoughby's book see [PEN.016.1062]

70 Willoughby, MLN. Paediatric Haematology, 1977, Churchill Livingstone, Edinburgh, London, New York, page 321 [PEN.016.1062] at 1065

71 Ibid [PEN.016.1062] at 1068; Rabiner & Telfer, 'Home Transfusion for patients with haemophilia A', New England Journal of Medicine, 1970; 283:1011

72 Willoughby, MLN. Paediatric Haematology, 1977, Churchill Livingstone, Edinburgh, London, New York [PEN.016.1062] at 1068

73 Professor Forbes - Day 17, pages 37 and 39

74 Minutes of UKHCDO meeting, 13 January 1977 [SNB.001.7117] at 7136-7138

75 Ibid [SNB.001.7117] at 7138-39

76 Ibid at 7139-40

77 Professor Ludlam - Day 18, page 65

78 Ibid page 89; and Professor Ludlam's statement on the use of blood product concentrates [PEN.015.0445] at 0458

79 Dr Boulton - Day 24, page 15

80 Professor Ludlam - Day 18, page 72

81 Ibid pages 32-36

82 Ibid page 35

83 Ibid pages 37-38

84 Professor Ludlam's paper, 'Clinician's perspective on availability and use of clotting factor concentrates for treating haemophilia in Scotland ....' [PEN.019.1003]

85 Professor Ludlam - Day 18, pages 76-77

86 Ibid pages 76-77; see paragraphs 21.261 onwards for an explanation of Dr Davies' policy.

87 Professor Ludlam's report, 'Edinburgh Haemophilia Treatment Policy' [PEN.015.0375] at 0379

88 Jones et al, 'Haemophilia A home therapy in the United Kingdom 1975-6', British Medical Journal, 3 June 1978; 1447-50 [LIT.001.0258]

89 Dr Winter - Day 15, pages 72-75; Prophylaxis, as pioneered by Swedish physicians, is the regular administration of Factor VIII or Factor IX for severely affected patients to prevent spontaneous episodes of bleeding.

90 Willoughby, MLN. Paediatric Haematology, 1977, Churchill Livingstone, Edinburgh, London, New York, page 324 [PEN.016.1062] at 1068

91 Minutes of UKHCDO meeting on 13 January 1977 [SNB.001.7117] at 7125-26

92 Professor Forbes, Day 17, pages 56-57

93 Minutes of UKHCDO meeting on 20-21 November 1979 [LOT.003.5015] at 5033-34

94 Professor Forbes - Day 17, pages 67-68

95 Professor Hann - Day 21, page 28

96 Ibid, pages 32-33

97 Professor Hann was a lecturer in haematology at the Royal Free Hospital from May 1980-December 1982.

98 The early history of developing knowledge of the risk of transmitting hepatitis associated with therapeutic products is discussed in Chapter 14, Knowledge of Viral Hepatitis 1.

99 See, for example, Maycock et al, 'Further Experience with a Concentrate Containing Human Antihaemophilic Factor', British Journal of Haematology, 1963; 9:215 [LIT.001.0063]. The focus was on short-term reactions to treatment, especially jaundice, reflecting a lack of understanding of the natural history of transfusion transmitted hepatitis. Dr Smith suggested that manufacturers of therapeutic products had a distinctive appreciation of the risks of virus transmission: Dr Smith's statement on viral inactivation to 1985 [PEN.012.1551] at 1554

100 Antibodies inhibiting the efficacy of factor therapy.

101 Agenda for meeting of Haemophilia Centre Directors, 5 April 1971, Appendix 1 [DHF.001.1811] at 1812

102 Ibid [DHF.001.1811]

103 The letter [DHF.001.1810] covering the Agenda for the meeting of Haemophilia Centre Directors on 5 April 1971 came from the Oxford centre, where Dr Biggs was then Director. The letter says 'I have prepared a written report...'. The report, [DHF.001.1811] at 1812, contains introductory material almost identical to the 1974 article by Dr Biggs discussed at paragraph 21.139. It therefore seems likely that Dr Biggs was responsible for the report to the 5 April 1971 meeting.

104 Agenda for meeting of Haemophilia Centre Directors, 5 April 1971, Appendix 1 [DHF.001.1811] at 1812

105 Ibid [DHF.001.1811] at 1812

106 Ibid [DHF.001.1811] at 1813

107 Ibid [DHF.001.1811] at 1814

108 Ibid [DHF.001.1811] at 1815

109 Ibid [DHF.001.1811] at 1816

110 Blumberg et al, 'A Serum Antigen (Australia Antigen) in Down's Syndrome, Leukemia, and Hepatitis', Annals of Internal Medicine, 1967; 66:924-931 [PEN.002.0764]

111 Agenda for meeting of Haemophilia Centre Directors, 5 April 1971, Appendix 1 [DHF.001.1811] at 1820

112 Ibid [DHF.001.1811] at 1816

113 In respect of clinically observed hepatitis, largely in patients with jaundice, it was probably correct that the majority of cases were indeed due to Hepatitis B. As was learned much later, a far smaller proportion of patients with NANB Hepatitis/HCV presented with overt jaundice.

114 Some commentators noted long-term sequelae, eg prolonged viraemia: see 'More about Australia Antigen and Hepatitis', The Lancet, 15 August 1970; 347-349 [DHF.002.7334]

115 Agenda for meeting of Haemophilia Centre Directors, 5 April 1971, Appendix 1 [DHF.001.1811] at 1821

116 Ibid [DHF.001.1811] at 1820-21

117 Jones et al, 'Haemophilia A home therapy in the United Kingdom 1975-6', British Medical Journal, 3 June 1978; 1447-50 [LIT.001.0258]

118 Cash, 'Principles of effective and safe transfusion', Proceedings of the Royal Society of Edinburgh, 1972; (B) 71 (Supplement) [PEN.002.0559] at 0563

119 'Viral Hepatitis: Report of a WHO Scientific Group' World Health Organization Technical Report Series, 1975, No. 512 [SGH.002.9746]. See Chapter 14, Knowledge of Viral Hepatitis, paragraphs 14.31-14.42

120 Individuals with persistent evidence of the presence of HBsAg in their blood.

121 'Viral Hepatitis: Report of a WHO Scientific Group', World Health Organization Technical Report Series, 1975, No. 512 [SGH.002.9746] at 9754

122 Ibid [SGH.002.9746] at 9761

123 Douglas AS, 'Plasma coagulation factors', Proceedings of the Royal Society of Edinburgh 1972; (B) 71 (Supplement):65 [PEN.002.0575]

124 See Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.20-14.26

125 Biggs, 'Jaundice and antibodies directed against Factors VIII and IX in patients treated for haemophilia or Christmas Disease in the United Kingdom', British Journal of Haematology, 1974; 26:313 [LIT.001.0099]. See Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.16-14.19

126 Biggs, 'Jaundice and antibodies directed against Factors VIII and IX in patients treated for haemophilia or Christmas Disease in the United Kingdom', British Journal of Haematology, 1974; 26:313 [LIT.001.0099] at 0102

127 Ibid [LIT.001.0099] at 0111

128 This was indeed correct in some patients who lost HBsAG, but retained HBsAB, in their blood. But this distinction was not understood for some years after the date of this paper.

129 Biggs, 'Jaundice and antibodies directed against Factors VIII and IX in patients treated for haemophilia or Christmas Disease in the United Kingdom', British Journal of Haematology, 1974; 26:313 [LIT.001.0099] at 0111

130 See Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.20-14.26

131 Buchholz, 'Blood Transfusion: Merits of Component Therapy', The Journal of Pediatrics, 1974; 84/2:165-172 [LIT.001.0141] at 0145

132 A powerful statement of the balancing of interests and the need to continue use of concentrates was set out in a letter by Kasper and Kipnis in Journal of the American Medical Association, 31 July 1972; 221/5:510 [LIT.001.0098]

133 Feinstone et al, 'Hepatitis A: Detection by Immune Electron Microscopy of a Viruslike Antigen Associated with Acute Illness', Science, 1973; 182:1026 [PEN.010.0110]. See Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.64-14.66

134 Prince et al, 'Long-incubation post-transfusion hepatitis without serological evidence of exposure to Hepatitis-B virus', The Lancet, 1974; 2:241-46 [LIT.001.0363]

135 See Chapter 14, Knowledge of Viral Hepatitis 1, paragraphs 14.65-14.67

136 Mannucci et al, 'Asymptomatic liver disease in haemophiliacs', Journal of Clinical Pathology, 1975; 28:620-624 [LIT.001.0132]. See Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985, paragraphs 15.37-15.39

137 Dr Garrott Allen's letter of 6 January 1975 to Dr Maycock [SGH.004.6061]

138 Mannucci, 'Side effects of antihemophilic concentrates', Scandinavian Journal of Haematology Supplement, 1977; 30:1-5 [LIT.001.0150]

139 Professor Forbes, Day 17, pages 46-47

140 Craske et al, 'An outbreak of hepatitis associated with intravenous injection of factor-VIII concentrate', The Lancet, 2 August 1975; 2:221-223 [LIT.001.0360]

141 Dr Craske's fellow authors were from the Bournemouth Haemophilia Centre.

142 Pyrexia is a fever and urticaria is a skin rash.

143 Craske et al, 'An outbreak of hepatitis associated with intravenous injection of factor-VIII concentrate', The Lancet, 2 August 1975; 2:221-223 [LIT.001.0360] at 0362

144 Ibid [LIT.001.0360] at 0362

145 Dr Winter - Day 15, pages 96-99

146 Dane and Cameron, 'Factor-VIII concentrate and hepatitis', The Lancet, 16 August 1975 [LIT.001.0358]

147 Dr Winter - Day 15, pages 99-100

148 Ibid pages 104-105. Dr Winter was wrong in suggesting that Mannucci and colleagues had done liver biopsy studies by 1975. Mannucci's first liver biopsy study came out in 1978: Mannucci et al, 'A clinicopathological study of liver disease in haemophiliacs', Journal of Clinical Pathology, 1978; 31: 779-783 [LIT.001.1624] at 1627-28

149 Dr Winter - Day 15, pages 107-108

150 For a transcript of the programme see [PEN.013.1400]

151 This would have been a reference to improved screening of donor blood for HBsAg.

152 World in Action transcript [PEN.013.1400] at 1411

153 Ibid [PEN.013.1400] at 1413

154 Ibid

155 John Watt was introduced in the programme as Scientific Director of the Scottish Blood Transfusion Association but at this time he was the Scientific Director of the PFC, Liberton.

156 World in Action transcript [PEN.013.1400] at 1424

157 Ibid [PEN.013.1400] at 1422

158 Ibid [PEN.013.1400] at 1424

159 Dr Winter's statement on the use of blood product concentrates [PEN.015.0292] at 0293

160 World in Action transcript [PEN.013.1400] at 1401

161 Dr Winter's statement on the use of blood product concentrates [PEN.015.0292] at 0293

162 Dr Winter - Day 15, page 85

163 Ibid pages 82-83

164 Ibid pages 86-87

165 World in Action transcript [PEN.013.1400] at 1402

166 Ibid [PEN.013.1400] at 1408

167 Dr Winter - Day 15, pages 91-92

168 World in Action transcript [PEN.013.1400] at 1418

169 Dr Winter - Day 15, pages 92-94

170 World in Action transcript [PEN.013.1400] at 1415

171 Dr Winter - Day 15, pages 94-95

172 Professor Forbes - Day 17, pages 30-31

173 Ibid page 32

174 Cash, 'Commercial and NHS factor VIII concentrates', The Lancet, 24 January 1976; 221 [LIT.001.0245]

175 Professor Cash - Day 25, page 75

176 Ibid pages 75-76

177 Dr Boulton - Day 24, pages 9-11; Dr Boulton took up the post of Consultant and Honorary Lecturer in Haematology and Blood Transfusion, BTS, Edinburgh in 1980; he became Deputy Director in 1982.

178 Dr Boulton - Day 24, pages 10-11

179 Starr, D. Blood, 2002 (2nd edition), Perennial, New York, 258 [LIT.001.2920] at 2928

180 Ibid

181 Kasper et al, 'Recent evolution of clotting factor concentrates for hemophilia A and B', Transfusion, 1993; 33:422-434 [SGH.002.1947]

182 Dr McClelland's statement on the use of blood product concentrates [PEN.015.0307]. See also Dr McClelland - Day 21, pages 88-91

183 Dr McClelland - Day 21, pages 161-162

184 Dr McClelland started working for the BTS in Edinburgh in 1977.

185 Dr McClelland - Day 21, pages 159-160

186 Ibid pages 160-161

187 Minutes of meeting of UK Haemophilia Centre Directors, 13 January 1977 [SNB.001.7117] at 7127; Report [SNB.001.7004]

188 Minutes of meeting of UK Haemophilia Centre Directors, 13 January 1977 [SNB.001.7117] at 7127

189 Ibid [SNB.001.7117] at 7127

190 Ibid [SNB.001.7117] at 7132

191 In the end this plan did not proceed. See Chapter 19, Production of Blood Products - Facilities.

192 Mannucci, 'Side-effects of antihemophilic concentrates', Scandinavian Journal of Haematology, 1977; 30:1-5 [LIT.001.0150]

193 Ibid [LIT.001.0150] at 0151

194 Ibid [LIT.001.0150] at 0153

195 Mannucci et al, '1-Deamino-8-D-Arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrand's disease', The Lancet, 1977; 869-72 [LIT.001.0354]

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

197 See, for example: Gader et al, 'A new vasopressin analogue and fibrinoloysis', The Lancet, 22 December 1973; 1417-18 [SNB.014.2443]; Prowse et al, 'Specificity in the Factor VIII response to vasopressin infusion in man', British Journal of Haematology, 1979; 41:437-447. [SNB.014.2934]

198 Lesesne, 'Liver biopsy in hemophilia A', Annals of Internal Medicine, 1977; 86/6:703-707 [LIT.001.3712]

199 Spero et al, 'Asymptomatic structural liver disease in hemophilia', New England Journal of Medicine, 1978; 298/25 [LIT.001.0177]

200 Mannucci et al, 'A clinicopathological study of liver disease in haemophiliacs', Journal of Clinical Pathology, 1978; 31:779 [LIT.001.1624] at 1629

201 Preston et al, 'Percutaneous liver biopsy and chronic liver disease in haemophiliacs', The Lancet, 16 September 1978; 592-594 [LIT.001.0387]

202 Report of the Haemophilia Centre Directors' Hepatitis Working Party - 1978 [SNB.001.7192]

203 Ibid [SNB.001.7192] at 7197

204 Craske et al, 'Evidence for existence of at least two types of Factor-VIII-associated non-B transfusion hepatitis' The Lancet, 1978; 2:1051-52 [LIT.001.0392]

205 Minutes of meeting, 12 February 1979 [DHF.002.4842]. See Chapter 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985.

206 Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985.

207 Wyke et al, 'Transmission of NANBH to chimpanzees by Factor IX concentrates after fatal complications in patients with chronic liver disease', The Lancet, 10 March 1979; 520-524 [LIT.001.0378]

208 Minutes of 9th meeting of UK Haemophilia Reference Centre Directors, 15 October 1979 [LOT.003.2997]

209 Hepatitis Working Party Report (October 1979) - Appendix 1 [SNB.001.7207]

210 Minutes of UKHCDO meeting on 20-21 November 1979 [LOT.003.5015]

211 Ibid [LOT.003.5015] at pages 5024 and 5032-33

212 Council of Europe Committee of Ministers, 'Recommendation No R(80) 5 of the Committee of Ministers to Member States Concerning Blood Products for the Treatment of Haemophiliacs'. (Adopted by the Committee of Ministers on 30 April 1980 at the 318th meeting of the Ministers' Deputies) [DHF.001.0507]

213 Ibid [DHF.001.0507] at 0509

214 Minutes of UKHCDO meeting, 30 September 1980 [SNB.001.7296]. Substantially the same material was repeated by Dr Craske at an International Symposium held on 1 and 2 October 1980 at the Royal College of Physicians, Glasgow, on Unsolved Problems in Haemophilia [DHF.003.0649]

215 Report of the Haemophilia Centre Directors' Hepatitis Working Party, 1979 [LOT.003.5679] at 5680

216 Ibid [LOT.003.5679] at 5680

217 Ibid [LOT.003.5679] at 5684

218 Minutes of UKHCDO meeting, 30 September 1980 [SNB.001.7296] at 7305

219 Minutes of meeting of SNBTS Directors and Haemophilia Directors, 30 January 1981 [SNB.001.5055] at 5056

220 Professor Cash - Day 25, page 113

221 Minutes of meeting of SNBTS Directors and Haemophilia Directors, 30 January 1981 [SNB.001.5055] at 5057

222 Professor Forbes - Day 17, pages 83-84

223 Note of meeting of Haemophilia and Blood Transfusion Working Group, 4 March 1981 [SNB.001.5064]

224 'Post-transfusion hepatitis', British Medical Journal, 1981; 283/6283: 1-2 [LIT.001.0227]

225 Ibid [LIT.001.0227]

226 Haemophilia Centre Directors' Hepatitis Working Party report for 1980-81 [DHF.001.1711]

227 Ibid [DHF.001.1711]

228 Ibid [DHF.001.1711] at 1712

229 Ibid [DHF.001.1711] at 1712

230 Minutes of meeting of UK Haemophilia Centre Directors, 9 October 1981 [SNB.001.7354] at 7372

231 Professor Forbes - Day 17, pages 63-64

232 Norkrans et al, 'Acute hepatitis non-A, non-B following administration of Factor VIII concentrates', Vox Sanguine, 1981; 41:129-33 [LIT.001.0743]

233 Starr, D. Blood, 2002 (2nd edition), Perennial, New York, page 244 [LIT.001.2901] at 2914

234 Ibid [LIT.001.2901] at 2914

235 Professor Forbes - Day 17, page 48

236 Programme for Symposium on Haemophilia, Royal College of Physicians and Surgeons of Glasgow, 19 September 1975 [SNB.001.6951]

237 Professor Forbes - Day 17, pages 48-49

238 Dr Winter - Day 16, page 78

239 Ibid page 77

240 Ibid pages 78-79

241 Professor Ludlam - Day 18, pages 88-89. See also Professor Ludlam's statement on the use of blood product concentrates [PEN.015.0445] at 0458

242 Professor Ludlam - Day 19, page 125. Professor Ludlam's report Edinburgh Haemophilia Treatment Policy [PEN.015.0375] at 0379

243 Professor Ludlam - Day 18, pages 70-73

244 Ibid pages 88-89. See also Professor Ludlam's statement on the use of blood product concentrates [PEN.015.0445] at 0458

245 Professor Ludlam - Day 35, page 28

246 Ibid page 26

247 Ibid pages 26-27

248 Professor Ludlam - Day 18, pages 46-48

249 Council of Europe Committee of Ministers, 'Recommendation No R(80) 5 of the Committee of Ministers to Member States Concerning Blood Products for the Treatment of Haemophiliacs' (Adopted by the Committee of Ministers on 30 April 1980 at the 318th meeting of the Ministers' Deputies) [DHF.001.0507]

250 Dr McClelland's statement on the use of blood product concentrates [PEN.015.0307]

251 Dr McClelland - Day 21, pages 153-154

252 The commercial products used in Edinburgh from 1988 were heat-treated.

253 Professor Ludlam's report, Edinburgh Haemophilia Treatment Policy [PEN.015.0375] at 0380

254 Professor Ludlam - Day 18, pages 68-69

255 Ibid pages 72-73

256 Dr Boulton - Day 24, page 16

257 Dr Boulton - Day 24, page 18

258 Ibid pages 102-103

259 See paragraphs 21.103-21.110

260 Note of a meeting between Professor Ludlam and the Inquiry Team, 19 April 2011 [PEN.012.0774] at 0775; Professor Ludlam - Day 35, pages 30-31

261 Professor Ludlam - Day 35, pages 29-30

262 Ibid page 28

263 Note of a meeting between Professor Ludlam and the Inquiry Team, 19 April 2011 [PEN.012.0774] at 0775

264 Ibid

265 Ibid

266 Professor Ludlam - Day 39, pages 21-22

267 Professor Ludlam - Day 35, pages 26 and 31

268 See Chapter 11, HIV/AIDS Aetiology, paragraphs 11.65-11.72

269 Professor Ludlam - Day 39, pages 16-17

270 Ibid pages 17-18

271 Ibid pages 19-20

272 The Inquiry contacted clinicians who worked at Yorkhill during the relevant period to see if they could recall the reason for the heavy use of concentrates in 1988. Professor Hann's response [PEN.019.1447], Dr Pettigrew's response [PEN.019.1450], Dr Gibson's response [PEN.019.1452]

273 Dr Willoughby's first statement on the use of blood product concentrates [PEN.019.1265] and Dr Willoughby's second statement on the use of blood product concentrates [PEN.019.1272]

274 Paragraphs 21.95 and 21.113

275 Professor Hann - Day 31, page 27

276 Paragraph 21.96

277 Willoughby, MLN. Paediatric Haematology, Churchill Livingstone, Edinburgh, London, New York, page 321 [PEN.016.1062] at 1065

278 Minutes of UKHCDO meeting, 30 September 1980 [SNB.001.7296] at 7301

279 Professor Hann's further statement on the use of blood product concentrates [PEN.015.0035] at 0037

280 Professor Hann - Day 21, page 28

281 Professor Hann's statement on the use of blood product concentrates [PEN.012.0203]

282 Professor Hann - Day 31, pages 80-82

283 Professor Hann - Day 21, page 28

284 Ibid page 29

285 Ibid page 29

286 Ibid pages 27-30

287 Dr Foster - Day 22, pages 129-130

288 Professor Hann - Day 21, pages 68-69

289 Professor Hann - Day 31, page 25

290 Ibid page 27

291 Professor Hann - Day 21, page 68

292 Professor Hann - Day 31, page 27

293 Professor Forbes' statement on information given to patients [PEN.٠١٢.٠٤١١] at ٠٤١٥

294 Ibid [PEN.٠١٢.٠٤١١] at 0411

295 Professor Forbes - Day 17, page 101

296 Lowe et al, 'DDAVP in Haemophilia', The Lancet, 17 September 1977; 614-615 [PEN.015.0368]

297 Professor Forbes - Day 17, page 114

298 Ibid page 116

299 Ibid page 105

300 Ibid page 113

301 Ibid page 123

302 Ibid pages 131-132

303 Ibid page 132

304 Ibid pages 134-134

305 Dr Hopkins' letter to Dr Crawford [SNB.007.4655]

306 Professor Forbes - Day 17, pages 137-138

307 Ibid page 22

308 Ibid page 23

309 Ibid pages 41-42 and 134

310 Ibid pages 134-135

311 Ibid pages 137

312 Professor Lowe - Day 39, pages 164-165

313 Professor Lowe's statement on information given to patients [PEN.016.1250] at 1251

314 Ibid [PEN.016.1250] at 1252

315 Department of Health table showing quantities of Factor VIII concentrate used in the UK, 1980 and 1981 [DHF.001.4517]

22. Haemophilia Therapy - Use of Blood Products 1985-1987 >