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Chapter 22

Haemophilia Therapy - Use of Blood Products 1985-1987


22.1 This chapter deals primarily with the treatment of patients with Haemophilia A following the introduction in Scotland in December 1984 of heat treatment of blood products.[1] The initial heat treatment protocol for Factor VIII was effective against HIV, but it was suspected, and later confirmed, that concentrates produced by the Protein Fractionation Centre (PFC) in Edinburgh and subjected to heat treatment continued to transmit Hepatitis C (HCV), then known as non-A non-B Hepatitis (NANB Hepatitis). That remained the case until the introduction of Z8, a heat-treated concentrate produced at the PFC and subjected to more rigorous heat treatment than its predecessor, NY. Z8 was issued to patients in Scotland from April 1987.[2]

22.2 Difficult decisions in the treatment of patients with Haemophilia A therefore required to be made during the period 1985-87. For some patients in some situations, blood product therapy for haemophilia was unavoidable. But it was becoming increasingly clear that NANB Hepatitis was a potentially serious disease.[3] By this time, it had become clear that the use of Factor VIII therapy carrying a high risk of transmission of NANB Hepatitis was a decision to be taken only with the greatest care. This was especially so where the patient had never previously been treated with blood products and could, therefore, be assumed to be free from NANB Hepatitis. Virally inactivated Factor IX for the treatment of Haemophilia B patients was introduced in October 1985.[4] The period during which options on treatment presented particular problems for these patients was therefore shorter.

22.3 Correspondence referred to in the Inquiry's Preliminary Report indicated that during the period 1 September 1985 to 30 June 1987 a total of 31 people in Scotland were treated for the first time with a blood product, either Factor VIII or Factor IX according to their index condition.[5] This information was provided for the purposes of a Scottish Executive Health Department (SEHD) Inquiry in 2000. The report of that inquiry stated that fewer than 10 of those people had tested HCV positive, although the status of a small number was unknown.[6] A further letter, dated 17 March 2000 (which was not available when the Preliminary Report was prepared) indicates that 29 patients were first treated between September 1985 and December 1987.[7] The Inquiry is not able to explain the reduction from 31 to 29, over a longer reference period, but it may be that there had been double counting in the earlier figure.[8] As indicated in Chapter 3, Statistics, this was a common problem arising from the registration of patients at more than one centre. Of the 29, six - all Haemophilia A patients - tested positive for HCV. The status of 14 patients (with Haemophilia A or B, von Willebrand's disease, or, in one case a Haemophilia B carrier) was not known. Most patients included in these figures will have been children when treated.[9]

22.4 As referred to in paragraph 22.76, the Inquiry is directly aware of the circumstances of two such individuals. It does not have data for how many people might have been infected in the period December 1984 to September 1985. The SEHD chose September 1985 as the start date for the period of its investigation by reference to the point when the Blood Products Laboratory (BPL) in England was issuing a 'hepatitis safe' product, 8Y. The Inquiry selected December 1984 as the start of the period for its examination of this topic because that was when an 'HIV safe' product was available from the PFC in Edinburgh and the focus thereafter shifted back to the risk of transmitting NANB Hepatitis.[10]

22.5 How treatment decisions were made during the relevant period, and the steps taken by clinicians to avoid the infection of patients with NANB Hepatitis, are matters examined in detail in this chapter.

Hearings of evidence

22.6 When hearings began in March 2011, this topic had not been designated as one to be considered at Oral Hearings of the Inquiry. On 4 May 2011, during the questioning of Professor Ludlam in relation to haemophilia treatment when AIDS was the principal risk of concentrate therapy, it became apparent that there was a gap in the topics insofar as this aspect was concerned.[11] A draft of a proposed additional topic was prepared and circulated amongst the Core Participants. The addition of the topic was formally confirmed by the Chairman of the Inquiry, and it was introduced and evidence was first led on Day 54.

22.7 The topic was expressed as follows:

The use of blood product concentrates in Scotland in the period between the introduction of NHS heat-treated products in 1984 and the supply of NHS products sufficiently treated to inactivate Hepatitis C.[12]

December 1984 guidance for haemophilia clinicians

22.8 The Haemophilia Reference Centre Directors met at the BPL at Elstree on 10 December 1984. The meeting was chaired by Professor Bloom, at that time chairman of the UKHCDO. `Factor VIII Concentrates´ was one of the items discussed. It was agreed that treatment options would vary depending on whether or not the patient was HIV antibody-positive. The minutes record:

It was agreed that HT [heat treated] product should be given to all patients, if freely available, to include those found to be antibody +ve. In the case of antibody -ve patients, it was agreed that from now on, treatment must be with HT material.[13]


It was agreed that priority for NHS HT material would be given to children and past users of NHS material.[14]


The Chairman advised that he would issue guidelines following the meeting. In summary, the first choice would be HT material followed by the judgement of the individual clinician.[15]

22.9 Professor Bloom prepared and sent guidelines, dated 14 December 1984 and entitled Haemophilia Centre Directors Organisation AIDS Advisory Document. The document listed the following options for treatment:

Options in probable decreasing order of safety from AIDS for Haemophilia A

1. Heated U.K. concentrate (note: still NANB hepatitis risk)

2. Single donor cryo. or FFP

3. Heated imported conc. (note: still NANB hepatitis risk)

4. Unheated U.K. conc.

5. Unheated imported conc - almost certain to be contaminated.

Note: Heated concentrates may still transmit hepatitis. Some of the distinctions e.g. between 3 and 4 are debatable and the long-term effects (e.g. immunogenicity) of using heated plasma proteins in this way are unknown....


1. Concentrate is still needed; bleeding is the commonest cause of disability and death.

2. Use DDAVP in mild Haemophilia and vWd[16] if possible.

3. For Haemophilia A needing blood products

(a) "Virgin" Patients those not previously exposed to concentrate, and children use cryo or heated NHS factor VIII (if available).

(b) Severe and Moderate haemophiliacs previously treated with factor VIII use heat treated NHS factor VIII, if available or heat treated US commercial.

4. Haemophilia B

(a) Mild Christmas Fresh frozen plasma if possible (otherwise NHS Factor IX).

(b) "Virgin" Patients and those not previously exposed to concentrate, use fresh frozen plasma (or NHS factor IX concentrate if essential)

(c) Severe and Moderate Christmas Disease previously exposed to factor IX concentrate continue to use NHS factor IX.[17]

22.10 Professor Lowe and Professor Ludlam were asked about this guidance and its application in their respective haemophilia centres in the course of their oral evidence. Professor Ludlam was at the meeting on 10 December, whereas Glasgow was represented at the meeting by Dr Forbes.


22.11 Professor Lowe told the Inquiry that treatment in Glasgow between the end of 1984 and 1986 reflected the guidance. He said:

[Practice in Glasgow was] very much in line with what you see there on the screen. The majority of our patients requiring factor concentrates were severe haemophiliacs. They had been treated for many years with Factor VIII concentrates. That was what they continued to have, and while patients could be told that the heat treatment was thought likely to reduce the risk of HIV, there was no evidence at the time that it would reduce the risk of non-A non-B Hepatitis. Hence, in patients who had not been previously exposed to concentrates, the desirability to try, as I have said, to limit the exposure to non-A non-B Hepatitis by considering the use of alternative products, cryoprecipitate or fresh-frozen plasma, according to individual circumstances.[18]

22.12 He was pressed on what the choice would have been between cryoprecipitate and heated NHS concentrate, given that cryoprecipitate was not treated to inactivate HIV and NHS heated concentrate still carried a risk of NANB Hepatitis. He answered:

As I recall, the majority of our patients had the heated SNBTS Factor VIII concentrate. There were a small number of patients who had not previously received concentrate and for those, if one was particularly concerned about non-A non-B Hepatitis, then cryoprecipitate or FFP, for patients with Factor IX deficiency, might be preferable.[19]

22.13 Professor Lowe said that Dr Forbes' policy had been very much to consider the individual patient. The introduction of screening of blood donations for HIV in October 1985 was an additional factor - cryoprecipitate was thereafter being made from donations which had been screened for HIV, improving its safety as a product. It was a period when the directors had to 'continuously weigh up what was happening'.[20]

22.14 Greater detail was sought from Professor Lowe as to the type of patients who posed particular dilemmas at that time. He felt that the group of patients who would not have been on heated Factor VIII at that time was very small in number and would have been dealt with by Dr Forbes. He struggled to remember individual instances of this dilemma, and it is not possible to be confident that his evidence of discussions reflects only recollection, free from an element of reconstruction after the event. Subject to that, he thought that the sort of conversation which would have taken place with infrequently treated patients who had moderately severe haemophilia would have been along the following lines:

"Well, you know, there is a choice. You can have a product which, while heat-treated, the concentrate, it's coming from thousands of donors and there is no guarantee that you will not get an episode of non-A non-B Hepatitis, which you don't want."

He added:

And particularly after the introduction of HIV testing of blood donors, cryoprecipitate, you know, while it could still have a small risk of HIV, had a very good safety compared to concentrate, a reduced risk of getting hepatitis.[21]

22.15 With von Willebrand's patients, there was an additional reason to prefer cryoprecipitate. If Factor VIII concentrate was used, the deficient von Willebrand Factor was not being replaced. Haemostasis was easier to achieve with cryoprecipitate than with concentrate.

22.16 Professor Lowe was then asked to apply his mind to the sort of choices that had to be made with patients whose haemophilia was mild. He alluded to the involvement in decision-making of the patients themselves: [I]t was very much part of the unit's policy to recognise that there was a risk of hepatitis and to share that with the patients'.[22] For a patient with mild haemophilia, the first choice would be to use desmopressin (DDAVP).[23] He could not remember any patients with mild haemophilia or von Willebrand's disease who had to have a blood product during the 1985-87 period. Even for the patient with mild haemophilia having a bleed, desmopressin was usually effective, because the transient increase in Factor VIII was usually enough to stop the bleed.[24] Sometimes even the physiological response to bleeding, whereby the levels of Factor VIII rise naturally, was enough to deal with the problem in a person with mild haemophilia.[25] But, Professor Lowe explained in later questioning, in a patient with haemophilia desmopressin is generally less effective in response to bleeding which has already started than it is in preventing bleeding.[26] With a joint or muscle bleed, concentrate therapy was 'much more likely' to be required.[27]

22.17 At that time, if a patient with mild haemophilia was having a major bleed, it would been necessary to discuss with him the use of concentrates and the risk of hepatitis. And even if cryoprecipitate were to be used, it would have been necessary to tell the patient that large doses over a period of days would also carry a risk of infection with NANB Hepatitis.[28] An average adult dose would use material from 20 donors.[29]

22.18 Professor Lowe was then asked about the 'steer' which might have been given to such a patient by medical staff. After some deliberation, he answered that if patients had asked what he personally would do in their situation, he would have told them he would opt for treatment with cryoprecipitate from 20 donors who were HIV tested.[30]

22.19 Considering the issue more generally, Professor Lowe agreed that there was a general desire among haemophilia treaters to avoid the use of concentrates at that time. The reasons for that were the awareness that initial heat treatment was not effective against NANB Hepatitis, which was 'more or less inevitable if you got concentrate' and the growing realisation that NANB Hepatitis was not, as had previously been thought, a 'relatively benign disease'.[31] In answer to later questioning, he agreed that the dose likely to be required was also a factor because, if the patient were to be having daily cryoprecipitate for two weeks, the advantages of cryoprecipitate over concentrates would vanish because of the patient's being exposed to several hundred donors.[32] For that reason, there was 'more of an equipoise for a small number of patients between cryoprecipitate and concentrate'.[33]

22.20 As far as Factor IX was concerned, it was decided in Glasgow in April 1985 to use commercial heat-treated product until the NHS heat-treated product became available in the autumn.

22.21 There is no record of the English product, 8Y, being used in Glasgow over the period 1985-1987, and Professor Lowe did not recall any such use.[34] In response to more general questions about knowledge at the time of the development of 8Y, Professor Lowe had no memory of hearing informally about the advances in England,[35] or of anyone proposing that Glasgow could attempt to obtain a small supply of 8Y to treat particular patients.[36] By way of explanation for his unfamiliarity with the then current position in England, Professor Lowe said that, even once he had been appointed as a consultant, Dr Forbes had made it clear that he was running the haemophilia unit and Professor Lowe was his assistant. Professor Lowe was developing services in relation to thrombosis, rather than haemophilia.[37] He was anxious, however, to correct any impression that there was a lack of communication between himself and Dr Forbes.[38]


22.22 Professor Ludlam agreed that in relation to the period under examination, it was fair to say that therapeutic policy was 'guided by a desire to avoid the use of blood products unless there was no alternative'.[39] In his statement to the Inquiry, Professor Ludlam had said:

When [the first heat-treated product] NY 68 degree/2 hour, was introduced in December 1984 ... it was widely acknowledged that it was very likely to transmit non-A non-B hepatitis.[40]

22.23 Later in his statement, Professor Ludlam informed the Inquiry that, during this period:

[I]n the majority of patients, the sole aim was to prevent HIV transmission and this was accomplished by using heat-treated concentrates, even although it was thought likely that they transmitted hepatitis viruses. The policy adopted in Scotland was as set out in the 14th December 1984 UKHCDO Circular by Professor Bloom.[41]

22.24 As far as cryoprecipitate was concerned:

Cryoprecipitate was a non heated product, prepared from individual donors, which could transmit HIV and hepatitis viruses. Once the lifetime patient exposure to cryoprecipitate reached approximately 100 donors (about 5 infusions in an adult) the risk of non-A non-B hepatitis approached 100%.

Until October 1985, donors were not tested for anti-HIV. After this date there was uncertainty about its efficacy to exclude all donations infectious for HIV. This was because there was uncertainty about the sensitivity of the anti-HIV test to detect all antibody positive donations. Furthermore there were potentially donors, recently infected with HIV, who were viraemic, but in whom the anti-HIV antibody had not yet arisen, and whose donation would therefore be infectious but would not be detected by the anti-HIV test. This is the so called 'window period' and can last up to about 6 months after primary infection with HIV. Later techniques were developed to detect HIV in the 'window period', in the absence of antibody, (NAT (nucleic acid testing)) and these are now in current use for screening donations).

During the period 1984-1987, if only a single, or very occasional, treatment with a blood product was required, it could be argued that cryoprecipitate was safer, with respect to non-A non-B hepatitis, than heat-treated NHS concentrate. The disadvantage of cryoprecipitate, however, was that it was not heat-treated and therefore could transmit HIV.[42]

22.25 Thus, treatment policy in Edinburgh during the period under investigation for patients with Haemophilia A or von Willebrand's disease who were probably not infected with NANB Hepatitis was as follows:

  • Children with severe or moderate haemophilia would be treated with cryoprecipitate or heat-treated Factor VIII.
  • For those with mild haemophilia and von Willebrand's disease, the options were: to manage without the use of a blood product; to use DDAVP where possible; to use cryoprecipitate occasionally for treatment of Haemophilia A when only small amounts of treatment were necessary; or to use heat-treated Factor VIII.
  • The heat-treated concentrate used would have been the PFC-issued NY, heat-treated at 68°C for 24 hours, apart from after August 1986, when a small supply of 8Y existed in Scotland and was available for patients not previously exposed to the virus who presented with a major bleed. [43]

22.26 For patients with Haemophilia B, the options were fresh frozen plasma or unheated NHS Factor IX, until October 1985, when product heated at 80°C for 72 hours became available in Scotland.[44]

22.27 In oral evidence, Professor Ludlam agreed that the incidence of NANB Hepatitis from unheated concentrates was understood at that time to be very, very high.[45] Specific information regarding the incidence in haemophilia patients in Edinburgh in 1989, shortly after HCV tests were developed, was available to the Inquiry. This was in the form of a letter sent by Professor Ludlam et al to The Lancet. Sera from 61 patients with Haemophilia A or B or von Willebrand's disease had been tested for antibody to HCV. Of the 48 who had received non-heated concentrates (before 1985), 41 were seropositive by this early anti-HCV test. It was not clear at the time why all 48 were not seropositive. The negative cases may have been or included individuals who had cleared the virus and, over time, had become anti-HCV negative or, given that it was an early test, they may have been HCV positive at the time but not identified by the test. Of the remaining 13, seven had received only heat treated concentrates and all were seronegative. Six who had received only cryoprecipitate or red cells were also negative.[46]

22.28 Professor Ludlam's awareness at that time of the severity of NANB Hepatitis was also explored. First, he was asked about the article entitled 'Progressive liver disease in haemophilia: an understated problem?' by Dr Hay et al in The Lancet of 29 June 1985.[47] The article was familiar to Professor Ludlam and he thought it would have been so at the time of its publication. He considered that the aspect which had not been previously appreciated up to that point was that the disease was progressive.[48]

22.29 Next, Professor Ludlam was shown an article from Blood, published in August 1985, entitled 'A study of liver biopsies and liver disease among hemophiliacs'.[49] The study had involved 155 patients with haemophilia, some of whom had received a lifetime exposure to more than 100,000 units of concentrate. The incidence of cirrhosis found was 15%, with chronic active hepatitis affecting 7%. The article recognised the possibility of insidious progression to cirrhosis. Professor Ludlam remembered noticing it at the time.[50]

22.30 A further letter on this topic (this time from Dr Schimpf) appeared in The Lancet of 8 February 1986, reporting results from the haemophilia centre in Heidelberg. The author agreed with Dr Hay and his colleagues that liver disease in haemophilia was an understated problem.[51] Professor Ludlam described Dr Schimpf as 'a very distinguished haemophilia treater'.[52] He was sure he would have seen the letter.[53]

22.31 In the light of this material, Professor Ludlam offered his view that it was around that period that it 'became clear that it [liver disease in haemophilia] was potentially serious and potentially progressive'.[54]

The London Hospital

22.32 Dr Colvin assisted the Inquiry by giving evidence both in relation to his own practice at the London Hospital, one of four centres in London, over the period examined, and also by endeavouring to put himself in the position of a haemophilia clinician in Scotland.

22.33 In his evidence, Dr Colvin was asked about the role of cryoprecipitate at that time. Initially, he expressed considerable reservations about the therapeutic potential of cryoprecipitate during the period under examination. He was referred to a study, published in Clinical and Laboratory Haematology in 1987, in which he had reported on six patients, not previously exposed to concentrates, who were treated with cryoprecipitate between October 1982 and July 1984.[55] No patient had shown signs of NANB Hepatitis. The report suggested that, following the introduction of screening of donated blood for anti-HIV in October 1985, the use of cryoprecipitate in selected cases should be reconsidered. Notwithstanding these published views, Dr Colvin felt that by the time of publication, 'the world had moved on, and I think by that time we had really given up using cryoprecipitate'.[56] In expressing these views, he highlighted the interval between the study and the date of publication of the article. He considered that the paper revealed the uncertainty of the period, and the range of options which were examined.

22.34 On his second day of giving evidence on this topic, however, Dr Colvin slightly refined his position on the use of cryoprecipitate:

I suspect that by 1986, despite my publication in 1987, I would have thought twice about using cryoprecipitate. But I think it would not have been an unreasonable point to have made, [that the safety of cryoprecipitate had been improved by HIV screening of donors] and the fact that I allowed my paper to be published in 1987 implies that I thought even at that time it was a reasonable approach to the problem. But you would have to take every case on its merits. As I implied in my previous answer, one had to factor such a lot of different issues into the equation before you made a decision, and the decision you made wasn't necessarily the right decision and it was perfectly possible for another physician to make a reasonable different decision.[57]

In other words, therefore, there was a period - a 'brief window'[58] - after the introduction of donor screening for HIV when cryoprecipitate could have been a possible treatment for some patients if one were worried about the safety of the available concentrate.[59]

22.35 On his first appearance on this topic, when asked how he would have treated patients had he been in Scotland during this period, Dr Colvin referred to the possibility of either postponing elective procedures to avoid the use of blood products or using desmopressin.[60] Where treatment was necessary:

[I]t was extremely difficult to know what to do. But I think that for very small usage in adults, where you were going to really have quite a small number of units and then not use any more, for instance for very mild haemophilia, where you couldn't use DDAVP, [cryoprecipitate] was an option. I think that for very small children, where tiny volumes of cryoprecipitate would achieve haemostasis, it was also an option but it was an option with diminishing benefits as the number of units went up.

Q. Yes. And I suppose the other consideration that struck me is that in this period, even with a child who has severe haemophilia, you could reason that a better product might be going to come along, so you are not talking about trying to assess how much cryoprecipitate this child will require for the next ten or 20 years. It might be for quite a short period?

A. That is exactly [what] my reasoning was in carrying on with cryoprecipitate until 8Y became available for the children.[61]

22.36 Dr Colvin referred again to the many uncertainties prevailing during this period. It was really only possible to 'do what seemed a good idea at the time'.[62]

I still feel that any decision made to use 8Y or the Scottish equivalent at that point was based on a kind of informed intuition. I certainly would have liked to have said at the time that I was convinced that one product was better than another. I think we were all extremely relieved when it became apparent that 8Y and the Factor IX equivalent in due course actually were safe. It was a piece of - I was going to say good luck; it wasn't good luck exactly but I think we were all extremely relieved that in retrospect this was the case. But I think there is huge danger of using the retrospectoscope to say that one should have taken the particular view because it later turned out that that was the answer.[63]

22.37 Had he been in Scotland, would he have tried, as Professor Ludlam did, to obtain a supply of the English product?[64] Dr Colvin thought it more likely that his course of action would have been to wait and see in relation to developments in England.[65]

22.38 On the second occasion on which he gave evidence on this topic, Dr Colvin was again asked about what he did during the relevant period and what he would have done had he been practising in Scotland. He replied:

I have suggested that I would have used heat-treated commercial Factor VIII concentrate where essential, especially for more significant bleeding episodes or major surgery, where the use of substantial quantities of concentrate was anticipated. So what we had really was a policy of trying to look after those who had been least treated and trying to look after, really, children. So until the spring/summer of 1985, I was still trying to use cryoprecipitate for the children but I then changed over to 8Y really as soon as it became available, and I think probably around the time of this letter [to haemophilia directors dated 24 July 1985[66]]. As far as adults were concerned, particularly, I am afraid, people who had been given a lot of treatment in the past, or who were due to have major surgery which would require a lot of concentrate to be given, then it was very often the case that we had to consider using commercial heat-treated concentrate because, as I think was made clear around that time, the provision of 8Y was only sufficient for a proportion of the patients under our care.[67]

22.39 For any individual adult patient, who had not previously received concentrates but required treatment, there would be questions as to how much was likely to be used. Dr Colvin would have wanted to avoid using too much 8Y for any one individual. But if only a small amount was going to be used, then it would have been 8Y: 'that was what was available to us and we thought that was the best concentrate to use at the time'.[68] In addition, such a patient was actually a valuable resource as far as new products were concerned, so Dr Colvin would have wanted to try to enter him in a trial if possible.[69]

22.40 In the last part of his testimony, Dr Colvin reminded the Inquiry that:

[I]t wasn't easy to know what the right answer was, and the responsible physicians acting within the spectrum of appropriateness sometimes came to different conclusions.[70]


Emerging information about safety

22.41 As previously noted, there appears to have been no use of the English heat-treated Factor VIII product, 8Y, in Glasgow.[71] But it was used in Edinburgh. It is therefore necessary to consider the background to the use of English product to treat patients in Scotland.

22.42 8Y was treated at 80°C for 72 hours.[72] It was issued routinely for the treatment of patients with haemophilia in England with effect from September 1985. The Inquiry was interested to ascertain when clinicians in Scotland became aware of this product, and what view they took of it.

22.43 In his statement, Professor Ludlam pointed out that:

The viral safety, with respect to transmission of non-A non-B hepatitis, of the BPL product, treated at 80 degrees/72 hours, introduced in England in September 1985 was unknown at that time. It was not until mid 1986 that evidence started to be reported to suggest that it might be a 'hepatitis reduced' concentrate.[73]

22.44 In evidence, he reminded the Inquiry that, although 8Y was of particular benefit to patients who had not previously been treated with concentrates, in that it prevented their being infected with NANB Hepatitis, the priority in England in 1985 was to protect all haemophilia patients from HIV.[74]

22.45 In relation to the view which clinicians had at that time of the safety of 8Y, Professor Ludlam recalled that there was no certainty at all that dry heat treatment to 80˚C would be effective in respect of removing NANB Hepatitis transmission risk, and there was a lot of international scepticism about dry heat treatment at any temperature being effective.[75]

22.46 The contemporaneous material was reviewed with Professor Ludlam in evidence. At PFC on 17 March 1986, a meeting took place between fractionators based in Scotland and England. In paragraph 5 of the minutes of the meeting relating to viral inactivation, it is recorded that:

Dr Smith outlined clinical trial results of the 8Y F VIII product so far. While results cannot be considered conclusive at this stage, he indicated that no cases of virus infection have occurred (attributable to 8Y material) after 12 months' experience of 8Y in virgin haemophiliacs.[76]

Professor Ludlam pointed out certain flaws in this information, but was willing to accept that these might be questions of the weight this information should bear.[77]

22.47 Turning to events in England, Professor Ludlam was shown the minutes of a meeting of the Central Blood Laboratories Authority (CBLA), Central Committee for Research and Development in Blood Transfusion on 9 July 1985.[78] The minutes referred to a trial, then ongoing, in which patients thought to be susceptible to NANB Hepatitis (because they had either never previously had concentrate or had not had it for a long time) were given 8Y. Several of them had already passed the point at which the first evidence of NANB Hepatitis transmission would have been expected. That information is also contained in an information sheet dated 24 July 1985, issued by BPL and distributed to all haemophilia directors and regional transfusion directors in England and Wales.[79] The sheet explains that the product has been heated at 80°C for 72 hours to reduce the risk of viral infection, and that 'further assurance is sought over freedom from risk of viral transmission'.

22.48 In the light of this material, Professor Ludlam was asked if, in 1985, he was hearing 'news from England'. Although he would not have received the information sheet, he told the Inquiry that he was aware the studies were going on, and pointed out the difficulty in recruiting patients for such an exercise. Whilst he found it difficult to recall conversations or other sources of information, he put the date of his knowledge - a 'general feeling' - about 8Y at 1986.[80] He also reiterated that there was 'a lot of scepticism' about how effective dry heat treatments would be.[81]

22.49 He was later asked if Dr McClelland had reported to him 'encouraging' signs regarding the English product that were mentioned at a subsequent meeting of the CBLA Central Committee for Research and Development in Blood Transfusion on 19 December 1985.[82] Professor Ludlam thought not.

22.50 It was also suggested to Professor Ludlam that there was a much more local source of information about 8Y. In January 1986, Dr Perry wrote a report for the regular joint meeting of SNBTS directors and the haemophilia directors.[83] In it, he recorded that the BPL was now issuing their product heated at 80°C for 72 hours and that 'preliminary clinical data' indicated that this material was 'non-infective with respect to HTLV III, NANB and Hepatitis B'.[84] The meeting was held on 5 March 1986; in fact Professor Ludlam sent apologies and, in evidence, he was not clear about whether or not he would have received the background papers.[85]

22.51 At a meeting of Haemophilia Reference Centre Directors on 22 September 1986, Dr Rizza presented the directors with a paper on the study into the effectiveness of the heat treatment of 8Y (and its equivalent for Haemophilia B, 9A).[86] The analysis was restricted to results in those patients who had no previous exposure to concentrates, although some had received cryoprecipitate. Fortnightly measurements had taken place to detect raised liver enzymes and the trial had also involved exposure to multiple batches, to create greater exposure in the patients. None of the patients had recorded an ALT or AST measurement above 2.5 times the upper limit of normal. Dr Smith acknowledged in his report that the data were inconclusive due to some gaps in follow-up, but might nonetheless further encourage haemophilia directors to use 8Y and 9A in previously untreated patients. A statistician had calculated that the number of negative cases found could still be consistent with an infectivity rate of up to 14%; that was plainly better than for unheated concentrates. This pilot study was to be followed by a more formal prospective controlled trial with a stricter protocol.[87]

22.52 As with the information presented at the meeting at PFC,[88] Professor Ludlam pointed out weaknesses in the data. But he agreed that the information was 'reassuring'.[89]

22.53 This report was also reviewed with Dr Colvin. He pointed out that the numbers of patients were very small. Although no infection was found in the patients treated, infection might have been apparent had a larger number of patients been involved. He also pointed out that some of those who were tested could previously have had NANB Hepatitis and cleared the virus, therefore if they had been infected by 8Y, that infection would not have been evident.[90] He was not, however, critical of the use of patients who had had some previous exposure to cryoprecipitate: 'the use of patients who were not truly untreated was a risk worth taking to get the data that one needed to be reasonably confident that a particular product was safe'.[91] There had been false dawns before - heat-treated products had previously been demonstrated to continue to transmit both NANB Hepatitis and HIV, so all those involved were understandably cautious about how safe any new product might actually prove to be.[92] Even as late as 1988, in an article dealing with a number of different studies which had been carried out into treated products, Mannucci and Colombo felt able to say only that Factor VIII concentrates treated at 80°C were 'presumed innocent'.[93]

Supply of 8Y to Edinburgh

22.54 Despite reservations, Professor Ludlam appears to have had about the information emerging in 1985 and 1986 regarding 8Y, he nevertheless took steps to obtain some for patients. On 27 June 1986, Dr Boulton, deputy director of the Edinburgh and South East Scotland Regional Blood Transfusion Service, wrote to Dr Cash about the development of heat-treated products in Scotland. In his letter, he related a conversation he had had with Professor Ludlam about trials of more severely heated product prepared in Scotland. 8Y had been mentioned:

Apparently a few weeks ago he was asking Brian McClelland if VIIIY could be made available in the event of a "virgin" haemophiliac being presented.[94]

22.55 Professor Ludlam thought that the background to this must have been that someone had passed on the latest information about 8Y. It probably then came up in conversation with Dr McClelland that 8Y was a better product than the Scottish heat-treated product insofar as the prevention of NANB Hepatitis was concerned.[95] He was asked why, given the limitations on the information then available about 8Y, he was still interested in obtaining some. For him it was an issue of comparative risk. It was highly likely that all SNBTS concentrate then available, heated at the time at 68°C for 24 hours, would transmit hepatitis. The evidence from the 8Y studies was that it appeared to be less likely to transmit non-A non-B Hepatitis. It was a matter of degree. 8Y would be an improvement on what was currently available in Scotland. It might not be hepatitis-free but it might be less infective.

22.56 Another letter from Dr Boulton dated 27 June 1986 was also examined in evidence with Professor Ludlam. This time, Dr Boulton was writing to Dr Perry at PFC.[96] His letter included the following passage:

A young haemophiliac who previously had minimal therapy with factor VIII received an infusion of the current heat-treated product a month ago. He now shows signs of liver enzyme rises indicating non-A non-B hepatitis. Christopher [Ludlam] is a bit ruthful with his own staff about this because he feels that this patient should have received VIIIY or an equivalent product. However, the patient is apparently quite well clinically.[97]

22.57 The Inquiry was interested to explore with Professor Ludlam whether the episode referred to in Dr Boulton's letter had been the impetus for his attempt to obtain a supply of 8Y.

22.58 The word used by Dr Boulton to describe Professor Ludlam's feelings at the time ('ruthful') was unusual. Professor Ludlam described himself as having been sad that his team had not had 8Y to give to the patient at the time. He did not disagree with Dr Boulton's articulation of these sentiments.[98] It was put to Professor Ludlam that this incident had the effect of sharpening his focus on obtaining some 8Y. He answered:

To be honest, I'm not certain which way round it occurred. I think it was in my discussions with the blood transfusion colleagues after it had happened, that the real potential, possible extra safety of 8Y was being highlighted in my mind.[99]

22.59 He emphasised to the Inquiry the preciousness of 8Y in England; for the first time, clinicians there had a heat-treated NHS product, after having been desperate for one in the first part of 1985. Every bottle was valued and he was not sure that he would be able to have any, should he make such a request.[100] He concluded:

So I'm sorry, I can't remember exactly how the sequence of thoughts went. But certainly this sad episode of a patient susceptible to non-A non-B [who] had acquired non-A non-B ... highlighted the issue.[101]

22.60 He was then asked whether, if he personally had been looking after the patient concerned and had had a supply of 8Y, he would have used it. Professor Ludlam thought that, in these circumstances, he would have been 'very tempted' to use it.[102]

22.61 The evidence concerning the dissemination of guidance to more junior staff about the treatment of patients and about the circumstances in which blood products should be used is discussed more fully in paragraphs 22.71 to 22.86 below.

22.62 As far as the obtaining of 8Y in 1986 is concerned, the Inquiry followed the trail of correspondence culminating in the sending to Edinburgh of a small stock of 8Y in August 1986. Dr Perry replied to Dr Boulton on 2 July 1986. The PFC was 'poised to introduce yet another FVIII product which will be heat treated at 80°/72hours and should therefore be comparable to 8Y'. As soon as this product was available, virgin patients (previously untreated patients, sometimes referred to as 'PUPs') would be able to gain access to it.[103] On 4 July, Dr Boulton wrote to Dr Perry,[104] asking him to confirm that Dr Boulton's notes of their telephone conversation the day before[105] were accurate. By letter dated 7 July, Dr Perry confirmed they were 'about right'. He added:

While there will be no PFC product virucidally comparable to 8Y until September '86, after that time it would be my intention to supply the Phase III product [the 80°/72 hours product, virucidally equivalent to 8Y] to "virgins" since we hope to demonstrate by that time that it is virucidally equivalent thus removing the need to go South. However, in the immediate future (July-September '86), we could probably get supplies of 8Y for special cases. It would of course be preferable if these were obtained and supplied through PFC.[106]

22.63 On 7 July, Dr Boulton wrote to Dr Perry again, apologising for 'pestering' him. Dr Ludlam had written to Dr McClelland asking if it would be possible to obtain some of the BPL products for use 'if a previously untreated haemophilic presented for replacement therapy'. Dr Ludlam was asking for 500 vials. Dr Boulton felt this was a large quantity. He wanted to know if it might be possible for Dr Perry to obtain perhaps 50 vials. This would be enough to cover an initial injection and, if necessary, more could be sought urgently from Oxford.[107] Accordingly, on 10 July, Dr Perry wrote to Mr Norman Pettet at the BPL, relaying the request for 50 vials.[108]

22.64 On 24 July, Mr Pettet replied. He said that he had tried to telephone Dr Perry the previous week. With Dr Lane's agreement, he had spoken to Dr Jim Smith, who had 'a novel proposal' for Dr Perry: 'perhaps Scotland would like to participate in our trial of Factor VIII Y!'. Dr Perry and the haemophilia directors involved would have to agree, and the patients would have to meet the criteria. But in case there were some patients who did not strictly meet the criteria, now or in future, Mr Pettet had put aside some 8Y for immediate despatch to PFC (or any other destination) if required. He could arrange for the product to be sent to PFC at that point, unless arrangements for cover had already been made with Dr Smith.[109] But on the same day, Dr Perry wrote to Dr Boulton. He had now confirmed that BPL were happy to supply 50 vials to PFC 'on the understanding that, in the event that the material is used in suitable virgin patients, appropriate serial samples would be taken to contribute to their overall infectivity study'. Dr Perry thought this arrangement was reasonable; he would pass the product to Dr Boulton as soon as possible and he would be grateful if Dr Boulton could inform Dr Ludlam of the arrangement.[110] Also on 24 July, Dr Perry wrote to Dr Smith at BPL, confirming the arrangement made by telephone and asking for a supply of 50 vials of 8Y as a contingency. This material would be issued on condition that BPL's clinical trial protocol was observed.[111] On 28 July, Dr Perry confirmed matters to Mr Pettet.[112]

22.65 On 1 August, Dr Smith wrote to Dr Perry, sending 50 vials of 8Y and some copies of the clinical protocol.[113] He referred in his letter to the use of the 8Y to protect 'Category 1 patients' - Dr Smith explained that these will have been previously untreated patients, though he was not able to remember the precise definition of such patients.[114] On 5 August Dr Perry wrote to Dr Boulton to inform him that the supply of 8Y had arrived and that 20 vials had been sent to the transfusion centre at the Royal Infirmary in Edinburgh.[115] On 7 August, Dr Perry wrote to Dr Boulton again, advising him that two batches of Factor VIII heated at 80°C for 72 hours had been manufactured and that PFC were on target to begin trials of this product at the end of August or beginning of September.[116]

22.66 Professor Ludlam gave evidence about his actual use of the 8Y thus obtained. This was a precious commodity: Professor Ludlam thought he would have told his own staff about the product, but they would not have been free to use it - they would have been expected to seek permission from him.[117]

22.67 Of the 50 vials, Professor Ludlam used 20 vials for a patient with an allergic reaction to PFC NY concentrate. He subsequently obtained some more 8Y from Newcastle. He could not remember if this was because the other 30 vials had been used up.[118] Professor Ludlam referred to himself as having breached the understanding on which the 8Y had been given, in that he used it not for a previously untreated patient but for a patient with an allergy to PFC product.[119] He also acknowledged that being allowed to have any at all was outwith the normal arrangements for the supply of products by the BPL:

[E]ach English region had an allocation of 8Y, depending on how much plasma it supplied to BPL. As Scotland didn't supply any plasma to BPL, it had, in a sense, no right of access to 8Y. So it was a concession that had to come out of somebody else's supply, one of the English health authority's allocation.[120]

22.68 It can be seen from the circular letter dated 24 July 1985 that the supply of 8Y to centres in England was tightly controlled, in view of the scarcity of the product. The circular provides:

It is recognised that, until the new production unit at Elstree is completed, output of 8Y will meet about one third of current demand for concentrate and for this reason, attempts have been made to define those patients likely to benefit most from the security inherent in 8Y.

Therefore, Haemophilia Centre Directors are being asked to compile lists of their patients considered 'at risk' and most Centres have complied. It is the considered view at BPL that, where possible, liaison between the Haemophilia Services and the BTS should aim at directing Factor 8Y to these patients, using the existing framework of distribution and supply.[121]

22.69 On his second day of giving evidence on this topic, Professor Ludlam was asked why no request for a supply of 8Y for previously untreated patients in Scotland was made before the summer of 1986. He suggested that such a question needed to be put to someone from the Blood Transfusion Service. As indicated above, he had been pressing Dr McClelland on supplies of 8Y, and Dr Perry thought that the PFC would have been the appropriate intermediary. In responding to subsequent questioning, he observed that, rather than his request being obviously the right thing to have done at the time, it might have transpired that he had 'rather jumped the gun' as the trial was still ongoing and the product might have turned out not to be materially better.[122]

Telling other clinicians in Scotland

22.70 Professor Ludlam was also asked whether this stock of 8Y was for the whole of Scotland.

Q. Just one last matter, professor. When this supply of 8Y was obtained in the summer of 1986, was it for Edinburgh patients or was it for everybody in Scotland?

A. Well, as I think is clear, I requested it and it was held primarily at the protein fractionation centre and therefore it was available for anyone who wished to apply to use it.

Q. Yes. And Dr Perry didn't send you all 50 vials?

A. He sent me 20, I think.

Q. But as matters turned out, I think you used the whole 50 vials. Did you ever mention to any of your colleagues in Scotland that that stock existed?

A. I assume that would be a responsibility for Dr Perry. He had a new product available for patients.

Q. Right. Is that a "no". Do you have any memory of ever saying in a conversation, "Oh, there is a stock of 8Y at PFC?"

A. I'm sorry, I can't remember.[123]

22.71 In light of this evidence, Dr Perry was also asked about the securing of this stock of 8Y, and whether there was an arrangement that this 8Y was available on a more general basis for patients in Scotland? He replied that colleagues at the BPL:

[W]ere prepared and able to supply small quantities of product for specific clinical situations, and the specific clinical situation was a previously untreated patient, and their positive response to our request demonstrated the principle that that was viable. I think if that had been then extended to an arrangement where BPL were being asked to supply product for all sorts of other reasons, an 8Y product, then I think they would have resisted that, for the reasons that I have described. So my clear understanding at the time was that this small supply of product was for very specific requirements.[124]

22.72 Dr Perry was asked whose responsibility it was to inform clinicians in other parts of Scotland that this small supply of 8Y was available. He replied:

A. There were basically two options, and, of course, with hindsight, the best outcome would have been that either myself or Dr Ludlam, as chairman of the Scottish haemophilia centres directors study group - either of us could have more widely notified the other four haemophilia centre directors that this product was available and, to the best of my knowledge, that didn't occur.

Q. Can you give us any explanation or indication as to why that may not have occurred?

A. I have attempted to give you the explanation why I didn't take that particular position, because I didn't think it was a responsibility. Again, against this backdrop of being quite clear to make sure that, as a manufacturer, we were not exceeding our brief, I thought it was not the responsibility of SNBTS or indeed the PFC director, the manufacturer, to make wider notification of this. This was a specific facilitating arrangement that we carried out on behalf of Professor Ludlam.[125]

22.73 Dr Perry was asked if he could have sent a circular advising of the stock of 8Y. He agreed that that could have been done.

I think, with hindsight, I would certainly agree that that would have been an appropriate thing to do but I would still suggest that a more appropriate thing to do would have been for the haemophilia centre directors themselves to have - in the knowledge that this was available - we had established the principle with Professor Ludlam - then there was a possibility that they too could have communicated amongst themselves.[126]

He continued:

But I think I'm trying not to suggest that we could not have had a role to play here, and I think with hindsight I would agree: if I had my time again, I think I could have quite simply ... written to other haemophilia centre directors - actually, it would have been to regional transfusion directors as well, who were responsible for supply of the product - and made them available [aware]. It's quite possible - I have absolutely no evidence that this took place, but through various informal channels and communications I would have mentioned that this actually happened but I have no evidence for that.[127]

22.74 In view of Dr Perry's reference to the Scottish Haemophilia Centres Directors' Study Group, the Inquiry has examined whether the directors were meeting as a group at this time. According to Professor Ludlam, the Scottish directors met as a group from about 1985.[128] In any event, they will have encountered each other regularly at meetings, and knew each other's identity and contact details. Information about the obtaining of a small supply of 8Y could have been disseminated among them by Professor Ludlam.

22.75 There also arises the question of how hospitals in Scotland which did not have haemophilia centres but which might find themselves dealing with a person with haemophilia in an emergency would know that there was a supply of safer product for such patients in Edinburgh. This is further referred to below at paragraph 22.98 in the context of 'horizontal dissemination' of guidance.

Dissemination of guidance

22.76 The Inquiry was contacted by two people with haemophilia who contracted Hepatitis C from blood products during the period 1985-87. One of these individuals was treated in Edinburgh, not by Professor Ludlam personally but by a junior clinician, at night. The other person was treated in a remote part of Scotland. The Inquiry explored in evidence the issues of how guidance was given by senior clinicians to more junior staff ('vertical dissemination') and, given that people with previously undiagnosed haemophilia might present at any hospital at any time, how guidance was distributed around Scotland ('horizontal dissemination').

Vertical dissemination

22.77 Professor Ludlam was asked what steps he, as a haemophilia centre director, had taken to ensure distribution of guidance on treatment during the relevant period to members of staff who might be encountering patients with haemophilia. In particular, he was asked about the guidance document prepared by Professor Bloom after the meeting on 10 December 1984.[129]

22.78 In response, Professor Ludlam indicated that he thought that what was in the guidance document represented practice in the Edinburgh centre at the time. The team was small: Professor Ludlam, a lecturer, a registrar and a haemophilia sister, and policies were 'generally accepted and well-known within the team'. He could not remember whether there were written policies, locally produced, at that time.[130]

22.79 Professor Ludlam confirmed that, during the period under investigation, the patients whose treatment raised the most difficult issues were those individuals with little or no previous exposure to blood products. He thought it would be 'quite clear' that such patients should be discussed at a senior level. At one extreme, if a baby without previous exposure came in with a life-threatening bleed, a major intracranial bleed, then his judgement would have been that that child required concentrate, because of speed of administration and known level of Factor VIII in the therapy.[131] He would almost certainly have been contacted.[132] As far as new staff were concerned, Professor Ludlam pointed to the continuity offered by the haemophilia sister, and the lecturer, whose post was a more permanent one.[133]

22.80 Professor Ludlam also told the Inquiry about weekly meetings:

We had weekly educational meetings, at which we would discuss our internal arrangements, our internal policies, we would have outside speakers. I seem to recall a speaker from the blood transfusion coming to talk about developments in clotting factor concentrates.[134]

These meetings took place at 8.30 am on Fridays.

22.81 The Inquiry was interested to probe further how medical staff would know that particular patients - the 1% who were not regular patients at the Centre - posed difficult questions as far as treatment of bleeding was concerned. Professor Ludlam's answer to this was that such individuals would obviously stand out. They would not have case notes. If that was because they were visiting Edinburgh they might have haemophilia cards, or they might be able to explain themselves what their normal treatment was.[135] Junior staff were always free to come straight to Professor Ludlam if they needed advice about a patient.[136] As far as those staff who might think they did not require advice were concerned, Professor Ludlam answered that he very quickly got an impression of the level of competence and understanding of a new member of staff. If over-confidence was a problem, he would speak to them. He always said to new staff to contact him if they had a query. He endeavoured to give staff as much responsibility as he could and as much as they felt comfortable with, whilst also equipping them with an understanding of the sort of areas and topics that he liked to be informed about.

22.82 Professor Ludlam's evidence on the matter of dissemination within the department ended with the following exchange:

Q. Professor Ludlam, because this is an Inquiry, I think I have to probe just a little bit further and put to you that the sort of scenario we have been discussing - that is the patient with mild haemophilia who needs treatment, who has had no or minimal previous exposure to concentrates, needing treatment, where there is a continuing risk of hepatitis, which is a very significant adverse consequence and the treatment decision is a very difficult dilemma - that whole package is something that called for specification, so a written document or an advance instruction from you communicated to all staff. Looking back, even just in retrospect, what's your response to that?

A. Well, it could give rise to the wrong therapy. Let me caricature. A patient with mild haemophilia is involved in a road traffic accident, comes into hospital unconscious, may have an intracranial bleed. The recipe, the guidance says give DDAVP for mild haemophilia. That would be totally inappropriate for many reasons I could go into, if you wanted to.

Q. I was wondering perhaps about a simpler response. What if the guidance said in block capitals "phone me"? Would that not help?

A. That is, in a sense, what the guidance was. Here is an unusual situation.

Q. But you didn't see the need for making that kind of provision in advance, as it were, for putting down in writing, so there wasn't debate, what you expected the response to be?

A. I expected people to get in touch with me if it was not clear how they should proceed with the medical care of patients. That applied not just to mild haemophilia. I looked after patients with leukaemia and lymphoma and a whole range of conditions, and if one of my staff had some doubt about how to proceed, then they asked me.[137]

22.83 It was not clear that this explanation dealt with the full range of possibilities giving rise to a need for the intervention of a more senior colleague. More junior staff might not be aware that the situation confronting them raised a problematic issue. They might think, wrongly, that it was clear how the patient should be treated. However, it is highly improbable that any form of general guidance could exclude the possibility of incorrect clinical judgement.

22.84 The question of what would happen if such a patient presented in the casualty department of the hospital was also covered with Professor Ludlam. He explained that if haemophilia was suspected, a clotting screen would be performed. If the results revealed mild haemophilia, then staff from the haematology department would go to see the patient themselves. That situation was very unusual.[138] Of course, if the patient had been investigated before, then the patient himself might be able to inform medical staff about any clotting problems. But with such investigations, wider questions might arise in borderline cases about whether or not a particular individual should be 'labelled' as having a clotting disorder, because of the implications such a diagnosis might have for other areas of his life, such as life insurance.[139]

22.85 Professor Ludlam was asked to consider what would have happened during the relevant period if a patient who was bleeding arrived in casualty and also informed staff of some sort of history of bleeding easily. His answer was that a clotting screen would have been performed - the threshold for such an investigation was very low.[140] As far as the mechanics of requesting and arranging a clotting test were concerned, Professor Ludlam explained the interaction between casualty and the haematology departments as follows:

The system was that clotting tests came - we get a lot of requests for clotting tests from Accident & Emergency and if one turned up with an unexpected abnormality, as might occur in haemophilia, then that result was reported back to the person who requested it, and our duty registrar was informed and our duty registrar would then use his judgement as to whether or not to follow it up, and certainly if there was a question of a screening test potentially identifying a patient with haemophilia, then he would make sure the Factor VIII and Factor IX levels to start with were measured, and he would go and liaise with the doctor in the Accident & Emergency department.[141]

22.86 Insofar as the decision about administering any blood products was concerned, Professor Ludlam would expect to have heard himself if a new patient with haemophilia was in casualty - although plainly circumstances might dictate otherwise if, for example, he was unavailable.[142] At first, Professor Ludlam thought that there was no written guidance issued to the casualty department by his department during the period being examined but, on reflection, he recalled that every two or three years, the haematology department met with the casualty department and updated a guidance sheet as to how staff in casualty should respond to a person who presented with haemophilia, or potential haemophilia.[143]

Horizontal dissemination

22.87 The Haemophilia Centre in Edinburgh was the reference centre for the centres in the east of Scotland, namely Dundee, Aberdeen and Inverness.[144] As reference centres, Edinburgh and Glasgow were part of 'a UK arrangement for overseeing haemophilia treatment'.[145] In view of this, Professor Ludlam was asked what steps he had taken during this period to give guidance to those treating patients with haemophilia in those other centres. In response, he explained that, prior to the setting up of the Factor VIII working party in 1988:

[T]he centres were much more independent, standalone centres and there was not a great deal of interplay between them. Occasionally I would get a phone call about a difficult patient or something that was causing a difficulty or a problem, but there weren't regular meetings like there are now, where we meet every two or three months.

Q. Right. You did use the word "overseeing" but it seems, from what you are now saying, as though, at least in the mid 1980s, it was more of a reactive role. So if somebody phoned you up for advice, you would be happy to provide it?

A. Yes, I think it evolved from being very separate, individual centres until the mid-1980s and, as a result of the development of all these new products and the need to test them, for one reason, brought us together to collaborate more.[146]

22.88 The guidance document, prepared by Professor Bloom in December 1984, would have been sent to the other east of Scotland centres by the UKHCDO, from Oxford.[147]

22.89 The Inquiry was interested in how physicians in other hospitals who might have to treat a patient presenting with haemophilia for the first time would have been aware of the most recent guidance. Professor Ludlam suggested that such clinicians would either use their best judgement, or telephone a haemophilia centre known to them.[148]

22.90 There did not seem to be any system for sending guidance from the UKHCDO to hospitals around the country which were not haemophilia centres but which might suddenly have to deal with a patient who had haemophilia and who was in the midst of a bleed. Professor Ludlam suggested that, had a small child presented to a hospital in the Highlands with a bleed thought to be haemophilia, transfer to Inverness or Glasgow would be 'the sort of usual [response]'.[149] He thought that, at the time which was being discussed, it would have been possible to get a small child to Inverness or Glasgow within 12 hours. He agreed that physicians in remote locations might not be aware of the most recent guidance on haemophilia, particularly with the centralisation of care which was already happening in the 1980s.[150]

22.91 It was also put to Professor Ludlam that no-one in Scotland appears to have had the responsibility to change the 1984 guidance as different options became available or as the relative merits of the different products changed. Professor Ludlam thought this was 'fair comment', although he also pointed out that this was 'a very, very confusing period'.[151] As far as general guidance for hospitals all over Scotland was concerned, Professor Ludlam was asked who would have been responsible for providing such advice:

Q. [W]e are thinking about this difficult period and if it were to be thought that it would have been a good idea for somebody to try to make sure that all hospitals in Scotland had some assistance with the current thinking on how to deal with patients with haemophilia presenting for the first time, say, or patients with mild haemophilia who hadn't had previous exposure to concentrates, the patients who present the particular dilemmas. If it had been thought that it would be a good idea for all the hospitals in Scotland to know what the thinking was, whose job would it have been to make sure that that sort of information is sent round?

A. Well, I suppose it's a medical policy decision. It perhaps should come from the chief medical officer.[152]

22.92 Later, when Professor Ludlam was pressed about this, and it was put to him that these were matters of individual clinical judgement, he highlighted the fact that, from time to time, circulars are produced by the health departments to alert physicians to particular situations, for example in the context of infectious diseases. It was suggested to him that there would be limits to what such guidance could offer:

Q. So if you are thinking of guidance from the chief medical officer, for example, I take it you are not thinking that the chief medical officer will say, "In this instance, use cryoprecipitate; in this instance, use Factor VIII concentrate," or are you anticipating that that sort of level of detail would be prescribed from government?

A. It would be very helpful if the chief medical officers would give that advice.[153]

22.93 It was suggested to Professor Ludlam both that any such guidance would have to have been obtained by the Chief Medical Officer (CMO) from the haemophilia directors anyway, and that there was in existence the guidance document from December 1984. He maintained his position that more guidance from others on therapeutic policy, would have been helpful. Haemophilia doctors felt that the problem was being 'left at our door'. For them to have had some guidance and 'potentially to address some of the issues that we have been thinking about between England and Scotland by ... the chief medical officers ... might have been helpful'.[154]

22.94 With these comments having been made by Professor Ludlam, those representing the Scottish Government sought and were granted permission to lodge a response from Dr Iain Macdonald, former chief medical officer for Scotland.[155]

22.95 Dr Macdonald dissented from Professor Ludlam's view as to what was public policy and what was medical policy. In his opinion, it was the responsibility of the medical profession to evolve treatment policies. This was what the Reference Centre Directors were doing in 1984.

22.96 Dr Macdonald acknowledged that there was a degree of sensitivity about the boundary between public and medical policies. Decisions about issues on which a CMO should write to his medical colleagues in the NHS lay in this sensitive area. There were circumstances in which it was established and accepted practice for CMOs to write to NHS colleagues. There were two broad categories in which this was normally done. These were: the prevention or limitation of the spread of infectious diseases, and the early detection of disease by screening populations at risk.

22.97 Concerning Professor Ludlam's proposition that a CMO letter outlining clinical matters would have been helpful, Dr Macdonald concluded:

I have to say that if this had been put to me as CMO, I believe that I would have concluded that the introduction of a government department into an essentially clinical matter being handled by UKHCDO would not have been helpful and probably not acceptable. I would therefore have felt bound to decline.[156]

It therefore appears that the provision of guidance on how to treat a person with haemophilia presenting in an emergency was not seen within the Scottish Home and Health Department (SHHD) as a government responsibility.

22.98 At the time, it might have been understood that haemophilia centres were willing to provide advice to any clinician in Scotland treating a patient with haemophilia. However, it is not clear how non-specialist clinicians would have become aware of guidance issued by the specialist organisation, the UKHCDO, to assist in dealing with a particular problem or how they would have known that a better product might be available in Edinburgh for previously untreated patients.[157] The latter observation also applies to the period after December 1986, when Scottish product more rigorously heated (at 75°C for 72 hours) was released by PFC for clinical trials; it is not clear that hospitals which were not haemophilia centres, or even those which were but which were not involved in the trial, were informed of the availability of this product.[158]


22.99 The period covered by this chapter was, on any view, challenging for those concerned with the treatment of patients with coagulation deficiencies. The 'golden interval', when the introduction and development of factor concentrates appeared to have been an 'enormous quantum leap' in therapy, had come to an end with the 'years of viral contamination problems'.[159] Transmission of HIV, and the consequences of infection with that virus, and growing appreciation of the risks associated with NANB Hepatitis were dominant issues in the middle years of the 1980s. In the light of later experience and research, it seems clear that the development of heat-treated factor products, introduced in Scotland in December 1984, provided effective protection against the risk of transmission of HIV by PFC's standard concentrates. It would not, however, be clear for some time to clinicians and others dealing with patients that that was the case. In the meantime, increasing understanding of the natural history of NANB Hepatitis was reflected in growing concerns about the use of those concentrates in routine therapy.

22.100 In attempting to capture the atmosphere of the period, it is necessary to bear in mind that different groups of medical experts and scientists would have different perceptions of risk and benefit from the use of therapeutic products. In addition, government and regulatory agencies, whether involved centrally or at the periphery of developing thought, would reflect, in their response to emerging knowledge, the understanding of their roles at the time. The clinical independence of the practitioner would have been accorded a higher priority than would be conceivable after the formation of the Scottish Intercollegiate Guidelines Network (SIGN) in 1993.[160] There is a need for caution against an assumption that, in the period with which this chapter is concerned, there were simple and uncontroversial answers to questions about the appropriate therapy to adopt, generally or in particular circumstances. The situation was altogether more complex; there were and are no easy answers.

22.101 A number of issues were focused in questions to be explored in evidence. The first question dealt with the period between the production and introduction of BPL's product 8Y and the development of PFC's product Z8, and was expressed in these terms:

Given that, with effect from Autumn 1985, the Factor VIII concentrate 8Y, produced in England, was more severely heated than the Scottish product, could a supply of 8Y have been obtained to be held for the treatment of any Scottish patients with haemophilia who had received little or no previous exposure to concentrates and who required treatment before the equivalent Scottish product was available?[161]

It is therefore necessary to examine the position concerning the availability of 8Y for Scottish patients.

Supply of 8Y for Scotland

22.102 The cross-border supply of therapeutic products for routine use for any class or classes of patients raises issues about the general relationships between Scottish fractionators and the SNBTS on the one hand and English fractionators and the NBTS on the other that are materially different from the transfer of materials for specific or limited use. When an official request was made for a limited supply of 8Y, arrangements were made, subject to conditions. Professor Ludlam was also able to obtain some 8Y from Newcastle, he thought probably on a personal approach to the haemophilia director there.[162] In one sense these two events show that, in absolute terms, it was possible to obtain some supplies of 8Y for use in Scotland.

22.103 The arrangements for the official supply were made after discussion in England. It is significant that in his letter dated 24 July, Mr Pettet records that he has 'spoken to Dr Lane' about the request. It was not treated as a matter of incidental interest.

22.104 The position generally was that the SNBTS and the PFC had responsibility for meeting the needs of the NHS in Scotland, and the NBTS and the BPL had responsibility for the needs of the service in England and Wales. How that came about is discussed in Chapter 19, Production of Blood Products - Facilities. Distribution of therapeutic products in England and Wales was managed on a basis that recognised that the BPL could not satisfy all domestic demand: the regions received the BPL products in proportion to their provision of raw materials. The shortage was particularly significant in the case of 8Y, at least until production facilities could be expanded. Initially, it was expected that output would meet about one third of current demand for concentrate. The arrangements (apart from the special needs of clinical trials to provide information for product licensing purposes) were that Factor 8Y would be issued through Regional Blood Transfusion Centres, unless special provisions existed by agreement for product to be sent direct to the Haemophilia Centre. Allocations to the BTS were to observe the pro rata requirements for distributions agreed between the BPL and the BTS.[163]

22.105 Haemophilia Centre Directors were asked to identify patients 'at risk' (patients who were HTLV III antibody negative and who had no history of hepatitis) as potential recipients of the new product. On 15 August 1985 a DHSS circular explained that output of heat treated product (8Y) at the BPL had been increased to the maximum level possible in the current plant.[164] The letter was circulated in England, Wales and Northern Ireland, but not Scotland.[165]

22.106 Information about the new product was not available uniformly in Scotland. Dr Foster did not know of the information sheet distributed in July.[166] He knew that BPL started issuing 8Y routinely in September 1985 and not before, but he did not know the stage reached in developments at April 1985.[167] In contrast, Dr McClelland who was a member of the Central Committee for Research and Development in Blood Transfusion, and Dr Forrester who attended as representative of the SHHD had information provided at the Committee's meeting in 19 December 1985 that Dr Rizza had been trialling the product for about nine months.[168] But it was not suggested that either communicated relevant information to Dr Foster. Dr Foster had his own source of information in Dr Smith, but that related to the scientific and development aspects of the product and not to its availability. For other information he depended on Dr Perry. The impression from this evidence was that Scottish officials received information on a casual basis about the new product. They were not involved, as Scottish officials, in the development and distribution of the product, which was consistent with the territorial division of responsibility, and with DHSS policy related to the distribution of 8Y.

22.107 There is no evidence that the BPL could have provided a significant supply of 8Y to Scotland for the treatment of previously untreated patients (PUPs) in the period 1985-87, or in any event could have done so without detriment to the interests of English and Welsh patients. Given that 8Y was the only HIV-safe NHS Factor VIII concentrate available from the BPL, routine supplies could only have been made at the expense of English and Welsh patients. The reasonable inference from the arrangements made for distribution of what was a scarce resource is that no such supply could or would have been forthcoming. Dr Smith's expedient of providing a small quantity as an extension of the trial of the product in England and Wales, and the sequence of steps taken before the request was granted, indicate that the actual supply was an exceptional event. For his part, Professor Cash would not have sought any 8Y. He would not have wanted to take a scarce resource from England and Wales where there were severe difficulties.[169] He thought the haemophilia clinicians might have taken a different view and that they might have considered that there should be an approach to England to obtain some.[170] But the basis for that opinion of the haemophilia directors was not clear.

22.108 The question is hypothetical: the issue was never tested. But the restrictive conditions on the official supply of the 50 vials, and the further arrangement to obtain supplies from Newcastle, added to the official position of the DHSS on actual supplies, indicate that, on balance, a request by the SNBTS or by individual haemophilia clinicians for a share of the BPL product would not have been successful. Whether some kind of barter or exchange could have been negotiated that might have offered comfort to NBTS Directors adds another layer of speculation. The SHHD or even Scottish Office Ministers might have been asked to intervene with UK counterparts. Possibilities can always be advanced, but it is not possible to conclude that a practicable arrangement could have been arrived at.

22.109 That is not quite the end of the matter, however, because of the small supply of 8Y (50 vials) which was obtained for Scottish patients in the summer of 1986. As narrated, this was at the behest of Professor Ludlam and the product was not used outwith Edinburgh. Moreover, it appears to have taken place in response to the realisation that a previously untreated patient had contracted NANB Hepatitis from treatment in Edinburgh in May 1986. That this small supply occurred does not demonstrate that a larger quantity could have been obtained. Indeed had the procurement of 8Y been publicised to other haemophilia directors in Scotland, growth in requests for more ad hoc supplies might have been met with refusal. But it is unfortunate that neither the existence of a small stock of product in Edinburgh nor the possibility of obtaining some from England for any previously untreated patient presenting for care seems to have been drawn to the attention of physicians in other areas of the country. Having regard to the way in which arrangements to obtain and store that supply were made, it would have been for the SNBTS, probably through the PFC, with its remit for all of Scotland, to direct attention to this therapeutic option. As Dr Perry himself recognised, he could have written to other Haemophilia Centre Directors and to Regional Transfusion Directors to tell them about the product. It might also have been expected that Professor Ludlam would share information about the supply of 8Y with other haemophilia directors in Scotland.

22.110 Two other questions were formulated which, in the light of the evidence, are, strictly speaking, superseded. They were (1) whether, if a supply of 8Y could have been obtained for the treatment of Scottish patients with haemophilia who had received little or no previous exposure to concentrates and who required treatment before the equivalent Scottish product was available (other than the small ad hoc supply procured by Dr Perry in the summer of 1986) such a supply should have been procured, and (2) when and by whom should such a supply have been obtained?[171]

22.111 If it had been possible to conclude that a general supply of 8Y could have been made available, should such a supply have been organised? In the abstract, it certainly appears desirable that a supply of product which seemed likely to offer a greater measure of safety to patients should be achieved. But in practice, the second question, which addresses the mechanics of organising that supply, is more important.

22.112 There are a number of practical issues that would have arisen if there had been an attempt to convert the hypothesis into reality. Obtaining a national supply would not have been a task for Dr Ludlam: his attention was focused on providing for the needs of patients in or attached to the Edinburgh centre. It appears that it would not have been thought to be within the responsibility of the SHHD or the CMO because they did not interfere in clinical matters. It might have been considered to be within the remit of the SNBTS to procure a supply for Scotland, although it is not clear by whom such an initiative could have been taken. On one view, it would not have been Dr Perry's responsibility to make the request: his sphere of responsibility was the production of NHS concentrates for patients in Scotland. On the other hand, he did envisage that the PFC would have been an appropriate channel for requesting material.

22.113 For England and Wales, the DHSS had a role in questions of supply: it appears clearly to have been their decision that restricted the general availability of 8Y to England, Wales and Northern Ireland, and targeting of particularly vulnerable patients was an aspect of that decision. Only the SHHD could have played a role in securing an adjustment of that policy for the benefit of similar vulnerable patients in Scotland.

Guidance for treatment of patients

22.114 The next question that arose was whether, in the absence of a supply of 8Y to treat patients with little or no previous exposure to concentrates, the general approaches to blood product therapy for haemophilia in Scotland in the period 1985 to 1987 were reasonable.[172]

22.115 Patient core participants have submitted that there was a failure to make provision for a sophisticated system to identify those who might be previously untreated patients with coagulation issues should they present for medical care (apparently at any level, general practitioner, health centre, or hospital).[173] The general care of patients who have or may have coagulation defects, is not within the Terms of Reference. There was, however, no evidence of a general issue that could have been dealt with systematically. There was no evidence that it would have been practicable to treat every patient who was not already receiving care as a haemophilia patient as potentially suffering from a coagulation defect.

22.116 Turning to more general questions of what ought to have been available by way of guidance, the objective of SIGN shows that in relation to clinical practice there was soon to be recognised a need for general guidelines. The objective of the organisation is:

The Scottish Intercollegiate Guidelines Network (SIGN) was formed in 1993. Our objective is to improve the quality of health care for patients in Scotland by reducing variation in practice and outcome, through the development and dissemination of national clinical guidelines containing recommendations for effective practice based on current evidence.[174]

22.117 It is clear that such guidelines are not perceived to threaten and do not threaten clinical independence. Indeed, the initiative for the formation of SIGN came from the Scottish Medical Royal Colleges.[175]

22.118 At this point, the dilemma confronting haemophilia clinicians continued to be whether to use concentrates although they knew that concentrates exposed the patient to risk of transmission of hepatitis viruses. As knowledge of the natural history of NANB Hepatitis developed, the balance in perception of risk/benefit inevitably changed. On one side of the equation, the natural history of haemophilia remained as it always was: the risk of bleeding that could extend to fatal bleeding into the gut or brain, and, short of that, could lead to the development of disabling disease of the joints, among other consequences. Haemophilia remained a serious and often life-threatening condition requiring treatment.

22.119 Against that background, it would be reasonable to suggest that the clinician would use the least damaging product that was available to him or her for effective treatment of the particular manifestation of the underlying disease that the patient was experiencing at the time.

22.120 That appears, generally, to have been the approach reflected in the guidelines, dated 14 December 1984, prepared by Professor Bloom and sent to Regional Directors: Haemophilia Centre Directors Organisation AIDS Advisory Document.[176] Although expressed primarily as guidance related to AIDS, then the most significant threat envisaged, it was more general in its approach. Available therapeutic materials were listed in order of safety, and the risk of NANB Hepatitis was specifically mentioned. The UKHCDO view was expressed that bleeding was the commonest cause of disability and death, and that concentrate was still needed. The use of DDAVP was recommended in appropriate cases. And where concentrates were needed, advice was tendered as to the priorities to be observed.

22.121 It was reasonable for haemophilia clinicians to follow this guidance in practice. Professor Lowe said that the advice was followed in Glasgow. Professor Ludlam based his practice in Edinburgh on the advice. So far as that advice was followed, it provided a reasonable underpinning of clinical practice in Scotland. The evidence of Professor Ludlam and of Professor Lowe that the policy of their respective centres was to follow the UKHCDO advice is accepted.

22.122 However, that led inevitably to a question whether the arrangements for the dissemination of general guidance to clinicians regarding haemophilia treatment during this period were satisfactory.

22.123 In some respects this is the more fundamental question. There may be little point in a small number of senior clinical consultants knowing a system, including any guidelines incorporated in it, if (a) their associates and subordinates and (b) clinicians outwith a narrow core of specialists (of which those senior clinical consultants are the characteristic members) do not know of the guidance and are not equipped to follow it.

22.124 There has to be a mechanism within a system of practice that ensures, so far as reasonably practicable, that guidance is disseminated as required to inform all practitioners likely to be called on to minister to patients' needs, and that ensures appropriate compliance with what is regarded as best practice from time to time. No system can anticipate, far less resolve, all of the issues that may arise in clinical practice. As Professor Ludlam observed, an over-prescriptive system that stipulated for the use of DDAVP in treating a mildly affected haemophilia patient would be counter-productive in the case of a patient who had had a serious road traffic accident. Emergencies will always demand ad hoc decisions adapted to patients' needs. A clinician faced with a patient in extreme pain may prescribe treatment that would normally be contrary to recommended practice if satisfied that the course is necessary to secure the patient's safety, for example, and nothing else is available. However, in this as in other circumstances, elaboration of exceptions tends to underline the need for the basic rule.

22.125 Two questions arise: were there basic guidelines, and who was responsible for disseminating them? Looking at the needs of Scotland as a whole, there clearly were not basic guidelines for general application. The UKHCDO guidelines prepared by Professor Bloom were addressed to a particular group of recipients who could be expected to understand the complex background and to be familiar with the issues implicit in the advice given. They were not designed for, and would have been less easily understood by, a general practitioner holding an occasional clinic in a remote cottage hospital. In one of the two instances of which the Inquiry has notice, an island hospital held a supply of PFC factor concentrate. Other outlying units might well have held such therapeutic materials. The need for guidance seems obvious - even if only to alert non-specialist physicians to the dilemmas arising in therapeutic decisions at this time, and the need to take advice.

22.126 The need for guidance extends beyond directions on reconstituting or otherwise preparing therapeutic materials for use. Taking a patient's informed consent to the use of therapy requires that the clinician is equipped with information on the risk/benefit balance of the use of the particular product, and both understands and has the advice necessary to communicate relevant issues to the patient.

22.127 These issues were probably not peculiar to haemophilia - they must have been relevant to other chronic conditions as well. The needs of small local hospitals or GPs in remote areas had to be considered and they should have been kept 'in the loop' of thinking. On the evidence available to the Inquiry, there was no such guidance.

22.128 This was a period in which there was increasing understanding that it was almost certain that patients treated for the first time with factor concentrates, or with little previous exposure, would be exposed to NANB Hepatitis infection on first receiving an infusion of any concentrate other than those most severely heat treated. There was a clear need for central direction and advice on the approach properly to be adopted to the use of available products and the implications for patients of their use.[177]

22.129 By today's standards, the arrangements appear very vague. Relying heavily on observations by Professor Thomas, the patient interest core participants have submitted:

The evidence available to the Inquiry suggests ... that little formal structure existed to ensure that important information and opinions about the risks of transmission of NANB hepatitis to uninfected patients, the known severity of the disease, what treatment options were available and how treatment decisions might be affected by this information was conveyed clearly and efficiently to anyone other than the most senior staff at Scottish haemophilia reference centre[s] (ie Edinburgh and Glasgow). In particular there would seem to be little evidence of formal efforts being made to communicate any such information to junior staff or to hospitals where such treatment decisions may have to be made outwith these main centres.[178]

22.130 The vertical dissemination of information within hospitals is discussed below. Otherwise, the submission is generally well founded. It is not appropriate to place as much reliance on the evidence of Professor Thomas in this regard as is set out in the patient core participants' argumentation in support of the submission: he was not and is not a haemophilia clinician and this was not his field.[179] But these points do not detract from the general validity of the submission.

22.131 There was no guidance from central government agencies, from the SHHD or the CMO. Irrespective of whether departmental involvement in the content of such guidance would have been appropriate,[180] it is unsatisfactory that the only facilities equipped with guidance were haemophilia centres, which had the material distributed by the UKHCDO. Patients with haemophilia needing emergency treatment could present at any casualty department in the country. Representatives of the SHHD were involved as members of or as in attendance at meetings of representatives of clinicians, scientists and medical members of the SNBTS. If it were accepted that it was inappropriate for them to participate in or guide discussion,[181] they nevertheless remained a conduit for the communication of information to government and had a distinct role in advising on the financing of research and development across a broad front. It would have been for the SHHD to arrange for the distribution of guidance to the NHS in Scotland as a whole. There was already a precedent for government involvement in delivery of haemophilia care in England and Wales in the shape of a DHSS Circular Family Practitioner Notice addressed to general medical and dental practitioners in January 1976, concerning revised arrangements for the care of persons suffering from haemophilia and related conditions.[182] According to that Notice, the functions of haemophilia centres included giving advice to general practitioners about the emergency treatment of haemophilia patients on their list. This Notice was appended to a DHSS Health Circular dated February 1976, addressed to Regional Health Authorities and Family Practitioner Committees for action, and to Area Health Authorities and Boards of Governors for information.[183] Whilst the Notice does not appear to have been formally circulated in Scotland, it was referred to and appears to have reflected the arrangements for haemophilia care in Scotland as well as in England and Wales.[184] It was, in any event, an indication of what was thought appropriate for a central government department to do in the field of haemophilia care. Although the 1976 document was a Circular and not a CMO letter, it did specify what sort of care was to be provided by a haemophilia centre and by a reference centre. Moreover, the need for a haemophilia centre to provide guidance to general practitioners on the emergency care of patients with haemophilia was specifically referred to. It did not mention providing guidance to 'local' hospitals, which might also be required to provide emergency care and, in that regard, may have been incomplete. But it illustrates a desire on the part of central government to establish and maintain a coherent system for the provision of care for people with haemophilia.

22.132 In another context, the Inquiry has noted the intervention of Dr Yellowlees, CMO, England and Wales, in May 1975 in a debate over the collection of blood donations in prisons, a matter otherwise considered to be within the responsibility of Regional Transfusion Directors.[185]

22.133 Efficient and effective provision for the care of vulnerable populations such as those with coagulation deficiencies is not a matter that should depend on narrow definitions of departmental or agency competency or their individual remits: responsibility rests ultimately with government as a whole. Ministers control budgets, subject to Parliamentary oversight. Whoever proposes, Ministers dispose in the funding of work in the national health sector. As a practical matter, the overall shape of the service, as distinct from clinical care of a particular patient, is the responsibility of central government departments and associated agencies. That responsibility shifts among departments and agencies as circumstances demand: there are few immutable principles that dictate current competencies and provide insuperable barriers to the resolution of issues affecting public health. Nor should there be. Any doubts about the competency of the health departments to issue guidance in this particular area would have been resolved had a challenge arisen.

22.134 The second aspect of this question relates to vertical dissemination of advice and instruction. It arises on the hypothesis that a particular hospital or other operating division of the service has available sources of advice and information at some, typically senior, level, and the question focuses on the approach adopted to the dissemination of that information and advice down through the particular organisation or part of the organisation concerned with immediate patient care.

22.135 The patient interest core participants submitted in this regard that:

  • Minimally treated patients included those who had received treatment in the past for their bleeding disorder, but not with factor concentrates or with large volumes of cryoprecipitate.
  • The treatment of virgin and minimally treated patients over this period merited special consideration by treating doctors on the basis that (a) the state of knowledge was such that it was highly likely if not certain that they would be infected with a potentially lethal disease if treated with the then available Scottish factor VIII concentrate (NY) and (b) it was probable that such patients would not yet be infected with that disease.
  • The then available Scottish factor VIII concentrate should not have been given to virgin or minimally treated patients over this period unless it was unavoidable.
  • The priority in the treatment of bleeding episodes in such patients should have been to try to achieve haemostasis with other treatments which carried less of a risk of transmission of NANB hepatitis, such as DDAVP (for mild patients) or cryoprecipitate or alternative products sourced outside Scotland before resorting to the use of SNBTS factor VIII concentrate.[186]

22.136 The third point is well made, against the background of the narrative in the first and second points, since it appears to recognise the need for clinical judgement. The fourth point is over-prescriptive and inappropriate. It is not for this Inquiry, nor would it have been appropriate for any general guidance, to dictate an order of treatment relating to the patient's underlying coagulation deficiency without regard to the circumstances requiring medical attention. Professor Ludlam's evidence relating to the use of DDAVP to treat a patient with a mild coagulation disorder following severe trauma, already referred to, illustrates that conclusively. However appropriate for routine purposes, DDAVP would be wholly inappropriate for a patient who was bleeding severely after a road traffic accident.

22.137 Professor Ludlam gave evidence about the arrangements in his department in Edinburgh. For present purposes this is but one example, and as such illustrates what could happen during the material period.

22.138 It is, however, difficult to derive a clear picture of the situation in Edinburgh at that time. Professor Ludlam's evidence frequently consisted of informed speculation about what would have been the position or must have been the position, without direct recollection of events as they happened. This perhaps followed necessarily from the passage of time and the lack of contemporaneous records and forms that might have been in use. The unsatisfactory nature of the evidence can best be illustrated by his change in position relating to written guidance to casualty staff on handling patients with haemophilia or potential haemophilia. He clearly had thought about his evidence after the first occasion on which he spoke of this subject, and, with the benefit of that, he changed position. It can be accepted that his revised evidence is reliable. But it does not resolve all difficulty. According to his revised evidence, there was a meeting every two to three years between haematology and casualty officers to update the guidance sheet issued from haematology. At any one time, therefore, almost three years might have elapsed since the guidance was last updated. During the period with which this chapter is concerned, the emphasis on seeking advice from the haemophilia clinicians or the haematology department generally would have been expected to have changed. The need to involve specialists to ensure an appropriate selection and use of coagulants would have required greater emphasis.

22.139 Within his department, Professor Ludlam conducted weekly tutorial sessions. That was an appropriate course of action. But it might best have been supported by notes for reference in the course of clinical practice. Reliable recollection of what is said at such sessions cannot be assumed generally, and certainly cannot be assumed in the context of an anxious response to the needs of a patient who might be in extreme need of immediate therapy. More precise protocols, including a requirement to refer issues to senior colleagues for definitive advice, would have been desirable. Without written guidance, there was inevitably a risk that junior staff, who might be satisfied that they knew the correct course of action, might act in a way that was inconsistent with the views of more senior colleagues.[187]

22.140 As observed by the patient interest core participants,[188] it is implicit in Professor Ludlam's evidence that it would have been beneficial (for him) to have had guidance from the CMO or government department, and that it would have been at least as beneficial for clear guidance to have been provided in turn for more junior members of his department.

22.141 The patient interest core participants have made a specific submission in these terms:

[I]nadequate steps were taken in light of the infection of a virgin patient in May 1986 in Edinburgh with NANB hepatitis to avoid a re-occurrence of this infection in similar patients around Scotland.[189]

22.142 As previously observed, the Inquiry had notice of two cases of transmission of NANB hepatitis to previously untreated patients in the relevant period, 1 September 1985 to 30 June 1987. There was no evidence available to the Inquiry of transmission of infection other than in the two known cases. It is not within the Inquiry's Terms of Reference to investigate specific cases other than as required to illustrate or inform general discussion. But the circumstances in which these patients were treated (one at night, without the involvement of the most senior haemophilia clinicians and the other in a remote part of Scotland) are precisely the sort of situations in which the need for up-to-date written guidance on the risks of NANB Hepatitis and the relative risks and benefits of the therapeutic products available was most pressing.


Availability of 8Y

22.143 The distribution of 8Y in England, Wales and Northern Ireland was strictly controlled under agreements between the BPL and the NBTS that provided for distribution of finished products pro rata to regions' supplies to the BPL of raw materials for fractionation.

22.144 It cannot be concluded on the evidence available that a barter or other arrangement could have been negotiated that might have procured a supply of 8Y for use in Scotland in exchange for reciprocal supplies of PFC products.

22.145 For these reasons, it is highly unlikely that regular supplies of 8Y would have been made available for use in Scotland.

22.146 It is the case, however, that BPL 8Y appears to have been available for use in Scotland on request in very limited quantities in exceptional circumstances at least from the middle of 1986.

22.147 A request for 8Y to treat a Scottish patient with haemophilia who had received little or no previous exposure to concentrates and who required treatment before the equivalent Scottish product was available was likely to have been successful if treated as part of the field trial of the product or if made ad hoc to satisfy particular and specific requirements of the patient's management acceptable to the BPL and the NBTS.

22.148 Once the arrangement for limited supplies of 8Y had been made in the summer of 1986 at the initiative of Professor Ludlam, no steps were taken to inform medical practitioners, in particular haemophilia treaters, that supplies of BPL 8Y might be procured even on a limited basis. There was accordingly a failure to provide information that could have informed clinicians of the possibility of obtaining access to the product in appropriate circumstances.

22.149 In addition, no steps were taken to draw to the attention of physicians outwith Edinburgh the fact that there was already a small stock of 8Y held there.

Blood product therapy in Scotland: 1985-87

22.150 UKHCDO's guidelines, dated 14 December 1984 and distributed as the 'Haemophilia Centre Directors Organisation AIDS Advisory Document', provided reasonable guidance for haemophilia clinicians to follow in practice in this period.

22.151 Those guidelines were distributed to Haemophilia Centre Directors. They were followed in Glasgow and Edinburgh, and probably at other Regional Haemophilia Centres with haemophilia directors.

22.152 There is, however, no evidence of the distribution of any guidance to practitioners in hospitals in Scotland which did not have haemophilia centres, who might find themselves dealing with a person with haemophilia in an emergency, on the use of blood products in coagulation disorder therapy.

22.153 It would have been the responsibility of the SHHD to have arranged for the provision of appropriate guidelines, probably in consultation with the UKHCDO and the Scottish haemophilia clinicians.

22.154 There is no substance in the suggestion that the issue of such guidelines by the SHHD would have infringed clinical independence in the management of individual patients.

22.155 Although guidelines for the service as a whole were less common in the period 1985-87 than they subsequently became, the principle of departmental guidance concerning the system of care for patients with haemophilia was established by 1976.

22.156 Guidance within institutions was a matter for the senior clinician in charge of haemophilia care and patient management.

22.157 Such guidance, in writing, was necessary, and it was necessary for it to be amended and updated as information available about therapeutic products, their effectiveness and likely side-effects changed with developing knowledge of the diseases to be treated.

22.158 Scottish Haemophilia Directors had no administrative authority to impose an obligation on each other or on clinicians in charge of haemophilia care in general hospital units to follow any such written guidance.

1 Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985, at paragraph 23.192.

2 Chapter 24, Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987, paragraph 24.157.

3 Chapters 15, Knowledge of Viral Hepatitis 2 - 1975 to 1985, and 16, Knowledge of Viral Hepatitis 3 - 1986 Onwards.

4 Chapter 24, Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987, paragraph 24.67.

5 Paragraph 9.326 of the Preliminary Report, drawing on information from the notes of a meeting held on 10 February 2000 [SGH.002.1597]

6 Report of Scottish Executive Inquiry, 2000 [SGH.001.4414] at 4419. From [SGH.002.1597], the number testing positive appears to be eight.

7 Letter from Dr Cachia to Dr Keel, 17 March 2000 [PEN.018.1483] at 1485

8 The possibility of double counting was mentioned at the meeting on 10 February 2000 [SGH.002.1597] at 1597

9 Professor Lowe - Day 54, page 60

10 The emergence of an understanding of the risk of NANB Hepatitis from concentrate therapy in the 1970s is dealt with in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985.

11 Day 19, pages 121-122

12 Day 54, pages 9-10

13 Note of the Haemophilia Reference Centre Directors Meeting, 10 December 1984 [SNF.001.3850] at 3853

14 Ibid [SNF.001.3850] at 3858

15 Ibid [SNF.001.3850] at 3859

16 Von Willebrand's disease.

17 Haemophilia Centre Directors Organisation AIDS Advisory Document, 14 December 1984 [SGF.001.2388] In evidence, Professor Ludlam confirmed that this document was 'pulled together' by Professor Bloom - Day 54, page 81

18 Professor Lowe - Day 54, page 17

19 Ibid page 18

20 Ibid page 19

21 Ibid page 22

22 Ibid page 24

23 In later questioning, Professor Lowe agreed that desmopressin becomes less effective after about 48 to 72 hours of use, and that it has some drawbacks with children in particular, principally fluid retention. See Day 54, pages 67-68.

24 Professor Lowe - Day 54, pages 25-26. Further discussion of the mechanisms involved in the use of desmopressin can be found in Professor Lowe's evidence at Day 54, pages 70-73.

25 Professor Lowe - Day 54, page 26

26 Ibid page 72

27 Ibid page 73

28 Ibid page 27. Professor Ludlam made the same point (see Day 54, pages 132-6): treatment with cryoprecipitate still carried a risk of NANB Hepatitis. Estimates given in evidence of the scale of the risk varied - plainly, this depended on the incidence of the virus in the donor population at the time. If the incidence was 0.4%, as it was found to be by Minor et al in their examination of donor samples ('Antibody to Hepatitis C virus in plasma pools', The Lancet, 21 July 1990 [SGF.001.1380]) then exposing a person to 250 donations in his life would be expected to cause infection. Professor Ludlam was more pessimistic, saying that an adult treated with cryoprecipitate for five days would 'almost certainly' contract NANB Hepatitis. See also Dr Colvin - Day 55, page 139. The incidence of Hepatitis C in the donor population is discussed more fully in Chapter 3, Statistics.

29 Professor Ludlam - Day 54, page 136

30 Professor Lowe - Day 54, page 30

31 Ibid page 33

32 Ibid pages 64-65

33 Ibid page 66

34 Ibid pages 40-41. UKHCDO data indicate that 8Y was first used in Glasgow Royal Infirmary and in Yorkhill in 1990.

35 Ibid page 44

36 Ibid page 46

37 Ibid page 47

38 Ibid pages 56-57

39 Ibid page 74

40 Professor Ludlam's statement on the use of blood product concentrates between 1984 and 1987 [PEN.017.1790]

41 Ibid [PEN.017.1790] at 1792

42 Ibid [PEN.017.1790] at 1793

43 Summarised from Professor Ludlam's statement on the use of blood product concentrates between 1984 and 1987 [PEN.017.1790] at 1794-5

44 Professor Ludlam's statement on the use of blood product concentrates between 1984 and 1987 [PEN.017.1790] at 1795

45 Professor Ludlam - Day 54, page 82

46 Ludlam et al, 'Antibodies to Hepatitis C virus in haemophilia', The Lancet, 2 September, 1989; 560-1 [LIT.001.3859]

47 Hay et al, 'Progressive liver disease in haemophilia: an understated problem?', The Lancet, 29 June 1985; 1495-7 [LIT.001.0335] This article, which reported finding progressive liver disease in 17 of 79 patients tested (these being patients selected for their exposure to blood products) is considered at Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985.

48 Professor Ludlam - Day 54, pages 85-86

49 Aledort et al, 'A study of liver biopsies and liver disease among hemophiliacs', Blood, 1985; 66:367-72 [LIT.001.0505]

50 Professor Ludlam - Day 54, page 88

51 Schimpf, 'Liver disease in haemophilia', The Lancet, 8 February, 1986; 232 [LIT.001.0341] at 0342

52 Professor Ludlam - Day 54, page 92

53 Ibid page 94

54 Ibid page 94

55 Colvin et al, 'A prospective study of cryoprecipitate administration: absence of evidence of virus infection', Clinical and laboratory Haematology. 1987; 9:13-15. [LIT.001.0640]

56 Dr Colvin - Day 55, pages 136-7.

57 Dr Colvin - Day 74, page 106

58 Ibid page 105

59 Professor Howard Thomas was referred in evidence to an article he co-authored with haemophilia clinicians: Kernoff, PBA et al, 'High Risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin', British Journal of Haematology, 1985; 60:469 [LIT.001.0800]. The article was submitted in 1984. In the conclusions, reference is made to patients with mild bleeding disorders now being 'more appropriately treated' with cryoprecipitate or desmopressin than with concentrates. See Professor Thomas - Day 52, pages 87-106. See also his further comments on cryoprecipitate at Day 52, page 156.

60 Dr Colvin - Day 55, pages 148-9

61 Ibid pages 151-2

62 Ibid page 156

63 Ibid page 157

64 Professor Ludlam's request for 8Y from England is narrated below at paragraph 22.54

65 Dr Colvin - Day 55, page 158

66 Information Sheet, Dried Factor VIII Concentrate: High-Purity, Heat Treated, issued to English and Welsh Haemophilia Directors and Regional Transfusion Directors by Blood Products Laboratory, 24 July 1985 [DHF.003.0476]

67 Dr Colvin - Day 74, page 89

68 Ibid page 90

69 Ibid page 92

70 Ibid page 103

71 See paragraph 22.21 above

72 The technical background to the achievement of this heating protocol in England is dealt with in Chapter 24, Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987

73 Professor Ludlam's statement on the use of blood product concentrates between 1984 and 1987 [PEN.017.1790] at 1791

74 Professor Ludlam - Day 54, page 99

75 Ibid page 100

76 Note of a meeting held at PFC on March 17 1986 [SNB.007.5664] at 5666. Dr Smith gave extensive evidence about the technological progress in developing 8Y and testing its effectiveness which is discussed elsewhere.

77 Professor Ludlam - Day 54, page 102

78 Minutes of the sixth meeting of the Central Committee for Research and Development in Blood Transfusion, 9 July 1985 [PEN.016.1142]. This meeting did not have representation from Scotland.

79 Information Sheet, Dried Factor VIII Concentrate: High-Purity, Heat Treated, issued to English and Welsh Haemophilia Directors and Regional Transfusion Directors by Blood Products Laboratory, 24 July 1985 [DHF.003.0476]

80 Professor Ludlam - Day 54, pages 106-107

81 Ibid page 108

82 Professor Ludlam - Day 55, pages 96-98

83 PFC Report for SHS Haemophilia/SNBTS Directors Meeting (March 1986) [SNB.001.5469]

84 Ibid [SNB.001.5469] at 5472

85 Professor Ludlam - Day 54, page 110

86 The Inquiry has a copy of a paper Surveillance of previously untreated patients for possible virus transmission by BPL Factor VIII and Factor IX concentrates, 8Y and 9A: Interim Report [SNF.001.1123], but the paper refers to information being summarised by Dr Jim Smith on 30 September 1986 - some revision of, or addition to, the paper must therefore have taken place between 22 and 30 September. The information quoted in paragraph 22.51 is drawn from the paper.

87 A fuller report, giving results in relation to 32 patients, was published as 'Effect of Dry-Heating of Coagulation Factor Concentrates at 80 c for 72 Hours on Transmission of Non-A, Non-B Hepatitis', The Lancet, October 8 1988; 814-816 [LIT.001.0330]. This was discussed by Dr Colvin in his report for this topic, [PEN.017.1674] and in evidence at Day 55, Page 145. Even this study did not fulfil the protocol for such research laid down by the International Society on Thrombosis and Haemostasis (ISTH) - Dr Colvin - Day 74, page 93.

88 See paragraph 22.46 above.

89 Professor Ludlam - Day 54, page 116

90 Dr Colvin - Day 55, page 143

91 Ibid page 144

92 Ibid pages 144-45; Dr Colvin's report on the use of blood product concentrates between 1984 and 1987 [PEN.017.1674]

93 Mannucci and Colombo, 'Virucidal Treatment of Clotting Factor Concentrates', The Lancet , October 1 1988; 782-785 [LIT.001.0456]

94 Dr Boulton's letter of 27 June 1985 to Dr Cash [SNB.007.5869]

95 Professor Ludlam - Day 54, page 119

96 Dr Boulton's letter of 17 June 1986 to Dr Perry [SNB.007.5871]

97 It appears that the patient was transfused in May 1986.

98 Professor Ludlam - Day 54, page 121

99 Ibid pages 129-130. See also Day 55, page 104, where Professor Ludlam accepted that this incident 'must have been part of the discussion'.

100 Professor Ludlam - Day 54, page 130. See also Day 55, page 112.

101 Ibid page 130-31

102 Ibid page 131

103 Dr Perry's letter of 2 July 1986 to Dr Boulton of [SNB.007.5909]

104 Dr Boulton's letter of 4 July 1986 to Dr Perry [SNB.007.5910]

105 Dr Boulton's notes [SNB.007.5911] The notes are shown in typed form in the Preliminary Report at paragraph 11.315.

106 Dr Perry's letter of 7 July 1986 to Dr Boulton [SNB.007.5913]

107 Dr Boulton's letter of 7 July 1986 to Dr Perry [SNB.007.5914]

108 Dr Perry's letter of 10 July 1986 to Mr Pettet [SNB.006.0336]

109 Mr Pettet's letter of 24 July 1986 to Dr Perry [SNB.007.5980]

110 Dr Perry's letter of 24 July to Dr Boulton [SNB.007.5982]

111 Dr Perry's letter of 24 July to Dr Smith [SNB.007.5984]

112 Dr Perry's letter of 28 July 1986 to Mr Pettet [SNB.007.5986]

113 Dr Smith's letter of 1 August 1986 to Dr Perry [SNB.007.5990]; Delivery note [SNB.007.5991]; Instructions for use [SNB.007.5992]

114 Dr Smith - Day 60, page 121

115 Dr Perry's letter of 5 August 1986 to Dr Boulton [SNB.007.6024]

116 Dr Perry's letter of 7 August 1986 to Dr Boulton [SNB.007.6048]

117 Professor Ludlam - Day 55, page 65

118 Ibid pages 141-2 and pages 119-120

119 Ibid page 120

120 Ibid page 121

121 Information Sheet, Dried Factor VIII Concentrate: High-Purity, Heat Treated, issued to English and Welsh Haemophilia Directors and Regional Transfusion Directors by Blood Products Laboratory, 24 July 1985 [DHF.003.0476]

122 Professor Ludlam - Day 55, page 109

123 Ibid pages 63-64

124 Dr Perry - Day 74, page 51

125 Ibid pages 53-54

126 Ibid page 56

127 Ibid page 57

128 Professor Ludlam - Day 18, page 7. Compare, however, other evidence set out at paragraph 22.87.

129 See paragraphs 22.8 to 22.9 above.

130 Professor Ludlam - Day 55, page 47

131 Ibid page 49

132 Ibid page 50-51

133 Ibid page 51

134 Ibid page 53

135 Ibid page 55

136 Ibid pages 55-56. See also page 87.

137 Ibid pages 58-60

138 Ibid page 69

139 Ibid page 71

140 Ibid pages 73-74

141 Ibid Page 75. See also pages 78 and 79, for evidence to similar effect.

142 Ibid page 76. See also pages 82-85.

143 Ibid page 86.

144 Professor Ludlam - Day 18, page 3

145 Ibid page 62

146 Professor Ludlam - Day 54, page 146. See 22.74 regarding the question of when the Scottish directors began meeting as a group.

147 Professor Ludlam - Day 54, pages 146-147

148 Ibid page 148

149 Ibid page 152

150 Ibid page 153

151 Professor Ludlam - Day 55, page 111

152 Ibid page 62

153 Ibid page 126

154 Ibid pages 126-8

155 CMO Letters - Comment by Dr Iain S Macdonald [PEN.018.0620], referred to at Day 74 page 109.

156 CMO Letters - Comment by Dr Iain S Macdonald [PEN.018.0620] at 0622

157 Professor Ludlam - Day 55, page 107

158 See Chapter 24, Viral Inactivation of Blood Products for Haemophilia Therapy 1985-1987, at paragraphs 24.132 to 24.137 for details of these events.

159 Dr Winter - Day 15, page 73

160 See paragraph 22.116 for further details.

161 List of issues proposed by Inquiry Counsel, 10 February 2012 [PEN.019.0843] at 0854

162 Professor Ludlam - Day 55, page 120. The Inquiry subsequently learned that this supply appears to have been arranged via Dr Boulton - see letter of 24 August 1987, [PEN.019.1535]. The letter indicates that Dr Boulton was exploring the possibility of obtaining a regular supply of 8Y from England.

163 Information Sheet, Dried Factor VIII Concentrate: High-Purity, Heat Treated, issued to English and Welsh Haemophilia Directors and Regional Transfusion Directors by Blood Products Laboratory, 24 July 1985 [DHF.003.0476]

164 DHSS circular [DHF.002.5543]

165 DHSS internal minute, 15 August 1985 [DHF.002.5542]

166 Dr Foster - Day 56, pages 50-51

167 Legal advice to the BPL at that time was to avoid sharing information with the PFC, for intellectual property reasons. Dr Smith - Day 60, pages 62-63.

168 Minutes of Central Committee for Research and Development in Blood Transfusion, 19 December 1985 [PEN.016.1152]

169 Professor Cash - Day 157, pages 153-5

170 Ibid page 156

171 List of issues proposed by Inquiry Counsel, 10 February 2012 [PEN.019.0843] at 0854

172 List of issues proposed by Inquiry Counsel, 10 February 2012 [PEN.019.0843] at 0854

173 Patient interest core participants: Submissions for the C3A Topic [PEN.019.0657] at 0657-59

174 Health Improvement Scotland (2013), Last accessed 13 May 2013.

175 McAlister G, The Scottish Intercollegiate Guidelines Network (SIGN), Guidelines in Practice, Vol 4, No 10. last accessed 17 June 2014.

176 Haemophilia Centre Directors Organisation AIDS Advisory Document, 14 December 1984 [SGF.001.2388]

177 Patient interest core participants: Submissions for the C3A Topic [PEN.019.0657] at 0663-64

178 Ibid [PEN.019.0657] at 0670-71

179 Professor Thomas's evidence at Day 52, pages 155-163 is general and rather second hand.

180 The appropriateness of involvement was disputed by the Scottish Government in its closing submissions [PEN.019.0274] at 0278 and 0335

181 As was submitted by the Scottish Government in its closing submissions PEN.019.0274 at 0278 and 0335

182 Family Practitioner Notice FPN 105 (HC(76)4) Organisation of Haemophilia Centres January 1976 [DHF.002.4280]

183 Health Circular HC(76)4 Arrangements for the care of persons suffering from haemophilia and related conditions, and accompanying memorandum February 1976 [DHF.001.2747] and [DHF.002.4280]

184 See references for example in minutes of meeting of Reference Centre Directors on 1 March 1982 [LOT.003.2907] at 2908 and in minutes of joint meeting of Haemophilia Centre Directors, SNBTS Directors and SOHHD on 12 May 1994 [LOT.003.1908] at 1913

185 See Chapter 26, Donor Selection - Higher Risk Donors, paragraphs 26.79 to 26.80

186 Patient interest core participants: Submissions for the C3A Topic [PEN.019.0657] at 0678

187 It is odd that there was no update of UKHCDO guidance between December 1984 and May 1988. But that would not bear on the need in Scotland to reflect in guidance changing knowledge of the effectiveness and relative infectivity of products.

188 Patient interest core participants: Submissions for the C3A Topic [PEN.019.0657] at 0679

189 Ibid [PEN.019.0657] at 0689

23. Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985 >