THE PENROSE INQUIRY
Final Report

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Chapter 27

Surrogate Testing of Donated Blood for non-A, non-B Hepatitis

27.1 This chapter deals with the topic of surrogate testing of blood donors for non-A, non-B Hepatitis (NANB Hepatitis) in the late 1980s. The chapter is divided into four parts: (i) an introduction to the topic, (ii) detailed narrative of events in the USA, Europe and the UK, (iii) discussion of the main issues that arise and (iv) the conclusions reached by the Inquiry.

Introduction

27.2 As indicated at the end of the last chapter, in the second half of the 1970s and early 1980s the existence of non-A, non-B viral hepatitis was first postulated and then established.^[1] There was, however, no serological or other test available for screening donated blood for markers of infection. In the USA a debate emerged as to whether to introduce tests for 'surrogate' (or 'indirect') markers of NANB Hepatitis infection and a programme of surrogate testing was eventually introduced there. Surrogate testing, described below, was not adopted in the UK generally or in Scotland in particular and the reasons for that became one of the issues for discussion at the Inquiry's public hearings of evidence. This chapter incorporates the Inquiry's discussion and findings related to that topic.

27.3 As more fully discussed elsewhere in this Report, the Hepatitis B virus (HBV) was identified in 1963,^[2] and screening of blood donors in Scotland for the Hepatitis B surface antigen (HBsAg) was introduced in the early 1970s. The Hepatitis A virus (HAV) was identified in 1973^[3] but was not associated with the transmission of hepatitis by transfusion. In 1974, however, a US study reported that an agent that was neither HAV nor HBV seemed to be responsible for a substantial proportion of cases of post-transfusion hepatitis.^[4] The term non-A, non-B Hepatitis came to be used for cases of hepatitis in which Hepatitis A and Hepatitis B were excluded.^[5]

Surrogate testing: ALT and anti-HBc as indirect markers of possible infection

27.4 Despite work by many researchers in the late 1970s and early 1980s, the virus responsible for most cases of NANB Hepatitis, the Hepatitis C virus (HCV), was not identified until 1988.^[6] In the meantime, research groups in the USA reported a correlation between elevated alanine aminotransferase (ALT)^[7] levels in donors and an increased risk of transfusion recipients developing NANB Hepatitis.^[8] The same research groups later reported an association between the presence of antibody to Hepatitis B core antigen (anti-HBc) in donors and an increased risk of NANB Hepatitis in recipients.^[9] It was therefore suggested that elevated ALT and/or anti-HBc might be useful 'surrogate markers' for NANB Hepatitis. A surrogate marker is a directly measurable physical entity (usually measured in a blood test) that correlates (has a statistical association) with a disease, where it is not possible to test directly for the disease or where any direct test would be problematic.

27.5 There were, however, difficulties with the use of either raised ALT or the presence of anti-HBc as surrogate markers for NANB Hepatitis.

27.6 The underlying difficulty with the use of surrogate tests to identify donors with NANB Hepatitis was twofold. First, such tests were by their very nature non-specific^[10] - there would be many 'false positives' where the test result for the surrogate marker (ALT or anti-HBc) was positive but the NANB Hepatitis virus (HCV) was not in fact present. Secondly, such tests also lacked sensitivity^[11] - there would be many 'false negatives' where the virus was in fact present, but was not detected because the test was not sensitive enough, precisely because it was not directly testing for HCV.

27.7 Despite the problems associated with using surrogate tests for the mass screening of donations, with the AIDS crisis and increasing knowledge of the potential seriousness of NANB Hepatitis infection, the arguments for introducing surrogate screening gained ground in the USA. The result was that surrogate screening of donors was first introduced in some centres in 1986 and very widely by 1987. The introduction of surrogate testing in the USA led to further consideration of the issue in Europe, including in the UK. While some European countries introduced surrogate testing of blood donors, most European countries, including the UK, did not.

27.8 In the event, the issue of surrogate testing was eventually superseded by the identification of the Hepatitis C virus - the virus responsible for most cases of NANB Hepatitis - in 1988 and the subsequent availability of a direct test which detected antibodies to that virus.

Events in the USA

27.9 This section sets out in detail the main events in the history of surrogate testing for NANB Hepatitis. Since developments in the USA formed a major element of the background to what happened elsewhere, and in the UK in particular, they are discussed first.

Developments in the USA to the end of 1985

27.10 Extensive research relating to the aetiology and natural history of NANB Hepatitis in the mid-1970s is discussed in Chapter 15, Knowledge of Viral Hepatitis 2. The debate on the effectiveness of screening of blood for ALT elevation and for the presence of anti-HBc as possible indicative markers of NANB Hepatitis infection emerged from that research. The debate took on added significance with the publication in 1978 of an interim report by the Transfusion Transmitted Viruses (TTV) study group,^[12] a project which arose in 1973 from an initiative of the Division of Blood Diseases and resources of the United States National Heart, Lung and Blood Institute, to assess the incidence and cause of post-transfusion viral hepatitis.

The Transfusion Transmitted Viruses study group

27.11 The TTV study was a major research exercise that began in 1974.^[13] The investigation was initially undertaken at blood transfusion centres in Los Angeles, St Louis and Houston and, from 1976, at the New York Blood Centre.^[14] Specimens from all patients enrolled in the study were tested for ALT activity following a standardised protocol and using the same reagents and standards. The same samples were also screened for markers of HBV infection, including anti-HBc.

27.12 The TTV group's interim report discussed the study of 1307 patients, followed between July 1974 and December 1976. There were 75 episodes of hepatitis among transfused patients, 10 of whom had been infected with HBV. The Inquiry's Terms of Reference did not require detailed discussion of the aetiology or natural history of HBV. The insensitivity of the available tests for Hepatitis B was a significant factor at this time, however, and a number of transfused patients still became infected despite screening. By about 1980 tests for HBV were more sensitive and this problem was materially reduced, though not eliminated. In analysing outputs from their research, the group used sophisticated techniques to identify potential correlations between specific cohorts of donors and recipients, and the ALT and other biometric values found. Volunteer donors alone were selected for this part of the study. Of the various outputs examined, it was found that only the highest donor ALT levels correlated with the development of post-transfusion NANB Hepatitis in recipients and that that correlation was more striking than the relationship with transfusion volume. It was tentatively concluded that there was a possible correlation between donors with markedly elevated ALT and an increased risk of recipients developing post-transfusion NANB Hepatitis.

27.13 The authors stated:

Since the TTV study is an on-going effort our sample size will continue to grow. Although our study suggests that screening donor units for ALT levels might be useful in reducing the incidence of non-A/non-B posttransfusion hepatitis, the data must be interpreted with caution since the number of patients analyzed to date is small. Also, there are a number of causes for an elevated ALT other than viral hepatitis, one possible reason why 41 of the 75 patients given blood with an abnormal ALT level did not develop evidence of hepatitis in serial follow-up. Furthermore, 30 of the 65 non-A/non-B cases received blood with normal ALT values.

....

Screening volunteer donor units for ALT may be useful in reducing the incidence of hepatitis although further study is warranted.^[15]

27.14 In 1978, Dr Harvey Alter and colleagues, who were conducting research at the US National Institutes of Health (NIH) into data on post-transfusion hepatitis from a number of countries, commented on the TTV study:

A finding of potentially great practical import was the observation in the TTV study that 30% of patients with [NANB] hepatitis received one or more blood units with an ALT of greater than 60 International Units/liter. This raises the possibility that donor screening for ALT might prevent some cases of [NANB] hepatitis, but it must be remembered that 70% of non-A/non-B cases received only blood with normal ALT and that 3% [sic - 56%^[16]] of blood units with elevated ALT did not result in hepatitis. This observation has vast implications for blood banks in that it will increase the time and cost of donor screening and will exclude a significant number of donors who probably do not represent a hepatitis risk. Nevertheless it is a provocative finding ....^[17]

27.15 Alter's group compared the donor ALT levels in their study group of patients with known cases of post-transfusion NANB Hepatitis transmission. They had limited data but commented that their initial findings did not substantiate the correlation suggested by Dr Aach in the TTV paper.

27.16 Before 1980 therefore, there was no consensus in the USA that ALT testing of donor blood would provide protection against the transmission of NANB Hepatitis.

27.17 A further report from the TTV study group, entitled 'Serum Alanine Aminotransferase of Donors in Relation to the Risk of Non-A, Non-B Hepatitis in Recipients, The Transfusion-Transmitted Viruses Study,' was published in the New England Journal of Medicine (NEJM) on 23 April 1981, ensuring wide circulation of the findings.^[18] This second article by Dr Aach and colleagues set out the history of earlier research and the controversy over whether ALT screening would provide an effective, routine method of donor evaluation. In common with other commentators,^[19] the TTV study had recognised that the exclusion of HBsAg-positive donors did not eliminate all cases of post-transfusion hepatitis, necessarily implying that an agent other than HBV was responsible for some cases of post-transfusion viral hepatitis. The report stated:

That observation directed the attention of the Study Group back to ALT screening of donors as one approach to reducing further the incidence of hepatitis in recipients ....

....

Systematically collected data for the period 1974 through 1979 now provide substantial evidence that the level of donor ALT is related to the occurrence of [NANB] hepatitis in transfusion recipients. The extent of the association is sufficient to raise the question of whether ALT screening of donors should be reconsidered.^[20]

27.18 The 1978 findings on ALT were confirmed. The article noted that, by this time, 1513 US transfusion recipients had been followed between 1974 and 1979 to evaluate the incidence of post-transfusion hepatitis and factors influencing its occurrence. The prevalence of post-transfusion NANB Hepatitis was 10%. At lower (low to normal) ALT levels the NANB Hepatitis 'attack rate'^[21] was 6% or lower. At higher ALT levels (definitely abnormal) the attack rate rose to 45%. The issue was clearly focused. The authors concluded that ALT testing was a potentially useful method of screening donors to reduce the incidence of post-transfusion NANB Hepatitis. The TTV group stated:

The observations in this report suggest that about 40 per cent of the cases of [NANB] post-transfusion hepatitis among recipients in this study could have been prevented by discarding units with an ALT level in the upper 3 per cent of the distribution (i.e. ALT ≥ 45 IU).^[22]

27.19 Having noted that the implementation of ALT testing would reduce the volume of blood available for transfusion, the authors continued:

Consequently, the benefits of initiating ALT screening must be carefully weighed against the number of potential donors that would be excluded, the overall incidence of hepatitis in recipients, and the severity of the disease.

....

Other considerations must be taken into account if widespread ALT testing of blood donors is to be initiated. These include the uncertainty about how long to defer a donor whose blood was rejected, as well as the problems that might occur in the quality control and proficiency of ALT testing on a nationwide basis. Advising donors of the implications of the ALT level would also pose a special problem. In addition, adjustments might have to be made for the observed differences between ALT levels in male and female donors and for the ages of donors. Nonetheless, it appears from this study that screening donor blood to eliminate units with elevated ALT levels would result in a substantial reduction in [NANB] post-transfusion hepatitis.^[23]

27.20 The paper concluded:

Although ALT screening lacks the sensitivity to detect all infectious units and lacks the specificity to detect only infectious units, the high correlation between an elevated ALT level and infectivity of transfused blood provides a compelling argument that such screening should be instituted.^[24]

27.21 In this paper, apart from noting that advising donors of the implications of findings posed a special problem (precisely because the test was a surrogate test that might indicate, but could not conclusively demonstrate, infection with NANB Hepatitis), little consideration was given to communication with, and care of, donors who were found to have elevated ALT levels.^[25]

The NIH Study

27.22 The proposal to introduce ALT screening did not meet with unqualified agreement. In an editorial in the same edition of the NEJM, Dr Paul Holland and colleagues (from the Clinical Centre Blood Bank, NIH: Dr Alter's group) argued against the immediate introduction of ALT testing.^[26] They acknowledged that the TTV study had presented the best evidence to date that blood donors with elevated ALT levels had a significantly increased likelihood of transmitting post-transfusion NANB Hepatitis but argued that the data did not support routine testing. 63% of patients receiving blood with elevated ALT did not get NANB Hepatitis and 7% of patients who received blood with below normal levels of ALT did apparently become infected. Predicting the outcome of implementation was problematical. They concluded that the 'manifold effects' of ALT testing had to be 'thoroughly considered' before wide-spread adoption of what would be an interim measure until specific tests for NANB Hepatitis viruses became available. The editorial commented:

The question is whether ALT testing of all blood donors should become routine. Is the expected benefit to the patient worth the drawbacks, especially to the donors and to the blood-service complex? In other words, what is the practicality of setting up ALT testing, and what is its impact? A number of questions have to be answered before adoption of the ALT test is to be recommended: How can the test be made uniform from one blood bank to the next? Above what level should donors be excluded? What should they be told when rejected, and should they be rejected permanently? Blood banks would have to add the cost of ALT testing to the cost of blood and recruit more donors to replace those rejected. Physicians would be asked to see patients with 'transaminitis'; for most, the cause would not be evident, nor would a treatment be forthcoming; hence there would be no means available to allay the apprehensions of these rejected donors. When compared with the test of hepatitis B surface antigen to detect carriers of hepatitis B, the ALT test is non-specific and would eliminate 10 to 20 times more blood donors. The manifold effects of ALT testing must be thoroughly considered before there is wide-spread adoption of such an interim measure (to be used until specific tests for non-A, non-B viruses become available).^[27]

27.23 At that stage, Dr Alter's group had itself completed a small scale study at the NIH which supported the TTV study group's data (discussed below). It noted that screening blood donors for ALT appeared to be a promising way to decrease the risk of transmitting hepatitis but it did not support the immediate introduction of screening. In substance they advised caution and developed their concerns in the published study report.

27.24 That NIH study into surrogate testing for NANB Hepatitis was reported on 7 August 1981.^[28] In it, 283 transfused patients were prospectively followed up after open heart surgery. All donors in the study were volunteers. Hepatitis^[29] developed in 9% of 231 patients who received blood from donors with normal ALT levels. In contrast, hepatitis developed in 29% of 52 patients who received blood from donors with elevated ALT levels. The NIH group stated:

The present study ... confirms the significant association of an elevated ALT level in donor blood and the development of recipient posttransfusion hepatitis; it suggests that pre-transfusion screening of donor blood for ALT level can identify some carriers of the NANB hepatitis virus and possibly prevent approximately 30% of transfusion-related hepatitis.^[30]

27.25 The paper went on:

It is important to emphasize the negative aspect of the donor ALT-recipient hepatitis relationship, namely, that 70% of PTH will not be prevented by screening donors for ALT. In addition, 40 (72%) of the 56 donors with elevated ALT levels were not associated with a case of PTH .... These imperfect correlations reflect the non-specific nature of the ALT test and emphasize that adoption of donor ALT screening will, at best, be an interim measure. Continued vigorous pursuit of a specific serological test for the agent or agents of NANB is mandatory.^[31]

27.26 The NIH group concluded:

For the blood recipient, the ALT test offers new hope for hepatitis prevention; for the donor, it offers new information, but perhaps information that is not really desired; for the blood supplier, it increases the complexity and cost of blood delivery and reduces the available amount of a product already in critically short supply. The ALT testing of donors is thus in a tenuous balance between risk and benefit. The balance shifts toward testing when one considers that approximately 30% of PTH might be prevented ... but this is tempered by the realisation that 70% will not be prevented and that even the prevention of 30% is in some doubt unless confirmed by a randomized clinical trial. The balance also shifts away from testing when one considers the estimated additional $20 million in the annual cost of blood in the United States alone and the potential national loss of 45,000 donors and more than 90,000 blood units. It is a difficult equation, whose solution will require thought and planning.^[32]

27.27 In subsequent correspondence in the following issue of the NEJM, the leader of the TTV group, Dr Aach, responded as follows to the suggestion that the recommendation to introduce screening was premature:

The [TTVS] Group did not recommend that routine screening of blood-donor ALT be initiated immediately on the basis of their findings presented in this article. A number of questions that we believed should be answered first were listed in the Discussion section of the paper .... The TTVS paper stressed the non-specificity and relative insensitivity of ALT screening as compared with the potential of a specific serologic assay for a [NANB hepatitis] virus (or viruses). A serologic assay is clearly preferable if and when it becomes available. However, despite more than five years of intensive effort by many investigators a confirmed, reproducible serologic test is not available, and even if it were developed in a research laboratory in the very near future, three to five years would be needed to adapt the test to large-scale screening. Until that time, screening of donor ALT might provide an interim means to reduce the incidence of [NANB] post-transfusion hepatitis in the United States ....^[33]

27.28 At this stage, then, two highly qualified research groups were converging on the view that ALT testing provided a promising possible approach to testing donor blood in the USA with the objective of limiting NANB Hepatitis virus transmission, pending the introduction of a specific serological test, but neither could mount an adequate argument on scientific grounds to justify immediate general implementation of ALT screening. Further, in its paper of 7 August 1981, the NIH group had developed the suggestion that, if populations with increased exposure to HBV also had increased exposure to the NANB Hepatitis virus, then the presence of antibodies to HBV might be used as an indirect measure of immunity to NANB Hepatitis.^[34]

Reaction to the studies

27.29 Following the 1981 reports by the TTV and NIH groups of a correlation between elevated ALT levels in donors and the development of NANB Hepatitis in recipients, the American Association of Blood Banks (AABB) set up an ad-hoc committee to consider the question of ALT testing of donors.^[35] The committee reported in 1982, concluding that the available evidence did not justify testing donors for ALT as a means of reducing the incidence of NANB Hepatitis. The committee listed its main concerns as follows:

1. The measurement of ALT, although a test for one aspect of liver function, is not a specific test for [NANB] hepatitis .... This lack of specificity will result in an intolerably high rate of unnecessary rejections ....

2. No study has shown that the actual elimination of donors with elevated levels of ALT will reduce the incidence of elevated levels of ALT posttransfusion, much less hepatitis ....

3. The significance of elevations of ALT after transfusion is unknown ....

4. There is insufficient information to establish a cut-off level that will separate acceptable from non-acceptable donors ....

5. The methods for ALT testing need to be evaluated ....

6. The effect on the donor base is unknown. The loss of an estimated three per cent of current blood donations may seriously stress the nation's already precarious donor supply. Studies on the effect of such reduction should be available to ensure that severe blood shortages do not cause more morbidity and mortality than might be prevented by universal testing .... More information is needed about the long- and short-term effects of an elevated ALT in otherwise healthy donors so that they and their physicians can be counseled appropriately.^[36]

27.30 Alter and Aach's publications were noted in Finland;^[37] Australia;^[38] Canada;^[39] the UK (see below) and elsewhere. In the USA, the results of a detailed economic analysis were published in November 1982.^[40] It was concluded that current information about clinically apparent post-transfusion NANB Hepatitis was not sufficient to provide the precision required to estimate the benefits of ALT testing for the purpose of policy decisions. Since there was no randomised prospective study showing that exclusion of blood from donors with elevated ALT levels reduced the incidence of either symptomatic or asymptomatic post-transfusion NANB Hepatitis, there was no way of establishing the appropriateness of the clinical model used in the analysis. Further, these deliberations were taking place against a background in which the natural history of NANB Hepatitis was largely unknown but was generally thought to be not very serious. Five years later this view would be changing.

The Vox Sanguinis forum and widening debate

27.31 In 1983, Vox Sanguinis, the journal of the International Society of Blood Transfusion, asked a number of transfusion doctors for their opinions on the following question: 'Based on your analysis of the benefits and costs of routine donor screening for ALT-GPT^[41] to reduce the incidence of post-transfusion non-A, non-B hepatitis in your blood services region, what action would you recommend on this matter?'^[42]

27.32 Dr Aach contributed to the forum.^[43] He rehearsed the factors supporting the need for caution, already set out by his TTV group and the NIH group; acknowledged that the cost/benefit ratio could not be assessed; and emphasised the uncertainty around the prospects of developing a specific test. Nevertheless, he argued that a decision could not be postponed indefinitely and, in what became something of a fall-back argument that some action was better than none, proposed that steps should be taken to develop instrumentation and standardisation of procedures with a view to implementing ALT detection. In his view, if a decision could not be taken, then a properly designed randomised study should be initiated immediately and a target date set for testing those donor populations in which an association with post-transfusion NANB Hepatitis had been established. Dr Rainer Müller from Germany, where ALT testing had been routine for many years for identifying parenchymal liver damage,^[44] thought that current practice there should not be abandoned.^[45]

27.33 In contrast to Drs Aach and Müller, most of the contributors did not support the introduction of ALT screening of donors without further research, in particular into the actual efficacy of ALT screening in reducing the incidence of post-transfusion hepatitis. In this group were William Bayer (Kansas, USA), Robert Gerety (Office of Biologics, USA FDA), Paul Holland (Clinical Centre Blood Bank, Bethesda, USA), Brian McClelland (SNBTS, Edinburgh), Ruthven Mitchell (SNBTS, Glasgow) and Henk Reesink and Eveline Reerink-Brongers (Amsterdam, Netherlands).^[46]

27.34 In a review article published in September 1983, Dr Jules Dienstag (Massachusetts General Hospital and Harvard Medical School) discussed the options for surrogate testing that had emerged by that date.^[47] For present purposes it is sufficient to note his views on testing for the Hepatitis B surface antigen (anti-HBs), anti-HBc and ALT.^[48] He was dismissive of anti-HBs testing, essentially on the grounds that there had been no confirmation of an association between anti-HBs in donor blood and enhanced risk of post-transfusion hepatitis in recipients. Relying on data from the TTV Study group, he commented that anti-HBc could theoretically serve as an indirect donor screening test: recipients of at least one unit of blood with anti-HBc were three times more likely to acquire NANB Hepatitis after transfusion than recipients of blood that was all negative for anti-HBc. The test would, however, involve the loss of twice the blood lost in ALT testing, without a corresponding advantage in recipient safety. His conclusions were:

If prospects for a specific test for NANB hepatitis were bright, this interim test might not be worth considering. On the other hand, an intensive search for serologic markers begun a decade ago has yet to bear fruit, and as many as 5-10 yr may pass before a specific, sensitive screening test is developed and introduced into practice. Therefore, despite the poor sensitivity and predictive value of the test, and despite the difficulties and questions generated by a policy of screening, ALT screening may be warranted until NANB-specific tests become available.^[49]

27.35 Dienstag noted that, although no policy to adopt ALT testing had been adopted officially, several large centres in the USA were screening and withholding blood with high ALT levels. Prospective studies were planned.

Continuing debate to 1986

27.36 The Vox Sanguinis forum was inconclusive but stimulated further debate. The data from the TTV Study that formed the basis of an association between raised ALT levels in donors and an increased risk of transfusion recipients developing NANB Hepatitis, were taken up and studied again in 1984 by Dr Cladd Stevens and others (New York and other US centres).^[50] This group analysed the data to test the hypothesis that '[e]pidemiologic circumstances predisposing donor populations to infection with hepatitis B virus may also favour exposure to [NANB] agents'. The issue was whether patients who received blood from donors who tested positive for anti-HBs and anti-HBc were at increased risk of developing NANB Hepatitis.

27.37 The authors reported an association between units of donor blood that were positive for anti-HBc and an increased risk of recipients developing NANB Hepatitis. Elevated ALT levels in donors had a similar association with NANB Hepatitis in recipients but would have resulted in fewer units of blood being discarded than would screening for anti-HBc (2.8% as against 5.1%). They did not find a statistically significant association between donors who were positive for anti-HBs and the development of NANB Hepatitis in recipients. The authors considered that 21.4% of cases of NANB Hepatitis might have been prevented by screening for anti-HBc, 29.9% of cases might have been prevented by screening for ALT and 39.2% of cases might have been prevented by screening for both anti-HBc and ALT. Adjusting these figures to take into account the incidence of NANB Hepatitis in non-transfused control patients resulted in figures of 33.3%, 47.4% and 61.2% respectively. Screening for both ALT and anti-HBc would have resulted in a loss of nearly 8% of donor units.

27.38 The authors emphasised that their calculations were only rough estimates of the potential impact of donor screening based on their data. Other critically important factors affecting the risk to recipients - such as the prevalence of NANB Hepatitis among donors and the susceptibility to infection among recipients - remained unknown in the absence of specific serological tests and were presumed to vary among both donor and recipient populations.

27.39 The paper noted that only eight per cent of anti-HBc positive donors had elevated ALT levels, with the result that 'these two markers identified overlapping, but different, donor subsets'.^[51] Having regard to the lesser quantity of blood that would be discarded by ALT screening when compared with anti-HBc screening, it was noted that 'the consensus of the study group is that ALT screening of donors is favored over anti-HBc screening'.^[52]

27.40 The same edition of the Annals of Internal Medicine also contained the following commentary by Drs Alter and Holland on the TTV study group findings:

The possibility that a specific marker for anti-HBc might be useful in detecting carriers of the [NANB] virus was an unexpected and confounding outcome of the TTV study. Of the potential explanations for this observation, the one favored by the TTV group is that persons exposed to the hepatitis B virus are also more likely to have been exposed to the [NANB] virus and, hence, that a marker for one is indirectly a marker for the other. This assumption would be more tenable if the same association could be shown for antibody to hepatitis B surface antigen (anti-HBs) because anti-HBs is an equally good indicator of past exposure to hepatitis B virus. However, in the TTV study, recipients of only anti-HBs positive blood were not at higher risk for [NANB] hepatitis, and in three previous studies no significant association between donor anti-HBs and recipient hepatitis was demonstrable.

....

If both the tests for ALT and anti-HBc are indirect indicators of the [NANB] carrier state, one by detecting subclinical liver disease and the other by indicating the likelihood of virus exposure, then both tests should detect the same [NANB] hepatitis carrier population. In fact, the tests do not .... These tests are identifying two different, seemingly high-risk populations. This dichotomy is disturbing, suggesting either that the tests are not really detecting carriers of [NANB] hepatitis and that their apparent association with [NANB] hepatitis is a statistical artifact, or that they are detecting two different carrier populations perhaps harbouring different agents for [NANB] hepatitis.^[53]

27.41 Alter and Holland commented as follows on the efficacy of surrogate testing:

The key question in this study is test efficacy: How effective would anti-HBc testing of donors be in preventing cases of transfusion-associated hepatitis? Unfortunately, true efficacy cannot be determined from this study or from the previous studies of ALT because none were randomized, controlled trials that compared tested blood with untested blood.^[54]

27.42 The reason for any association between anti-HBc in donors and an increased risk of NANB Hepatitis in recipients thus was, and in fact remains, something of a puzzle, as was the lack of overlap between the groups of subjects testing positive for elevated levels of ALT and anti-HBc. In his evidence to the Inquiry, Dr John Gillon, SNBTS, said:

[T]his has always been a huge puzzle to me and it's one of the things that instinctively did not make sense about this whole business. There should be a very considerable overlap, and there just isn't. And I think reading [what] Harvey Alter said then^[55] is what I felt. And I do remember at the time ... I tried to stratify theoretical hundreds of donors into categories who got 1 unit of blood, 2 units, 10 units, 20 units and worked on different prevalences of the putative infection, the ALT, [anti-HBc] and stratified them. And I became convinced that a lot of the association was coincidental, that it was entirely - well, not entirely but at least substantially a function of having a large volume of transfusion, so that ... patients who got, say, 15/20 units of blood at given prevalences were much more likely to get one thing and the other thing, more or less by coincidence, compared with people who only got one unit of blood, when it was much more unlikely that there would be a coincidence.

....

So I still don't have a satisfactory explanation for that, but it was part of the instinctive feeling that there was something going on here which was not just about you use a test and you identify somebody who might transmit [NANB] Hepatitis. So it was not as simple as that. And I remain convinced there was a statistical artefact. That doesn't mean that identifying people with high ALT wouldn't have prevented Hepatitis C but it does call into question the exact relationship between the two and the exact outcome if you did it prospectively.^[56]

27.43 In due course, later studies were carried out to investigate whether there was an association between donors testing positive for anti-HBc and an increased risk of NANB Hepatitis in recipients. While some studies found such an association,^[57] others did not.^[58] Of these later studies, the NIH study^[59] investigated whether the presence of antibodies to HBsAg in the donor correlated with the development of NANB Hepatitis in the recipient and, like the TTV study, found that it did not.

27.44 Dr Alter's views on surrogate testing in 1985 were as follows:

The question of whether or not the ALT test should be routinely adopted for donor screening was widely debated and currently remains an essentially unresolved issue. Inherent in the debate were questions as to whether the predicted efficacy could actually be achieved in clinical practice, and questions relating to test standardization, non-specificity, responsibility to the donor and the ability to sustain the donor loss which would ensue. The major organizations of the national blood delivery complex, ARC,^[60] AABB^[61] and CCBC,^[62] opted not to adopt routine donor ALT testing until additional data were available, whereas the New York Blood Center initiated such testing and subsequently proved its feasibility though they did not accumulate additional efficacy data.^[63]

27.45 Dr Alter referred to a small-scale prospective study carried out by the NIH into the impact of ALT testing on the incidence of post-transfusion hepatitis. In 1981 the NIH had introduced ALT testing and had excluded all blood donations with high ALT levels. Perhaps surprisingly, it was found that '[t]he incidence of NANB hepatitis in the 3 years post-ALT testing was virtually identical in both patients and non-transfused controls to that in the 2 years prior to ALT testing'. That is, there was no significant decline in the incidence of hepatitis after ALT testing was introduced. Alter observed that, therefore, '[e]fficacy cannot be reliably predicted; it must be randomly and prospectively demonstrated'.^[64]

27.46 Dr Alter set out three options in respect of ALT testing: (i) to decide that existing data were inconclusive and that, given the difficulties with ALT testing, it was best not to adopt such screening at that time; (ii) to decide that, although the data relating to ALT efficacy were not definitive, they were scientifically valid and, overall, were sufficiently compelling to warrant the introduction of donor testing and (iii) to decide that existing data were inconclusive but were sufficiently compelling that a definitive answer must be sought by means of a randomised, controlled study, to be instituted as rapidly as possible. Dr Alter noted that implicit in the second option was the assumption that 'if an interpretive error is to be made, it is best to err on the side of recipient safety and that to withhold such testing is ethically unjustified'.^[65]

27.47 Dr Alter's preference was for the third option:

It is my opinion that option 3 is the most tenable alternative. Had this controlled study been performed three years ago when first proposed, a definitive answer would be at hand. Instead, the same uncertainties persist. A randomized, controlled trial could be completed in 1½ years, could address both the ALT and anti-core issues and could provide a definitive and rational basis for making these complex decisions. Even at this late date ... we find ourselves still far from the core (or the ALT) of this issue.^[66]

27.48 In the period 1984-85, therefore, scientific opinion in the United States remained divided on the usefulness of surrogate testing, whether for anti-HBc or for ALT. Neither could be fully justified on scientific criteria alone but practical steps were beginning to be taken by some blood transfusion organisations to implement ALT testing - an understandable approach in a litigation-driven society such as the USA. In the event, no definitive controlled study, as proposed by Alter, was ever carried out in the USA.

1986: A change of direction in the USA

27.49 On 21 February 1986, Blood Bank Week, the official publication of the AABB, reported that:

The Blood Products Advisory Committee of the Food and Drug Administration will recommend that both ALT and anti-core testing be performed on donated blood to reduce the incidence of transmission of [NANB] hepatitis through transfusion. In a February 13-14 meeting, the panel received reports on two studies showing that recipients of blood from donors with elevated ALT and anti-core had a higher incidence of NANB hepatitis.^[67] While questions were raised about the data, it was noted that the carrier rate of NANB is higher than previously thought, that cases are underreported and that NANB is now considered to be a much more serious disease.^[68]

27.50 The views of Dr Alter on the introduction of surrogate testing appear to have changed around this time. While, as discussed above, Dr Alter had expressed the view in 1985 that a randomised prospective study into the efficacy of surrogate testing in reducing the incidence of post-transfusion hepatitis should first be carried out, in February 1986 he co-authored a paper with Dr Dienstag in which the opinion was expressed that, despite the negative features of ALT and anti-HBc screening already reported:

[T]he accumulating data that chronic NANB hepatitis leads to cirrhosis in 10 to 20% of cases has served as compelling evidence for the need to rely on indirect assays as an interim measure until such time as specific NANB hepatitis assays are developed .... [I]ncreasing documentation of the chronic sequelae of NANB hepatitis and the continued high incidence of this disease after transfusion have tipped the balance in favour of adopting indirect assays for NANB hepatitis carrier detection.

....

Specific therapy for either acute or chronic NANB hepatitis is not available .... In the absence of effective treatment, the need for prevention assumes even greater importance.^[69]

27.51 In this careful review no new scientific evidence was produced to support a change of opinion on the sensitivity or specificity of either surrogate test for NANB Hepatitis. The major participants in the 'blood delivery complex' were at the time considering the adoption of either the ALT test or the anti-HBc test or both. Dr Alter might be thought to have bowed to the inevitable consequences of pressure from the blood delivery complex, although increasing evidence of the potential seriousness of NANB Hepatitis infection emerging in the USA and Europe, compared to what had been perceived to be the position about four years earlier, was clearly influential and was taken into account in this landmark opinion. A similar view was expressed by Dr Alter's NIH group in April 1986 when the authors re-visited their earlier data to investigate further the association between anti-HBc in donor blood and the development of transfusion-associated hepatitis.^[70]

27.52 Two factors entered into the decision whether to adopt either test: the unlikelihood that a specific test would become available in the near future and the developing knowledge of the severity of NANB Hepatitis. It was now estimated that up to 7500 cases of cirrhosis might be induced annually in the USA by NANB Hepatitis. The high risk of developing progressive liver disease resulting in serious liver damage tipped the balance for Dr Alter's group:

If, as predicted, surrogate screening of blood donors could prevent approximately one third of these cases [of NANB Hepatitis], then this could represent an annual reduction of 50000 cases of hepatitis and 2500 cases of cirrhosis. The potential to achieve this degree of disease prevention now appears to outweigh the disadvantages inherent in the adoption of surrogate tests for the [NANB] virus carrier state.^[71]

27.53 In August 1986, the AABB recommended that all donor blood be tested for ALT and anti-HBc with effect from 30 November 1986 in an attempt to reduce NANB Hepatitis transmission.^[72] Despite the difficulties with surrogate screening, the AABB believed that 'the importance of a potential increase in the safety of the blood supply outweighs the negative aspects of this testing'. As discussed so far, the scientific basis for this view remained questionable but the perceived interests of patient recipients had influenced the decision.

27.54 In his evidence to the Inquiry, Professor Juhani Leikola of the Finnish Red Cross Blood Transfusion Service accepted that patient safety was a factor behind the introduction of surrogate testing in the USA.^[73] However, the impression of the experts attending the meeting of the Expert Committee of the Council of Europe in May 1987, discussed below, was that the decision in the USA to introduce surrogate testing had also been taken for non-scientific reasons, in particular because the transfusion community had been criticised for being slow to react to the AIDS crisis and because of the fear of litigation. He also stated that the information from the TTV and NIH studies had made it clear that NANB Hepatitis was a serious risk associated with transfusion.^[74] He explained that important factors in the USA were 'the higher incidence' of NANB Hepatitis than seemed likely in northern Europe and also 'public opinion and media coverage'.^[75]

27.55 Surrogate testing was introduced generally in the USA between 1986 and 1987. In an article published in Nature on 4 September 1986, the positions adopted by the major bodies were summarised.^[76] The AABB, as noted above, expected its members to implement surrogate testing (apparently by raised ALT levels) of all donated blood, by 30 November 1986. The American Red Cross was also implementing ALT testing at its blood banks. Its programme had begun on 7 July and was expected to be completed by 1 October 1986. A third organisation, the Council for Community Blood Centers (CCBC), had not officially declared a position on ALT testing but its President was reported as saying that 'most members [would] go ahead with ALT testing'. The article stated that the use of anti-HBc testing was far more contentious. A major concern for all blood centres was the loss of donors due to false positives in both surrogate tests and the cost of testing. Notwithstanding these concerns, the President of the AABB considered that the tests were 'essential to increase the safety of the blood supply'.^[77]

27.56 Throughout the period of developing thought, from the paper by Aach and others in 1981 to the observation of the AABB last quoted, the emphasis was on reducing risk for transfusion recipients. There was relatively little discussion of the implications for donors found to have significantly elevated ALT levels or of the need for care and counselling of such donors.

27.57 For the time being that concluded the issue in the USA. The history provides an appropriate point of reference for discussing events in Europe where, among other significant differences, there was considerably more concern about donors' interests.

The European response

27.58 In his written evidence to the Inquiry, Professor Leikola set out the position in Europe in the early to mid-1980s, referring in the first place to the AABB view in 1982 that ALT screening of donors was not justified:

In the early 1980's the conclusion by the AABB ad hoc committee was considered reasonable, and there was no move in Europe to introduce surrogate testing. It was recognized that the incidence of NANBH varied from country to country and in different donor populations. In northern parts of Europe there were less cases of NANBH than in the south, and there were differences between urban and rural populations. Australia was considered to belong to the lowest prevalence countries, similar to Northern Europe and dissimilar to the United States.

There was a general feeling that more information was needed of the possible correlation between screening for surrogate markers and prevention of NANBH. The journal Vox Sanguinis published in 1983 nine short articles .... All contributors took a cautious view on ALT screening.

....

The American finding that anti-HBc correlated with NANBH was disturbing and could not be explained .... There were soon reports appearing, notably from France, the Netherlands and the United Kingdom, showing that in the European donor populations studied anti-HBc did not correlate with recipient NANBH. The pattern was clearly different from the American donors: Incidence of NANBH much less and anti-HBc meaningless as a surrogate marker. There was some association between elevated ALT and recipient NANBH, but its efficacy as a possible surrogate test was considered weak. This view was supported by the negative findings of the NANBH incidence after ... ALT screening in Germany on one hand and in the New York Blood Center and at the NIH on the other.^[78]

27.59 There was soon progress. Professor Leikola continued:

After the American organizations decided to recommend the introduction of routine ALT and anti-HBc testing it was necessary to decide also in European countries whether or not to follow ... suit. There was a consensus among the scientific and blood transfusion expert community that prospective studies were urgently needed before a decision could be taken.^[79]

27.60 The Council of Europe Committee of Experts on Blood Transfusion and Immunohaematology met in May 1987.^[80] The general impression from the returns to questionnaires sent to Member states was that the incidence of NANB Hepatitis was rather low but varied widely among different regions. The value of surrogate tests such as ALT and anti-HBc had been studied by various groups but there was doubt about their cost and effectiveness. After discussion by the Committee, it was decided that a working group would prepare a report and, if possible, make recommendations. In due course the working group reported and, in summary, concluded:

(i) The use of a non-specific test for the purpose of reducing the incidence of transfusion-associated NANB Hepatitis and its possible value as a public health measure remained controversial issues.

(ii) If a stance was taken that blood should be as safe as possible, then tests would be introduced, but the benefits derived from this testing would not be uniform throughout every country. There was also no guarantee that, in a given country, there would be a significant reduction in the transmission of NANB Hepatitis.

(iii) The introduction of non-specific tests might compromise the blood supply and this was a factor which had to be taken into account.

(iv) When non-specific testing was introduced in a country, provision would have to be made for the interviewing, counselling and further medical examination and treatment which might be required for donors found to have raised ALT levels or who were anti-HBc positive.

(v) The Committee could not make a general recommendation on the routine introduction of non-specific tests for evidence of the NANB Hepatitis infectivity of blood donors. Individual countries would have to assess the situation locally and decide on the appropriate action to take.^[81]

27.61 In his written evidence to the Inquiry Professor Leikola stated:

Most countries that I know elected in 1987 not to blindly follow what the Americans did but to first find out the situation in their own donor population. Thus, the attitude towards surrogate testing was not negative per se, but before making a decision in Europe the expert community wanted to know whether the concept would really produce results.^[82]

27.62 Professor Leikola explained that, in Finland, the decision of the US blood banks in 1986 to commence surrogate testing prompted further consideration of the issue by the Finnish blood transfusion service which, in 1987, decided to undertake a new study 'to determine the current incidence and types of post-transfusion hepatitis among open-heart surgery patients from all parts of Finland.' A second objective was 'to obtain donor samples for future evaluation of possible preventive strategies'.^[83] A doctoral student was engaged to organise the study and the service had the resources to collect and analyse the samples.^[84] The study began in the beginning of December 1987 and lasted one year. It was carried out at all five of the Finnish university hospitals and included 685 patients and 8346 donors. Several candidate surrogate markers were investigated, as were (retrospectively) tests for antibodies to HCV once they became available.^[85] A correlation between elevated ALT levels in donors and an increased incidence of post-transfusion NANB Hepatitis in recipients was established.^[86] In his oral evidence Professor Leikola said that Finland did not introduce ALT testing before the study was done and that that reflected the general view in the mid-1980s of the European transfusion community, that surrogate testing was not something to be started without first performing such a study.^[87]

27.63 The situation in Europe generally in 1989 was set out in a document compiled by Dr Harold Gunson^[88] on behalf of the Council of Europe's Committee of Experts following their meeting in May 1989. Significantly, by this stage it was known that Chiron had discovered HCV (see paragraphs 27.238-27.241 below) and that an anti-HCV test had been developed (see Chapter 31, The Introduction of Screening of Donated Blood for Hepatitis C). The document stated:

1. Replies to the questionnaire were received from 10 countries.

2. Examination of the replies revealed that in 4 countries routine screening of donations with ALT is being performed. These countries are the Federal Republic of Germany, France, Malta and Switzerland. Anti-HBc is routinely performed in France.

3. There are several studies being undertaken in some countries to determine the policies which should be undertaken to protect the blood supply with respect to the transmission of [NANB] hepatitis. These countries are Denmark, Norway, United Kingdom and Finland.

4. There is clearly an interest in the Chiron anti-HCV test and several countries are planning to conduct trials with this test.

5. There is a potential difficulty with respect to the use of the surrogate ALT and anti-HBc testing of donations with particular reference to source plasma for fractionation. The practice of routine ALT testing by the Federal Republic of Germany for many years means that plasma or its fractions, cannot be imported into that country unless the starting plasma has been ALT tested. This could have considerable implications for the standardisation of the quality requirements for plasma in 1992.^[89]

27.64 In his evidence to the Inquiry Professor Leikola explained:

In Europe, France was one of the few countries which decided to go for surrogate testing any way. ALT testing became mandatory in April 1988. In the aftermath of the "tainted blood affair" (HIV contaminated blood) the decision is understandable. It was not motivated by ... scientific knowledge but by ... political necessity. Something had to be done, whether or not it truly reduced the risk of NANBH transmission by blood. Northern countries with low NANBH incidence such as the Netherlands, Denmark, Norway, Sweden and Finland decided not to introduce surrogate testing before more was known of the efficacy in the respective donor populations. There were many articles published by UK authors in the Lancet and Vox Sanguinis advising against a hasty introduction of surrogate testing.^[90] These opinions in the prestigious medical journals were not without influence in the international community.^[91]

27.65 Professor Leikola agreed with the suggestion that the introduction of surrogate testing was 'a sort of emotional reaction to the situation that says we really have to do something, rather than a scientific or logical answer to the situation'.^[92]

27.66 In a 2001 court case, A v The National Blood Authority and others,^[93] it was noted that, '[n]ot many countries apart from the United States (both tests) and Germany (ALT only) introduced surrogate tests'.^[94] The full picture was stated to be as follows:

Table 27.1: Introduction of Surrogate Testing

Germany	1965	ALT[95]
Italy	1970	ALT[96]
USA	Sep 1986 onwards	Both[97]
Luxembourg	1 Oct 1986 Mid 1987 onwards (for new donors)	ALT Anti-HBc
France	15 April 1988 3 Oct 1988	ALT Anti-HBc
Switzerland	1 June 1988	ALT
Malta	Early 1989	ALT

27. 67 It was also noted that:

There was some partial routine ALT testing in certain centres in Austria, Belgium and Spain, from about 1987, and Queensland (alone of the Australian states) introduced compulsory ALT testing in about April 1989. Dr Högman told the Council of Europe in 1987 that Sweden was to introduce anti-HBc testing for first time donors, but he explained in evidence that this was intended in fact as a supplementary Hepatitis B screening. No other countries, so far as is known, ever introduced either test.^[98]

27.68 From the above, it is apparent that most European countries did not introduce surrogate testing of blood donors on account of the association of ALT with NANB Hepatitis^[99] and that, with the exception of France, those that did carried out their own preliminary evaluations before doing so.

27.69 As reflected in Professor Leikola's evidence, there were particular concerns about the relevance of the anti-HBc test. There seemed to be no logical basis for a correlation between the presence of antibodies to one disease in donors (Hepatitis B) and the presence of a different disease in recipients (NANB Hepatitis). The most plausible theory appeared to be based on 'lifestyle' factors, in that a donor whose lifestyle (such as injecting drug use) exposed them to HBV infection might have been at a higher risk of being exposed to other blood borne diseases such as NANB Hepatitis. The difficulty with that hypothesis was that, if it were correct, one would also have expected there to be a correlation between the presence of HBsAg in donors (which was an indicator of Hepatitis B infection) and recipient incidence of NANB Hepatitis. The TTV and NIH studies did not find such a correlation. In addition, while some studies showed a correlation between donor anti-HBc and recipient NANB Hepatitis, other studies showed no such correlation.^[100]

27.70 As regards the possible correlation between anti-HBc and NANB Hepatitis, Professor Leikola observed:

[M]ost people thought that ... it really doesn't make any sense and therefore these European studies that showed that there was no correlation between [anti-HBc] and [NANB] Hepatitis was, for me at least, a relief, to see that ... it wasn't logical to include hepatitis core antibody in this whole exercise, and therefore I was quite happy to see that it was confirmed in our material and also in the other European [studies].^[101]

27.71 To this day it is quite unclear why some studies found this association.

The position in the United Kingdom

27.72 Having regard to the variety of positions adopted in Europe, it is clearly necessary to consider developments in the UK specifically. There are, however, some points that should be kept in mind. Until the developments in 1986 described above, there was no consensus in favour of the adoption of surrogate testing in the USA and still less in Europe. When the introduction of surrogate testing became a real issue for blood transfusion services, following the advice of the AABB in the USA, it was recognised that the decision for individual regions had to be taken in light of local factors that required specific investigation. There were also other developments that would inevitably have had a bearing on the course adopted. For example, in the UK progress with virus inactivation would inevitably have become a consideration in assessing the cost/benefit balance of implementation as far as blood products (particularly coagulation factor concentrates) were concerned.

1970s to early 1980s

27.73 In the late 1970s there were no reliable data on the prevalence of NANB Hepatitis in the UK. The Medical Research Council (MRC) report published in 1974 has already been mentioned.^[102] In his evidence to the Inquiry, Dr McClelland stated that when he read the 1974 study in the early 1980s he realised that it did not really tell relevant practitioners what they needed to know.^[103]

27.74 As discussed more fully in Chapter 15, Knowledge of Viral Hepatitis 2 - 1975-1985, the discussions in the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody led to an ad hoc meeting at the MRC on 12 February 1979 to consider the question of NANB Hepatitis.^[104] The meeting concluded that a survey of post-transfusion hepatitis was not warranted.^[105] Professor Cash commented that the decision was a serious blow to those BTS colleagues who believed that surrogate testing of blood donations in the UK should only be considered when appropriate prospective studies had been carried out. In Scotland, research showing that there was NANB Hepatitis infection in the blood donor population began to produce results only in the second half of 1979.^[106]

27.75 Following the meeting at the MRC in February 1979 a Working Party on Post-Transfusion Hepatitis was set up and met for the first time on 14 February 1980.^[107] The Working Group was chaired by Dr Gunson.^[108] Its functions included examining the position of research to characterise the agent(s) associated with NANB Hepatitis and to derive diagnostic tests.

27.76 At that meeting, Dr McClelland advised that work was progressing at the South East Scotland Regional Transfusion Centre (RTC) into the problem of NANB Hepatitis associated with blood transfusion and suggested that a multi-centre study might be sponsored by the MRC into the problem of transfusion-associated NANB Hepatitis transmission. The minutes state: 'It was agreed, however, that this matter should be deferred until candidate laboratory tests were available'.^[109]

27.77 It was noted at the meeting that the following problems required investigation: (i) the identification of donors and units of blood associated with possible cases of NANB Hepatitis; (ii) research into methods of identifying the viruses associated with NANB Hepatitis and (iii) epidemiological surveys to assess the size of the problem in relation to blood transfusions. The minutes record that, following the ad hoc meeting at the MRC in February 1979, three special project grants had been supported for research into the incidence, epidemiology and clinical features of NANB Hepatitis and a fourth would probably soon be approved. It was noted that it was 'open to the Working Party to initiate fresh projects in this field'.^[110]

27.78 The second and, as it turned out, last, meeting of the MRC Working Party was on 25 June 1981.^[111] At that meeting Dr McClelland tabled a protocol for a prospective study of post-transfusion hepatitis in the UK (to be carried out at Edinburgh and Manchester) based on the protocol used in the TTV study.^[112]

27.79 Dr McClelland had reported to a meeting of SNBTS Directors on 23 June 1981 that he had prepared the protocol for presentation to the MRC on 25 June for a two-centre study. The directors agreed that similar studies might be made in Scotland generally. Discussion noted at the meeting recorded that:

Dr McClelland offered to circulate to the Directors the text of a leading article in the New England Journal of Medicine of 23 April 1981 and (if the MRC permitted) the document which he had prepared for the MRC. Scottish Directors would not proceed with liver function tests on existing donations for the time being.^[113]

27.80 The objectives of Dr McClelland's proposed study included: (i) to establish the incidence and causes of transfusion-related hepatitis; (ii) to establish the incidence of elevated ALT in donors to evaluate the effectiveness of methods of donor screening; (iii) to establish a library of samples for future serological studies; (iv) to provide data for assessing the effectiveness of any new methods of donor screening and (v) to establish the long-term outcome of post-transfusion NANB Hepatitis by prolonged follow-up of all cases identified. Dr McClelland emphasised the desirability of obtaining accurate data concerning the incidence of transfusion-transmitted NANB Hepatitis in the UK.

27.81 The minutes of the June 1981 meeting of the MRC Working Party note Dr McClelland's position when tabling his protocol:

Apart from the desirability of obtaining accurated [sic] data concerning the incidence of [NANB] transfusion hepatitis in the UK, it was also important to obtain information as to whether the screening of blood donors by the [ALT test] might be of value in the UK. It was also essential to obtain well documented specimens of serum from known cases of [NANB Hepatitis] for evaluation of any tests which might be of value for the diagnosis of this disease, and the screening of blood donors.^[114]

27.82 In oral evidence, Dr McClelland repeated his belief that it was essential to assess the importance of the NANB Hepatitis problem as a basis for the planning and evaluation of future donor screening strategies.^[115]

27.83 Dr McClelland's proposal had noted that there had been no prospective study in the UK of the incidence of sub-clinical hepatitis following transfusion of blood or single-donor blood products. That provoked a reaction from Professor Arie Zuckerman of the London School of Hygiene and Tropical Medicine.^[116] The minutes note that Professor Zuckerman pointed out that a study had already been undertaken in the 1970s and that the sera from that study were available for the evaluation of any candidate tests for NANB Hepatitis.^[117] A fresh study could cost from £50,000 to £100,000 to undertake. In Professor Zuckerman's view, a 'careful evaluation' of the need for such a project should be carried out before the Working Party could recommend to the MRC that a fresh study should be sponsored as 'the administrative difficulties encountered in the last project had been very hard to solve'. It was also noted that an evaluation of ALT screening of blood donors had been carried out at North West Thames RTC, Edgware, and that problems had been encountered as it had proved difficult to trace the fate of donors found to have raised ALT values.^[118]

27.84 In his evidence to the Inquiry, Dr McClelland explained that he had felt encouraged by the discussion at the meeting in February 1980 and particularly the reference to establishing fresh projects to produce proposals. Professor Zuckerman was very eminent, however, and his view, which carried particular weight, was that a study into post-transfusion hepatitis had already been carried out (the MRC study reported in 1974) and 'it didn't need to be done again'.^[119] The Minutes record that Professor Zuckerman left the meeting before discussion of this topic was concluded. Dealing with the period after his departure, the minutes note that the Chairman, Dr Gunson, would write to Professor Zuckerman and to Professor Sheila Sherlock of the Royal Free Hospital, London, to see if the patient records and serum samples from the previous MRC study were still available and that 'Dr McClelland's project could then be reconsidered in the light of the specimens and clinical data available from the earlier study'.^[120]

27.85 In the event, the MRC Working Party did not meet again. The Working Party's parent committee, the MRC Blood Transfusion Research Committee, was disbanded in July 1982, the MRC Board having concluded, in the light of activities of outside bodies and the proposal to set up a British Society of Blood Transfusion, that the committee's work was being duplicated elsewhere.^[121] This view was not shared by Professor John Cash, Medical Director of the SNBTS, who tried unsuccessfully to form a joint UK transfusion services' research committee to fill what he saw as a gap.^[122] He was concerned in particular because he knew as a council member of the recently formed British Blood Transfusion Society that the Society could not fund the studies advocated by the sub-committees of the MRC Blood Transfusion Research Committee.

27.86 In addition, the sera from the earlier MRC study would turn out to have been destroyed. Dr McClelland, who was perplexed by the decision of the MRC Board,^[123] persisted in his efforts to persuade colleagues of the need for a study. That position would be vindicated in 1987 by the Council of Europe's Committee of Experts on Blood Transfusion and Immunohaematology, as described by Professor Leikola and discussed above, although Dr McClelland considered, and continues to believe, that it was by that time too late. It will be necessary to return to a discussion of that matter later. In the meantime, further research was ongoing.

27.87 An editorial in The Lancet in July 1981 gave the flavour of the thinking at that time.

Despite 40 years' efforts to find ways of preventing it, hepatitis still arises after transfusion of blood and blood products. The discovery of the hepatitis B virus and the development of increasingly sensitive tests for markers of hepatitis B infection was a major step forward, but a bigger contribution came from the recognition that paid blood donors, probably because of their lower socioeconomic status, were much more likely to transmit hepatitis than unpaid donors. In the United Kingdom, since the introduction of hepatitis B screening, transfusionists seem to have been mesmerised by this one virus and the thrust of hepatitis prevention has been towards introducing ever more sensitive tests for it, even though the evidence is that little additional protection is gained from tests more sensitive than the widely used haemagglutination assay. When non-A non-B hepatitis was first recognised, many British workers seemed to regard it as a purely American problem. Lately, non-A non-B hepatitis has been accepted in the U.K. as a serious hazard of treatment with factor VIII and factor IX concentrates, which are prepared from very large pools of donor plasma, but no-one has paid much attention to this type of hepatitis in the patient who receives a few units of blood or platelets. In a UK prospective study of post-transfusion hepatitis,^[124] frank hepatitis developed in 1%, there were sustained increases of alanine aminotransaminase (ALT) in 4.5%, and the ALT was raised at some time after transfusion in 20%. Although only a small proportion of these cases of hepatitis and "transaminitis" seemed to be due to hepatitis B virus, nothing has been done to assess the value of preventive methods other than hepatitis B screening.

American workers have been less complacent.^[125]

27.88 The editorial traced some of the developments in the USA suggesting a need for careful examination and proceeded:

There are some other questions. How important in clinical terms is silent transaminitis after transfusion? Although regular users of blood products do get chronic liver disease which is probably due to non-A non-B agents, there is not much information about the long-term consequences of subclinical hepatitis after a single transfusion episode. In the U.K. there is no report about long-term follow-up of transaminitis patients from the earlier study. Furthermore, the value of ALT or other non-specific tests would have to be tested prospectively in various circumstances; after all, there are many reasons why the ALT may be raised, and in some communities a high proportion of blood donors might have to be rejected when the real reason for the abnormal result was alcohol.

If a new donor screening programme was set up, the high cost might be the least of the problems. Today, all transfusion services are aware of the plight of would-be donors who prove to be symptomless carriers of hepatitis B virus. Once these people are labelled as carriers, they may face difficulties in securing medical or dental care. We should be very much aware of the risks of creating a new and much larger group of donors who are rejected because of a new "hepatitis" test which does not necessarily signify infectivity, and which may be detecting a form of infection whose natural history we know very little about.^[126]

27.89 Indirectly, this provided eloquent support for Dr McClelland's proposals.

27.90 In July 1981 the need for research into post-transfusion NANB Hepatitis in the UK was raised by the Advisory Group on Testing for the Presence of HBsAg and its Antibody (also known as 'the Maycock Group' as it was chaired by Dr William Maycock) in its 3rd report.^[127] While the Group's remit dealt with testing for Hepatitis B, its report also covered NANB Hepatitis. HBsAg screening of donations destined for fractionation was recommended, implying that all donations collected for transfusion purposes at RTCs would be tested for HBsAg.^[128] Anti-HBs tests were recommended for as many new donors as possible to identify high titre donors to meet demand for the production of hepatitis B immunoglobulin. In relation to Anti-HBc, the report stated:

19. Blood donations which are negative for HBsAg by RIA and negative for anti-HBs, but positive for core antibody (anti-HBc) may occasionally transmit hepatitis B. Some of these donations are from donors recovering from unrecognised hepatitis B infections who still have minute but undetectable amounts of virus in their blood. At the present time there is no evidence that this type of donation causes more than a few cases of post-transfusion hepatitis (PTH) in the UK.

20. Screening all donations for anti-HBc would be costly and result in discarding many harmless donations from immune donors unless tests for anti-HBs were also carried out.

21. We recommend that there should be no general screening of donations for anti-HBc, but that all donors implicated in cases of PTH should be tested at reference centres for anti-HBc as well as for other hepatitis markers so that more information can be obtained on the dangers of HBsAg negative, anti-HBsAg negative, anti-HBc positive donors.^[129]

27.91 At this stage, the difficulty in assessing the frequency of post-transfusion NANB Hepatitis was, firstly, that there was no marker to show who had contracted it and, secondly, that most cases were asymptomatic. The Maycock Group's report noted further:

22. [NANB] hepatitis viruses are a common cause of PTH in the United States and are thought to have been responsible for cases of PTH in the UK.^[130] Hepatitis due to these viruses is common among haemophiliacs and follows the administration of imported, and occasionally of British Factor VIII and Factor IX. There is evidence for the occurrence of sporadic cases of [NANB] hepatitis in the general adult population and in association with cryoprecipitate therapy in the UK.

23. There are at the present time no screening tests for detecting [NANB] hepatitis viruses in blood donations.

24. We recommend that research is undertaken in the UK to determine the extent and severity of PTH due to [NANB] hepatitis viruses. Unless this is done we will not have the knowledge on which to base any possible future recommendations about screening blood donations for these viruses. Regional Transfusion Directors should encourage hospital haematologists to report all cases of post-transfusion jaundice and where these could be due to [NANB] hepatitis, the facts should be reported to the appropriate Adviser in Blood Transfusion at the Department of Health and Social Security (DHSS) or Scottish Home and Health Department (SHHD).^[131]

27.92 The same report dealt with 'Liver Function Tests':

25. Several categories of people are found to have raised blood transaminase levels which are not associated with viral hepatitis. Some 3% of new donors may be excluded if the criteria of one raised transaminase level is applied. In addition to the need for confirmatory transaminase testing the worry and inconvenience caused to donors would be unlikely to be compensated for by any clinical benefit. Therefore, we advise against these tests in screening blood donors at the present time but the subject should be kept under review.

26. Sporadic cases of apparent post-transfusion hepatitis due to the hepatitis B virus will continue to occur despite the most rigorous screening of donor blood samples because there are routes of infection other than transfusion; by coincidence, a transfusion may appear to have been responsible. Very few cases of PTH will continue to occur from donations with antigen below the present possible detection level. The donors involved may be in the early stage of incubating Hepatitis B.^[132]

27.93 Professor Cash was a member of the Maycock Group at this stage and the Group's third report was discussed at a meeting of the SNBTS Directors on 22 September 1981.^[133] It was noted at the meeting that the transfusion services had various groups examining different topics but that hepatitis testing was not one of them. It was agreed that Professor Cash should write to Dr William Wagstaff^[134] to propose that the UK transfusion services establish a post-transfusion hepatitis working group.

27.94 Dr McClelland was by no means an isolated voice calling for research at this time, though it was to emerge that colleagues on relevant working parties, which may have held the key to organising and funding such studies, may not have shared his enthusiasm - as was to appear from the transactions of the next working party to be set up by the transfusion services: the Working Party on Transfusion Associated Hepatitis.

27.95 The Working Party on Transfusion Associated Hepatitis met for the first time on 27 September 1982.^[135] The Working Party comprised senior officials representing a range of transfusion interests in the UK. It was chaired by Dr Gunson, Regional Transfusion Director, Manchester, and its members were Dr John Barbara, North London, Dr Brian McClelland, Edinburgh, and Dr Mitchell, Glasgow, all RTDs, as well as Dr John Craske of the Public Health Laboratory, Dr Richard Lane of the Blood Products Laboratory, Dr Bruce Cuthbertson of the Protein Fractionation Centre (PFC),^[136] Edinburgh, and Dr Howard Thomas of the Royal Free Hospital, London. The agreed Terms of Reference were:

To promote the investigations of the epidemiology of transfusion-associated hepatitis, to promote research into the methods of prevention, and to make recommendations to the Directors of the UK transfusion service regarding procedures and screening tests necessary for its prevention.^[137]

27.96 At the first meeting of the Working Party, the minutes record that Dr Gunson felt that existing reports provided an inadequate estimate of the true incidence of transfusion-associated hepatitis. It was agreed that a library of existing information on post-transfusion hepatitis would be collected for consideration at the next meeting, that Dr McClelland would produce an outline protocol for a prospective study of either the incidence of transaminitis (elevated liver enzymes such as ALT) in recipients or for determining the incidence of post-transfusion hepatitis in recipients of blood positive for existing putative markers of NANB Hepatitis, and that an attempt would be made to see if samples from the 1974 MRC study were still available.^[138]

27.97 In A v The National Blood Authority it was said that in 1982 Dr Gunson, in the name of the National Blood Transfusion Service (NBTS), applied for a grant to carry out a study in the UK into surrogate testing for NANB Hepatitis and that the application was refused. Documentary evidence of the grant application, or to whom the application may have been made, or its refusal, has not been found.^[139]

27.98 The Working Party met for the second time on 18 January 1983^[140] and preparations for a study were discussed. The minutes note that '[i]t was agreed that some form of study was needed so that the UK is equipped to answer queries about any specific or non-specific tests for [NANB Hepatitis] offered from abroad'.^[141] Dr McClelland circulated an outline proposal for a prospective study of NANB Hepatitis.^[142] The outline proposal stated that a large scale prospective study of transfusion recipients and their respective donors, along the lines of the US TTV study, was not considered further because a similar study had previously been done in Britain^[143] and samples were said to be available for reanalysis. It was further noted that a preliminary look at the financial implications indicated that a large scale multi-centre study would cost £250,000 to £500,000 and that, without further resources, Dr McClelland was not in a position to prepare even an initial outline of a study on that scale. Dr McClelland on this occasion appears instead to have suggested a more modest study 'to investigate the possible value of one or more putative markers of [NANB Hepatitis] in predicting the ability of a given blood donor to transmit the disease to a transfused recipient.'^[144] Although the proposed study appears to have been smaller than the study Dr McClelland had proposed at the meeting of the MRC Working Party on Post-Transfusion Hepatitis on 25 June 1981, the study proposed on 18 January 1983 continued to include the follow-up of recipients. It was estimated that this proposed study would cost £63,000 and members of the Working Party were asked to provide Dr McClelland with their comments.

27.99 The minutes of the meeting record that Dr Gunson would make a further attempt to ascertain from the MRC whether the samples from the MRC study reported in 1974 were still available and whether the recipients had been followed up to look for long-term effects. The minutes of the meeting noted that, '[i]f MRC samples are not available the working party will put forward proposals for some form of study to the MRC and DHSS'.^[145]

27.100 The Working Party met for the third time on 20 April 1983.^[146] It was by then known that the samples from the 1974 MRC study had been destroyed.^[147] Dr McClelland had been sent the results of a prospective study at Newcastle involving the follow-up of 248 patients.^[148] As regards Dr McClelland's outline proposal for a prospective study of NANB Hepatitis, it was noted that '[s]o far a source of funding has not been found.'^[149] It was thought that there would be a low incidence of post-transfusion NANB Hepatitis at Edinburgh. It was suggested that the North London RTC, Edgware, might provide a higher incidence area for the study. Dr John Barbara agreed to discuss matters with his Director at the Edgware centre and plans for a joint study with Edinburgh might then be submitted to the MRC by the Working Party.

27.101 In his evidence to the Inquiry Dr McClelland commented on the attitude of the Working Party to a study into post-transfusion NANB Hepatitis in the UK involving the follow up of transfusion recipients:

Q: And what was the view of this working party of the need for a study of the type you proposed?

A: Well ... there was really very little enthusiasm. There was polite interest. But when it says ... [in] the minutes, "No source of funding has been found", no source of funding had been seriously sought. Nobody had gone back to the MRC, and I wasn't going to go back to the MRC at that stage myself as an individual because I knew I wouldn't get anywhere .... [I]t was perfectly clear there was going to have to be a major effort made to obtain major funding for this study.

....

Q: Obviously, you were of the view that there should be such a study?

A: I was strongly of the view but I was beginning to get a little bit worn down by that time actually because, you know, there is only a certain amount one can do as an individual and it wasn't lighting fires for anyone else.

Q: By anybody else, do you mean the other members of this working party or do you mean more widely?

A: Well, I mean other members of this working party because this was the first jumping-off point to get something done. If the working party had - looking at the membership of the working party, if those people had all put their shoulders behind this, something probably would have happened but that didn't happen.

Q: So you were largely driving forward this proposal by yourself?

A: I was endeavouring to, yes.^[150]

27.102 Dr Ruthven Mitchell, Director of the Glasgow and West of Scotland RTC, was also a member of the Working Party. In his evidence to the Inquiry he explained his view of the difficulties in undertaking a large scale study of the type proposed by Dr McClelland. A large number of patients would require to be enrolled in the study to make it statistically valid, patients would require to be followed over a number of years and many patients who received transfusion would have died of their underlying condition (necessitating blood transfusion) before meaningful data on post-transfusion NANB Hepatitis might come to light.^[151] Dr Mitchell's view was that a prospective study into post-transfusion hepatitis involving the follow-up of patients was '[a] very good idea in theory but not practical - very difficult to do practically'.^[152]

27.103 The Working Party met for the fourth time on 27 September 1983. While the subject of transfusion-associated hepatitis, including the question of carrying out prospective studies into the disease, appeared on the agenda for the meeting,^[153] the minutes of the meeting contain no reference to any discussion of transfusion-associated hepatitis; instead, the discussion was dominated by AIDS.^[154] In his evidence to the Inquiry Dr Mitchell was asked why there does not appear to have been a discussion of hepatitis at the meeting and stated, 'I think it was a preoccupation with another, much more lethal problem that we had [that is, HIV/AIDS].'^[155]

27.104 As it turned out, the transfusion services' Working Party on Transfusion Associated Hepatitis did not meet again until it was reconvened in late 1986. The reasons for that are discussed below. Dr McClelland's view that there was very little enthusiasm in the Working Party for his proposals clearly understates what was at least tacit opposition from senior members of the group.

27.105 As noted above, a team at Newcastle carried out a prospective study of post-transfusion hepatitis in cardiac surgery patients and reported in November 1983.^[156] The study involved 248 patients who received a total of 1796 units of blood or blood components. All surviving patients were seen six months after surgery and were tested for ALT.^[157]

27.106 Six patients were found to have an increase in ALT levels which was unexplained and reached over 100 IU/L (normal < 40 IU/L). The authors considered that the incidence of 'acute short term incubation' post-transfusion NANB Hepatitis was therefore 2.4% (6/248). While these six patients had normal liver function six months after transfusion, a further two of the surviving 228 patients had raised ALT levels at six months. In one of these, liver biopsy disclosed chronic persistent hepatitis;^[158] in the other, alcoholic liver disease was suspected. Overall, the authors considered that the incidence of 'significant chronic liver disease' after blood transfusion possibly attributable to an NANB Hepatitis agent was only 0.4% (ie 1/248). The paper concluded that '[NANB] hepatitis after blood transfusion from a largely British blood donor group probably leads to clinically significant chronic liver disease very rarely indeed'.^[159]

27.107 In oral evidence Dr McClelland said that the interpretation placed upon their data by the Newcastle group was consistent with the understanding of post-transfusion NANB Hepatitis at the time.^[160]

27.108 As noted already, Vox Sanguinis conducted a survey in 1983 of the opinions of various experts relating to the costs and benefits of routine donor screening for ALT. Dr McClelland expressed the following view in his contribution to the forum:

The only action which I would recommend at present is that there should be a thorough prospective study to determine the frequency with which post-transfusion hepatitis occurs in the regions served by this centre, or in a closely comparable population.

If the results of such a study indicate that post-transfusion hepatitis due to [NANB] viruses (PTH) occurs sufficiently frequently to cause concern, I would recommend further study be carried out to determine whether the introduction of a donor ALT screening programme does in fact reduce the attack rate for PTH. As an alternative it may well be possible to study simultaneously the attack rate for PTH in the recipients of ALT screened or nonscreened blood.

I consider that without undertaking thorough studies along these lines, the potential and actual scale of the 'benefit' side of the cost benefit calculation is unknown and therefore no rational decisions can be taken ....

I would therefore recommend that we are careful to establish the benefits before we become committed to the costs. We must know what improvement in the quality of our blood and blood products we are asking the community to pay for.^[161]

27.109 Dr Mitchell expressed the following view in the publication:

As ... ALT testing has obviously high false-positive and also high false-negative rates, we have no intention of suspending 3% of our volunteer blood donors on the basis of an ... ALT test when they may have only transient elevations. Furthermore, such a policy would discourage donor recruitment among the few willing to donate for the good of the community and would cause some anxiety in donors and their families when we cannot offer anything more than the argument that [NANB] hepatitis may exist. We have been most disturbed by the treatment or lack of treatment for unrelated diseases available to HBsAg positive blood donors and fear that donors with elevated ... ALT levels may suffer the same problems.

We await the development of a specific serological test for [NANB] hepatitis. The use of nonspecific tests such as ... ALT can have deep sociological and psychological effects on established blood donors and would necessitate the recruitment of voluntary nonremunerated replacements.^[162]

27.110 It is significant that within the Scottish service such strongly differing views should have been expressed by the Directors of the two major Regional Transfusion Centres. Faced with such a powerful statement by Dr Mitchell, Dr McClelland was most unlikely to make progress with his proposal.

1984-1985

27.111 The Inquiry has found little evidence to show that the issue of surrogate testing was considered in the UK in 1984 and 1985 or that consideration was given in these years to carrying out a UK study into the prevalence of post-transfusion NANB Hepatitis and its association with surrogate markers in donors. As noted above, for example, the transfusion services' Working Party on Transfusion Associated Hepatitis last met on 27 September 1983 (when discussion was dominated by AIDS) and did not meet again until, as discussed below, it was re-convened in late 1986.

27.112 At a meeting called by the National Institute for Biological Standards Control (NIBSC), on 9 February 1984, Dr Terry Snape (BPL, Elstree, the manufacturer of NHS blood products for England and Wales) commented that screening for serum ALT had been considered in the USA but not used in the UK; this appears simply to have been a factual comment.^[163] In the discussion that followed, there was no reference to its possible use in the UK. In the context of AIDS, testing for anti-HBc was discussed but there was no general agreement that the test should be part of the routine screening carried out on donors: its possible relevance to hepatitis was not mentioned.

27.113 Dr Edward Follett and Dr Brian Dow,^[164] reporting on a study of NANB Hepatitis in the West of Scotland in 1984, wrote:

Evidence from USA would suggest that if ALT/SGPT testing is performed on all blood donations and those with high levels excluded, around 29-40% of non-A, non-B PTH cases could be prevented with the loss of around 3% of blood donations.

A total of 10,655 West of Scotland blood donors have been tested for elevated SGPT(ALT) levels.^[165]

27.114 The table of results showed the concentration of ALT (measured in U/ml) in blood samples. Levels exceeding 35 U/ml were found in 367 individuals (3.4%), levels exceeding 92 U/ml in 55 individuals (0.51%) and those exceeding 125 U/ml in 41 individuals (0.38%). Prison session donors showed ten times more donations with grossly elevated ALT levels than others.^[166]

27.115 Drs Follett and Dow had shown that 'around 3% of blood donations' in the West of Scotland had elevated ALT values. Recipients of the donations were not followed up and no data were gathered on the use of the 10,655 donations or their destination within the blood services. Data were available of clinically likely cases of post-transfusion NANB Hepatitis reported to the Glasgow and West of Scotland BTS: there had been reports of nine cases only. The notification requirements related to 'infective jaundice'.^[167] They were not well adapted to generate reports of NANB Hepatitis which was, in fact, seldom associated with clinical jaundice. In addition, reports of notifications of an infectious disease whose characteristics were poorly understood by clinicians generally were most unlikely to provide sound evidence of prevalence of the condition. Without follow-up of the donations tested, the study did not provide a basis on which the prevalence of post-transfusion NANB Hepatitis could, or should, have been drawn. Unfortunately, it was concluded on the basis of the reported cases that post-transfusion NANB Hepatitis was 'not a major problem' in the region. That conclusion was not based on sound evidence. Nor did it indicate the potential value of ALT surrogate testing, or a basis for assessing that value.

27.116 Even more unfortunately, as will be seen below, the conclusions from the report were for several years used to support the contention that post-transfusion NANB Hepatitis was not a significant problem.

27.117 After an outbreak of post-transfusion NANB Hepatitis following the use of certain BPL immunoglobulin concentrates,^[168] Professor Andrew Lever, Professor Howard Thomas^[169] and others contrasted the lack of tests for the NANB Hepatitis virus(es) with tests for other viruses, at the end of 1984:

Sensitive radioimmunoassays for hepatitis B surface antigen and IgM anti-HB-core allow identification of cases of post-transfusion hepatitis caused by the hepatitis B virus, and similar assays exist for the diagnosis of hepatitis A, cytomegalovirus, and Epstein-Barr virus infections which are rarer causes. Most post-transfusion hepatitis, however, is caused by a group of unidentified viruses designated non-A, non-B.^[170]

27.118 As others had, they commented that a screening test was needed to identify NANB Hepatitis. However, by this time there had been no progress on that front and, in general terms, the 1984-85 period saw a low level of activity in post-transfusion hepatitis research.

27.119 One significant reason for the relative lack of consideration given to post-transfusion NANB Hepatitis in this period was the priority given to tackling AIDS. In Dr McClelland's written evidence to the Inquiry, for example, he stated that, '[l]ooking back, I think it is the case that the work related to AIDS, firstly developing donor information and selection procedures and later evaluating and introducing the test for HIV antibody, distracted the attention of both the SNBTS and the [NBTS] from [NANB] hepatitis for about 3 years'.^[171] A further reason for the apparent lack of consideration given to post-transfusion NANB Hepatitis in the UK at this time is likely to have been, as discussed above and below, that post-transfusion NANB Hepatitis was regarded as having a low prevalence in the UK (at least when compared with the USA) and that it was considered to be a relatively mild disease.

1986

27.120 The SNBTS Directors continued to follow developments in the USA and so became aware of the FDA's 1986 recommendation on surrogate testing. A copy of the February 1986 edition of Blood Bank Week was circulated for the 25 March 1986 meeting of the SNBTS Directors.^[172] Dr John Forrester, Senior Medical Officer, SHHD, attended the meeting and was noted in the minutes as stating that it was highly unlikely that the UK Departments of Health would fund testing based on data from the USA. Dr Forrester said that he would be glad to hear of research proposals but could not guarantee funding. The minutes record that, after a full discussion, the Directors agreed to give consideration to funding someone to undertake research. Professor Cash was to think about the possibilities in association with Dr Ian Fraser, Director, Bristol RTC,^[173] and make proposals to the Directors.

27.121 In the meantime, Professor Cash had made direct contact with the American Red Cross. He wrote to Dr Gerry Sandler of the American Red Cross Blood Services on 17 February 1986 to ask what had transpired at the meeting of the FDA Blood Products Advisory Committee with regard to surrogate testing for NANB Hepatitis and what the American Red Cross had decided.^[174] Dr Sandler replied on 4 March advising on the position at that stage: there was a divergence of view and the Red Cross was not proceeding to test but would review the position.^[175]

27.122 Dr Forrester produced a note of the SNBTS Directors meeting for his SHHD medical colleagues, Dr Archibald McIntyre, Principal Medical Officer (PMO) and Dr Graham Scott, Deputy Chief Medical Officer (DCMO).^[176] As regards testing of blood donations for NANB Hepatitis, Dr Forrester noted that in America it was proposed to reduce the transmission of 'this medley of conditions' by testing all blood donations for evidence of faulty liver function. Dr Forrester's note went on:

Since any additional test of this kind must necessarily be non-specific and could well prove expensive, I have as you know immediately made further enquiries, and have discovered that the number of cases in Scotland due to blood transfusion is probably exceedingly low, there is a solid body of work (a Ph.D. thesis)^[177] exploring the matter, and I am securing Dr Dan Reid's opinion in writing in the near future. It was argued at the meeting that urgent action was called for rather than a search for reliable information, and that the case was comparable with that of AIDS. I pointed out however that the steps taken to deal with AIDS were taken in face of a rapidly rising incidence, while in the present case the incidence so far as I know is small and steady. There is thus no justification for panic measures. I also indicated that the Department was perfectly open to proposals for funding research in this field, if research is required to determine the true size of the problem and the likely effect of any proposed remedy.^[178]

27.123 Dr Forrester wrote to Dr Reid on 26 March 1986 seeking information on the likely incidence of NANB Hepatitis in Scotland, the proportion attributable to blood transfusion and how far any proposed test could reduce this proportion.^[179]

27.124 Despite the views of the SNBTS Directors on the need for research into transfusion-associated hepatitis, there seems to have been little appetite among the Transfusion Directors in England and Wales for such research. At the meeting of the English and Welsh Directors on 24 and 25 April 1986 the question of whether a study into NANB Hepatitis should be carried out was raised. The minutes state:

The Chairman reported that this had been discussed by the Scottish Directors and that he had agreed to raise it with RTDs. [Name redacted] reminded Directors of two previous attempts, one by the MRC and one by the Transfusion Associated Hepatitis Working Party, to study this problem. After discussion it was agreed that this should not be pursued because of lack of time and resources.^[180]

27.125 Around May 1986, the SNBTS prepared its submission for the 1986 Public Expenditure Survey (PES).^[181] This was an annual bidding process in which public bodies submitted applications for funding to the government. The Common Services Agency (CSA)^[182] submitted the application for funding for all of the activities within its remit, including the SNBTS, to the SHHD. The administrative officials in the SHHD critically examined the funding application, taking advice from their medical colleagues on medical matters, before deciding on the items which should be forwarded to the SHHD's Finance Division. The Finance Division would then further examine funding applications before they were put to the relevant minister for approval, before ultimately being voted upon by Parliament.^[183]

27.126 In its 1986 bid, the SNBTS included a sum of £810,000 to commence new mass donation screening programmes in 1987-88, with a forward projection of £836,000 for 1988/89.^[184] The fate of the funding request is discussed below. The reason for the funding request was set out in the 1986 PES, which was drafted by Professor Cash, as follows:

Despite the absence of specific tests to detect donations which transmit [NANB] hepatitis there is increasing evidence that both in Europe and North America formal moves will be made, within the next 12-18 months, to introduce surrogate testing of all donations (liver function and [anti-HBc] tests).^[185]

27.127 In May 1986, Dr Dow, then a Senior Grade Scientific Officer in the Glasgow and West of Scotland RTC, produced a special report for the SNBTS Directors on 'Surrogate tests for non-A, non-B Hepatitis'.^[186] Drawing on the work undertaken as part of his 1985 PhD thesis^[187] and, in particular, looking at the extent to which reported cases of post-transfusion NANB Hepatitis in the West of Scotland were associated with surrogate markers in donor blood, Dr Dow was of the view that '[e]ven if the combination of anti-HBc and ALT tests were shown to be 100% effective the economics involved in conducting these tests would greatly outweigh the costs of hospitalization of the few reported NANB PTH cases'.^[188] He concluded that:

The present UK policy of accepting donors with raised ALT levels (i.e. not routinely ALT testing), anti-HBc or histories of jaundice would appear to be correct. It would appear from the study that the introduction of such surrogate screening procedures would have little impact on reducing the already low level of NANB PTH cases at present reported within the West of Scotland region.^[189]

27.128 Dr Reid replied on 4 June 1986 to Dr Forrester's letter of 26 March.^[190] He sent a copy of Dr Dow's thesis and, from Dr Forrester's note next referred to, appears not to have recommended surrogate testing. Dr Dow's thesis was then the only piece of work which related specifically to Scotland.

27.129 On 12 June 1986 Dr Forrester produced a note, 'Transmission of [NANB] hepatitis by blood and blood products: is it practicable to reduce or prevent it by introducing ALT testing of donations?' Dr Forrester set out the outcome of his enquiries as follows:

1. The information in this note is mostly derived from the PhD thesis entitled "Non-A, Non-B Hepatitis in West Scotland", completed in 1985 by Dr BC Dow under the supervision of Dr Follett and others.

2. Hepatitis can be transmitted by blood and blood products, and is in Scotland an occasional but serious consequence of blood transfusion. In contrast, in USA as many as 10% of recipients may develop it. Established causes include Hepatitis B virus, Hepatitis A virus, Epstein-Barr virus and cytomegalovirus. Hepatitis B virus is now successfully excluded by testing of donations. Hepatitis A has caused little trouble because virus is only found in blood over a brief period.

3. [NANB] hepatitis is not a specific disease, but a heterogeneous collection of diseases. The hepatitis conditions due to the Epstein-Barr virus and cytomegalovirus are a substantial part of it, but there is general belief that some as yet unidentified virus infection is also part of it. Thus there can be no accepted test capable of detecting the virus in blood; detection is by exclusion of other conditions such as those mentioned.

4. [NANB] hepatitis, thus defined, is not uncommon in the population; Dr Dan Reid reckons an incidence for Scotland of 154 cases per year, but has little confidence in this estimate because it can only be derived by starting from the total of all hepatitis cases reported (probably under-reported) by clinicians, and deducting the cases of hepatitis B detected in laboratories (probably fully reported). It is common among drug-abusers. But in association with blood transfusion [NANB Hepatitis] is very uncommon in the west of Scotland. Over the last 8 years, 1-5 cases are found each year there, and there is no upward trend. There are peculiar difficulties in identifying its presence in haemophiliacs, since their blood exhibits diverse reactions because of repeated administration of blood products, but Dr Dow found no evidence of any substantial problem. Dr Dow reckons that the proportion of donations infected with [NANB] hepatitis may be 18 per hundred thousand [0.018%].

5. The condition is not as a rule serious, and most of the cases detected have not even been jaundiced. There may however be a tendency for it to become chronic, and the long-term outlook is inevitably not yet known. The case fatality rate is estimated in a textbook consulted by Dr Dan Reid at less than 0.1%, except in pregnant women, who are at much greater risk...

6. In the absence of a specific test, for some years the suggestion has been made that an enzyme test ("ALT") which detects faulty liver function should be applied to every donation. The advantage is that some donations might thus be excluded which would transmit [NANB] hepatitis. The drawbacks are that some infective donations might still be missed ("false negatives") and some harmless donations might be excluded ("false positives"). The American evidence is that both drawbacks are serious: only perhaps 38% of the genuinely infective donations are detected, and some 70% of the apparently infective donations are harmless. Rejection of donations might reach 3% - a grave loss.

7. ... Dr Dow concludes that in Scotland "cost would be extremely high and benefit minimal, especially when only a few cases of [NANB] post-transfusion hepatitis are reported each year."

8. Dr Dan Reid and Dr Follett do not recommend the introduction of ALT testing of Scottish blood donations, for the above reasons.^[191]

27.130 The issue of surrogate testing was considered by the SNBTS Directors at their meeting on 25 June 1986.^[192] The minutes note that there was increasing evidence that the USA and several European countries were introducing surrogate testing of blood donors in an effort to minimise the risks of NANB Hepatitis transmission through blood and blood products. Professor Cash was noted as believing that the SNBTS would soon come under pressure from clinicians to introduce testing. A limited study involving the follow-up of donors (but not recipients) with abnormal liver function tests was about to take place in Edinburgh. Dr Fraser (Bristol) and Dr Contreras (Edgware) were keen to set up a small group to explore the feasibility and practicability of this development and hoped that a Scottish RTC would contribute. The Scottish Directors agreed to await the outcome of joint deliberations by Dr Fraser and Dr Contreras and to discuss the matter again at that time.

27.131 Further pressure was placed on the UK transfusion services by the recommendation in August 1986, noted above, from the AABB that all donor blood be tested for ALT and anti-HBc with effect from 30 November 1986, in an attempt to reduce NANB Hepatitis.^[193] The positive response of the major blood delivery institutions in the USA, including the Red Cross, added to the pressure.

27.132 Again, the SNBTS Directors were aware of developments in the USA. In a letter to Dr Fraser on 28 August 1986 on the question of surrogate testing, Professor Cash stated, 'I have a feeling that as the drums are beating louder and louder in other parts of the world on this topic the Brits remain fast asleep'.^[194] While he noted that the suggestion of a UK prospective trial had been raised at the recent NBTS meeting and 'went down like the proverbial lead balloon', Professor Cash considered that the matter could not be left as it was. He proposed a meeting to look at the issues associated with donation testing, with a view 'to see whether we can reach conclusions which would enable us to make some clear operational decision[s] and that these would be transmitted to the various Departments of Health'.

27.133 In his evidence to the Inquiry, Professor Cash stated that he did not support the introduction of surrogate testing at that stage but, instead, wanted more information upon which to base a decision. He explained that the benefit surrogate testing would bring to patients in the UK was unknown, the financial cost of testing would probably be taken from elsewhere in the NHS budget, the use of surrogate markers would cause uncertainty and concern among individual donors and blood collection would go down. He stated, '[t]his was making a major tactical moral position and we needed the data. So I supported ... getting the data very strongly'.^[195]

27.134 Dr Fraser replied to Professor Cash's letter and expressed the hope that if he, Professor Cash and Dr Contreras 'rowed hard enough' they could 'get our colleagues to move in the same direction'.^[196]

27.135 On 8 October 1986 the English and Welsh Transfusion Directors met.^[197] In a discussion of surrogate testing the minutes noted:

The Chairman [Dr Fraser] reminded Directors that the possibility of screening for anti-HBc had been discussed previously .... Developments in America meant that this topic must be considered again as anti-HBc/ALT screening were soon to be essential for the accreditation of Blood Banks in the USA. The Chairman proposed that RTDs should approach the DHSS to fund a prospective study of 10,000 donations to see if the incidence of anti-HBc had changed since this was last examined. He added that Haemophilia Directors were pressing for plasma for fractionation to be tested both for anti-HBc and for abnormal ALT levels. It was agreed that a further trial should be undertaken at Edgware, Bristol and, possibly, Manchester and that an approach be made to Dr Smithies and Dr Moore^[198] for assistance with this. It was recognised however that even if the incidence had reduced significantly since the last trial, because of self exclusion or for other reasons, the introduction of anti-HBc/ALT screening seemed very likely.^[199]

27.136 It is interesting to contrast the position of the English and Welsh Transfusion Directors in April 1986, when there appeared to be little interest in undertaking a study into NANB Hepatitis,^[200] with their position in October of the same year when, following the introduction of surrogate testing in the USA, they considered that the introduction of surrogate testing in the UK now seemed 'very likely'. Dr Fraser was, in his own terms, 'rowing hard', having aligned himself with Professor Cash's position.

27.137 The SNBTS Directors met on 9 October 1986.^[201] Dr Gunson was present and, in a discussion on surrogate testing, advised that three English centres (Edgware, Bristol and Manchester) were to study the incidence of raised ALT levels and anti-HBc in their donor populations. It was agreed by the Scottish Directors that the UK Working Party on Transfusion Associated Hepatitis^[202] was the most appropriate body to pursue the issue of implementing surrogate testing in RTCs and that Professor Cash would write to Dr Gunson on behalf of the SNBTS Directors, formally requesting that this Working Party be reconvened with a view to making proposals to the Department of Health.^[203]

27.138 On 16 October 1986 Dr Scott, DCMO, sent a minute to Dr Forrester and Mr Alexander Murray, a Senior Executive Officer in the SHHD, on the question of NANB Hepatitis screening. Dr Scott's minute stated:

I should like to know where this stands. CMO DHSS is worried that if we go ahead England and Wales will have to follow suit.

I think there must be consultation with DHSS before we agree to provide funds for this screening.^[204]

27.139 Dr Forrester replied on 17 October:

The recent situation is described in paragraph 5 of my note of the SNBTS Directors' meeting of 9 October, which runs:

"Dr Cash is pressing the English BTS to seek a start of this, apparently on the grounds that UK are lagging behind "other parts of the world". The initial - and very prudent - response is likely to be a call for research. Some has already been done last year in Scotland,^[205] but turned out discouraging to Dr Cash's purposes; certainly he never mentions it. Dr Gunson of English BTS believes that "external pressures" will compel a start of Surrogate testing. One may guess that this testing would cost the UK about £8m."

....

There seems no justification for introducing this screening without gathering further British evidence, because the American experience of frequent post-transfusion hepatitis does not seem to be duplicated here.^[206]

27.140 Also on 17 October 1986 Dr Forrester wrote to Dr Alison Smithies, DHSS,^[207] enclosing a copy of his note of 12 June 1986,^[208] a letter dated 4 June 1986 from Dr Reid of the Communicable Diseases Centre,^[209] the special report on surrogate testing compiled by Dr Dow for the SNBTS Directors in May 1986^[210] and the 1983 discussion in Vox Sanguinis.^[211] Dr Forrester ended his letter:

I have no reason to think that Scotland is imminently about to adopt Surrogate testing. I hope that the message south and north of the Tweed will be "research first, action later."^[212]

27.141 On 21 October 1986 Mr Murray responded to Dr Scott's minute of 16 October.^[213] In his response Mr Murray stated that 'the bid we are making to our Finance colleagues for money for the SNBTS in 1987/88 makes no provision for [NANB] Hepatitis screening'.^[214]

27.142 In his written evidence to the Inquiry, Mr Murray stated that '[i]t was technically my call not to include funding for screening in the overall bid as I was the person responsible for drafting and submitting the bid to Finance Division, but I made my call based on advice from my medical colleagues'.^[215] It is apparent that the decision was, in substance, treated as a matter for the medical officers of the SHHD. The timing of the decision reflected in Mr Murray's minute is significant. In particular, it was before the sequence of events described in the following paragraphs.

27.143 As a result of the suggestion by the SNBTS Directors at their meeting in October 1986 that the issue of surrogate testing should be pursued by the UK transfusion services' Working Party on Transfusion Associated Hepatitis, that Working Party was re-convened with a view, amongst other matters, to making proposals to the DoH (see paragraph 27.137 above).^[216]

27.144 In advance of the meeting of the re-convened Working Party, Dr Gunson circulated a report dated October 1986 on ALT and anti-HBc screening of blood donations.^[217] In his report, Dr Gunson stated that the best estimate of the incidence of transfusion-associated NANB Hepatitis in the UK was 3%. If it was assumed that the 2.3 million donations in the UK were transfused to 750,000 recipients annually then one would expect 22,000 icteric or anicteric cases of NANB Hepatitis (cases, that is, with or without clinical jaundice) in each year. If the morbidity pattern of the disease was similar to that in the USA then one might expect half of these patients to have chronic ALT elevation and 10% (that is, 2250) to develop cirrhosis. As regards the projected value of ALT and anti-HBc screening in preventing transfusion- related NANB Hepatitis, the report stated that if 30-40% of NANB Hepatitis could be prevented by the use of these tests then the reduction in the number of cases would be 6750-9000 a year and, by extrapolation, 675-900 cases of cirrhosis. The argument followed the approach of Dr Alter's group in February 1986 when it changed direction and supported surrogate screening.^[218]

27.145 The report went on to say, however, that qualifications required to be made to these estimates. In summary, these were:

(i) The course of the chronic disease in NANB hepatitis was thought to be mild and it was therefore thought that many cases probably remained undiagnosed, even when cirrhotic changes occurred. Dr Gunson felt certain that was why they had not been aware of what appeared to be quite serious statistics. It was also necessary to bear in mind that approximately 50% of patients died of their primary disease within one year of transfusion.

(ii) The incidence of NANB Hepatitis had been determined in the USA, often with multiply-transfused patients and in the TTV study there was clearly a dose relationship. Even in the second of the two UK studies the patients (6) received an average of 6.28 units each.

(iii) The data from the USA was from transfusions administered in the 1970s and early 1980s and even the more recent studies in the UK were undertaken before attempts to encourage the self-selection of donors.

(iv) It had to be questioned, therefore, whether the incidence of transfusion-associated NANB Hepatitis was as high as the estimates suggested.^[219]

27.146 As regards the likely effect of surrogate screening on blood collection, Dr Gunson's report estimated that ALT screening might cause the loss of 0.7-0.9% of donations, anti-HBc might cause the loss of 1% of donations and, assuming some overlap between these two groups, one might expect a loss of donations of approximately 1.5-1.75%. Since the data were largely from the time period before self-exclusion of donors for HIV infection, it was considered 'important to determine in a new study, preferably carried out in three Centres in England ... how many donations are rejected. Preferably, also one Centre in Scotland should join the study .... [A]nalysis of the results should yield information from which a prediction of loss of donations throughout at least England and Wales, can be estimated'.^[220] Other topics for discussion mentioned in the report were the costs of implementing ALT and anti-HBc screening, the effect of screened donations in lessening the occurrence of NANB Hepatitis from fractionated products derived from pooled plasma and how donors would be managed if routine screening was introduced.

27.147 Dr Gunson's report was considered on 24 November 1986 at the meeting of the re-convened UK Working Party on Transfusion Associated Hepatitis. The Inquiry has not been able to recover the minutes of the meeting. The Inquiry does, however, have a copy of Dr McClelland's handwritten notes of the meeting^[221] and a note of the meeting prepared by Dr Forrester on 1 December 1986.^[222] Dr Forrester's note, expressing his personal view and intended for his SHHD colleagues, states:

1. Is the American experience of frequent [NANB] hepatitis in recipients of blood and blood products reproduced here? If so, a 40% reduction in it would follow screening. The answer is No. Such evidence as exists does not bear out the American experience, but to examine the question properly would be a long and expensive business ....

2. ... Dr McClelland put the proportion of local donations showing an ALT test in excess of 45 i.u. (a credible place for the line) at ... 3.4%. The proportion excluded by [anti-HBc] screening is put at 1 to 1.8% .... It is clear that much "innocent" blood would be excluded.

....

4. Is research indicated? The meeting felt that a prospective study to discover the present burden of transfusion-associated [NANB] hepatitis was impracticable on grounds of cost and huge sample size. They propose instead a study to identify in three centres (1 Scottish) donors positive for ALT or core antibodies, and search for other risk factors in them ....

5. There was some discussion of the cost of screening all donations (perhaps £8m). I asked the Chairman [Dr Gunson] whether he would advise screening if it were free of cost. He said No.^[223]

The position explicitly reached at the meeting is to recommend research of no great significance or scientific interest because the prospect of research would serve to counter pressure from for example haemophiliacs and Haemophilia Directors to embark on an indirect and largely ineffective form of screening, which would also lose us a certain amount of perfectly harmless blood. Figures were produced at the meeting for the total number of [NANB] hepatitis cases encountered annually among haemophiliacs (A and B) and patients with von Willebrand's disease. The average UK total per year is 35 over the past 6 years, but 1985 saw a sharp decline to 11 in all. A proportion of these cases among haemophiliacs and similar patients are asymptomatic.^[224]

27.148 It is difficult to reconcile Dr Forrester's note of the total number of NANB Hepatitis cases encountered annually among patients with haemophilia, with UK reports from the early 1980s showing that most haemophilia patients who received Factor VIII and Factor IX blood products for the first time, whether manufactured by the NHS or by commercial companies, were likely to develop NANB Hepatitis.^[225] In his evidence to the Inquiry Dr McClelland thought that what was reported by Dr Forrester in this regard must have been a misunderstanding of what was said at the meeting.^[226] Whether or not that is the case, Dr Forrester's note contains the information circulated to SHHD colleagues, including the inaccurate assessment of the prevalence of NANB Hepatitis infection among haemophilia patients before effective viral inactivation was introduced. Dr McClelland also cast doubt on the accuracy of Dr Forrester's description of the meeting, indicating that the suggestion that they would 'do some research to shut people up', would be untypical and uncharacteristic of the sort of discussion that took place at such meetings. Dr Alison Smithies, a member of the Secretariat to the Working Party, also expressed surprise at the suggestion that the position explicitly reached at the meeting was to recommend research which was of 'no great significance or scientific interest' in order to 'counter pressure' for the introduction of surrogate screening. She, too, considered that such a position would have been uncharacteristic of the discussions of the Working Party and refuted the suggestion that the study was put forward for any reason other than to clarify the likely consequences of introducing surrogate screening and to provide information which would allow the number of lost donations to be estimated.

27.149 As indicated above (paragraph 27.141), a decision had already been taken before this meeting that provision would not be made in the PES bid for funding the SNBTS for screening in 1987/88. It appears that opposition to screening within the SHHD, at least on the part of Dr Forrester, became more deeply entrenched at the meeting.

1987

Product liability

27.150 In 1985, a European Directive was adopted which provided for strict liability for harm caused by defective products.^[227] Member states were required to implement the Directive in their national legal systems by July 1988. In the UK, the Department of Trade and Industry (DTI) was the lead department responsible for implementing the Directive. The Consumer Protection Bill was drafted to give effect to the Directive and, in due course, the Bill became the Consumer Protection Act 1987. The part of the Act providing for strict civil liability for harm caused by defective products came into force on 1 March 1988.^[228]

27.151 During 1986 Professor Cash had expressed concerns about the implications of the proposed legislation^[229] and had made representations for blood and blood products to be removed from the ambit of the legislation with a view to preventing the transfusion services and, possibly, blood donors being held strictly liable for harm caused to patients by treatment with blood and blood products.

27.152 Dr Graham Calder, Chief Pharmaceutical Officer, SHHD, raised Professor Cash's concerns with the DTI who, by letter dated 9 February 1987, advised that they were not persuaded that there was any justification for removing blood and blood products from the provisions of the legislation.^[230]

27.153 By a minute dated 13 February 1987, Mr Calder advised Dr Scott, DCMO, and the SHHD administrative officials of the DTI's response.^[231] By letter dated 13 March 1987, Mr Hugh Morison, Under Secretary, SHHD, wrote to Mr Jim Donald, General Manager, CSA, advising him of the decision by the DTI that blood and blood products would remain within the provisions of the Act.^[232] Mr Morison sent a copy of that letter to Professor Cash.^[233]

27.154 The risk of product liability became a new and material factor influencing policy.

Surrogate screening

27.155 The reconvened UK BTS Working Party on Transfusion Associated Hepatitis met for the second time on 22 January 1987. Dr Forrester was present and wrote a note of the meeting.^[234] Those present were still not happy about proceeding with ALT screening and anti-HBc tests without further research to ascertain the infectivity of the donations and the meaning of the presence of anti HBc. There was discussion on the proposal for research into ALT and anti-HBc screening. It was hoped that the research might start on 1 April, subject to funding.

27.156 On 26 January 1987, Dr Forrester produced a note, 'Material for PMO Report'. He made the following comments on blood transfusion and NANB Hepatitis:

This "hepatitis" is a residual rag-bag when Hepatitis B and Hepatitis A are excluded, and consequently no specific test can detect it. It is relatively benign. But U.S. blood banks have noted that the combination of a liver function test and a test for the core (not the surface) antigen of Hepatitis B distinguishes perhaps a third of blood donations which would convey [NANB Hepatitis] and allows them to be excluded. Exclusion is far from complete, and besides, some 2% of "innocent" donations may also be excluded.

....

Here, it is intended instead to enquire into the number of relevant donations and the characteristics of the donors, before taking any further step.^[235]

27.157 Dr Forrester's unqualified statement that NANB Hepatitis was 'relatively benign' would have been difficult to sustain in the light of research published by the end of January 1987. (See Chapter 16, Knowledge of Hepatitis 3 - 1986 Onwards, paragraphs 16.5 and 16.6.)

27.158 The SNBTS and Haemophilia Centre Directors met on 9 February 1987.^[236] Dr Forrester reported on the recent meeting of the Working Party on Transfusion Associated Hepatitis and the proposal to set up a UK study based on four centres, one of which would be in Scotland. The purpose of the study would be to discover the number of donations affected, what a positive test result meant about the donor, the effect of giving blood positive on this screening and the cost of screening. Professor Cash noted that commercial products, if derived from screened plasma, might enjoy an advantage over products derived from unscreened plasma. The Haemophilia Directors indicated that they would not elect for commercial products on that basis. Their preference was to be supplied with heat-treated products. The cost of screening in Scotland was estimated to be approximately £750,000 per annum.^[237]

27.159 On 10 February 1987, having received a letter from Dr Susan Lader (Medical Officer, DHSS) on the proposal for a multi-centre study of ALT and anti-HBc in blood donations,^[238] Dr Forrester wrote a memorandum to Dr Boyd Moir, Director of the SHHD's Chief Scientist Office on Scottish participation in the research project.^[239] The SNBTS had sought approximately £600,000 to institute screening and conduct it for a year. That request was declined. Dr Forrester noted that joint consideration by the SNBTS, SHHD, DHSS and the English transfusion service indicated that 'instead of blindly adopting American practice, research should be conducted' and that 'a project involving 3 English and 1 Scottish transfusion centres' was being planned. Funding for the Scottish component of the research was sought from the CSO, to be determined in cooperation with the Research Management Division, DHSS. Dr Moir replied in a memorandum dated 17 February 1987.^[240] He had very strong reservations about funding a research project including a Scottish transfusion centre, stating that the proposal would appear to 'merely repeat a study we have already carried out' over a three year period by Drs Follett and Dow, reported two years earlier and funded by the CSO. If the SNBTS wished to formulate a research proposal for funding from the CSO it should be submitted as an application for formal review by the Biomedical Research Committee.

SNBTS Directors meeting on 3 March 1987

27.160 The SNBTS Directors met on 3 March 1987.^[241] The minutes of the meeting record the discussion of surrogate testing. It was reported that the UK Working Party on Transfusion Associated Hepatitis had been reconvened to pursue the issue of implementing surrogate testing for NANB Hepatitis. The proposal for a study which would include the Glasgow or Edinburgh Transfusion Centres had been modified and no Scottish Centre was now being asked to participate. It was noted that the Haemophilia Society might adopt a position which put pressure on BPL to ensure surrogate testing was introduced. The Directors discussed the options open to Scotland and agreed to recommend to the SHHD that surrogate testing for NANB Hepatitis should be implemented with effect from 1 April 1988 as a national development requiring strictly new funding. The individual Directors were to let Professor Cash know what funds would be required in each region, assuming that both anti-HBc and ALT testing would be undertaken in the regional transfusion centres.

27.161 In oral evidence Professor Cash explained that by early 1987 surrogate testing had commenced in the USA and he was aware that his colleagues in Europe were considering the issue. He said:

I began to get the jitters that once again in the UK we had gone to sleep, we were off the ball, and I felt that I had a duty as national director to advise my colleagues that we should get in an application for money in the event - knowing that in the event of the Department of Health saying, "Yes, okay, go," at least the budget was there to get down to the detailed difficulties of doing it.^[242]

27.162 He was asked what the reasons were for the Directors' recommendation that surrogate testing should be introduced and replied that '[t]he reasons were that the rest of the world seemed to be walking in that direction ... and associated ... the product liability and the whole question of patient safety'.^[243] Professor Cash was asked how it was envisaged that the recommendation would be taken forward and replied that the attendance of an SHHD official (in this case, Dr Forrester) at the Directors meeting was one means. He went on:

The other method, which was in parallel, was going through our PES submissions ... that would go into the department and we thought that would generate discussion and debate and so on and so forth, and we would get the thing going.

What we were concerned about is that we didn't seem to be able to get it going in the ... post-transfusion hepatitis working parties^[244] ... Harold [Gunson] was alerting to us in interactions with the DHSS. What we were doing was saying, "We have a responsibility here. Let's lead off and get the debate going," and the way we can get this going that we felt most comfortable with was a suggestion that we need some money to do that and that would, we felt, trigger off debate.^[245]

27.163 It was put to Professor Cash that if the SNBTS was serious about the recommendation to introduce surrogate testing then the SNBTS should have formally made the case by some form of detailed, reasoned, submission to the SHHD. Professor Cash said that the case he and his colleagues were trying to make was weak because of the lack of data on patients.^[246] Consequently, they required to rely on the fact that other countries appeared to be moving towards such testing and that the UK licensing authority now recognised that ALT testing improved product safety. He was, simply, trying to draw their attention towards testing that he perceived as existing elsewhere.

27.164 In his oral evidence Dr McClelland stated that he had no recollection of the meeting of the Directors on 3 March 1987 but was surprised on recently reading the minutes to see the clarity of the recommendation that surrogate screening should be implemented. He considered that it must have been primarily motivated by the awareness of what was going on in the USA. His recollection was that there wasn't much enthusiasm among the other Scottish Directors for the introduction of surrogate testing.^[247] In a memorandum dated 18 May 1987, Dr Forrester recorded his astonishment that Dr McClelland had agreed to the proposal, although he had heard Dr McClelland say on other occasions that he viewed the institution of screening as inevitable.^[248]

27.165 In his oral evidence, Dr Mitchell stated that if American blood banks and fractionators introduced surrogate testing then the UK might have been 'forced' to do the same thing. Impending product liability legislation was also a factor. He was very doubtful, however, whether surrogate testing would have materially increased patient safety, in particular against the background of very few reports in his region of patients developing post-transfusion hepatitis.^[249]

27.166 In his written evidence to the Inquiry Dr Macdonald, CMO, referred to:

[T]he increasing pressure perceived by SNBTS from about mid-1986 to introduce surrogate testing. A major source of this pressure was that moves were afoot elsewhere in the world, including particularly among commercial producers in USA, to introduce surrogate testing. The existence of these commercial producers cast a long shadow over fractionation activities within the NHS.^[250]

27.167 During his oral evidence Dr Macdonald was asked what he meant by the reference to commercial producers casting 'a long shadow' over fractionation activities within the NHS and explained:

I think this was a very peculiar situation, in which the NHS was itself a producer and in that sense it was in competition with commercial producers, in a way that I don't think was replicated anywhere else in the service. I think what struck me at the time, when I wrote that ... [was] that commercial producers, particularly in the United States, were beginning to introduce surrogate testing. In the way in which commercial operators work, they would be presenting this in the publicity in their advertising as an advantage. My stuff is better than your stuff. I wouldn't be sure that that was altogether fair but we, really, I don't think I felt that we could quite adopt these standards.

So there was a lack of balance.^[251]

27.168 Professor Cash stated that the SNBTS was concerned that the UK Medicines Licensing Authority was being persuaded that the introduction of surrogate testing of the plasma feed-stock of commercial fractionators would further enhance the safety of their products and that this unproven claim could be included in package inserts and marketing materials. He noted that the SNBTS view was that it had a moral obligation to patients in Scotland, Scottish based Haemophilia Directors and tax payers who had invested in the PFC, to seek funding to enable the SNBTS to follow this lead. Consequently, the PES proposal that they put to the SHHD was not 'directed to routine blood transfusions but to large pooled high risk PFC products'.

27.169 Dr Macdonald agreed with the suggestion that the Directors' recommendation to introduce surrogate testing came as something of a surprise and, in particular, that it was such a firm recommendation, although there was an awareness that it was coming. He would have expected the interests of donors to have been given more attention.^[252]

27.170 Dr Macdonald was also asked about the working relationship between the SNBTS and the SHHD at the time and replied that it was 'a little difficult'.^[253] He stated:

What I learned, I suppose mostly from casual conversations with colleagues like Dr Scott and Dr McIntyre - I think they had some difficulty in understanding, at times, just where the regional directors stood and would be a little uncertain if the position that they seemed to be taking was the position they were going to hold. I'm not referring specifically to this surrogate testing issue, but I think there was an uneasy relationship.^[254]

27.171 As noted below, there were different views in the SNBTS on whether surrogate testing should be introduced. In his evidence to the Inquiry Dr McClelland said that that did not worry him very much because 'I felt it was a matter that was highly controversial and there was nothing particularly wrong with having a lively debate in the organisation. Not everybody felt that way about it'.^[255] In a subsequent letter to Professor Cash, responding to a draft paper by Dr Gillon in which Dr Gillon had expressed the view that surrogate testing should not be introduced without further research, Dr McClelland acknowledged that there was undoubtedly a problem in facing in both directions. The obvious difficulty was that, on commercial competitive grounds,^[256] the SNBTS needed to introduce screening, but on scientific and value for money for the health service grounds they should be opposing it. He did not know if there was any way out of this dilemma.^[257]

27.172 In due course Dr Gunson was sent a copy of the minutes of the meeting of the SNBTS Directors of 3 March 1987. By letter dated 21 April he advised Professor Cash that he was 'dismayed' that the SNBTS Directors were putting forward proposals for the funding of surrogate tests for NANB Hepatitis in Scotland from 1 April 1988.^[258] Dr Gunson enclosed a copy of the proposals for research submitted by the UK Working Party on Transfusion Associated Hepatitis. Edinburgh was included as a participating RTC (contrary to what was stated in the minutes of the meeting of 3 March that there were no participating Scottish RTCs). The cost of participation by the Edinburgh Centre was not to be met from non-recurring funds; a bid would probably be made to the Chief Scientist for a research grant. He stated:

This decision seems to go against the proposal ... to which I thought that the SNBTS was a party.^[259] Of course, I accept that it might be prudent to have funds ear-marked should the recommendation of the study be that such testing should be introduced, but the tenor of this minute does not suggest that consideration of the results of the multi-centre [study] would be a factor before introducing surrogate testing. Also, I recall your telling me that Scotland would not take unilateral action in this matter without consultation with RTDs in England and Wales.^[260]

27.173 Professor Cash replied on 27 April. He stated:

I don't think you should take the content of minute 3(f), with regard to the introduction of surrogate testing for NANB, too seriously at this stage. I think it would be appropriate to say that it was a decision made with our PESC submission in mind and, I suspect, a view that we have often expressed - that the results of the UK study are unlikely to have a material affect on future operational practice.^[261]

27.174 In oral evidence Professor Cash explained that in that letter:

I think I was conveying something that Harold [Gunson] actually knew from our conversations, that whatever submission we made, and however we thought we may go off on our own, we couldn't and wouldn't, simply because we would need significant funding and this would have to be approved by the [SHHD].

So any panic that he had in seeing these things, he could relax because this would all be part of the UK exercise, hence reference to the PESC submission.

I think I was also explaining to him, which he knew very well, that we didn't really think the currently floated new study of the transfusion hepatitis working party would materially affect any of the ultimate outcomes in terms of practice, if we in fact implemented it all.^[262]

27.175 Professor Cash was asked at the Inquiry how serious the Directors' recommendation to introduce surrogate testing was and he replied:

[I]t was serious in the sense we were trying to alert the people, the minister, ultimately, that things were happening outside the UK that we believed - we were not certain - could have an influence upon us; and that concept was very serious indeed.^[263]

27.176 He continued:

What I'm meaning for him [Dr Gunson]: do not take it seriously in [the] sense you are going to wake up tomorrow morning and the Scots are testing and you are caught. That is what I was signalling to Harold.^[264]

27.177 Professor Cash was asked whether the position of the SNBTS was that it was alerting the SHHD to something which might be on the horizon and which might be unstoppable and that there might be a need to make provision for funding it. He replied: 'Absolutely. We were later to discover that Brian McClelland's opinion was doing a big study - we were too late. The whole world was moving on and we accepted that, perhaps too easily, but we accepted that.'^[265] Professor Cash stated that the position of the Directors, ultimately, was that they did not wish to introduce surrogate testing because they did not have clear evidence of its value (because a large scale prospective study had not been carried out in the UK) but they thought they might have to introduce such testing because other countries either had done so or were moving in that direction. He said, 'we felt we were drifting, and the effort we made was one last effort to stop the drift and get people to sit down and seriously talk about it'.^[266] He went on: 'I think what we want and what we are being forced into by dint of other people's practice doesn't, sometimes, match.'^[267]

27.178 On 14 May 1987 Dr Forrester sent a memorandum to Dr McIntyre, Dr Scott and Mr Macniven.^[268] He reported that the outcome of Dr Gillon's discussions with Dr Forbes was that the Scottish component of the UK NANB Hepatitis research project was being abandoned. He said that Dr Gillon's Director, Dr McClelland, was unlikely to press it as his current view was that the SHHD had better simply institute screening.

27.179 On 19 June 1987 Dr Archibald McIntyre, SHHD, wrote to Professor Cash about Scottish participation in the proposed UK research project on transfusion-associated NANB Hepatitis.^[269] Dr McIntyre noted that there appeared to have been some confusion on the subject. He observed that on 22 April application forms for funding had been sent to the Edinburgh and South East Scotland RTC. For reasons Dr McIntyre had not fully understood, it was decided by the RTC not to proceed with the application. Following a telephone conversation on 15 June between Dr McIntyre and Professor Cash, Dr McIntyre understood that the SNBTS did now wish to proceed with the research project and would submit an application to the CSO for funding. The application would be considered at the meeting of the Biomedical Research Committee on 25 September. The outcome of the research would have considerable implications as it was unlikely that funds would be made available for the routine screening of blood donations for NANB Hepatitis unless it could be clearly shown that such screening was practicable and worthwhile.

27.180 In due course, the SNBTS PES bid submitted in 1987 made provision for the introduction of surrogate testing, for expenditure in 1988-89 and 1989-90, on the basis that it was likely that a new mass screening programme would commence in the foreseeable future.^[270] It was suggested that surrogate screening might be made a special project with separate funding. The accompanying narrative stated:

The SNBTS Directors have now decided that in the light of the advent of new Product Liability laws in 1988 and an emerging unchecked private sector blood collection services^[271] it would be prudent to plan to commence this programme in the financial year 1988/89. The costing are estimates only and it is proposed that we plan to ensure the financial burden covers two financial years but begin in July 1988 (the date new Product Liability legislation will be introduced).^[272]

27.181 The initial provisions were for £300,000 for 1988-89 and £105,000 for the following year. At that stage there was no provision for 1990-91.

27.182 At their meeting on 10 June 1987 the SNBTS Directors noted Dr Gunson's letter of 27 April to Professor Cash and Professor Cash's reply.^[273] It was noted that Dr McClelland would probably apply to the next meeting of the Chief Scientist's Office^[274] for a research grant in respect of the cost of participation by the Edinburgh centre in the proposed UK research into surrogate testing. The need for synchrony with England and Wales was noted.

The Scottish Home and Health Department

27.183 The evolving position of the Transfusion Directors from the early summer of 1986 to the spring of 1987 reflects a degree of inconsistency of approach among them on the question as to whether surrogate testing should be introduced. On the other hand, the SHHD had consistently resisted the introduction of surrogate testing: as already noted, Dr Forrester indicated at the SNBTS Directors' meeting on 25 March 1986 that it was unlikely that the UK Departments of Health would fund testing on the basis of data from the USA (paragraph 27.120 above); Dr Forrester's advice to colleagues on 12 June 1986 summarised his reasons against introduction of surrogate testing at that time (paragraph 27.129 above); and the SNBTS bid for funding in the PES programme for 1987-88 was rejected prior to 2 October 1986 (paragraph 27.141 above).

27.184 While Dr Forrester was present at the meeting of the SNBTS Directors on 3 March 1987 at which the recommendation to introduce surrogate testing was made, the Inquiry has been unable to recover a copy of any note he sent his medical or administrative colleagues reporting on the meeting or the recommendation that surrogate testing should be introduced. In his evidence to the Inquiry, Dr Forrester had no recollection of the meeting or recommendation but did not think that he would have been the messenger for transmitting the recommendation to the SHHD and thought, instead, that it would have been transmitted formally, in writing, through a different channel, perhaps via the PES funding bid.^[275]

27.185 Regardless of the means by which the Directors' recommendation was supposed to reach the SHHD, it is clear that the SHHD was aware of the Directors' recommendation that surrogate testing should be introduced, as Dr McIntyre's minutes to Drs Scott, Forrester and Moir and Messrs Morison and Macniven dated 6 April 1987 show.

27.186 Dr McIntyre's minute to Dr Moir dated 6 April 1987, explained that the bid by the SNBTS of £810,000 to introduce surrogate screening of all donations in 1987-88 was not advanced because:

[T]he research already conducted in the West of Scotland with CSO^[276] funding indicated that the impact there of transfusion-association '[NANB] Hepatitis' was not great; also that the indirect screening proposed would be expensive, could not in any event abolish the transmission of this 'Hepatitis' by blood and blood products, and would lead to a loss of a perceptible amount of 'innocent' blood which nevertheless failed to pass the screen. We also wished to await DHSS thinking on this subject.^[277]

27.187 He reported that the DHSS had now invited the UK Transfusion Associated Hepatitis Working Party to consider the issue.

27.188 On the question of Scottish participation in the proposed UK multi-centre study into surrogate markers in donors, the minute stated:

The Directors of SNBTS are unanimous, and are now pressing fairly strongly, that this screening should be instituted; though perfectly aware that it would be costly and could not abolish transmission [of NANB Hepatitis] completely, they could then claim to have taken all steps open to them to reduce transmission. Before embarking on such an expensive programme it would seem logical to participate in the proposed research^[278] and to delay any further action until the results of this were known.

If recipients of this minute are agreeable that this is the correct line to adopt then the Edinburgh SNBTS will be asked to prepare a detailed proposal along similar lines to that of their English counterparts.^[279]

27.189 The minute contained a handwritten note by Mr Hugh Morison^[280] as follows:

Mr Macniven,

Advise please. My initial reaction is -

(a) it would not make sense to screen all blood for [NANB Hepatitis] as benefits appear out of all proportion to the risks,

(b) we should therefore participate in the research,

(c) CSO should be encouraged to fund it.^[281]

27.190 In a minute dated 7 April 1987 Dr Scott, DCMO, agreed with Dr McIntyre that further research should be carried out into surrogate testing, stating:

We must do whatever we can to prevent the BTS going ahead with a full scale introduction of this testing - or at least trying to blackmail us into the provision of funds.

The research proposal from Edinburgh will of course have to be subject to the scrutiny of the appropriate CSO group and the availability of finance. I would not like to see it fail on the grounds of finance because the stakes are high.^[282]

27.191 Mr Macniven responded on behalf of himself and Mr Morison. They agreed with the comments in Dr Scott's minute and expressed the view that:

It is important that the decision on whether or not to screen all blood for [NANB] Hepatitis, which will not be cheap and may not be certain, should be taken on the basis of the sort of UK research you suggest.^[283]

27.192 The strong support of the SHHD for the multi-centre study proposed by the Working Party on Transfusion Associated Hepatitis seems, on the face of it, surprising given Dr Forrester's note following the meeting of the Working Party on 24 November 1986 that the proposed research was 'of no great significance or scientific interest'.^[284] Similarly, it is not entirely clear what Dr Scott meant in his minute of 7 April 1987, above, that he would not like the research proposal to fail on the grounds of finance 'because the stakes are high'.

27.193 In his evidence to the Inquiry Dr Macdonald stated:

I think one must be truthful and say that - and I think this applied at that stage [late 1986] to - certainly to the directors in England and perhaps a bit later for the ones in Scotland. But we were really trying to, I think, give ourselves a bit more time and not be rushed by the pressure coming from the commercial producers.^[285]

27.194 Dr Macdonald was later examined as follows:

Q: [One] might think ... that there was a preoccupation within SHHD with undertaking research, whatever its purpose, at all costs, as a means of putting off making a decision about surrogate testing ....

A: I think it was reasonable to argue that we didn't have sufficient information to know exactly how it would work out in our population and therefore we should look to the possibility of research. At the same time, I think it has to be admitted that that would postpone a final decision inevitably.

Q: But was it the postponement of the final decision that was really the priority at this time?

A: It certainly - it is certainly fairly clear that neither DHSS nor SHHD were persuaded that we should go ahead with surrogate testing.^[286]

27.195 The reasonableness of the SHHD position is discussed further below.

Correspondence in The Lancet

27.196 The picture in the second half of 1987 is confused, with different groups of Scottish experts expressing apparently conflicting views. Debate on the introduction of surrogate testing became focused in a chain of correspondence in The Lancet beginning in June, to which SNBTS specialists contributed. It is necessary to note the positions that had been reached in research by Scottish scientists by June. The work of Dr Dow and Dr Follett has been discussed above. As noted in paragraph 27.127 above, Dr Dow's view was that there was a low level of post-transfusion NANB Hepatitis in the West of Scotland region (with 23 possible cases reported in eight years) and that the introduction of screening would have little impact. In Edinburgh and the East of Scotland, Dr Gillon and colleagues had carried out research between April and November 1986 into ALT activity in a cohort of regular blood donors.^[287] They had concluded that the introduction of ALT/anti-HBc screening tests as an indicator of NANB Hepatitis carrier status in blood donors could not be justified at that stage.

27.197 The chain of correspondence in The Lancet began with a letter from Dr Catherine Anderson and colleagues at the North London BTC, Edgware, in April 1987, arguing against the introduction of surrogate testing without further research.^[288] The authors argued that a national study was required to assess the incidence of raised ALT levels and anti-HBc in donors in different parts of the country; the incidence of acute post-transfusion NANB Hepatitis; and how many of those affected developed evidence of chronicity and serious clinical sequelae. The authors concluded:

Before we are forced to accept two screening tests of unproven benefit, which have high revenue implications, we need a national study to assess the incidence of raised ALT and anti-HBc in donors in different parts of the country. Also, and perhaps more importantly, a study is needed to assess the incidence of acute post-transfusion NANB hepatitis and to assess how many of those affected develop evidence of chronicity and serious clinical sequelae.

If the true incidence of post-transfusion NANB hepatitis and its serious clinical sequelae are at a much lower level than reported from the USA, then screening of donations to reduce the incidence of NANB hepatitis may not be cost effective in the UK.^[289]

27.198 In effect, the Edgware RTC group was repeating the call for a large, prospective, well organised and resourced study of post-transfusion NANB Hepatitis originally put forward by Dr McClelland in 1980-81.

27.199 A similar view was expressed on 2 June 1987 in a paper by Dr Valerie Mijovic and colleagues (also at the North London BTC) reporting on a study of ALT testing in 2000 North London blood donors.^[290] The percentage of the total donor population with raised ALT levels (4.6%) was greater than that found in earlier studies at the same centre in 1973 (2.8%) and 1982 (3.1%). The increase in donors with raised ALT values had occurred despite the intensification of donor education and the subsequent self-exclusion of donors in groups at high risk of HIV. The authors considered that as confirmation that many other factors, apart from NANB Hepatitis, affected ALT activity. Those other factors included high alcohol consumption, obesity, medication, strenuous activity and inhalation of solvents. The authors stated:

Before we even consider testing blood donors for ALT, a well designed prospective trial is needed to compare the incidence of hepatitis associated with transfusion in patients who have received blood only from donors with normal ALT activities with those receiving untested blood .... [E]ven in the United States the predictive value of ALT testing of blood donations for NANB hepatitis is very poor. The costs of testing and discarding donor blood would need to be examined as well as the costs of informing and counselling donors found to have ALT values repeatedly above the normal, or donors with excessively high values at any one time. Extrapolating data from the United States to this country without knowing the magnitude of the problem or its preventability would be ill advised.^[291]

27.200 In his evidence to the Inquiry Dr McClelland stated that he could not remember his reaction at the time to the suggestion by Anderson and colleagues that a prospective study should be carried out before surrogate testing was introduced but said:

I think I was in one sense probably glad that somebody was saying what I had been trying to say for quite a long time but at the same time ... I was aware that the study would take several years and I think I would probably have felt it was a bit late....

I felt that we had been prevaricating about this for a long time, and to sort of prevaricate for another three years, which was the minimum time it would have taken to do a decent prospective study, we were too late.^[292]

27.201 The suggestion had a greater impact on Dr Dow and Dr Gillon, and their respective research colleagues.

27.202 In a letter in The Lancet on 13 June 1987 Drs Dow, Mitchell and Follett of Glasgow reported on Dr Dow's study of post-transfusion hepatitis in the west of Scotland. Their findings were analysed briefly and said to indicate that if ALT and anti-HBc tests had been carried out routinely over the eight-year period of their study, at an estimated cost of more than £1 million, with a loss of about 4% of the blood supply, only five of the reported cases of infection might have been prevented. They expressed the view that:

It would be prudent to do a UK study to assess the real incidence of acute post-transfusion NANB hepatitis and to assess the proportion of those chronically affected, before considering following the American surrogate testing policy.^[293]

27.203 In the same edition of The Lancet, Dr Gillon and his colleagues at Edinburgh reported the findings of their 1986 study into surrogate markers in blood donors attending their centre.^[294] It stated:

Our findings confirm the doubts expressed by Dr Contreras and her colleagues [at Edgware] on the wisdom of introducing surrogate testing for NANB hepatitis into blood transfusion practice in the UK. We found a strong association between a raised ALT and both obesity and alcohol ingestion, and these two factors alone might account for 82% of the abnormal ALT values found .... Those who support ALT testing should recognise the tendency ... of ALT levels to fluctuate: the loss of donated blood would be far in excess of that suggested by published studies, and most of the excluded donors would not be NANB hepatitis carriers.

If the degree of benefit claimed from the retrospective American studies were to hold for the UK, the blood transfusion services would have to spend well over £5 million more every year (2½ million donations at £2-3 per donation). Account must also be taken of the consequences of identifying up to 5% of the donor population as being potential carriers - not just the costs of further laboratory tests, clinical assessments, and counselling but also the anxiety raised in the donors themselves.

The Americans have concluded that a large, prospective, randomised trial to test the hypothesis that surrogate testing carries clinical benefit will never be done. Of the four small prospective studies, two using ALT screening and two using anti-HBc, three failed to demonstrate any reduction in post-transfusion NANB hepatitis as a result of donor screening and one found an apparent association between anti-HBc in donor units and recipient hepatitis.^[295]

We conclude that the introduction of ALT/anti-HBc screening tests as an indicator of NANB hepatitis carrier status in blood donors cannot at present be justified.^[296]

27.204 In his evidence to the Inquiry, Dr Gillon said:

I think nobody would have denied that introducing surrogate testing would have identified some donors who were carriers of [NANB] Hepatitis. We knew that. We just didn't know how many. We didn't know enough about whether this test would perform as it was being predicted in the American literature.^[297]

27.205 Dr Gillon also advised that he had visited the USA in early 1985 and was aware of work being done there, and elsewhere, to try to identify the agent or agents responsible for NANB Hepatitis. While he had no particular knowledge in 1987 that a breakthrough was imminent, he said:

[T]he other thing I had in my mind was that there was the likelihood that there would be a scientific solution to this problem, we would hope in a very short time ....

....

[T]o say that ALT was the only show in town was perhaps true, but it's not that we didn't have other avenues that were opening up in a much more rigorously scientific way of dealing with this problem.^[298]

27.206 On 16 June 1987, three days after these letters had been published in The Lancet, the SNBTS Co-ordinating Group held an extra meeting.^[299] All of the Scottish Transfusion Directors were present, along with Professor Cash and Mr John Francis of the SNBTS Finance Department. The SNBTS scientists contributing to The Lancet correspondence were not represented. Their view that surrogate testing was not justified on scientific grounds was noted, however, and acknowledged by the Directors. Dr McClelland tabled a draft letter to The Lancet 'in expansion of the SNBTS view of the need to commence surrogate marker screening of blood donations for NANB in the context of product liability and of competition from commercial producers who would be introducing it'.^[300] After a few editing points were made the Directors agreed the terms of the letter.

27.207 The letter from the SNBTS Directors was published in The Lancet on 4 July 1987 under the title, 'Testing blood donors for [NANB] hepatitis: irrational, perhaps, but inescapable'.^[301] In the letter the Directors noted the recent correspondence by Drs Anderson, Dow and Gillon and colleagues to the effect that the UK transfusion services should not start donor screening until prospective controlled studies had been carried out in the UK to find out how many cases of post-transfusion hepatitis would be prevented. While the SNBTS Directors agreed that the size of the benefit to be gained from surrogate testing could not be accurately established without such a study, they considered that the time for such a study had already passed: 'Starting now will give us an answer in 3-4 years - and that is probably 3 to 4 years too late'. That conclusion clearly reflected Dr McClelland's considered position at this stage and his oral evidence was consistent with it.

27.208 The letter stated that the introduction of surrogate testing was 'virtually inescapable' for a number of reasons. In summary, these were:

• Legislation would soon come into force providing for strict liability for harm caused by products unless all known methods had been taken to avoid the risk.
• Surrogate testing might modestly reduce the level of infectivity of pooled plasma products, in particular, pending the validation of methods of viral inactivation in large-scale trials and many would argue that some improvement was better than none.
• The UK transfusion services could not ignore the wishes of consumers to be supplied with 'NANB tested' products, when such testing had been introduced by commercial manufacturers who would market their products as being safer.
• Having regard to the number of cases of post-transfusion hepatitis that may be prevented, the cost of preventing morbidity by surrogate marker testing for NANBH might be no greater, and could be less, than that accepted for existing screening tests for Hepatitis B and HIV.

27.209 In their letter the Directors concluded that 'the decision which has to be made is when rather than whether the UK transfusion services follow the lead of the United States and other European countries in donor screening'.^[302]

27.210 Dr McClelland was asked how strongly the various SNBTS Directors felt at the time about the issue of surrogate testing and replied that most of them were still 'pretty lukewarm' and that he didn't think they were 'enthusiastic'.^[303] He explained that part of the reason he had drafted the letter was that:

[H]aving repeatedly failed to get anywhere ... on grounds of patient safety ... I thought it might be worth deploying some other arguments, because people were worried about ... the European directive on strict product liability which was about to be translated into the Consumer Protection Act, and that was quite exercising people in the transfusion service at this sort of time.^[304]

27.211 Professor Cash was asked whether, although the ultimate decision was unanimous, some Directors had been uneasy about the idea of surrogate testing. He replied:

I think that all of us, certainly including myself, but all of us were very uncomfortable with finding our position - and we were not in that letter recommending the introduction; we were saying, "It's too late. We are going to be forced into doing it." But none of us wanted to go down that track and I think it is quite important that I make that very plain ....^[305]

27.212 He continued:

[A]ll of you keep saying we recommended it. We just simply said, "It's inevitable. It's going to happen. We are going to be caught here and we need to plan for that eventuality."

....

[W]e were all very unhappy about this. We were not saying, "This is excellent, let's go for it". We were saying, "We are caught"... [P]lease, we did not recommend that we started it. We simply said, "The writing is on the wall, we think, as best we can judge".^[306]

27.213 In his evidence to the Inquiry, Dr McClelland confirmed that he was of the view at that stage that surrogate testing, using both ALT and anti-HBc, should be introduced. He was asked for the main or the determining factor or factors that led him to recommend that surrogate testing should be introduced and replied:

I felt there was - even in the absence of a proper ... a definitive prospect of [a] randomised controlled study to provide a real answer, that there was sufficient evidence - the evidence which had convinced the Blood Products Advisory Committee of the FDA that surrogate testing needed to be introduced and led to the decision in the United States was, while not complete and not definitive, very, very difficult to ignore and I had no conviction that the epidemiological situation, the sort of prevalence, the amount of ... [NANB] Hepatitis infection in the UK was really that much less than it was in America, in 1986, because, you know, commercial paid donors had stopped. They had introduced similar changes in donor selection in relation to AIDS that we had, and I felt if, in the light of ... those two major changes, the United States felt it had to introduce this testing, we were in a very, very poor position to not follow suit in the UK, unless we had convincing evidence that it really genuinely wasn't a problem .... And we didn't have that.^[307]

27.214 As indicated in paragraph 27.208, Dr McClelland was deploying different arguments. It was, as he said, his 'sort of last throw on this topic'. When asked to what extent patient safety was a factor in his consideration he replied it was 'the' factor in his consideration.^[308] He went on to explain that his view was essentially an application of the precautionary principle: he was concerned that 'despite the persisting uncertainties about the real safety gains that might be achieved, failure to introduce testing could constitute a failure to protect patients from some degree of avoidable risk'.^[309] There was evidence which, while imperfect, suggested that surrogate testing might increase the safety of blood, and:

[I]f something might make a patient safer, then you have to do it. That is in a very crude way, as I understand [it] ... the precautionary principle. And depending on whether you are a health economist or concerned primarily with the nation's economics or whether you're concerned with the public health or you are concerned with the health of an individual, you will view those things in different ways. There ain't no right answer.^[310]

27.215 Whether or not justified on the precautionary principle, the letter exposed the conflicting opinions within the SNBTS at this stage, in mid-1987. The letter also attracted considerable criticism and a degree of confusion about its purpose and the intentions of the SNBTS. The SNBTS Directors later acknowledged, at their meeting on 18 August 1987, that the rapid succession of the publications by the scientists and by the Directors 'had caused readers of The Lancet to be puzzled'.^[311] Dr Mitchell, for example, had been a co-author of the letter published in The Lancet on 13 June 1987 which argued against the introduction of surrogate testing until further studies had been carried out, but was also a signatory to the letter of 4 July 1987 in which the SNBTS Directors argued that the time for further studies had passed and that the introduction of surrogate testing was virtually inescapable.

27.216 Professor Cash had sent a pre-publication copy of the Directors' Lancet letter to Dr Fraser (Bristol) who replied on 2 July 1987, advising that:

I think you will find that the Transfusion Directors in England and Wales will not be very pleased at reading this letter.

....

We all managed to work together to introduce HIV antibody testing on the same date. I think it is only a shame that we have not been able to have the same type of discussion to agree whether or not to implement ALT and/or core antibody testing in the UK.^[312]

27.217 Professor Cash replied to Dr Fraser on 8 July 1987. He stated:

1. The SNBTS Directors do not wish, and currently have no intention, of introducing NANB surrogate testing unilaterally.

2. Current views, which as you know were crystallised last March, are being expressed to support our Public Expenditure Survey (PES) submissions to SHHD for the next 5 years.

3. We have no doubt that an important forum for the continued debate is indeed the BTS/NIBSC group(s) and the current NANB debate (which began some 2 years ago here) and the confused central management attitudes to the Medicines Act and Product Liability had much to do with driving me to seek the establishment of this joint enterprise.

4. I really don't believe you should view The Lancet letter as any more than part of a debate which was initiated in this journal's columns by our friends and colleagues at Edgware. It can also be viewed as yet another attempt to persuade central management (DHSS) to give renewed thought to the way the transfusion services interface with the Medicines Act and forthcoming legislation on product liability and perhaps even to ways for improving the co-ordinated management of the transfusion services on a UK basis.^[313]

27.218 In a minute dated 21 July 1987, Dr McIntyre brought the SNBTS Directors' Lancet letter to the attention of Mr Macniven and others. In the minute Dr McIntyre stated:

The purpose of this minute is not to discuss all the relevant issues, but to point out that SNBTS may institute testing without further discussion as a fait accompli.

....

Professor Cash has assured Dr Fraser of Bristol NBTS, in a letter dated 8 July, that he will not institute testing 'unilaterally'. We have however no assurance that he will not do so in the near future without specific funding and without necessarily reporting what he has done to CSA or SHHD.

DHSS have expressed their concern and dismay at the letter by Professor Cash and colleagues and have interpreted this as being SHHD policy; we have attempted to reassure them that it is not so. Their concern is that if we should commence testing unilaterally they will feel obliged to follow.^[314]

27.219 It was noted that the SNBTS had been given the opportunity to engage in a research programme to evaluate the need for testing but had declined as they felt that the time for this study had already passed.^[315] The background to that comment was confused. As indicated in paragraph 27.159 above, the proposal for Scottish participation in the UK programme envisaged in early 1987 was directed into the CSO funding process by Dr Moir, SHHD. The project seems to have made little progress for some time after that point, but was revived ('after much manoeuvring' by the SHHD)^[316] in June 1987 when it was decided that an application would be made to the CSO. It was made in the names of Dr McClelland and Dr Gillon on 6 August but was later rejected.^[317]

27.220 The debate in The Lancet continued. Two English Directors, Drs Contreras and Barbara, responded to the Scottish Directors' letter to The Lancet in the edition published on 1 August. They argued that the transfusion service must not bow to irrational pressure to introduce surrogate screening, described as 'measures whose efficacy is unproven'.^[318]

27.221 At their meeting on 18 August 1987 the SNBTS Directors noted reactions to the Scottish Directors' letter to The Lancet.^[319] Dr McClelland's application to the Chief Scientist Office for funding to enable him to participate in the UK study was reported. The Directors agreed that to be consistent with their policy decision (on the introduction of screening) it would be prudent to proceed to a Scottish national study to evaluate ALT and anti-HBc testing. Dr Cuthbertson and the SNBTS Microbiological Validation Group would consider how the SNBTS should examine the available technology for these tests.^[320] At this stage, therefore, there were two lines of research for which funding would be required: Dr McClelland's UK project and a national Scottish project that had been remitted to the SNBTS Microbiological Validation Group.

27.222 Preparatory work was started to cover the possibility that surrogate screening might be introduced. On 6 October 1987 the SNBTS Directors were told that Dr Cuthbertson's SNBTS/NBTS Microbiological Validation Group was due to make a proposal to the Directors concerning ALT and anti-HBc testing methodology.^[321] The SNBTS Directors met on 8 December 1987.^[322] It was reported that the Microbiological Validation Group was to reconsider to what extent it was necessary for every centre to be involved in evaluating the technology for ALT testing and would report on the matter by 31 March 1988. It was agreed not to consider anti-HBc testing until the report on ALT testing had been received and discussed by the Scottish Directors.^[323] That work did not proceed quickly, however; when the SNBTS Directors met on 13 December 1988, it was reported that the Validation Group had not done any significant work since the last meeting. The Directors agreed that the group 'had more important matters to fulfil'.^[324] The proposal for a national Scottish evaluation of surrogate screening appears to have proceeded no further after that point.

27.223 Meanwhile, the commercial pressure anticipated by the Scottish Transfusion Directors in 1987 was indeed to become a reality and was noted within the SHHD. On 17 December 1987 Dr Forrester sent an internal SHHD memorandum to Mr Tom Macdonald and others.^[325] He noted that commercial producers of blood products were being allowed by the DHSS to include in their product inserts a statement that the product was derived from donations which had been ALT tested and that that was likely to stimulate pressure for the introduction of surrogate testing in Scotland.

Funding for Edinburgh RTC to join the multi-centre study

27.224 As noted in paragraph 27.219, Drs Gillon and McClelland submitted an application to the Chief Scientist Office (CSO), SHHD, on 6 August 1987 for a research grant to enable the Edinburgh RTC to participate in the proposed UK multi-centre study into surrogate markers in donors.^[326]

27.225 On 20 August 1987 Dr Forrester (SHHD) sent a memorandum to Dr William Forbes (CSO) and others.^[327] Dr Forrester wrote that the Department was required to make a well-informed decision on whether or not to support surrogate testing of blood donations for NANB Hepatitis. The benefits of such testing were not clearly established and there were drawbacks. The memorandum suggested a lack of significant support for the project at this stage. It stated:

The Department are well aware of the work by Dr Dow supported by CSO, and indeed so are the organisers of the current application .... The Department however do not believe that his work alone is a sufficient guide at present, because:

• It did not study [anti-HBc] ....
• More searching investigation is now possible into the significance of these antibodies ....
• It took place before the advent of screening for HIV antibodies, which may exclude some donations conveying in addition some non-A, non-B hepatitis agent; and
• It is not necessarily typical of the UK as a whole ....^[328]

27.226 In view of the interest of the SHHD, it was said that Dr Forrester or Dr McIntyre would welcome the opportunity to be present at the meeting of the CSO Biomedical Research Committee on 25 September. A manuscript note on the memorandum informed Mr Tom Macdonald, the branch head, that Dr Forrester was pressing forward with getting CSO money for the proposal, with the support of colleagues.

27.227 In a minute to Mr Macniven dated 1 October 1987, Dr Forrester stated that the Gillon/McClelland grant application had been considered, and rejected, at a meeting of the CSO Biomedical Research Committee (BRC).^[329] Dr Forrester was present at the meeting and noted on 25 September 1987 that the Committee had rejected the application on scientific grounds, which he agreed were 'substantial'. While the Inquiry has been unable to recover a minute of the BRC meeting of 25 September 1987, the surrounding documentation makes it reasonably clear that the BRC was of the view that restricting the proposed study into surrogate markers to donors and not including the follow-up of recipients, was of little or no scientific merit: it would not provide information on the prevalence of post-transfusion NANB Hepatitis, nor would it provide information on whether the presence of surrogate markers in donors was associated with the development of post-transfusion NANB Hepatitis in recipients.^[330] These are substantially the reasons for the view that the Follett and Dow study of September 1984 provided no basis for arriving at conclusions on the prevalence of transfusion-transmitted NANB Hepatitis or on the likely efficacy of surrogate testing in reducing the incidence of transmission of the disease.

27.228 In his minute to Mr Macniven of 1 October 1987, Dr Forrester indicated a major interest in the formulation of the BRC's reasons for rejection of the grant application. He had asked Dr Forbes, CSO, to ensure that the minutes of the BRC decision would confirm that the reason for rejection was not that research was 'superfluous', which he noted was the SNBTS position. He also asked that announcement of the decision should be withheld until 'CSO have put their act together with DHSS Research Management Division'. He had also asked for a statement in writing of the reasons for rejection, which he anticipated would take some time to prepare. In a summary he noted that, while agreeing that the scientific evidence was incomplete, the SNBTS nonetheless maintained that their general obligation to the recipients of blood and blood products required screening to start immediately, despite its recognised drawbacks and cost; that the Health Departments, along with the NBTS, were pressing for more scientific evidence before making any decision to screen; and that the gathering of the evidence, at least in Scotland, was obstructed by the limitations of the research proposal. These limitations meant that the results of the proposed research could prove inconclusive, which was a serious objection to undertaking it. In respect of the outstanding application by the SNBTS for funds to introduce surrogate testing he stated:

[I]f there is no hurry to reach a decision ... [I] would prefer to do so when the written statement of reasons for rejection [of the Edinburgh grant application] has arrived, and when our CSO and the DHSS have reached a common stance.^[331]

27.229 Mr Macniven replied to Dr Forrester on 2 October 1987. He noted that the PES timetable required a decision to be reached very soon on whether to earmark funds for the SNBTS for surrogate screening to commence in the second half of 1988. He had, however, taken steps to get round the problem by registering with Finance Division that a need for NANB Hepatitis testing may emerge but that it would be premature to allocate money to the SNBTS for that purpose at that time. Mr Macniven stated in his minute:

But I am a little anxious about the timescale implied by your minute. I am very anxious indeed [that] our decision (on whether or not to put resources into NANB testing) should be properly informed by research evidence. If that evidence justifies testing, then it is very important that we should be able to find the money to start it quickly. If it does not justify testing, it is equally important that we should not have allocated money to the SNBTS for the purpose, thereby sterilising it for other uses. But I think the worst of all possible worlds is that research cannot get off the ground: I fear that, in those circumstances, we would be subjected to increasingly irresistible pressure to spend the money in any case, for the sake of improving (at any price) the safety of blood and blood products.

... [I] can well understand the general CSO disinclination to "repair" research proposals: but I hope that too much stress does not need to be placed on that principle in this case, because of the substantial patient safety/expenditure issues which are stake.^[332]

27.230 In his evidence to the Inquiry, Mr Macniven agreed with the suggestion that the memorandum was consistent with him keeping an open mind on the subject of surrogate testing and that, if he had been persuaded on the evidence, he would have sought to ensure that funding was available. As he put it, 'funding should not be the obstacle'^[333] and 'I was very keen to make sure that funding should not be the limiting factor if the scientific/technical light turned to green.'^[334] He explained that it would be 'the worst of all possible worlds' if research could not get off the ground because 'we would be taking the decision on information which was not properly informed by research evidence'.^[335]

27.231 Drs Gillon and McClelland were written to on 19 November 1987 advising that their grant application had been declined.^[336]

1988

Funding for the multi-centre study in England

27.232 On 20 January 1988 a paper was produced for the Central Blood Laboratories Authority. 'Screening of NBTS blood donors'^[337] proposed that the BPL should come into line with all other major fractionators of human plasma by including ALT testing in the specification of source plasma collected by blood donor centres. The drive for ALT testing was said to have been strongly augmented by manufacturers' liability and the demands of patients to eliminate NANB Hepatitis as a sequel to treatment, with the development of severe liver disease in up to 60% of sufferers.^[338] The paper noted that the scientific basis for introducing ALT screening of donors was far from satisfactory and that, as regards Factor VIII, the BPL was distinguished from competitors by the use of dry heat virus inactivation and the use of plasma unscreened for ALT and so outside the 'state of the art' practised in the USA and Europe. The BPL had a clear commercial motivation for screening which was independent of safety issues. It would be necessary if surplus products were to be sold in Europe.

27.233 The risk that the pressure on the BPL would result in the introduction of testing prompted a reaction in the DHSS. A DHSS minute in January 1988 reveals that an application for funding for the English part of the multi-centre study into surrogate markers in donors had been refused by the DHSS Research Management Division.^[339] The minute argued that the study should nonetheless be funded for policy reasons and noted, particularly, that all major producers of blood products now used plasma from ALT-tested blood, which put pressure on the BPL to do likewise. In addition, if the BPL was forced to introduce ALT testing of the plasma used in its products, that would involve 'writing off' its stockpile of plasma, worth around £40 million, and importing commercial products at a further cost of around £10 million. The author of the minute, Mr Harris, noted that embarking on the proposed multi-centre study would reduce the likelihood of pressure from haemophilia centre Directors and the Haemophilia Society to introduce surrogate screening, in that the study might demonstrate (i) the low incidence of NANB Hepatitis carriers in the NBTS donor pool and (ii) the low utility of the ALT test. The minute concluded:

Such a study could (against all expectations) prove the need for the ALT test, even so it would then have provided scientific justification for the resulting expenditure. Even having a study in train, would give Ministers a valid reason for not being "bounced" into accepting ALT testing.

The R&D programme cannot find room for this study - cost £72,000. In view of the serious financial consequences for the HCHS [Hospital and Community Health Services] can it be exceptionally found from the HCHS central fund?

I feel that Ministers would not thank us for failing to head off this folly.

27.234 The arguments in the minute in favour of the study were, presumably, persuasive in that funding for the English part of the multi-centre study was duly found from the relevant DHSS policy division.^[340]

27.235 In a minute of 14 April 1988 Dr Forrester noted that the English part of the multi-centre had received funding and commented:

From now on the tables are turned. We will have to watch what England do, because they will be first to get the relevant research data; and they are, even now, under more external pressure to institute testing for ALT. The pressure here is still evidently internal: SNBTS striving to keep up with any competition.

... [I] think we cannot help being left behind - but in this particular context, there may not be drawbacks.^[341]

27.236 Commenting on Dr Forrester's minute, Dr Moir, Director, CSO, noted that he had discussed matters with Dr Jeremy Metters of the DHSS who had advised that his DHSS colleagues with policy interests felt particularly vulnerable. They were aware that there were some Scottish data on the prevalence of the problem whereas there was no comparable data in England and Wales.^[342] Dr Moir noted:

[Dr Metters] also felt that a substantial part of his policy colleagues' interests in funding this "research" study was that it would allow them to "play for time" in the hope that instead of ALT a more suitable screening assay could be found which would act as a marker for [NANB] Hepatitis.^[343]

27.237 At their meeting on 12 April 1988 the SNBTS Directors confirmed that it had been agreed not to introduce ALT testing in Scotland until it had become UK policy.^[344] The Directors, however, wished to reserve their position in light of reports of ALT testing in at least one RTC in England and Wales.^[345] It was noted that imported commercial products were being marked 'ALT tested'.

27.238 Studies continued to be reported that showed a low prevalence of ALT and anti-HBc in the general population. In 1988 Dr Alan Kitchen and colleagues reported on a study to determine the incidence of anti-HBc in donors at the North East Thames Regional Transfusion Centre.^[346] In the study, 1893 donors were tested, of whom 35 (1.85%) were repeatedly positive. The authors commented that, at that time, there was likely to be very little benefit in the introduction of anti-HBc screening of blood donors. The loss of approximately 2% of available donors because of deferment would cause problems for those transfusion centres facing shortages of donors, especially those serving the Greater London Area. The costs of testing donations for the presence of anti-HBc were high and, in the prevailing financial climate, would be hard to justify. A further consideration was the need to counsel those donors found to be anti-HBc positive. Although the authors accepted that the introduction of surrogate testing might eventually be unavoidable, they believed that only a controlled prospective study would provide the necessary information to determine the significance of donor anti-HBc levels in relation to post-transfusion hepatitis, especially NANB Hepatitis, in the UK.

27.239 At the annual meeting of the SNBTS Directors and the Scottish Haemophilia Centre Directors on 5 May 1988, Dr Forrester reported that the multi-centre study into NANB Hepatitis surrogate screening was being carried out in England and that a decision whether to introduce screening would probably wait upon its outcome.^[347] Dr McClelland and Professor Cash were both uncomfortable with the delay involved. In effect, the funding process had excluded the SNBTS from participation in continuing research by the NBTS into the effectiveness of surrogate screening of blood donations.

The Chiron announcement

27.240 This was the position reached in the UK immediately before Chiron Corporation, USA, made the important announcement, on 10 May 1988, that had identified, cloned and expressed proteins from an NANB Hepatitis virus and had developed a prototype immunoassay that might lead to a screening test.^[348]

27.241 The announcement heralded the beginning of a transitional period between the discovery and the production of a marketable test during which surrogate testing for NANB Hepatitis remained of significant interest. The issue at this stage, in 1988, was whether it was appropriate to postpone a decision on the introduction of surrogate testing for NANB Hepatitis, using the assays then available.

27.242 The SNBTS Directors noted the Chiron announcement, at their meeting on 14 June 1988.^[349] Professor Cash was to enquire about the availability of the test in the UK; at that stage, he thought that 'specific NANB testing kits will be available in about 2 years'.^[350] A subsequent letter from Ortho Diagnostic Systems Ltd, which had entered into an agreement to manufacture the test kits under licence from Chiron, advised that the kits might be available 'towards the end of 1989'.^[351] The 1988 SNBTS PES bid, which appears to have been prepared in June 1988, sought funding for ALT testing in 1989-90 and funding for use of the Chiron/Ortho test in 1990-91.^[352] In particular, PES bids for funding for testing were submitted by the CSA as follows:

(i) 1989-90 ALT £85,000

(ii) 1990-91 ALT £25,000; NANB^[353] £300,000

27.243 There was discussion of the Ortho anti-HCV test when the SNBTS Directors met on 27 September 1988.^[354] The test had been the subject of a workshop at the International Society of Blood Transfusion Conference in July 1988. As understood by the Directors, the availability of the test was not imminent and the data presented had been inconclusive. The antibody was a late-developing one which would present similar problems in relation to the 'window' between infection and the production of measurable antibodies, as was the case with HIV. In the SNBTS Directors' view, ALT remained the earliest available indicator of infection. Notwithstanding the Chiron discoveries, therefore, there was likely to be a period, of indefinite duration, in which surrogate testing for ALT or anti-HBc remained a relevant and material issue for the SNBTS. The Directors agreed not to plan any medium-term policy on the basis of the successful introduction of Chiron technology and that ALT would remain the test of choice in the meantime.

27.244 At the end of 1988, however, the SNBTS Directors continued to take the view that Scotland should not commence surrogate testing, pending the outcome of the UK study. At their meeting on 13 December 1988, Dr Wagstaff informed the Directors that the DHSS had funded three centres to carry out a study of ALT technology and of anti-HBc screening. Professor Cash confirmed that the Scottish Directors would not commence surrogate testing 'until the Department of Health and the SHHD supported and funded the project', which would be a task for the soon-to-be-formed UK blood transfusion services' Advisory Committee on Transfusion Transmitted Diseases (ACTTD).^[355] The issue would also engage the Advisory Committee on the Virological Safety of Blood (ACVSB). The topic had moved into a new phase, with advice being taken from duly constituted expert bodies.

27.245 Dr Gunson had, early in 1988, discussed with Dr McClelland and Dr Pickles the formation of a UK group to determine policy with respect to transfusion-transmitted diseases.^[356] In the event, two groups were formed. The ACTTD was a UK BTS group on transfusion-transmitted diseases. The ACVSB was a DoH group on the virological safety of blood. The ACVSB had a wider remit than blood transfusion medicine, embracing transplantation and other aspects of disease transmission. It was a UK advisory committee and included Scottish members. The establishment of the ACVSB and the ACTTD and the groups' initial discussions relating to the introduction of anti-HCV testing in the aftermath of Chiron's discoveries, are described in Chapter 31, The Introduction of Screening of Donated Blood for Hepatitis C. In this chapter, it is necessary to trace only the fate of the investigations into the use of surrogate testing that continued into the period from 1989 onwards.

1989

27.246 The ACTTD had among the terms of reference agreed at its first meeting on 24 February 1989: 'To consider the epidemiological, clinical and laboratory aspects of diseases which may be transmitted by the transfusion of blood and blood products.'^[357]

27.247 The continuing three-centre study of ALT technology and anti-HBc screening in England and Wales was also within the group's remit.

27.248 At that meeting, Dr Contreras (North London RTC) outlined the results of the study to that date. Notwithstanding the decisions on funding already discussed, research continued in Scotland. Dr Mitchell reported on the study of 5000 donations in Glasgow, in which 2.8% of donors had elevated ALT levels. With respect to anti-HBc tests, in a separate study 17 out of 2000 donations were found positive, of which 15 results were reproducible. Professor Cash reported that the methodology for ALT testing and follow-up had been examined in Scotland and that a standardised method had been agreed. This would be available to the RTCs if the general introduction of ALT testing was agreed.^[358] It was again agreed that there should be no recommendation to institute ALT testing until the current study in England was completed.^[359] It was noted, however, that there was a degree of inevitability about the introduction of the test, which was required by regulatory authorities in other countries to determine the acceptability of fractionated plasma products. That would be discussed with the BPL in the near future.^[360] At this stage, therefore, the ACTTD was resolved to continue research into surrogate testing, but with acknowledgement that external marketing considerations would come to drive the agenda (that having been recognised to be the case for some time).

27.249 In the meantime, steps had been taken to implement the decision of the UK health ministers, originally proposed the year before, to set up the ACVSB. The decision was intimated in a letter of 8 March 1989 sent out by Dr E Harris.^[361] The ACTTD and other committees would report through the ACVSB, which would provide formal scientific advice to the UK Government and its agencies. The terms of reference of the ACVSB were:

To advise the Health Departments of the UK on measures to ensure the virological safety of blood, whilst maintaining adequate supplies of appropriate quality for both immediate use and for plasma products.^[362]

27.250 The ACVSB became the main advisory committee to the UK Government on whether surrogate testing of blood donors for NANB Hepatitis and screening of donors for Hepatitis C should be introduced. The first meeting of the group took place on 4 April 1989 under the chairmanship of Dr Harris.^[363] The intention was that the next meeting would concentrate on viral hepatitis.

27.251 The multi-centre study of ALT and anti-HBc testing, funded by the DHSS (see paragraphs 27.230-27.233), and coordinated by Dr Gunson, had proceeded with surrogate test trials, though impending developments relating to the Chiron discoveries were anticipated. Progress was reported in a paper subsequently submitted to the ACVSB at its second meeting on 22 May 1989.^[364] The paper (ACVSB 2/7) stated:

This study (supported by the Health Departments) is being co-ordinated by Dr Gunson on behalf of the UKBTS. It is too early to report on this yet, but all the samples have now been collected and screened for ALT and anti-HBc. Much of the follow-up has been done, but this is not yet complete. It is hoped that in June a review of the study will take place although conclusions cannot be drawn until the results of the Chiron tests are known.^[365]

27.252 The paper gave up-to-date information on Chiron's progress as published, including information on the cloning of cDNA and the development of a specific assay for NANB Hepatitis. The paper concluded:

At present there does not appear to be any urgent need to introduce routine surrogate testing for NANB hepatitis among voluntary blood donors in the UK in respect of public health.

The position should be reconsidered by this Committee [the ACTTD] when the results of the UKBTS NANB study are available .... The availability of the Chiron test will help with interpretation of the data obtained. The Chiron test may also make surrogate testing obsolete ....^[366]

27.253 Professor Zuckerman's Taipei paper was also before the ACVSB; it continued to present the possibility of more than one agent of transmission of NANB Hepatitis. He commented that several 'non-specific' (surrogate) tests had been recommended for screening units of blood, until specific tests became widely available for NANB Hepatitis. Of these, the non-specific indicator which had received most attention was said to be ALT levels in blood donors. Several studies had shown that the risk of post-transfusion NANB Hepatitis was directly related to the ALT level of the donor. However, lack of sensitivity and the variability of ALT levels with age, sex, alcohol use and geographical region were factors. His view was that ALT levels would therefore not be useful as a surrogate marker of NANB Hepatitis.^[367]

27.254 The minute of the meeting of the ACVSB on 22 May 1989 noted that:

The Department would keep the issue of testing under review. The use of Chiron or surrogate testing would be influenced by Chiron data once released; MRC might be asked to consider. Members regarded the matter to be a priority.^[368]

27.255 At this stage, it was the consistent position of both the ACVSB and the ACTTD that surrogate testing for NANB Hepatitis should not be introduced by the transfusion services before Dr Gunson's study had been completed.

27.256 The minutes of the next meeting of the ACVSB, on 3 July 1989, record the Advisory Committee's understanding that the results of Dr Gunson's NBTS study of ALT and anti-HBc testing had shown that raised ALT levels were identified in 25% of the donors sampled.^[369] Members expressed concern that this type of study 'revealed nothing of specificity'. The figure of 25% appears to have reflected the information made available at the meeting. It was not a correct indication of the proportion of donors who would have been rejected on the grounds of elevated ALT. In subsequent reports, the average was given as 3.2%, with results from individual centres of 3.06%; 4.56% and 1.97% (see, for example, the entries for 3 November 1989 below).^[370]

27.257 Dr Gunson's paper for the Council of Europe's Committee of Experts in Blood Transfusion and Immunohaematology, analysing replies from ten countries to a questionnaire on NANB Hepatitis, was also available.^[371] As already noted, routine ALT testing of donations was carried out in four countries: Germany, France, Malta and Switzerland. France also routinely performed anti-HBc testing. Denmark, Norway, the UK and France were undertaking studies to determine their policies. Members of the ACVSB supported the Council of Europe view that anti-HCV testing alone was not sufficient to eradicate post-transfusion hepatitis.^[372] Members cautioned against the overtly commercial stance of test manufacturers. It was reported that first time recipients of Factor 8Y had been screened by the Chiron test and had shown no positive results. Further study of stored sera from haemophilia patients was advocated. Dr Phillip Mortimer, Public Health Laboratory Service (PHLS), thought that there was a persuasive case that the Chiron test results were reliable. The outcome was that the (new) Chairman, Dr Metters, considered that all the available data should be compiled and provided for the next meeting. Members were asked to forward all contributions on NANB Hepatitis to the Committee's secretariat.^[373]

27.258 On 3 November 1989 Dr Gunson produced the final report of the multi-centre study in England and Wales into surrogate markers for NANB Hepatitis in donors.^[374] The study was carried out between September 1988 and April 1989, during which time a total of 9741 blood donors at the North London, Bristol and Manchester RTCs were tested for elevated ALT and the presence of anti-HBc. In summary, the report stated:

• Taken overall, 3.2% of donors would have been rejected for raised ALT and 0.63% for anti-HBc seropositivity. However, if only donors with a raised ALT on two successive samples were rejected, the number would have been reduced to 1.1%. A 'disturbing finding' was the variability of ALT testing in the three centres.
• It was difficult to conclude how many of the donors with a raised ALT, or who were seropositive for anti-HBc, might have transmitted NANB Hepatitis. To determine that, a prospective study would have to be performed.
• However, it was evident that the ALT test was non-specific since the correlation with alcohol intake and obesity was striking. Similarly, the significance of a positive anti-HBc result was unknown.
• Following the introduction of the anti-HCV test the only justifications for routinely performing the ALT and anti-HBc tests were:

  o The possibility that ALT (in particular) would identify a 'window' of infectivity prior to seroconversion to anti-HCV.

  o The possibility that anti-HCV identified only one of a number of viruses which caused NANB Hepatitis.

• The introduction of other specific viral markers and increased sensitivity of the anti-HCV test might in due course render the subject of surrogate testing of academic interest. Meanwhile, the desirability of introducing these tests remained an issue of health economics.^[375]

27.259 Dr Gunson's report was considered at the fourth meeting of the ACVSB on 6 November 1989.^[376] Dr Gunson drew members' attention to the non-specificity of ALT testing brought out in the report. He also reported discussion at a meeting in Rome sponsored by Chiron. The debate on use of the Chiron test is discussed in Chapter 31, The Introduction of Screening of Donated Blood for Hepatitis C. So far as surrogate tests for ALT and anti-HBc are concerned it is reported that Dr Gunson commented that there was a question mark hanging over their status. After discussion of the Chiron test, it was the feeling of the Advisory Committee that there was no case for using surrogate tests for NANB Hepatitis. That was largely the end of the issue of general surrogate testing in the UK as consideration turned instead to the evaluation and eventual introduction, on 1 September 1991, of the Chiron/Ortho test for antibody to Hepatitis C.

UK Postscript-1990s

27.260 Apart from sporadic references to surrogate screening for specific purposes, there was no independent consideration given in Scotland at this time to the introduction of surrogate testing, consistent with the decision that the procedures would not be introduced before the DHSS and the SHHD, on the advice of the expert advisory bodies, supported and funded them.^[377] On 12 March 1990, Mr David McIntosh (General Manager, SNBTS) wrote to Dr McIntyre (SHHD) on the subject of ALT donation testing.^[378] Subject to advice from the ACVSB, Mr McIntosh's understanding was that neither the SNBTS nor the NBTS would be introducing ALT testing for the time being and that neither the SHHD nor the DoH recommended that such testing should be introduced. Equally, however, it was anticipated that there could be a need to start new testing procedures, probably including ALT testing, in conjunction with another test or tests. There was a possibility of having to take rapid steps during the course of the summer. Consistent with that possibility in July 1990, a revenue bid for funding for ALT and anti-HBc testing was submitted by the SNBTS for 1991-92.^[379] It was, however, considered highly unlikely that ALT and anti-HBc tests would be introduced into routine practice in the forthcoming financial year and the provisions were carried forward to the next year. In the event, the introduction of HCV testing superseded the need for provision of surrogate testing.

27.261 The NBTS and the SNBTS were awaiting the outcome of the Ortho anti-HCV trial in progress before taking a decision but the broad policy issues had by this time been referred to the ACVSB. It was that body's advice that, in November 1989, effectively brought to an end the active consideration of general surrogate testing of blood donations and blood donors in the UK. By that time the practice had already been adopted in the USA and in some European countries.

27.262 On 8 February 1990 the American Association of Blood Banks, the American Red Cross and the Council of Community Blood Centres issued a joint statement: 'Guidelines for planning the implementation of anti-HCV testing of blood and components for transfusion'.^[380] The statement recommended that ALT and anti-HBc screening of blood donations should continue until it could be demonstrated that NANB Hepatitis agents other than the Hepatitis C virus were not a significant cause of transfusion-associated hepatitis.

27.263 In this respect, however, practice in the USA does not provide guidance. Pragmatic considerations dictated the continuance of established practice in the USA and there was nothing to suggest that the decision had been driven by new insights into the efficacy of surrogate testing.

27.264 Professor Cash drew the Inquiry's attention to evidence that consideration had been given in England in the early- and mid-1990s to the ALT testing of plasma sent to the BPL for the manufacture of albumin and intravenous immunoglobulin.^[381] While it is unclear whether ALT testing of plasma for the BPL was actually introduced in England,^[382] it appears that the consideration given to such testing was based solely on economic factors (as such testing would allow excess fractionated products manufactured by the BPL to be sold abroad rather than destroyed) and it was expressly disavowed that the use of ALT testing of plasma that was to be used for the manufacture of blood products implied any safety benefit.^[383]

Studies conducted after the Ortho anti-HCV test became available

27.265 It is convenient at this stage to consider various studies that were carried out after the Ortho anti-HCV test became available. In short, while studies indicated that ALT screening of donors is likely to have materially reduced the incidence of transfusion-transmitted NANB Hepatitis, it is not possible to quantify that reduction with any degree of accuracy. Furthermore, the results of these studies were not available until after anti-HCV screening had been introduced in the UK, in September 1991.

27.266 In common with the rest of the UK, Scotland introduced anti-HCV screening on 1 September 1991. In the first six months of testing the prevalence of HCV infection among blood donors was 0.088%.^[384] Of the 159 HCV positive donors identified, 151 responded to the invitation for further counselling and follow-up and 59% (89) of these 151 HCV-positive donors had ALT levels above the upper limit of normal.^[385] This was not a random sample, however, but a self-selected group and, importantly, it could not be inferred that excluding all donors with elevated ALT (ie above the upper limit of the laboratory's reference range) would have prevented 59% of cases of transfusion-related Hepatitis C infection. As Dr Gillon explained:

[T]he vast majority of the carriers of Hepatitis C were at levels below the cut-offs that were proposed. And looking at this 59[%] figure, that was based on a relatively low cut-off - well, in Edinburgh it was 40 units per litre. It was probably the same elsewhere, which is not what we would have used in practice.^[386]

27.267 Once more sensitive HCV tests became available, Dr Dow and colleagues tested samples stored from his study undertaken between 1980 and 1984.^[387] In the study, a total of 54 donations - 50 from prison donors and four from other donors - were found to have ALT values in excess of 2.5 times the upper limit of normal. Thirty-two of these samples were stored frozen and tested with various HCV tests including the Polymerase Chain Reaction (PCR) test. Twenty-one of the 32 stored samples (65.6%) were positive on PCR testing. This was a relatively high proportion on any view. However, it probably reflected the higher incidence of Hepatitis C in the prison population in the first half of the 1980s and cannot be held to be representative of the correlation between surrogate markers and HCV infection generally.

27.268 The 1989 evaluation study of the first generation Ortho anti-HCV test by Dr Dow and colleagues should also be noted.^[388] Granted the insensitivity of this test, it is interesting nevertheless to note that only 15 of the 2745 donations tested (0.54%) were positive on initial screen test and, of these, 13 were repeatedly reactive on repeat testing in duplicate. All 2745 donations had been tested for ALT levels in the earlier exercise in 1987 and 1988. Only one of the 15 initial screen positive donations had an abnormal ALT level.

27.269 Later studies have indicated that, in some countries at least, surrogate testing was more effective in screening out HCV from donor blood than the UK study and, indeed, the early TTV and NIH studies in the USA had suggested it might be. Once anti-HCV tests became available, the NIH and TTV study groups tested stored sera collected from a relatively small number of patients in whom NANB Hepatitis had developed after transfusion.^[389] The NIH group estimated that in their study ALT and anti-HBc screening would have detected approximately one half of the anti-HCV positive donors involved in the transmission of hepatitis.^[390] The TTV group reported that just over 70% of cases of post-transfusion Hepatitis C in their study were associated with the presence of surrogate markers in donors.^[391] The tests used were of the first generation, however, and lacked sensitivity, as discussed in Chapter 31, The Introduction of Screening of Donated Blood for Hepatitis C.

27.270 Another large US study (carried out in Baltimore and Houston) found that the introduction of surrogate testing had reduced by 60% the risk of patients developing anti-HCV.^[392] In particular, of 912 patients undergoing cardiac surgery who received transfusions between April 1985 and September 1986, at a time when donors were not screened for surrogate markers, 35 patients seroconverted^[393] to anti-HCV (an attack rate of 3.84%). Of 976 patients who received transfusions after surrogate testing was introduced in October 1986, only 15 seroconverted to anti-HCV (an attack rate of 1.54%).^[394] In interpreting the data from this study, however, one must bear in mind that, even without the introduction of surrogate testing in the USA, rates of post-transfusion hepatitis may have reduced as a result of the HIV exclusion measures taken from 1984 onwards. In his evidence to the Inquiry, for example, Dr McClelland noted that the authors of the Canadian paper discussed below had observed that there had been a similar reduction in the prevalence of post-transfusion hepatitis in Canada over the same period, in the absence of the introduction of surrogate testing.^[395]

27.271 That Canadian study into post-transfusion hepatitis was carried out between 1988 and 1992.^[396] In one group of patients who received blood transfusion, units which were positive for NANB Hepatitis surrogate markers were withheld, while in the other group of patients such units were not withheld. Samples from 2277 patients in the group in which units positive for surrogate markers were not withheld were tested retrospectively when the anti-HCV test became available. It was found that 10 patients (0.44%) had developed Hepatitis C. Of 2311 patients in the group in which units positive for surrogate markers were withheld, only three patients (0.13%) developed Hepatitis C.^[397] The authors concluded that withholding blood containing surrogate markers reduced by 70% the rate of post-transfusion HCV in their study.^[398] Interpreting the study, however, may be complicated by the fact that Canada introduced screening of donors for anti-HCV in May 1990, part way through the study.^[399]

27.272 In Finland, a prospective study was carried out between 1987 and 1989 which aimed, as one of its goals, to determine the predictive value in donor screening of surrogate marker candidates.^[400] Stored samples were tested with first generation anti-HCV tests once these tests became available. Six of the 145 recipients (4.14%) of at least one unit of blood with raised ALT levels^[401] developed NANB Hepatitis (as measured by elevation of ALT levels post-transfusion). That figure is in contrast to five of the 540 recipients (0.93%) who received only blood with normal ALT levels.^[402] The positive predictive value of ALT (the percentage of cases of NANB Hepatitis among all recipients of blood with elevated ALT) was only 4.1%.^[403] No correlation was found between the presence of anti-HBc in donors and the development of NANB Hepatitis in recipients.^[404]

Discussion

Prospective study of post-transfusion NANB Hepatitis in the UK

27.273 At any time during the period 1981-88, the introduction of surrogate testing for NANB Hepatitis virus infection of donor blood, or of blood components and products, would have involved significant expenditure. It would have been considered a matter of such importance at the time to have required ministerial approval.^[405]

27.274 Ministerial decisions might have involved political considerations and almost certainly would have required the balancing of competing demands for funding. Before that stage was reached, however, the preliminary course that had to be negotiated, before ministers were consulted, would have included scientific and medical input and administrative discussions and decisions.

27.275 The benefit of surrogate testing would have depended on the efficacy of the test or tests used in identifying blood and blood components that carried risk for the recipient. A decision to introduce testing would have required information and advice on a number of interrelated factors, including:

• The prevalence of infection in the relevant donor population or populations.
• The sensitivity of the tests as applied to those people (a measure of the efficiency of the test in identifying people with the target disease).
• The specificity of the tests as applied to those people (a measure of the efficiency of the test in identifying people without the target disease).
• The incidence of post-transfusion hepatitis.
• The clinical significance of post-transfusion NANB Hepatitis.
• The impact of testing on the donor population or populations.
• The cost/benefit balance found on analysis of all relevant information.

27.276 The issue of whether or not to introduce surrogate testing of blood donors for NANB Hepatitis was never put to ministers and the reasons for that changed through the 1980s. This section deals with events at the beginning of the period that had long-lasting consequences. Those events, involving discussions within scientific and medical advisory groups, prevented research into the first three factors listed above: the prevalence of infection and the sensitivity and specificity of available tests.

27.277 The MRC report of the Maycock Group study into post-transfusion hepatitis carried out between 1969 and 1971, was published in 1974.^[406] As previously noted, it carried the authority of Professor Zuckerman and Professor Sherlock in addition to that of Sir William Maycock. The findings were influenced by the approach adopted: elevated ALT values alone were not regarded as providing sufficient evidence of hepatitis. The overall incidence of icteric and anicteric hepatitis (that is, hepatitis with or without clinical jaundice) was calculated to be 1% - lower than in other countries, at least in part due to the factors stipulated by the authors as prerequisites of diagnosis. A range of factors that might have influenced the result were considered in the discussion part of the paper but none of them was thought to undermine the overall assessment. The MRC study was regarded for many years as proof that the incidence of post-transfusion NANB Hepatitis in the UK was not a significant problem whereas, when properly analysed and having regard to the limitations of the study, it could offer no such assurance.

27.278 As was the case with Dr Rosemary Biggs' report of the incidence of episodes of jaundice among haemophilia patients treated with blood products, also published in 1974,^[407] the data discussed in the MRC report were collected before the existence of NANB Hepatitis was postulated. The seminal article by Alfred Prince and others was published on 3 August 1974.^[408] Dr Biggs' data were drawn from returns from Haemophilia Centres for the period 1969 to 1971 and reflected the perception at that time that jaundice was the appropriate focus for assessment of the incidence of transmitted virus infection.^[409]

27.279 When the MRC ad hoc meeting took place on 12 February 1979^[410] to discuss, amongst other matters, growing anxiety about the threat of NANB Hepatitis, it was recognised that ALT (referred to by its alternative name, SGPT in the minute) testing could be a useful pointer to NANB Hepatitis infection. The views of Dr Tom Cleghorn and Professor Sherlock that post-transfusion hepatitis 'must now be rare' were countered by Professor Zuckerman's observation that much NANB Hepatitis might be anicteric and might progress to chronic liver disease, however mild the initial infection. It is also clear that Sir William Maycock recognised that there was a lack of data on the prevalence of post-transfusion hepatitis. His proposal that a survey of post-transfusion hepatitis be set up was, however, rejected. The prevailing view was that until there were specific markers, a survey of post-transfusion hepatitis was not justified.

27.280 Having regard to the published data from 1974, the effect of the decision, so far as the MRC was concerned, was that other research concerning viral hepatitis should proceed in the absence of relevant data about the prevalence of NANB Hepatitis in the UK. Dr McClelland's evidence to the Inquiry that the report of the 1974 MRC study did not, in his view, provide the information required, is accepted as accurate generally.^[411]

27.281 The outcome of the meeting of 12 February 1979 included a decision to set up the Working Party on Post Transfusion Hepatitis which met on 14 February 1980.^[412] Its agreed functions included investigations to assess the incidence of NANB Hepatitis in the UK, particularly as associated with blood transfusion, the characterisation of the agent of transmission and the development of diagnostic tests. There was discussion of the intelligence available to the participants about cases of NANB Hepatitis. Against that background, Dr McClelland who to the other members of the Working Party was then a colleague without an acknowledged reputation in developing and directing large complex studies, suggested that a multi-centred study of transfusion-associated NANB Hepatitis might be sponsored by the Working Party. The minute of the meeting is rather perplexing in that, on the one hand, it noted that it was agreed that Dr McClelland's proposal should be deferred until candidate laboratory tests were available (an agreement that he did not remember)^[413] and, on the other hand, it records agreement that there should be epidemiological surveys to assess the size of the problem in relation to blood transfusion. The minute also reported that MRC studies had already received a grant for research into the incidence, epidemiology and clinical features of NANB Hepatitis.^[414]

27.282 Dr McClelland clearly did not consider that he had been precluded from developing his proposal and discussed it with the SNBTS Directors on 23 June 1981 before presenting a draft protocol for a multi-centre study to the MRC Working Party on 25 June 1981.^[415] It is not necessary to resolve the questions that arise from the minute of 14 February 1980; what happened at the meeting on 25 June 1981 is of greater significance. Significantly, as recollected by Dr McClelland, Professor Zuckerman insisted that a study into post-transfusion hepatitis had already been carried out (a reference to the MRC study reported in 1974) and 'it didn't need to be done again'.^[416] The minute of the meeting noted that Professor Zuckerman commented on the earlier study, noted that the sera collected were available for evaluation of candidate tests for NANB Hepatitis and said of Dr McClelland's proposal: 'A careful evaluation of the need for such a project should be carried out before the Working Party could recommend to the MRC that a fresh study should be sponsored.'^[417] Professor Zuckerman left the meeting before the discussion was concluded. The remaining members of the Working Party decided that Dr McClelland's proposals could be reconsidered later. They clearly believed that the group had a future. However, the MRC Working Party did not meet again and the prospect of an MRC sponsored study along the lines proposed by Dr McClelland disappeared.

27.283 The initiative passed to the transfusion services' Working Party on Transfusion Associated Hepatitis which, as discussed above, met on 27 September 1982 and on three occasions in 1983 before lapsing and being reconvened on 24 November 1986. While Dr McClelland had continued to advocate a large-scale prospective study into NANB Hepatitis in the UK when the Working Party met in 1982 and 1983, by the time the Working Party was reconvened in late 1986 the view of the members was that a prospective study was impracticable on the grounds of both cost and the requirement for a large sample group.

27.284 As more fully set out above, the view of the Scottish and English transfusion services in the late 1980s (and which was supported at various times by officials in the SHHD and the DHSS) remained that it was not feasible to carry out a large-scale prospective study of NANB Hepatitis and that, instead, there should be a limited study into the incidence of surrogate markers in donors. Such a study would not include the follow-up of recipients and thus would be of little or no assistance in determining the efficacy of surrogate screening in reducing the incidence of post-transfusion NANB Hepatitis.

27.285 Despite the best efforts of Dr McClelland, no sufficiently large-scale prospective study was ever carried out on a coordinated basis to determine the likely prevalence of post-transfusion NANB Hepatitis in the UK. Without such a study having been carried out it was, and remains, difficult to come to an informed view on the likely prevalence of post-transfusion NANB Hepatitis in the UK generally and in Scotland in particular.^[418]

27.286 In his oral evidence Professor Leikola commented, with reference to the later 1980s:

I think that what was regrettable was that no ... large study was performed in the UK in order to find out what would be the value of especially ALT, both in recipients of blood and donors of blood .... We [in Finland] did not introduce ALT testing before our study was done ....^[419]

27.287 If he had a criticism of events in Scotland, it related to the failure to carry out a prospective study into post-transfusion NANB Hepatitis involving the follow-up of recipients (in the UK as a whole), rather than the failure to introduce surrogate testing.^[420]

27.288 However, in considering Professor Leikola's criticism a number of matters ought to be borne in mind. The first is that the Finnish study, 'Post-transfusion hepatitis after open-heart surgery in Finland - a prospective study' states that it was carried out between 1987 and 1989, and the second is that the Finnish Red Cross Blood Transfusion Service charged the hospitals for their products and services and could, therefore, finance the study themselves. The SNBTS was dependant on funding from the SHHD or other bodies for such a study, and that had a material effect on its ability to carry it out. Professor Leikola indicated that the catalysts for the Finnish study (which started in December 1987) were the decision made in the USA in 1986 to introduce surrogate testing and the discussions at the Council of Europe in 1987. The Council's Committee of Experts on Blood Transfusion and Immunohematology had not then recommended the introduction routinely of non-specific tests for evidence of NANB Hepatitis infectivity of blood donors but had indicated that '[i]ndividual countries would have to assess the situation locally and decide on the appropriate action to take'.^[421] By March 1987 the SNBTS Directors had agreed to recommend to the SHHD that surrogate testing for NANB Hepatitis should be implemented with effect from 1 April 1988 as a national development requiring strictly new funding. In their letter of 4 July 1987 to The Lancet, entitled 'Testing blood donors for (NANB) Hepatitis: irrational, perhaps, but inescapable' they explained why they considered the introduction of surrogate testing, despite the absence of relevant data, to be 'virtually inescapable'. In particular, they adverted to forthcoming legislation that would provide for strict liability for harm caused by products unless all known measures had been taken to avoid the risk, to the possibility that such testing would reduce the level of infectivity of pooled plasma products and to consumers' wishes to be supplied with 'NANB tested' products, in light of the fact that commercial manufacturers were now doing such testing and would be likely to market their products as being safer. Haemophilia Directors had unrestricted clinical freedom to opt either for NHS fractionated products or commercially fractionated products. Had surrogate testing been introduced then blood used for blood products, blood components and whole blood would have been screened.

27.289 It is regrettable that Dr McClelland's proposals in the early 1980s were dismissed and that they were not taken up by others. Whilst the results of a large scale prospective study might not have led to the introduction of surrogate testing, data about the prevalence of NANB Hepatitis and the likely efficacy of surrogate testing in reducing the incidence of post-transfusion NANB Hepatitis would have led to more informed decision making. In addition, a library of samples might have been available for preservation to use in subsequent research into the Chiron anti-HCV test. In short, there were adverse long-term consequences of the decisions made by the wider scientific and medical community, first, not to follow the initial suggestion of Sir William Maycock in 1979 and, secondly, not to follow Dr McClelland's proposals in the early 1980s. However, it must be borne in mind that in Finland, despite the existence of the small 1979 study, a new, larger study was considered necessary in 1987 in consequence of the international developments described above and the effect of the AIDS risk in 1983 and 1984 on donor selection criteria. Had the SNBTS undertaken a study in 1987, as occurred in Finland, it is unlikely that it would have been completed before May 1988, when Chiron announced that they had identified, cloned and expressed proteins from an NANB virus and had developed a prototype immunoassay that might lead to a screening test. According to the Directors' letter in The Lancet, the study would produce no 'answer' for three to four years.

The administrative context

27.290 The ultimate responsibility for deciding whether surrogate testing should have been introduced lay with the UK Government.^[422] The Secretary of State for Scotland had cabinet responsibility, but ordinarily the junior Scottish minister, whose remit at the relevant time included Scottish health matters, would have been involved before an issue was referred to the Secretary of State. The minister would have acted on advice received from appropriate committees and from officials including, in particular, SHHD medical officers. However, apart from issues raised at ministerial level in the first place, it was for SHHD administrators to decide what issues should be referred to ministers for decision. In that context, there could be a material difference in approach depending on whether or not positive action was proposed.

27.291 In the SHHD, the issue of surrogate testing was dealt with on a day-to-day basis by Dr Forrester, Senior Medical Officer, and Dr Archibald McIntyre, Principal Medical Officer. On occasion Dr Scott, DCMO, was also involved in considering the issue. Dr Macdonald, CMO, said in oral evidence that he was kept informed of the issue.^[423] On the administrative side of the SHHD, surrogate testing was dealt with at a day-to-day level by Mr Alexander Murray, Senior Executive Officer, and by Mr Macniven, Assistant Secretary. On occasion, the issue reached the level of Mr Hugh Morison, Under Secretary.^[424]

27.292 In his evidence to the Inquiry Mr Macniven agreed that the introduction of a new screening test, such as surrogate screening with its significant financial implications, would have required ministerial approval. He was asked whether a decision not to introduce a screening test, in particular one that was recommended by the SNBTS Directors, was also a matter of such importance that a ministerial decision ought to have been sought. He replied:

Not necessarily. Obviously, although the Secretary of State ... had at that time statutory responsibility for the health service in Scotland, and a great many other things beside, it would have been impracticable for the Secretary of State personally or indeed a junior minister personally to take a decision on every question that the Scottish Office, as it was then called, was considering. It's a matter of judgment when a topic should be put to ministers, and it looks as if our judgment at the time, certainly the documentary evidence suggests that our judgment at the time was that that did not need to be put to ministers.^[425]

27.293 In addition to matters arising from the general administrative structure, applications for major research funding might require formal review by the CSO Biomedical Research Committee.

27.294 While the views of SNBTS staff were an important element in the picture, the question as to whether or not surrogate testing should be introduced was not put to Scottish Ministers for decision and, on the evidence as a whole, was never resolved at official level.

27.295 A decision was not taken by anyone, whether an official of the SHHD or a minister, not to introduce surrogate testing but, instead, SHHD officials took the view that there was not sufficient evidence to recommend to ministers that such testing should be introduced.^[426] Dr Macdonald's evidence suggested that there never was a resolution:

I'm not quite sure that a final decision was ever taken. I think we were still agonising over the question of setting up research. Frankly, I just don't quite remember the end of it, except that we didn't do it.^[427]

27.296 SHHD officials, in particular medical officers, considered that there were good reasons for not introducing surrogate testing.^[428] The fact that the Department of Health did not support the introduction of surrogate testing was also an important factor in their consideration.

27.297 Dr Macdonald said:

If departmental medical staff had been persuaded, after consulting colleagues with relevant expertise, that surrogate testing for NANBH was a reliable procedure which would give few false results (positive or negative) and be free from adverse effects, they would have advised administrators accordingly and it would have been highly likely that funding would have been provided. In the event departmental medical staff were not sufficiently persuaded and advice reflected this.^[429]

27.298 Dr Macdonald was not personally involved in the consideration being given in the Department to surrogate testing^[430] but he was kept informed of what was happening and did not see any need to intervene.^[431] He further explained that if the advice from his colleagues appeared to be veering towards introducing surrogate testing, he would have found it necessary to intervene. He explained his reasons:

One is that ... it wouldn't be the complete answer to the problem as far as the recipients of blood and blood products were concerned, but it would also have repercussions on the donors. Testing the donors ... would undoubtedly have yielded a fairly appreciable number of positives, some of which would be false and, at the other end, a fair number of negatives, some of which would be false.

If you then - what are you going to do about the positives? You won't know which are false and which are genuine ... there was some risk that we would find that donors would be disturbed by this situation and I think that was something which we really should not have risked doing. That's one side of it.

The other is a point ... about DHSS ... the point that I think has to be made is that DHSS and the Scottish Office, which included SHHD, and for that matter, the Welsh Office, were three different departments of the same government, each responsible to a Secretary of State in that government and the Secretaries of State were sitting together round the same cabinet table.

On an issue of this kind, where there was a group, the Haemophilia Society, and perhaps others, watching all our moves carefully, if one of us - and it might have been us - ... decided to institute testing and the other didn't, that would be extremely difficult to explain. One of us must be right, one must be wrong, would be the reaction.

But it goes a little further than that because, as I recall it, we were facing a situation in which the Scottish [D]irectors were pressing for the introduction of testing and the English [D]irectors - I think pretty unanimously at that stage, the English Directors were against it. I don't think we could ignore the fact that there was a well informed body of opinion, not very far away, with a different view.

So I think in that situation I would certainly need to have become involved.^[432]

27.299 It was suggested to Dr Macdonald that the primary consideration of the SHHD throughout the relevant period was that there should not be any divergence in practice between England and Wales and Scotland. He replied:

I don't think that that - it was an important consideration, certainly, but I think that the staff in SHHD did attempt to form an opinion of their own and that opinion was that we should not go ahead. I think that, if we had agreed with the Scottish [D]irectors' view, Dr Scott would have said so, even if the outcome eventually ... had been different.^[433]

27.300 Dr Macdonald also said that, if he had intervened in the middle of 1987 on the question of surrogate testing, his involvement would have been to say to his medical colleagues that such testing should not be introduced rather than simply to say that there were wider issues which required to be considered.^[434]

27.301 Dr Macdonald's succinct explanation as to why surrogate testing was not introduced was that: 'Essentially, there was too much uncertainty about various aspects of surrogate testing to justify introducing it.'^[435] He referred to these concerns as relating to 'the quality of the testing'^[436] and that 'the screening method was not really good enough'.^[437]

27.302 That explanation is acceptable as an accurate reflection of the factual position at the end of November 1987: the poor sensitivity and specificity of the proposed surrogate tests were likely to give rise to significant difficulties if used for mass screening of blood donors.

The relationship between the DHSS and the SHHD

27.303 Dr Macdonald was asked whether it would have been open to Scotland to introduce surrogate testing in the event that the SHHD had taken the view that it was justified but had been unable to persuade colleagues in the DHSS of that justification. He replied:

I think in a very theoretical sense. This was never tested. I think what would have happened, I can, I believe, have advised Scottish ministers that testing should be introduced in Scotland. The CMO and DHSS could have advised his ministers that it should not be tested in England. I think we would have been bound, each of us, to tell our ministers that the other minister was being given the opposite advice. I don't know what would have happened then.^[438]

27.304 He said that it could have become a matter for ministerial decision, possibly at cabinet level.^[439] Before pressing matters that far, officials would have had to ask themselves whether they felt so strongly in favour of it that they really wanted their minister to press it.^[440]

27.305 Realistically, the introduction of surrogate testing was not, and was most unlikely ever to have become, an issue requiring a cabinet decision at this time. So far as officials were concerned - and in the first instance the initiative lay with them - it never reached the level of requiring Scottish ministerial decision. Scottish officials were far from convinced that there was an issue worth pressing. However, the possibility of independent action in Scotland led to a discussion of the relationship between the SHHD and the DHSS.

27.306 There were issues of external perception that would have influenced ministers. Internally, the DHSS would have been expected to take a lead on major policy matters. It was the biggest department and, as Dr Macdonald put it:

SHHD and the Welsh Health Department, would have been expected to fit their policy around that. In other words, there can be a bit of a variation for local circumstances, but broadly the policy would be evolved in DHSS.^[441]

27.307 Practical expedients were adopted to avoid problems. Often an expert group would be assembled, sometimes very formally by ministers, and sometimes by the departments. There would usually be Scottish members who would contribute and would be able to give an account of the views of colleagues in Scotland, and an iterative debate would take place. Dr Macdonald thought that on the whole it worked reasonably well. The profession in Scotland was content with it but would have been less content if the DHSS involved only their English colleagues, though the DHSS was sensitive to the issue.^[442]

27.308 Dr Macdonald's view would not necessarily be shared by everyone who had ever participated as a sole Scottish representative on a UK committee dominated by English colleagues. Professor Cash could never have imagined Scotland being allowed by the SHHD 'to go off on our own'. In any event, he considered that there were good reasons relating to seeking to avoid legal liability, team work and the sharing of information for centres, or at least groups of centres, to act in unison in relation to introducing a new test.^[443] While acknowledging the positive reasons for collaboration, his assessment of the prospects of Scotland being permitted to take independent action on a matter of this kind is accepted.

27.309 Dr McClelland took a typically practical view of the position:

I think the decision probably rested with ... the Scottish minister responsible for health, ultimately, as it were, delegated down the line through the department and the [CSA], which was the channel through which our funding arose. But I think that's oversimplistic. I think the minister would inevitably be heavily dependent on the burden of the advice that he or she was given, and if there was very strong, clear, consistent, well-argued and rational advice coming from, say, the clinical and scientific community through the [SHHD] to the minister, I find it hard to believe that most ministers would not have acted according to it. And it's perfectly clear that the advice that was, as it were, coming from the relevant professional community was not clear and consistent.^[444]

27.310 He thought that while there were many obvious advantages in having a coordinated approach throughout the UK. If that meant that something he felt was important to patient safety, such as surrogate testing, was not going to be done, he would have given that a higher priority over 'keeping things tidy and avoiding problems of cross-border differences in practice'. He did, however, consider that surrogate testing could not have been introduced in Scotland without government funding and approval.^[445]

27.311 Dr McClelland's final observation reflected the ultimate reality: where UK government funding was required for major projects, the SHHD had limited scope for major independent initiatives.

27.312 However, for immediate purposes, it was not a live issue: Scottish administrative officials never promoted for ministerial approval an independent Scottish scheme of surrogate testing. While influenced by the thinking of DHSS colleagues, that was a Scottish decision based on local advice.

The state of knowledge of NANB Hepatitis in the SHHD

27.313 There is an issue whether the SHHD had the resources to form views on the threat posed by NANB Hepatitis generally or in particular relation to Scotland. In considering the state of knowledge expected of medical officers in the SHHD at the time Dr Macdonald said:

Generally speaking, we were not individuals who were taking up anything resembling specialist positions. There were one or two examples at variance with that, but broadly speaking we ... would have regarded ourselves as generalists.

....

[I]t is this kind of - relative lack of specialisation, maintaining a degree of generality that is what we wanted.^[446]

27.314 Dr Macdonald was asked what he would have expected his medical officers to do to inform themselves on a particular subject:

In broad terms, I would have expected them to keep up-to-date. I would - how shall I put this? I would perhaps warn him, if I was giving advice, that he has always to remember that the people he is dealing with in the subject know a lot more than he does and he is not going to get himself on to that level.

....

I think they have to go some way towards mastering the subject, but I think what we really expect of them is to be able to come in and tell us what people out there are thinking and be able to explain, to some extent, why they are thinking it, but not to go too deeply into the subject itself .... I think our function was to know enough about medical matters to know what we ought to be asking.^[447]

27.315 He and his colleagues would keep up to date with developments in medicine by reading journals, such as the British Medical Journal, The Lancet and several public health journals and by attending conferences.^[448] As regards NANB Hepatitis, another source of information would be physicians who specialised in the diagnosis and treatment of patients with the disease. They might also have obtained information from the SNBTS Directors, the Scottish Haemophilia Directors and Professor Cash, as National Medical Director of the SNBTS.^[449] In addition, SHHD medical officers attended meetings of various advisory committees and working parties as observers and, in that way, would also be able to obtain expert views and advice.^[450]

27.316 In his evidence to the Inquiry Dr Forrester stated that when he joined the SHHD he did not have a great deal of knowledge of problems among haemophilia patients. He explained that he was 'a relayer of information and the gatherer of information from the different sources it could come in'.^[451] He did not 'attempt to fulfil the role of a free-standing authority in these matters at all'.^[452] Dr McIntyre, Principal Medical Officer, had more experience and expertise in matters relating to the blood transfusion service. Dr Forrester considered that Dr McIntyre 'was always in a position of overlooking what I had done and I put it to him in writing and if there was anything amiss he would have told me'.^[453]

27.317 In various notes and minutes made at the time Dr Forrester commented on the clinical significance of NANB Hepatitis.^[454] The general tenor of his comments in documents between 1986 and 1988 was to the effect that the disease was 'relatively benign', at least in the short term. Notwithstanding the risk of serious liver disease, he said that the expression 'relatively benign' was 'a numerical question'. A disease could be 'relatively benign in most cases - in practically all cases'.^[455] In a follow-up e-mail to the Inquiry Dr Forrester explained:

Among the meanings of the word "benign" there are two that I believe apply. The first is that in medical and medico-scientific circles, if one form of a fatal disease takes much longer to prove fatal, and does so in fewer cases than another, it is usually termed "benign" in comparison. [Dr Forrester's minutes were directed at such circles.] But in ordinary discourse, and especially if oneself or one's relations are involved, no form of a disease that may prove fatal or disabling can be called "benign".^[456]

27.318 Dr Forrester's view on the prevalence and clinical significance of NANB Hepatitis was influenced by Dr Dow's PhD thesis and by advice received from Dr Reid of the Communicable Diseases Centre. Unfortunately, the Inquiry has been unable to obtain Dr Reid's written replies to Dr Forrester and can only rely on Dr Forrester's record made at the time of his understanding of Dr Reid's views.^[457] As regards Dr Dow's thesis, its inadequacy as a means of estimating the true incidence of post-transfusion NANB Hepatitis has already been discussed.

27.319 Dr Dow's study did not include as one of its purposes an attempt to investigate the clinical significance of NANB Hepatitis. As Dr Dow said to the Inquiry: 'There was no attempt to evaluate the seriousness of the disease, which would have required clinical evaluation by gastroenterologists.'^[458] Dr Dow agreed with the suggestion made to him that one would have required to read his thesis along with the wider literature to obtain a more informed view of NANB Hepatitis.^[459] He was surprised that a copy of his thesis had been sent to the SHHD but said:

[I]t was probably the only study done on Scottish patients ... and it probably did give a grass roots level [view] of what was actually happening. It may have given the wrong impression but it was what we actually saw at the time and it was mild in comparison to Hepatitis A and Hepatitis B which really are very severe diseases in their acute form.^[460]

27.320 For his PhD thesis, Dr Dow had the benefit of supervision by Dr Follett, and of his expertise. No criticism is made by the Inquiry of that thesis which was, inevitably, of limited scope and influenced by the state of medical knowledge at the time, for example in relation to the association then made between 'infective jaundice' and NANB Hepatitis. It covered a discrete topic and was never intended to be an exegesis of the whole of contemporary knowledge of NANB Hepatitis.

27.321 His surprise that the thesis was submitted to the SHHD was both admirable and realistic. Since he himself went on to conduct further research, it can reasonably be inferred that he would have indeed been surprised to learn of the degree of authority accorded within the SHHD to his original work.

27.322 In his evidence to the Inquiry Dr Macdonald was asked whether there was a greater awareness of NANB Hepatitis among SHHD medical officers than the relatively brief comments contained in Dr Forrester's notes and minutes and said that he thought there was.^[461] Dr Macdonald agreed with the suggestion that what was set out in the 7th edition of Patrick Mollison's standard textbook on blood transfusion medicine in the UK in 1983^[462] represented the standard or level of knowledge that one would expect of a medical officer in the SHHD who was considering the subject (whether or not that knowledge was derived directly from Mollison's book). He suggested a need for caution when making statements in 1986, for example, about the seriousness of NANB Hepatitis.^[463] Dr Macdonald was taken to the statement in the Preliminary Report that '[f]rom about 1985 onwards there appears to have been a growing awareness that [NANB] Hepatitis was a potentially serious and progressive disease which could lead, over time, to cirrhosis of the liver, hepatocellular cancer and death'.^[464] He was asked whether that statement was consistent with the statement by Dr Forrester in his note dated 26 January 1987, 'Material for PMO Report', that '[t]his "hepatitis" is a residual rag-bag when Hepatitis B and Hepatitis A are excluded, and consequently no specific test can detect it. It is relatively benign'.^[465] Dr Macdonald replied: 'Yes. Well, I think perhaps something should be added to the relatively benign statement to qualify it. Yes, I think a little more could have been said.'^[466]

27.323 In his evidence to the Inquiry Dr McClelland stated:

I think it's entirely reasonable that the relatively small cadre of medical staff in the Scottish Home and Health Department at that time couldn't be expected to be experts in hepatitis.

It does seem ... looking with the wisdom of the retrospectoscope [with the benefit of hindsight] that they were guided very much by one single piece of work, which was the Dow and Follett research, and didn't show - there wasn't much to see in the documentation that they had actually seriously tried to take a more independent look at the literature and the information that was available.^[467]

27.324 When considering Dr Forrester's contemporaneous comments about NANB Hepatitis one must be cautious. First, the records recovered are often relatively brief and may not represent a complete account of Dr Forrester's knowledge at the time. Secondly, Dr Forrester was a generalist public health doctor who would be reliant on the views of experts in particular fields. Thirdly, he was the most junior level of SHHD medical officer (and there is no documentation available to the Inquiry from a more senior medical officer correcting his understanding of the disease). Fourthly, at the material time, Dr Forrester was relatively new in position. Lastly, Dr Forrester's notes must be seen in their wider context - namely, that views in the medical profession about the potential long-term seriousness of NANB Hepatitis did not change overnight, but instead, evolved over time, from about 1985 onwards, as more evidence became available of the risk of progression to cirrhosis. As Dr Forrester put it in relation to his own understanding of the position: 'My impression was this was the way it did seem to able minds at the time. It doesn't mean it was true in the end.'^[468]

27.325 Of course, the available textbooks were slightly out of date: Sherlock had last published her standard textbook in 1981 and Mollison in 1983, and their views were widely relied on in more general textbooks of the period. English colleagues of Dr Forrester used Dr Dow's work as a peg on which to hang their own applications for funding, implicitly suggesting that it contained authoritative data on the position in Scotland.

27.326 It is clear that Dr Dow came to appreciate that further study was necessary: the Dow, Mitchell and Follett letter to The Lancet on 13 June 1987^[469] demonstrated that. They drew particular attention to the result of introducing abnormal ALT levels to the diagnosis of post-transfusion NANB Hepatitis in the USA where, when this was done, the rate of infection rose from 0.1-0.2 cases per 1000 units transfused to the significantly higher rate of 10-28 cases per 1000 units transfused. Furthermore, 99% of hepatitis cases were never brought to the attention of transfusion centres. In advocating a prospective study, they demonstrated that they had realised that the conclusions drawn earlier might have been wrong. It is unfortunate that SHHD officials did not adopt this view of the situation but, rather, persisted in according Dr Dow's original work such a high degree of authority.

27.327 It is regrettable that the preliminary conclusions of Dr Dow's thesis became so firmly established as received wisdom within the SHHD until at least late 1987. Dr Forrester appears by 20 August 1987 to have understood the limitations of the study and clearly sought to influence the terms of the Biomedical Research Committee decision (on the Gillon/McClelland application for funding to join the UK multi-centre study) in his memorandum to Mr Macniven of 1 October 1987 to ensure that the need for new research was not excluded by that decision.^[470] It is unclear whether others in the SHHD took the same view. Adherence to the view that the Dow research was a sufficient basis for a decision can only have been because relevant medical officers did not have the knowledge or experience required to assess and understand its limitations in the context of NANB Hepatitis. Given that they were essentially generalists, Medical Officers in the SHHD might have been expected to be less inclined to form and to express views on the highly specialist issues that arose. Instead, they might have been expected to take more formal, structured advice from experts, perhaps engaging a technical committee to advise them in the way indicated by Dr Macdonald and/or by liaising with their counterparts in the DHSS to form a UK committee such as the Advisory Committee on the Virological Safety of Blood, which was eventually set up in April 1989. However, it would be pure conjecture, at this juncture, to attempt to speculate what any advice from such a hypothetical committee would have been.

Clinical significance of post-transfusion NANB Hepatitis

27.328 Apart from issues relating to the specificity, sensitivity and general effectiveness of surrogate screening tests as perceived in November 1987, other matters influenced official thinking. The clinical significance of NANB Hepatitis was among these. The evolving state of medical and scientific knowledge in respect of NANB Hepatitis/Hepatitis C is discussed more fully elsewhere in this report.^[471] At the beginning of the 1980s NANB Hepatitis was considered to be a generally mild disease with an 'uncertain but probably benign' prognosis.^[472] From the mid-1980s onwards there was a gradual move away from that assessment towards NANB Hepatitis being viewed as a potentially serious and progressive disease that could, for some patients at least, lead over time to cirrhosis of the liver, hepatocellular cancer and death.^[473]

27.329 There remained a persistent view throughout the 1980s in some quarters, however, that despite an increasing body of evidence to the contrary, NANB Hepatitis was only rarely transmitted by blood and was usually not particularly serious.^[474]

27.330 For administrators, however, the question was not whether one or other view of the risk of transmission or of the seriousness of the disease was correct in absolute terms. Rather, the issue was whether there was a sufficient body of reliable opinion that NANB Hepatitis did present a serious risk, to bring that into account in determining whether research was required and should be funded and what the scope of that research should be. It is clear that SHHD officials, including medical staff, were not competent to make that judgment themselves. They were confronted by conflicting views from people they were entitled to look to for expert advice. That was an additional factor pointing to the need for structured study of the problem, with the benefit of an expert committee to advise them. It is a matter of regret that by late 1987 sufficient information had not been gathered to reach an informed view.

27.331 Apart from the fundamental question of the natural history of NANB Hepatitis, however, two further factors came to prominence in 1988: the impact of surrogate testing on the blood supply and the problems associated with counselling of donors.

Impact on the blood supply

27.332 Several studies were carried out into the likely loss of donations in the event surrogate testing was introduced.

27.333 Dr Gillon's study of Edinburgh blood donors found that 2.4% of a cohort of regular donors had elevated ALT levels^[475] and 2% was positive for anti-HBc. There was no overlap between these two donor groups with the result that, based on these findings, combined screening would have led to an initial loss of 4.4% of donations (from this cohort).^[476] It was concluded that:

In view of the medical and economic implications of the introduction of these screening tests, and the poverty of data on the clinical significance of post-transfusion [NANB] hepatitis ... such a screening programme cannot be justified at present. Further studies are required, including a prospective controlled trial of the effects of screening.^[477]

27.334 The evaluation of ALT testing equipment by the SNBTS Microbiological Validation Group found that a cut-off of 2.5 standard deviations above the mean would lead to the exclusion of approximately 1.5% of donations and that a cut-off of 2 standard deviations above the mean would lead to the exclusion of approximately 5% of donations.^[478]

27.335 The multi-centre study in England found that 3.2% of donors would have been rejected using ALT screening, that 0.63% of donors would have been rejected using anti-HBc screening and that there was little overlap between these groups of donors.^[479]

27.336 Looked at overall, had both ALT and anti-HBc screening been introduced in Scotland it seems likely that between 3% and 5% of donations would have been excluded on initial screening.^[480] In the case of regular donors, the loss would remain as long as they continued to have elevated test results.

27.337 As noted by Dr McClelland:

These numbers may have underestimated the longer term effect on donor attendances, because later research has shown - perhaps not surprisingly - that donors who are rejected on one occasion are unlikely to return to volunteer again, and this tends to have a cumulative effect that is not measured by the initial rate of deferral.^[481]

27.338 At the time of the SNBTS Directors' recommendation on 3 March 1987^[482] that surrogate testing should be introduced with effect from 1 April 1988, there was no recorded discussion of the effect on the blood supply of introducing such testing.

27.339 By 1988, a fall in donor attendances had become a matter of concern. In the introduction to the SNBTS 1988 PES bid (prepared around June 1988), Professor Cash stated:

1987/88 has been the year when, perhaps, for the first time since its foundation in the early 1940s, serious doubts have arisen with regard to the ability of the SNBTS to sustain the quantity and volume of its service to the [Scottish Health Service] and meet the needs of the future.^[483]

27.340 The problems included a decline in total donor attendances, an escalation in demand for blood products and resulting problems in supply and self sufficiency.

27.341 As regards the decline in donor attendances, Professor Cash noted that there had been a 'sustained decline' in attendances since 1985 which had 'become more evident in the last 18 months'.^[484] The total annual donor attendances showed that, from a high of 338,278 in the year ended 31 March 1985, there was a decline to 333,112 attendances in 1986, 331,089 in 1987 and 315,845 in 1988.^[485] Investment totalling £221,000 was sought in the 1988 PES to appoint a national donor recruitment and blood collection manager, to fund a permanent media publicity programme and to improve the conduct of blood donor sessions.^[486]

27.342 As regards the escalation in demand for blood products, Professor Cash explained in the 1988 PES that '[t]here has been a significant and substantial increase in the clinical demand/use of SNBTS blood and blood products over the last decade' which was 'out of control'.^[487]

27.343 As far as supply and self-sufficiency were concerned, the 1988 PES noted that 'major difficulties' had emerged for RTCs in meeting demand centred primarily on the provision of platelet concentrates and supporting the fresh plasma needs of the PFC.^[488] It was noted that 'further significant increases in fresh plasma for PFC cannot be obtained from the existing blood donation input (which is falling in any event)' and that the major contribution to any planned increases in plasma were likely to be by a mixture of plasmapherisis and optimal additive solution (OAS).^[489] Investment of £650,000 was sought in the PES to address these concerns.^[490]

27.344 In a letter to Mr Donald of 25 July 1988, Professor Cash ranked the various bids in the 1988 PES in order of priority.^[491] The sums sought to address escalating demand, supply and self-sufficiency and falling donor attendances were included in the highest priority category. In contrast, the sums sought for ALT testing were in the medium priority category.

27.345 In his evidence to the Inquiry, Dr Mitchell was asked whether a loss of 4% or 5% of donors in the west of Scotland would have created a problem for the blood supply and he replied that it would.^[492] He was then asked whether that would have been an insurmountable problem and replied:

With sufficient drive perhaps it could have been overcome ....

And so the answer to that is, yes, we could probably have overcome the problem. It would have taken a lot of additional advertising, and it's difficult to see how you would recruit donors faced with the knowledge that you were imparting through their colleagues at the workplace, who were not infected, but had a marker which was putting them off-service. They would be saying to themselves "Well, I'm not going. If you are not going to go, I'm not going because I might be turned down the same as you". And once you are turned down, then you have a problem. I have said to you many, many times, a donor becomes a patient ....^[493]

27.346 Dr Gillon stated:

The situation became serious to the extent that a substantial injection of resources was necessary around 1990, with most of the money and effort going into a television advertising campaign which reversed the decline in donor numbers. Whether it would have been possible to weather a loss of donations of the order of at least 4-5% and so maintain self-sufficiency with or without such funding is doubtful, but this is speculative in the extreme.^[494]

27.347 Professor Cash was asked whether, given the difficulties in blood collection in the second part of the 1980s, it would have been feasible to introduce surrogate testing at any time between 1987 and 1990. He replied that, had he been asked about surrogate testing at the end of 1987, his position would probably have been: 'Go away ... forget it in the meantime.' He stated that in 1988/89, 'we would have been struggling a little.' Progress was, however, being made in that unnecessary use was being reduced, stocks were being moved around and the problems in the west of Scotland were eventually resolved.^[495]

27.348 Although these problems were dealt with, it appears that the Scottish service was not well placed at this time to withstand any further reductions in donations, in particular if self-sufficiency in blood products was to be maintained. The potential sensitivity of donors to the implications for them of surrogate testing added to the difficulty.

Counselling of donors

27.349 As noted above, surrogate tests such as ALT and anti-HBc markers were non-specific indicators of the presence of NANB Hepatitis.

27.350 In his written evidence to the Inquiry Dr McClelland stated:

Low test specificity ... has serious consequences when a test is used to screen a member of a healthy population. A substantial proportion of the individuals who test "positive" and who therefore will be rejected as donors because of the risk of transmitting [NANB Hepatitis], will not in fact, have [NANB Hepatitis] nor will their blood contain the relevant infectious agent. Nevertheless, such individuals have to be informed that their donations can no longer be accepted and the risk that their blood could transmit hepatitis must be part of the explanation. This can have the effect of converting a person who correctly considers themselves to be in good health into one who has been given information that indicates that they may be afflicted with a serious infection. This problem can only be avoided if there is some form of additional test (often termed a confirmatory test) that can reliably demonstrate the presence or absence of infection.^[496]

27.351 Until the Hepatitis C virus was identified in 1988, and a test for antibody to Hepatitis C became available the following year, there was no direct test - far less a confirmatory test - for the agent or agents responsible for NANB Hepatitis.

27.352 Taking Dr McClelland's oral evidence as a whole, it is clear that there was concern as to how the SNBTS would have managed donors who were rejected on the basis of a surrogate test. It was suspected that in most cases a positive test would not indicate infection.^[497] Effective counselling of donors who tested positive for surrogate markers would have been a 'challenging problem' for the service. Further thought required to be given to the practical arrangements for counselling the many thousands of donors who would test positive for surrogate markers and the SNBTS had little practical experience of such counselling to draw on.^[498] The numbers involved in Hepatitis B and HIV testing had not been large and, furthermore, in relation to these infections confirmatory tests were available.

27.353 On reflection, Dr McClelland accepted that the SNBTS Directors 'certainly had not ... prepared a systematic sort of management plan and costed out the stuff involved'. He remained 'absolutely confident', however, that, looking at the implications for the other hospital departments and GPs, the issue of donor counselling 'could and would have been addressed'.^[499]

27.354 Dr Mitchell was altogether less confident. He emphasised the uncertainties that arose from the fact that ALT levels could fluctuate and that elevated ALT had many different causes, many or most of which had nothing to do with hepatitis.^[500] In his view, a donor who tested positive for a surrogate marker would become a patient.^[501] Asked whether that would not have been a reason to avoid testing, Dr Mitchell commented:

No, provided the basis on which you make him a patient is justifiable ....

What do you say, "Go and see your GP"? The GP immediately phones us and says, "What does this mean?", "I don't know what it means, but I know what you are getting at", but he says to me, "But this chap is sitting in front of me and he is dead scared, he's worried, "What's going to happen to me?" I can't tell him anything". I say, "Neither can I".^[502]

27.355 On Dr Mitchell's approach, there were many questions for which practitioners had to have answers before proceeding to implement surrogate testing.

27.356 Dr Gillon's experience with donors supported the view that there was a problem with counselling. Donors in his study into surrogate markers who were found to have elevated ALT levels 'were quite anxious, they were very keen to know the next set of results, and they were really quite concerned about this'.^[503] Dr Gillon also had experience of counselling plasmapheresis donors with elevated ALT and stated:

As soon as you see somebody, sit them down and say, "There may be something wrong with your liver, you may be carrying some nasty virus that may or may not cause chronic liver disease. We may have to send you to a specialist. They may stick a needle in your liver". It was not trivial. It is absolutely not trivial.^[504]

27.357 Dr Macdonald said:

It's not simply a matter of counselling and advice but there would be a number of donors identified who would have to be referred to a physician, subjected to laboratory tests, reviewed for a period of at least some months, I would have thought, before it would be possible to offer them an opinion as to whether they were infected or not. In other words, whether they were the false positives or genuine positives. Yes, there is quite a lot involved in this.^[505]

27.358 Notwithstanding Dr McClelland's confidence that a solution would have been found, and quite irrespective of the numbers involved, the introduction of surrogate testing would have required resolution of the many issues relating to informing donors, providing counselling and regulating follow-up, all of which were inherent in using a mass screening test of such poor specificity and sensitivity.

27.359 The scale of the problem - the number of donors who might have required counselling and investigation - added to the underlying difficulty. In the mid- to late-1980s approximately 300,000 blood donations were collected annually in Scotland.^[506] The number of donors is likely to have been considerably lower. As noted in Chapter 18, Collection of Blood in Scotland: General, paragraph 18.14, at the date of the Inquiry's hearings 80% of donors bled were not 'new' and return donors contributed about 85% of all donations. These percentages must fluctuate and a 'new' donor in January may become a return donor in May and September. On the evidence, a return donor might give 1.06 donations a year on average. It is not possible to extrapolate on any reliable basis from the findings of a limited study to an estimate of the potential loss to the blood supply. However, for illustrative purposes only, total donors for 300,000 donations might be the sum of new donors (300,000 x 15% = 45,000 individuals) and return donors (255,000/1.06 = 240,566), a total of 285,566 individuals. If ALT testing had been introduced then, on the best current estimates, approximately 3% of donors might have been expected to have had elevated levels, just over 8500 donors per year. Dr Gillon's study had found that about 80% of donors with elevated ALT had a 'non-viral' explanation, such as obesity or alcohol.^[507] Based on Dr Gillon's findings, about 6800 might be expected to have had a 'non-viral' explanation for their condition, leaving 1700 - 0.6% of the total number presenting with a view to donation - who would have elevated ALT for which a viral explanation was possible. In a Finnish study by Freja Ebeling and colleagues, the authors considered that the positive predictive value (the number of true positive results amongst the 'positive calls') of an elevated ALT level in identifying those donors who transmitted NANB Hepatitis was about 4%.^[508] While for a number of reasons one must be very cautious about relying on that figure, for purely illustrative purposes it would suggest that if about 1700 donors a year in Scotland were found to have elevated ALT levels deemed to be associated with NANB Hepatitis, about 68 donors would be infective and the remaining 1632 would be 'false positives'.

27.360 The concerns about the impact on donors, often advanced by practical transfusion doctors, were significant. Giving a label of uncertainty to individuals who were likely in the nature of things to be immediately anxious would have been a serious matter. Had it been intended to introduce surrogate testing of donated blood generally, it would have been necessary to have developed clear guidance on how donors found to have elevated ALT or to be positive for anti-HBc were to be dealt with and, in particular, counselled. The risk of false positive results would have presented a particular challenge. That stage was not, in the event, reached. The evidence of Dr Mitchell, Dr McClelland and Dr Gillon made it clear that finding a satisfactory solution that would have had general support would not have been easy.

The perceived benefits of surrogate testing

27.361 The preceding discussion has considered the various difficulties with using surrogate tests to screen donors for possible NANB Hepatitis infection. One must also, however, consider the evidence that was available at the time in respect of the advantages of surrogate testing including, in particular, the extent to which surrogate screening may have reduced the incidence of transfusion-transmitted NANB Hepatitis infection. A full cost/benefit analysis does not appear to have been carried out, and, indeed, such an analysis could not have been carried out in any meaningful way in the absence of a large-scale prospective study of the prevalence of NANB Hepatitis in Scotland and of the efficacy of surrogate testing here. As discussed above, such a study would have been required to extend beyond the investigation of the prevalence of surrogate markers in donors and to have included investigation of the link, if any, between such surrogate markers and the development of post-transfusion NANB Hepatitis in recipients. A study of that scope was never properly considered or carried out in the UK. The perceived benefits of surrogate testing in the late 1980s can therefore be considered only on a more general basis.

27.362 Dealing, first, with patients with blood disorders, the size of pools (containing many thousands of donations) used to manufacture Factor VIII and Factor IX meant that most were likely to have contained at least one donation containing HCV (which donation would potentially have infected the whole pool). Given the poor sensitivity of surrogate testing as a screening test, it was never likely to have been effective in identifying and excluding all infective donations. The safety of factor concentrates, therefore, depended not on surrogate screening of donations but on the development and introduction of manufacturing processes that inactivated any virus in the pool. By the end of 1987 the PFC had already issued products sufficiently heated to inactivate HCV-infecting source plasma. In particular, heat-treated Factor IX concentrate (DEFIX) was issued in August 1985 for routine clinical use in the treatment of Haemophilia B.^[509] The PFC's heat-treated FVIII concentrate, Z8, was issued for routine clinical use in the treatment of Haemophilia A in April and May 1987.^[510] Patients receiving factor concentrate therapy with NHS products after those dates would not have been infected due to the inactivation procedures. Surrogate testing of blood donations would not have added to the security of recipients of these products in haemophilia therapy.

27.363 Further, most patients who had routinely received blood products before the introduction of the heat-treated concentrates had almost certainly already been infected with NANB Hepatitis/HCV. That was the conclusion of a number of studies: most haemophilia patients, whether treated with NHS concentrates or concentrates produced by commercial companies, were likely to have developed NANB Hepatitis on first exposure to concentrates that had not been virally inactivated.^[511] Only haemophilia patients receiving single or small numbers of doses of cryoprecipitate (made from pools of around 10 donations), who were in broadly the same position as medical and surgical patients receiving transfusions of blood or blood components, might have benefited. The topic of relevance is primarily in those cases.

27.364 As regards transfusion of whole blood and its components,^[512] the TTV and NIH studies suggested in 1981 that in the USA (and therefore in the context of the specific characteristics of that country's blood donor population), ALT testing might have reduced the incidence of post-transfusion NANB Hepatitis by 30-40%.^[513] The same studies, reporting in 1984 and 1986, suggested that anti-HBc testing might reduce the incidence of post-transfusion NANB Hepatitis by about one third.^[514] The ALT and anti-HBc tests largely identified different groups in the donor population. However, even if these predictions had been correct, on average two-thirds of the pre-screening risk of transmission would have continued despite screening.

27.365 Importantly, the TTV and NIH estimates of the extent to which surrogate testing might have reduced the incidence of post-transfusion NANB Hepatitis were predicted efficacies (based on an historical analysis of existing data) rather than actual efficacies (based on a randomised prospective study whereby one group of patients was given blood which had been screened for surrogate markers and the other was given blood that had not been so screened). Very few randomised prospective trials were carried out and published before the late 1980s to establish the actual efficacy of surrogate testing in reducing the incidence of post-transfusion NANB Hepatitis. Those that were published in the early- to mid-1990s were too small for reliable conclusions to be drawn from their results.

27.366 The letter from Dr Gillon and his colleagues published in The Lancet on 13 June 1987 commented on the published literature as at mid-1987:

Of the four small prospective studies, two using ALT screening and two using anti-HBc, three^[515] failed to demonstrate any reduction in post-transfusion NANB hepatitis as a result of donor screening and one^[516] found an apparent association between anti-HBc in donor units and recipient hepatitis.^[517]

27.367 The information available at the time on the likely benefits of surrogate testing therefore remained inconclusive. The majority of small-scale prospective studies had failed to demonstrate the reduction in post-transfusion NANB Hepatitis that was predicted by the TTV and NIH studies when blood with surrogate markers was withheld.

27.368 There was an additional difficulty in relying on these data. Prevalence in the US donor population could not be assumed to be representative of the prevalence of NANB Hepatitis elsewhere. Prevalence in the USA was generally believed to be relatively high and, as Professor Leikola said, most countries that elected to introduce surrogate testing in 1987 first conducted research to find out the situation in their own donor population and did not simply follow the US example.

27.369 There are other difficulties in trying to estimate the extent to which surrogate testing might have reduced the incidence of post-transfusion Hepatitis C in Scotland. Dr Gillon, for example, took the view that predictions of a reduction of cases of post-transfusion NANB Hepatitis by 30% or 40% following ALT testing would almost certainly have been too high for a number of reasons, including that donors rejected on surrogate screening would have to be replaced with new donors. The introduction of anti-HCV screening had shown that new donors had an increased prevalence of HCV when compared with existing donors. That factor, unknown and unknowable in extent, would require to be taken into account when calculating the efficacy of surrogate testing. Dr Gillon explained: 'I know Harvey Alter talked about a corrected efficacy to try to accommodate that, and that dropped his predicted efficacy from 40% to 20%, but it was totally speculative.'^[518]

27.370 Developing knowledge of other causes of elevated ALT became significant. Hepatitis C causes liver damage and elevated ALT is an indicator of liver damage (from whatever cause). It was reasonable to infer that donors with Hepatitis C were more likely to have elevated ALT than donors who were not infected. Elevated ALT is, however, also associated with other factors, such as obesity and alcohol intake, and these required to be excluded before an inference of Hepatitis C infection could be drawn from the finding. In addition, as Dr Gillon explained:

The segment of the population with the highest mean [ALT] levels is in males aged 30 to 40 ....

In most studies of HCV-positive blood donors, there is found to be a preponderance of males, typically in the age range 30-40. There is therefore a coincidental association between higher ALT levels and the donors most likely to have been exposed to HCV. It is therefore likely that ALT is to some extent an epiphenomenon in statistical or epidemiological terms [that is, a secondary phenomenon without a necessary causal relationship to the primary disorder] as Alter and Holland suggested.^[519]

27.371 The information available from later investigations suggests that, viewed exclusively in terms of efficacy, surrogate testing for elevated ALT would probably have reduced the incidence of transfusion-transmitted hepatitis for some recipients of blood, blood components and single donor preparations such as cryoprecipitate, if introduced between 1988 and 1991. The extent to which that would have happened cannot be quantified, given the difficulties with the evidential material previously discussed.

Product liability

27.372 Council Directive 85/374/EEC, imposing strict liability for harm caused by defective products came into force in the UK on 1 March 1988 under the Consumer Protection Act 1987.^[520] In A v The National Blood Authority and Others, Mr Justice Burton decided on 26 March 2001 - for the time being conclusively - that as of 1 March 1988 recipients of blood or blood products which transmitted HCV infection, had suffered harm for which a remedy was available under the terms of the Directive. The circumstances of the case are discussed in Chapter 31, The Introduction of Screening of Donated Blood for Hepatitis C, at paragraphs 31.432-31.437.

27.373 SNBTS officials, particularly Professor Cash but including the Transfusion Directors generally, anticipated that there would be strict liability under the Directive and engaged that risk by contending that surrogate testing should be introduced. The 'irrational but perhaps inescapable' conclusion was perhaps most clearly expressed in the letter to The Lancet dated 4 July 1987 and discussed at paragraphs 27.206-27.207.

27.374 As originally argued by Professor Cash, the risk of strict liability, for the SNBTS in particular, was presented as a reason for the UK to attempt to exclude blood and blood products from the scope of the legislation. That argument failed to achieve support from the DTI and it was accepted by the SHHD that blood and blood products would remain within the scope of the act. Once that position was accepted, the success of the UK public sector producers of blood products and of the transfusion services in escaping liability, inevitably depended on the view taken by the court of the effect of the legislation and, in some respects more critically, of the facts found by the court on the evidence before it.

27.375 The facts found in A v The National Blood Authority and Others are not determinative of the factual issues that arise on the evidence before the Inquiry which remain facts for the Inquiry to determine. In particular why surrogate testing was not introduced and whether it should have been introduced are issues the Inquiry must deal with on the evidence now available.

Why surrogate testing was not introduced and whether it should have been introduced

27.376 Central to this discussion are questions as to whether the UK Government departments, particularly the DHSS and the SHHD, were wrong to have first delayed and then failed to institute general surrogate testing of blood donations for high ALT levels and anti-HBc. Since HCV screening was introduced generally on 1 September 1991, the relevant period for considering these questions can be taken to have ended on that date: there was no general safety issue to be addressed by surrogate screening thereafter, whatever commercial reasons fractionators might have had for continuing with the practice. The issue had, however, already changed in the course of the period ending on that date. It is relevant and material to note that as the period proceeded it became clear (and was certainly clear by the date of the introduction of HCV screening) both that the large majority of cases of post-transfusion NANB Hepatitis/HCV were attributable to a single virus and that screening and confirmatory tests for HCV were increasingly of reasonable sensitivity and specificity. As the tests improved, particularly in relation to those genotypes of HCV prevalent in the UK, the potential relevance of surrogate testing diminished.

27.377 There is, however, a short and compelling answer, at least from March 1989 onwards, when the ACVSB was set up: given the advice of the committee, the appropriate expert advisory group established to provide objective and independent advice to government, that the blood transfusion services should not introduce surrogate testing, there was no medical or scientific basis on which the DHSS and the SHHD could properly have done otherwise.

27.378 The issue is not whether, having regard to subsequent developments in medical and scientific knowledge, the expert advice tendered was correct or incorrect. The members of the ACVSB included eminent experts of national and international repute who were leaders in their fields. Professor Zuckerman, for example, appears from the record to have been a significant voice influencing the direction of thought throughout this important period. It would be inappropriate with the benefit of hindsight to analyse his advice and, in comparison with others' views, comment on the validity of his opinions. The Inquiry is not tasked with an assessment of professional opinions responsibly held and expressed as guidance to government. At the time, the NHS, the Scottish agencies, the SHHD and the government generally were entitled to rely on the advice given by appropriate experts and to act accordingly. Ministers would have required clear and powerful scientific advice to the contrary before taking a different course. At no point was there clear and powerful advice in favour of the introduction of surrogate testing in Scotland or the rest of the UK.

27.379 Before the ACVSB was set up, however, the question was more open. Until the decision of the AABB (in the USA) in August 1986, there was no consensus anywhere that surrogate testing was appropriate as a method of screening blood for NANB Hepatitis. In the UK, there was never a medical and scientific evidential basis to justify the introduction of a mass screening test of such poor sensitivity and specificity. The lack of sound medical and scientific reasons for the introduction of surrogate testing was recognised by the SNBTS Directors who instead, in their letter to The Lancet of July 1987, pointed to other factors which they considered meant that surrogate testing was 'irrational, perhaps, but inescapable'. These other factors included forthcoming product liability legislation already referred to and pressures arising from the practice of commercial manufacturers.

27.380 It was suggested in closing submissions to the Inquiry that the SNBTS Directors failed to explain properly to the SHHD their reasons for recommending the introduction of surrogate testing, including the benefits to patient safety and that, for their part, the SHHD failed in not asking the SNBTS Directors to clarify the reasons for their recommendation.^[521] The Directors' reasons for making their recommendation were stated at the time to be based on the fact that blood banks and fractionators elsewhere, in particular in the USA, were introducing ALT testing and because of new product liability legislation. The SHHD officials were aware of the SNBTS Directors' concerns in that regard, even if they did not agree with them.

27.381 Given the lukewarm support of the SNBTS Directors for surrogate testing and the lack of data in the UK as to its efficacy in preventing or reducing transfusion-transmitted NANB Hepatitis, it would be unrealistic to proceed on the basis that the Directors should have been expected to provide much more by way of clarification of their reasons for 'recommending' the introduction of surrogate testing. It was not a fully reasoned response to the problem, which remained that surrogate testing was a controversial topic which did not command widespread scientific support outwith the USA. The Directors' reasons for their recommendation, so far as they were developed and expressed, were known to the SHHD. They were not persuasive without the backing of relevant research.

27.382 There was, at least potentially, an independent question for the SHHD: whether, having regard in particular to the impending product liability legislation, a full cost/benefit analysis would have tended to support surrogate testing, notwithstanding its limitations. That was, however, never carried out. It would have been a complex exercise, not least because of the incalculable impact on donors and the blood collection complex of inefficient screening technology. It would not be appropriate to speculate on what the outcome of such an analysis might have been.

27.383 In his written evidence Professor Leikola commented on the fact that surrogate testing for NANB Hepatitis was not introduced in the UK. Even on the basis of all that is now known, it was reasonable and correct, in his view, for the UK not to have introduced surrogate testing.^[522] So far as anti-HBc testing was concerned, its use as a surrogate marker could not be validated. He considered that ALT testing might have been more logical but observed that it was used in some countries, not because of a scientific basis and logical reasoning but because of public pressure.^[523]

27.384 As noted above, Dr Macdonald explained that surrogate testing was not introduced because, '[e]ssentially, there was too much uncertainty about various aspects of surrogate testing to justify introducing it.'^[524] He referred to these concerns as relating to 'the quality of the testing'^[525] and that 'the screening method was not really good enough'.^[526]

27.385 Dr Macdonald was also asked whether, with the benefit of current knowledge of Hepatitis C, he would be any more positive towards surrogate testing; he replied that he did not think he would be, given the non-specific nature of surrogate testing, the number of false positives that would arise and the fact that such testing would not be able to completely eliminate infection.^[527] He was also asked whether, hypothetically speaking, if it was reasonably believed that the introduction of surrogate testing was likely to reduce the incidence of post-transfusion hepatitis by, say, 30-40%, he considered there then arose a reasonable case for introducing surrogate testing. He replied:

No, I think I would still have argued against it. I think too much uncertainty still remained and I would have put considerable weight on the possibility that donors would find it disturbing. I think the one thing that we really had to avoid, almost at any cost, was disturbing donors because the whole enterprise depended on them.^[528]

27.386 While in his evidence to the Inquiry, Dr McClelland stated that patient safety was 'the' reason why he favoured the introduction of surrogate testing,^[529] that can only have been in a very general and inchoate way, given the fundamental problem that one could not make a fully reasoned and scientific case for its introduction, including quantifying any benefit in recipient safety, because of the lack of adequate evidence and research in the UK into the prevalence of post-transfusion NANB Hepatitis and the likely efficacy of surrogate screening in reducing the transmission of the disease through transfusion. Furthermore, the issues identified by Dr Mitchell and Dr Gillon around the risk of turning thousands of healthy donors, found to have elevated ALT levels on surrogate testing, into patients concerned about the implications of test results for their long-term health that could not be resolved, were real obstacles to the introduction of the tests on a routine basis. The impact on the blood supply was also a legitimate concern, in particular against the background of a fall in donor attendances around this time, an increase in demand for blood products and the resulting difficulty in maintaining a policy of self-sufficiency in blood products.

27.387 From May 1987, the general European position was that each country should ascertain the prevalence of NANB Hepatitis infection in its own region and take a decision on that basis. In Finland, a decision to carry out a study was implemented, the study beginning in December 1987 and lasting a year. Had Scotland followed the Finnish pattern, the results of such a study would not have been available before the ACVSB was established. The timescale anticipated by the SNBTS in their letter to The Lancet in July 1987 was three to four years. However, Dr McClelland had been pressing for such a study since 1981. As narrated, his early efforts failed in consequence of decisions taken by the MRC and the transfusion services' Working Party on Transfusion Associated Hepatitis. Had his early efforts received a positive response then it is likely that the results of such a study would have been available before the AABB decision in 1986. Whether an additional study would have been required in consequence of the effects of the AIDS risk on donor selection policies cannot now be known. Professor Leikola, however, was clear that he was not critical of the decision not to introduce surrogate screening into Scotland and his opinion on this matter is accepted.

27.388 Importantly, while such a study would have led to more informed decision-making, given the difficulties discussed above that arise from using a test of such poor sensitivity and specificity to screen hundreds of thousands of donors, it cannot be concluded that had such a study been carried out at some point in the 1980s in Scotland, or in the UK, surrogate screening would, or should, have been introduced.

Conclusions

The relevant period

27.389 The period during which consideration of the introduction of surrogate screening of blood for possible signs of NANB Hepatitis infection was a significant issue for the SNBTS and Scottish Government officials, began with the recommendations of the Council of Europe Committee of Experts on Blood Transfusion and Immunohaematology in May 1987.

27.390 The period ended with the introduction of specific testing for antibodies to HCV on 1 September 1991.

Recipient populations potentially affected by the lack of surrogate testing

27.391 By May 1987, blood products used in Scotland for the treatment of patients with blood coagulation disorders did not expose recipients to a risk of transmission of HCV that might have been removed or alleviated by surrogate testing because:

• Commercial products imported from the USA were prepared from blood donations that were subject to surrogate testing.
• PFC Factor VIII and Factor IX concentrates were already heat-treated in such a way as to effectively inactivate any virus in the product (Factor IX DEFIX with effect from October 1985 and Factor VIII 8Y with effect from April/May 1987).

27.392 The recipient populations potentially exposed to risks following the failure to carry out surrogate testing of donations during the relevant period were surgical, medical and other patients receiving transfusions of whole blood or blood components from donations that were not screened for elevated ALT or for anti-HBc.

The surrogate tests available and their effectiveness

27.393 Before the relevant period, research studies, mainly carried out in the USA, reported a correlation between elevated ALT levels in blood donors and an increased risk of transfusion recipients developing NANB Hepatitis.

27.394 Other research from that time also reported an association between the presence of anti-HBc in blood donors and an increased risk of NANB Hepatitis transmission to transfusion recipients.

27.395 These findings supported the view that elevated ALT and/or anti-HBc might be useful 'surrogate markers' for NANB Hepatitis in donated blood.

27.396 No acceptable scientific basis for a correlation between the presence of anti-HBc in donated blood and the transmission of HCV was established on the evidence before the Inquiry and the failure to institute routine anti-HBc screening is not significant.

27.397 In individuals, ALT levels fluctuate from time to time. There are different causes of ALT elevation, many of which have nothing to do with hepatitis, including obesity and the effects of the excessive consumption of alcohol. A single, isolated elevated test is not a reliable indicator of underlying infection.

27.398 Generally, the poor sensitivity and specificity of ALT tests meant that the majority of infected donations were unlikely to be detected and, of the many thousands of donations that tested positive, the vast majority were likely to be false positives.

27.399 The likelihood that ALT testing would provide an acceptable surrogate test varied from country to country. There was no guarantee that, in a given country, ALT testing would result in a significant reduction in the transmission of NANB Hepatitis.

27.400 It was recognised in Europe that individual countries would have to assess the situation locally and decide on the appropriate action to take. In particular, the prevalence of NANB Hepatitis in the local population generally, and in the blood donor population in particular, was a significant consideration.

Decision-making in Scotland

27.401 Subject, ultimately, to Parliament's over-riding control, the decision as to whether or not to introduce ALT testing in Scotland was a matter for ministers with responsibility Scottish afffairs, based on the advice of officials.

27.402 Scottish officials were not obliged to submit the introduction of ALT testing to ministers unless they were satisfied that there was evidence and expert advice justifying the introduction of the procedure. It was part of their function to consider the evidence and advice available to them and to form a view as to whether or not to seek a ministerial decision on the issue.

27.403 In the event, SHHD officials were not persuaded of the merits of surrogate testing and did not put the issue to ministers for a decision. As a result, ministers did not take part in the decision-making process, for which they were responsible.

The lack of a decision on surrogate testing

27.404 After the AVCSB was set up in early 1989, government, at the UK and Scottish levels, had a source of guidance from well reputed experts on which ministers and officials were entitled to rely for scientific and medical advice in formulating policy on surrogate testing. Before that time, Scottish officials had to rely on local expertise and such indirect sources as were available from the DoH.

27.405 Scottish officials never had adequate information on the prevalence of post-transfusion NANB Hepatitis in the Scottish population or any material cohort of that population. Further, the predictive value of raised ALT levels in donors was limited, due to its known lack of specificity.

27.406 The lack of data was the result of decisions taken in the 1980s that there should not be a large-scale prospective study of the prevalence of post-transfusion NANB Hepatitis in the UK as a whole or in Scotland in particular.

27.407 On the evidence before the Inquiry, it was too late by the beginning of the relevant period to initiate such a large-scale prospective study. Such an exercise could not have been expected to have produced reliable results in time to inform decisions on the introduction of surrogate testing. It appears that those reliable results would not have been available before early 1990 at the earliest.

27.408 There were conflicting expert views on many of the factors relevant to surrogate testing, including the prevalence of post-transfusion NANB Hepatitis, its potential seriousness for patients infected by the virus and the different viruses postulated as infective agents.

27.409 It was, however, generally acknowledged that the available tests had poor sensitivity and specificity for their effective use in the mass screening of donors and that the lack of a confirmatory test meant that it would be difficult or impossible to distinguish between a true and false positive result.

27.410 These difficulties would, in turn, have given rise to real difficulties in counselling donors and in maintaining a sufficient blood supply.

27.411 While surrogate testing is likely to have prevented some cases of transfusion-transmitted NANB Hepatitis, it is not possible to quantify the percentage reduction with any degree of confidence, given that the prevalence of NANB Hepatitis at the time was not known and the likely efficacy of surrogate testing in reducing the transmission of NANB Hepatitis was speculative.

27.412 With the establishment of the ACVSB in early 1989, it was reasonable for government to act on the expert advice received from that committee. The ACVSB did not, in the event, recommend the introduction of surrogate testing.

27.413 In the final outcome, there was no definitive decision by Scottish officials whether or not to recommend the introduction of surrogate testing.

Practical consequences

27.414 While it seems likely, on the balance of probabilities, that ALT testing would have reduced the incidence of transfusion-transmitted Hepatitis C to some extent, given all of the difficulties set out in this chapter it was not possible at the time, nor is it possible now, to say to what extent the incidence of post-transfusion Hepatitis C would have been reduced in recipients of blood and blood components by transfusion, or at what 'cost' in terms of impact on donors and impact on the blood supply.

27.415 The Inquiry does not attribute blame for the fact that surrogate testing was not introduced, given the diversity of respected medical and scientific views over the period 1986-91. There was no consistent support for the procedure on tenable scientific or medical grounds that would have made it possible to conclude that officials should have recommended the introduction of ALT testing, or that the question was so narrowly balanced that it required to be referred to ministers for decision.

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28. Donor Selection - AIDS >