Volume 7: Medicines and Cosmetics
6. Ensuring medicinal products complied with the guidelines
Discussion
What needed to be done?
The response by the Licensing Authorities
1. The response on veterinary products
2. The response on human medicinal products
3. The response on medical devices and other matters
4. Our general conclusions on follow-up to the guidelines
5. General conclusions on medicines and BSE

What needed to be done?

6.264 From March 1989 onwards, officials were in a position to apply the guidelines to all new licence applications and to the review of Licences of Right. They appear to have lost no time in doing this.

6.265 The questionnaire review covering existing licences, though admirably comprehensive for filling in the information gaps, was a different matter. Because of its sheer scale alone it was bound to involve much time and effort. Unfortunately, for reasons we develop below, this process did not run speedily or smoothly. The original six-week deadline for returns proved a pious hope and in the event the exercise as a whole took years to complete.

6.266 What faced officials was a major administrative exercise in order to manage and apply the results. In particular they needed to:

1. chase up replies, and decide which required further investigation;
2. assess risk and supply considerations where bovine materials were involved and seek the advice of the expert committees on problem cases; and
3. take follow-up action to ensure manufacturers dropped objectionable products or found new supply sources, and phased out contaminated stocks as speedily as possible.

6.267 We discuss below the way these tasks were tackled by each of the three groups of officials concerned respectively with veterinary medicines, human medicines, and medical devices. For brevity we generally refer below to bovine products, but many of the actions taken applied also to ovine and caprine products, which were recognised as raising similar issues.

6.268 As stated at the beginning of this chapter we had difficulty in pinning down precisely when stocks of products, particularly vaccines, manufactured with UK bovine material were used up. The MCA was not able to provide us with this information and the report of the audit of manufacturers carried out in 1996 did not deal with the issue of phasing out stocks. We have done our best to piece together what we could about the use of stocks of vaccines, but the information is still vague. Although there is no evidence at this stage that vaccines or any medicinal products were implicated in transmitting the disease, the possibility cannot be ruled out entirely. Should that be the case, accurate tracing of what happened to products would then be helpful. We found the overall lack of information concerning the phasing out of existing stocks of products frustrating.

6.269 We begin our discussion by reviewing three background factors that directly affected the response:

1. Handling uncertainty.
2. The management context.
3. Perceptions about the risk posed through medicines.

(i.) Handling uncertainty

6.270 As explained in Chapter 2, the elaborate licensing system rested on medical and pharmaceutical assessments of technical data. Tests and trials might take years to complete and be validated. The actual grant or revocation of licences was performed by administrative staff acting on behalf of Ministers. They were advised by professional branches and they consulted expert committees as necessary. Their decisions had to be founded on proper evidence and were subject to appeal.

6.271 A key function of the 'Yellow Card Scheme' for recording adverse reactions in humans and animals was to alert officials to where licensing action might be justified. In the case of BSE there were no demonstrable adverse reactions among users to justify intervention. There were no tests available to detect contamination and no guaranteed methods of sterilisation to rule it out. On the other hand there were demonstrable medical benefits from most of the products under suspicion, and large investments at stake.

6.272 Professional and administrative assessments about the balance of risks and benefits in allowing existing products using bovine materials to remain on the market were therefore going to be peculiarly difficult. In the end they could be no more than value judgements by officials and the expert committees they consulted, drawing on what was known about other TSEs. It was bound to be attractive to make the maximum possible use of the flexibility the guidelines allowed if manufacturers stalled for time to find 'clean' sources or dispose of existing stocks. The alternative might be a time-consuming string of Medicines Act appeals.

(ii.) The management context of the review exercise

6.273 The case-by-case approach of the review exercise meant that each of many hundreds of returns had to be scrutinised and assimilated with existing material. Judgements had to be reached on each return's adequacy and accuracy and if need be more information obtained. A view then had to be reached on whether advice should be sought from the expert committees.

6.274 These considerable tasks were being superimposed on a creaking system which, as the management reviews had shown and as witnesses testified, was overloaded and understaffed. The record systems were antediluvian. Parallel hierarchies of professional and administrative staff diffused the management responsibility. To address this state of affairs, agencies were in the process of being set up. While this shake-up in the organisation had admirable goals, it meanwhile was a new factor affecting reporting lines and the priorities of top management, just as the BSE information-gathering exercise was being put in train.

6.275 New Directors had taken up post in April 1989, as the heads respectively of the MCA and VMD. Neither had firsthand knowledge of the previous debate over BSE and medicines safety nor of what lay behind the choice of wording in the Southwood Report, the CSM statement and the letters to companies.

6.276 Dr Gerald Jones's successor, Dr Keith Jones, whose previous career had been in commercial pharmaceutical management, told us he was heavily preoccupied over the next 18 months in setting up the MCA as an agency, no doubt in the process tackling the matters criticised in the management reports. He told us he had little independent recollection of his involvement with BSE during his early years at the MCA, not only because of the passage of time, but because creating and funding the new organisation was the primary focus of his attention. ¹ The BSE review exercise continued to operate as before on a collective basis and old reporting lines - the traditional 'team effort'.

6.277 Dr Little's successor, Dr Rutter, who had come from the Institute of Animal Health to head the new VMD, registered his interest in BSE in June 1989 by asking that VMD and the MCA should keep one another informed on progress. ² Thereafter, follow-up action was handled by Dr Aileen Lee.

(iii.) Mixed messages on the urgency of the exercise

6.278 Dr Keith Jones and Dr Rutter were not alone in assuming the exercise might be allowed to proceed in a routine way. The tight initial deadline of six weeks had been set for the questionnaires to be returned. This having proved unattainable, thereafter there was no set timetable. On the contrary, the wording of the Southwood Report and the message conveyed in the CSM statement and accompanying letters were now being interpreted in both VMD and the MCA as taking the heat off medicines. While follow-up action needed to be pressed ahead, a flexible line on timing and on existing stocks seemed reasonable.

6.279 Thus, the low-key presentation of risk from injected products, which had been so carefully crafted to avert public alarm about the vaccination programme while remedial action was being taken, had the pernicious result of being taken as the message itself. Few of those handling the follow-up, certainly at top management level, would have known about the earlier deep concern of Sir Richard Southwood over injectable products, and his attempts to get assurances that action was being taken on these.

6.280 The gap in perception applied equally to VMD and the MCA. It encouraged a slackening of tempo in delivering the action on which the assessment of remote risk actually depended. Thus the first meeting of the BSEWG was advised by MCA officials that the Southwood Report had stated the risk to man via medicinal products was remote and that it was important not to undermine this considered advice by demanding unnecessary assurances and information from manufacturers. ³ We discuss in Volume 4 the Southwood Working Party's assessment of risk.

6.281 VMD had a similar view. Dr Little suggested to NOAH on 21 February that the Southwood Report had so far turned out to be a damp squib ⁴ and Mr Kidd told us in his statement how

manufacturers were advised to change the sources of supply of bovine and ovine materials as quickly as possible, where necessary, to minimise the risk of contamination of products. However, manufacturers were allowed to exhaust existing stocks as the Southwood Report and the VPC and CVL specialists in BSE had considered that the risk of BSE transmission by medicinal products appeared remote. ⁵

6.282 The mixed messages on urgency clearly influenced the attitude of the two Departments. Reassurance that action was purely precautionary and that the guidance was a 'gold standard' must also have influenced the manufacturers whose cooperation and action were needed.

The response by the Licensing Authorities

6.283 We turn now to consider, in the light of these factors, the action taken on veterinary products by VMD, on human medicinal products by the MCA and on medical devices and other matters by PD/STD.

6.284 Given all the background considerations, the way Departments were organised and the message, we do not think individuals are to be criticised for their handling of the response. Each decision taken, viewed in the circumstances of the time, was reasonable. However, unfortunately overall they contributed to a lengthy process, particularly in the case of some vaccines.

6.285 We were and remain concerned about some general aspects of the arrangements that produced this outcome and the light that outcome shed on their weaknesses. It seems to us that some of these persist today. We conclude this chapter with comments on these matters.

1. The response on veterinary products

The basis for action

6.286 In theory MAFF already had a head start on veterinary products. Talks with manufacturers had begun in mid-1988 about draft guidance. NOAH had undertaken to provide information and the VPC had urgently reviewed bovine hormone products.

6.287 However, to keep in step with DH, and pending the findings of the Southwood Report, MAFF had reined back on its draft guidance and modified it somewhat. It now needed to pick up momentum again and secure action by the industry on the products of concern.

Whose job was this?

6.288 It was not the role of the BSE Working Group to advise on veterinary medicinal products, as Professor Collee made plain at its first meeting. ⁶ Expert advice on their safety continued to be the responsibility of the VPC. The VPC held only two discussions about the review, in September 1989 and December 1990. Otherwise matters were dealt with entirely by officials in VMD.

6.289 From August 1989, the lead on following up the questionnaire fell to Dr Aileen Lee, who headed the division responsible for biological products. She acted as VMD link with the BSEWG, attending all its meetings. Her function there appears to have been to report how matters stood on the veterinary products exercise, rather than to engage in discussion of BSE issues vis-à-vis veterinary medicinal products. Likewise she was asked to keep the Biologicals Committee of MAFF informed about progress. The BSEWG papers and discussions on human risk must have been of great assistance to her and to VMD in providing up-to-date material and opinions on risk as background to their own consideration of difficult items. ⁷

6.290 Dr Rutter told us that Dr Lee maintained contact with Mr Bradley and Mr Wilesmith of the CVL as information on BSE emerged. ⁸ We noted from their written statements that Dr Purves, Dr Adams and Mr Sloggem all looked to Mr Bradley throughout the period rather than to Dr Lee for informal handling advice, in particular in relation to international developments.

Securing action

6.291 The starting-point had to be adequate information about products using bovine material. The veterinary products industry had not yet delivered the details MAFF had asked for through NOAH, though discussions had begun with suppliers of biological materials to manufacturers.

6.292 The deadline of 1 May 1989 for all questionnaire returns from the 248 companies approached proved to be unduly optimistic. In the end the review exercise on veterinary products was no speedier than that on human products. The issue of existing stocks was dealt with on a case-by-case basis. Existing stocks were in some cases allowed to remain on the market until exhausted, although manufacturers were encouraged to replace these sooner. ⁹

6.293 As we noted in Chapter 5, MAFF had already tackled what it saw as the highest-risk item: hormone-based products. In July 1989, it was sent the MCA categorisation of risk. At the first BSEWG meeting in September, when this list was discussed and endorsed, Dr Lee reported that VMD was concentrating on products that could be identified as having a possible risk of BSE contamination. ¹⁰

6.294 We infer on the basis of various references in the papers we have seen that, as in human medicines, these were items containing brain and lymphoid tissue as ingredients, vaccines and sutures, and that VMD followed pari passu the line taken within the MCA. We were not, however, shown any contemporary VMD papers confirming this as a policy line.

6.295 What we did see were the successive reports that Dr Lee prepared for the BSEWG and her two reports to the VPC. These made clear the extent of effort going into letters, telephone calls and meetings chasing up non-responders and seeking further information where returns were inaccurate or incomplete. Unfortunately the reports and associated brief minutes lack details of the items of concern and their usage, the stocks in hand and the dates when these were eventually removed. But it is clear from the final report to the VPC in December 1990 that at least some veterinary vaccine stocks remained in use long after the guidelines were issued. The table at Annex 3 provides the most comprehensive picture, but it too lacks details of the stocks in hand and when they were eliminated. ¹¹

6.296 Should VMD have secured speedier results and taken a tougher line on stocks? Transmission between animals via contaminated medication was a direct and obvious risk and the risk of a vaccine scare with life-threatening consequences did not hold the same force as with human medication. However, VMD believed that the Southwood message was that risk through medicines was remote. Continuity of vaccine supplies was important because intensive farming methods created their own hazards. Non-validated alternative sources of supply of materials might hold other perils. Given what was known at the time, and the background considerations to which we have referred, we consider that its approach was reasonable.

6.297 One point that puzzled us in this story was the apparent tailing off after March 1989 of the earlier close liaison between VMD and NOAH on BSE. It did not appear that VMD sought to enlist NOAH's assistance in pressing manufacturers to comply swiftly with the guidelines.

6.298 When in July NOAH raised with VMD some of its members' difficulties over the guidelines, VMD advised it that comments would be useful and were best addressed to DH as it had 'fronted the exercise'. This too was surprising. NOAH was 'its' trade association for consultation purposes and it seemed to us that MAFF was in a better position than DH (or, as it turned out, the BSEWG) to discuss practical problems with 'clean' sourcing and harvesting of animal material.

6.299 We draw attention to this aspect of events because other factors in the BSE story suggest that working together with trade associations can be an efficient and effective approach.

Our general conclusion on the handling of veterinary medicines

6.300 We concluded it was not unreasonable of VMD to pace and match its efforts with those of the MCA. As was demonstrated in the disagreement that arose over Dr Lee's paper to the Royal Society of Medicine, the line had been firmly established at the beginning of 1989 that animal medicines should take their cue from the handling of human medicines.

6.301 That said, we think it was unfortunate that playing second fiddle was one of the factors that led to a less urgent and decisive approach, in particular in respect of existing stocks, than was originally contemplated. This was a contrary outcome. We are in no doubt that a further factor was the falsely reassuring messages that the Southwood Report and the CSM statement were perceived to convey. The overall impact on BSE from veterinary medicines may never be known. It is impossible to say today whether continued use of bovine-based medication may have added to the total of cattle born after the ban on ruminant feed of 18 July 1988 that developed BSE (BABs).

2. The response on human medicinal products

The basis for action

6.302 The three factors we have identified as bearing on MAFF - handling uncertainty, the management context and perceptions of risk - applied with equal force to DH. Over and above that, some of the problems facing MAFF in managing the exercise were writ even larger in DH, in particular:

1. the volume of products for review was much greater and the backlogs of work were worse;
2. the organisational arrangements, both in terms of officials involved and of committees, were more complex; and
3. supplies of products regarded as vital to individual humans' immediate health and survival (insulin, sutures) had to be maintained while alternatives were sought.

6.303 The MCA did not have the advantage MAFF enjoyed of several months' prior contact with producers about the draft guidelines. However, it seems to us that it was not starting entirely cold.

1. Some firms making human medicinal products were also involved in products for veterinary use and would have been alerted on their MAFF grapevine.
2. The February ring-around about children's vaccines, which we referred to in Chapter 4, would have placed manufacturers on high alert.

6.304 The MCA now had to collect in, as speedily as possible, the information it needed not only in the interests of medicines safety generally, but also to resolve the difficult and politically charged issue of risk through the vaccination programme, which had been left hanging fire.

Whose job was this?

6.305 Although Dr Keith Jones had taken over from Dr Gerald Jones when the MCA was established in April 1989, he told us the triple reporting arrangements and structures were left unchanged for some time. ¹² It was 'business as before'. It remained the case that no branch was actually in the lead on BSE within the newly established MCA.

6.306 Various witnesses referred to a team effort. We accept this as a valid description of some of the joint pieces of work and preparation of papers that were put in hand. However, teamwork does not just happen. It needs a leader to prescribe what it is expected to achieve overall and who is to do what and by when. There were both significant processing and judgemental matters to be managed.

The impact of the MCA on handling

6.307 Dr Jefferys told us: 'Considerable resource and attention was directed during the second half of 1988 and the whole of 1989 to the introduction and establishment of the new Medicines Control Agency from the former Medicines Division.' ¹³ Mr Hagger told us the division of work became known from about August 1989 and began to influence working arrangements from then. In about February 1990, senior staff started to run shadow businesses as precursors to the distinct MCA organisation.

6.308 Dr Jefferys became head of the new Business A, Licensing, which led on BSE issues. ¹⁴ In his new post Dr Jefferys maintained and added to his former MB3A role. He took over responsibility for Mr Bewley's CSM secretariat branch, in addition to maintaining his role on the CSM and BSC. ¹⁵

6.309 Mr Hagger was initially given a lead role in Business E, Executive Support, but in May 1990 he moved to head Business B, Abridged Licensing. Thereafter he 'became more detached in relation to the work being done on BSE' save in respect of the CDSM and as line manager for Dr Raine. ¹⁶ Business B did, however, provide some clerical support to Business A, including the administrative secretary of the BSEWG, Mrs Shersby.

6.310 As discussed below, the BSEWG was the key adviser to the CSM and other committees during this period. Mr Hagger told us that Business A would have had primary responsibility for the lead in relation to the BSEWG, although in planning the agenda for such a meeting Business A would have consulted with Business B. ¹⁷

6.311 It appears some confusion reigned during all these changes. Mr Hagger told us he continued to get many papers because the directory was out of date, and he was a 'familiar name' and 'the point of contact in Medicines Division/MCA rather than specifically for my input'. ¹⁸ He passed them on as appropriate. 'The ethos of the Division was such that one continued to provide advisory support if need be to those who might be new to a particular area of responsibility.' ¹⁹ Dr Purves told us that at the end of 1990 an administrative group was set up to assist in liaison on BSE between the different Departments, and more particularly to circulate relevant papers. ²⁰

6.312 Later, when the focus moved to the EC, with the preparation of European guidelines, the brunt of the DH action was borne by Dr Purves and Mr Sloggem. Together with Dr Rotblat they had been involved throughout in advising on biological products in respect of BSE, first in the 'triple-line' arrangement of Medicines Division and then, from 1990, in the Biological Unit, as part of Dr Jefferys's Business A in the reorganised MCA.

Identifying and following up the risk products

6.313 The MCA, like VMD, quickly found that obtaining full responses to 4,000 letters by May 1989 was impossible. The paper for the BSEWG prepared by the MCA in June to rank risk products was a useful and timely framework for setting priorities. However, it did not discuss timing.

6.314 As Mr Burton's minute of 2 June 1989 flagged up, collecting the data was not the only problem. The MCA had resource problems over organising and analysing the data. ²¹ For these reasons they postponed the first meeting of BSEWG until September. We did not explore with witnesses how practicable it would have been to stick to the original July date and thus move things along rather faster. It did strike us, however, that there might have been things to discuss even at this stage of the exercise.

6.315 The paper on risk categorisation gave the 'initial steer' to the new Working Group, both about matters where its expert opinion was needed and about the style with which the exercise was to be pursued. It quoted the Southwood Report findings, 'the risk to man via medicinal products is remote' and added its own gloss: 'it is important not to undermine this considered advice by demanding unnecessary assurances and information from manufacturers'. ²²

6.316 This bore particularly on the difficult question of items still in production or held as stocks - postponed in February until more was known. As discussed in Chapter 5, the overwhelming opinion of the professionals at that time had been that on the basis of judging between two evils, existing products and stocks should not be immediately withdrawn. As Dr Schild, Director of NIBSC, put it in his statement to us:

The risk posed by bovine materials to humans was entirely theoretical at the time; the risk posed to the public by the withdrawal of vaccines from the market was, on the other hand, a real one. ²³

6.317 However, the corollary was that injectable medicines derived from suspect bovine material should be replaced as soon as possible. This was already being forgotten.

6.318 The statement in the paper for the BSEWG carried that process a stage further in intimating that there should not be excessive pressure on manufacturers to reply to the questionnaire and to conform.

The role of the BSEWG

6.319 We were particularly interested in the role played by the BSEWG and how it influenced decision-taking within the MCA on human medicines. As the chronology shows, it held four important meetings in 1989-90 to discuss the line to be taken on existing products using bovine material.

6.320 The Working Group's role was purely advisory. It had no powers to make binding decisions nor any kind of executive role. The members were busy people with many other responsibilities. Information gathering and negotiations with manufacturers rested with officials who proposed the BSEWG's agendas and prepared its discussion papers with recommendations. The main problem for all the advisory committees was to avoid overload with what the Cunliffe Report described as the norm for the VPC:

unconscionable quantities of paper which it would be impossible to read in entirety in the time available. ²⁴

6.321 The BSEWG was a somewhat unusual committee. It was common practice to have cross-membership of the key advisory committees. Dr Purves told us 'it ensured there was consistency of approach among the different organisations'. ²⁵ However, in this case the powerful membership included the chairmen of the CSM, CRM, CDSM and JCVI. It also included Dr Tyrrell and three members of SEAC. The full list of members and observers is at Annex 1.

6.322 Because of its membership, endorsement by the section 4 committees of its recommendations was virtually guaranteed. The complexity and difficulty of the subject matter added to the likelihood of this.

6.323 There were obvious merits in this arrangement. It directly drew on knowledge from experts who were advising government in other capacities, notably Dr Taylor, Dr Kimberlin, Dr Will and Dr Schild. It also fostered shared understanding of issues and concerns, and speedy communication of recommendations between all the committees reviewing the use of bovine materials in medicinal products. This was valuable because official minutes tend to be economical and discreet in what they record and can take some time to circulate.

6.324 There were, however, risks associated with a working group composed in this way. It was in effect a powerful network for delivering its own decisions. Its findings were not being assessed by the committees to which it reported in quite the arms-length way it might appear. Important alternative perspectives and views might be lost.

6.325 It seemed to us that, despite these risks, the BSEWG was an effective device for securing a coordinated approach and quickly sharing information between the various DH advisory committees and beyond that, the VPC. It provided for officials a convenient collective expert view on priorities, risks and possible solutions, and valuable backing for action.

6.326 However, responsibility for collecting and analysing information and deciding when to seek the Working Group's advice, then following that up with pressure to conform, all lay with officials. As we have seen, their first paper had signalled that dealings with manufacturers were going to be handled with a light touch, in order not to undermine the Southwood Working Party's advice.

6.327 The Working Group recommended at its meeting that non-complying companies should be encouraged to comply as soon as possible, but left it to the Licensing Authority, ie, officials, to agree the timescale 'for each individual product as appropriate'. No overall time horizon for replacing all existing risk material, other than 'as soon as possible', appears to have been urged by it. ²⁶

6.328 We examined what happened on the three most sensitive groups of products: (i) those derived from brain and other high-risk material, (ii) sutures and (iii) vaccines.

(i.) How high-risk products were handled

6.329 The March guidance had been categorical that no brain and other high-risk material was to be used. The questionnaires were eventually to demonstrate little current use of these as direct constituents of medicines. We noted that the Working Group immediately recommended (and CSM endorsed) modifying the original guidance to permit the use of materials from outside the British Isles. The formal guidelines were never publicly changed to reflect this (and were overtaken by European guidelines in 1992). However, the change must have informed the way officials dealt with existing licences. This BSEWG advice, by offering manufacturers an alternative to totally changing their formulation, would have enabled clean stocks to be produced more quickly.

6.330 We thought the response on high-risk products was adequate. Only two groups of products caused concern. The first of these, a range of homoeopathic products, was quickly identified as being sourced from Germany and the CRM considered that no further action was necessary as the products complied with the BSEWG's recommendations.

6.331 The second group was a range of allergens. The BSEWG advised that a changeover to Australasian sources should be insisted upon. Discussions with the manufacturer were continuing at the time of the BSEWG meeting in July 1990 and a report was promised for the subsequent meeting. The report presented to the October 1990 meeting confirmed that the manufacturer had now made satisfactory progress in complying with the guidelines.

6.332 As we saw in Chapter 4, bovine insulin was identified at the CMO's meeting with MAFF in March 1988 as potentially a high-risk product: it contained bovine material as an active ingredient and was administered by injection. Dr Rotblat and Dr Purves listed 42 licensed bovine insulin products in their September 1988 paper. ²⁷ However, no insulin product featured among the products upon which the BSEWG's advice was sought following the responses to the questionnaire. We inferred from this that none of the products used UK sourced bovine insulin. This appeared to be confirmed when the safety of bovine insulin was raised with the MCA in March 1990 by the British Diabetic Association. In his reply at the end of April, Dr Jefferys stated that manufacturers of bovine insulin had responded to the request for information and added, 'There are no bovine insulins sourced from cattle in the UK or Ireland.' ²⁸

(ii.) How absorbable sutures were handled

6.333 These were a widely used and essential surgical material implanted into patients. Because they were obtained from intestines where lymphoid tissue was located, they were ranked as medium risk.

6.334 As we noted in the chronology, since June 1989 ways of complying with the guidelines had been under discussion between the CDSM team in the MCA and the major UK manufacturer whose licence was due for renewal. A detailed paper was presented to the BSEWG in September 1989, setting out the company's proposals in the short and long terms. ²⁹

6.335 The BSEWG did not find this a straightforward matter, and there was evidently a considerable divergence of views. Professor Collee told us of his personal concern about the use of catgut in neurosurgery, which led him to add a chairman's note to the meeting minutes about the minority view that such use should not take place. ³⁰ We could well understand that concern, based, as Professor Collee's note said, on logic and scientific consistency.

6.336 Of the three reasons for the majority view recorded in the BSEWG minutes, the first two did not seem to us to be compelling. The first reason, the fact that the use of ovine sutures had not caused CJD, was not an answer; it could not be assumed that BSE would behave like scrapie, and the other action taken by the Government recognised that. The second argument, namely that the material was seldom used in neurosurgery, suggests that a ban would not have caused any great practical difficulty, and was no reason for failing to act in the small number of cases where the risk might in practice arise. The third reason, not dmaging the public perception of the safety of other bovine products, was in reality a judgement about presentation, not the merits of the case. It was interesting in demonstrating the continuing preoccupation with avoiding public doubts about bovine products, including among doctors. ³¹

6.337 We have noted the further reason identified by Professor Berry, Chairman of the CDSM, which subsequently endorsed the BSEWG advice, namely that the selection of materials other than those established by clinical experience could expose patients to hazards greater than those posed by catgut. ³²

6.338 In the light of what was known at the time and the difficulty of quickly finding the huge quantities of material from a reliable long-term source elsewhere, we consider that the experts' recommendations on sutures for general use were reasonable. On the specific question of continuing use in neurosurgery, there was an issue of judgement as to whether the increased risk warranted a different course of action. The issue was not easy; witness the split in views. We do not criticise the judgement that was made at the time, although with hindsight it might have been preferable if the minority view had prevailed.

6.339 Clearly Ethicon made energetic efforts to comply with the guidelines. It ceased to use UK sourced bovine material in November 1989, and by June 1990, 100 per cent of the material it supplied to the UK market was sourced from Australasia.

6.340 As with insulin, we note that there is so far no evidence that neurosurgery using these sutures figured in the history of any of the vCJD victims. Given that introduction into the brain is normally a speedy route for disease transmission, we take the absence of such cases as a hopeful sign that the continued availability of these sutures until June 1990 had no adverse consequences.

(iii.) Vaccines

6.341 The third and most difficult category, making up most of the products of concern, were vaccines. Vaccines were used to prevent a wide range of childhood diseases such as mumps, measles, diphtheria and whooping cough, as well as more exotic diseases.

6.342 As we discussed in Chapter 5, the fear that withdrawal of existing products, or warnings about them, might undermine the national vaccination programme for children had been the main factor in the decision to play matters low key and to allow production and use of existing stocks to continue. We noted that the issue was not the deliberate inclusion of material in the finished product, but the effects of its use as a medium to nourish the growth of cells that in turn would produce an antigen or virus for the vaccine.

6.343 One problem was lack of information; were the growth media infective, and if so was there a possibility that infective material might be present in the finished product despite the 'washing' and other production processes? The only way to resolve this was through transmission experiments. The NIBSC seminar in 1988 had identified a need for studies of foetal calf serum, ³³ but these do not appear to have been undertaken. The NIBSC interest in doing research work on this was dropped for a number of reasons. ³⁴ The subject was also raised in a recommendation of the Tyrrell Committee Interim Report about studies of infectivity of bovine serum albumin, foetal calf serum and other media using bovine material. ³⁵ We discuss in Chapter 7 how that proposal fared. It was not until 1993 that the results of work at the NPU into the infectivity of bovine serum were reported. These results proved negative. ³⁶

6.344 The BSEWG therefore had no firm evidence about infectivity to help it decide what to recommend when considering the four vaccines identified by Dr Rotblat from the questionnaire responses as giving cause for concern. It discussed the problem at its second meeting in terms of 'the hazard-to-benefit ratio'. This was a purely pragmatic judgement on the familiar lines that the benefits from the vaccination programme outweighed the theoretical risk from BSE. It indicated that negotiations should take place to ensure that sources were changed as soon as possible and to replace existing stocks with new material whenever feasible. ³⁷

6.345 By its third meeting in June 1990, Professor Collee, in an effort to obtain some firm evidence, had contacted Dr Taylor of the NPU, who was himself a member of the Working Group. In his statement, Professor Collee told us the BSEWG discussed these materials in great detail and concluded the risk could be described as very remote rather than merely remote. ³⁸ One of the Working Group members, Dr Schild, head of the NIBSC, which sets standards for and tests biological products, told us in his statement that calf serum was and still is considered a very low-risk material. ³⁹

6.346 These reassuring views must have formed the context in which the BSEWG assessed reports at that meeting about the protracted process of establishing 'clean' stocks of the four vaccines that did not comply with the guidelines. As is evident from the chronology, it looked at the position on each of those products in detail, allowing in some cases a certain latitude, depending on considerations such as the availability of alternatives and the nature of the material used. However, as time passed, its attitude hardened about allowing more time. By November 1990, Professor Collee was telling CSM that it was unreasonable to allow vaccines associated with UK bovine products to be used when they could be replaced with new batches. The BSEWG line of advice was hardening and he wanted CSM 'to count me amongst the hawks on this'. ⁴⁰

6.347 As we indicated above, viewed in the circumstances of the time, which we have explored in this volume, the decisions taken about these four vaccines were reasonable ones. However, it can be seen with the benefit of hindsight that they contributed, overall, to a protracted process of achieving compliance with the guidelines.

Our general conclusions on the handling of human medicines

6.348 It seems to us that taken case by case, the 'flexible response' was reasonable. The consequence overall, however, was that existing stocks of some products may have been used until late 1991 and possibly longer. It seems highly unlikely that so long a period of grace was what those who took the decision not to require an immediate withdrawal of stocks had in mind. A key factor, as in veterinary medicines, was the perception shared by MCA staff and BSEWG members alike that the risk was remote. The urgency of removing existing products had become forgotten. Instead, perversely, the reassuring message about low risk undermined the action necessary to achieve it.

6.349 However, the lack of urgency also seemed in part attributable to the somewhat chaotic state of affairs in the MCA already discussed. The reorganisation into businesses added to the turmoil and, as Mr Sloggem and Dr Purves discovered in 1994, the black hole continued in the management of its data system. All this contributed to poor accountability in the arrangements being operated. ⁴¹

6.350 Matters were being dealt with by a range of different people ad hoc in competition with a great deal of other work. There does not appear to have been an overall management strategy. Officials were seeking views where and when they judged it helpful, but this was obligatory only where sanctions were envisaged, not where latitude was being extended. The pace of action was in their hands.

6.351 The progress reports to the BSEWG appear to be the only form of accountability for progress, and these, as we have seen, were vague on many details. Moreover, the BSEWG was their adviser, not their manager. Because of the closed nature of medicines licensing and the earlier decision to keep as low a profile as possible, there was no external pressure on officials or on companies to defend the slow speed at which matters were moving. We discuss at the end of this chapter some general questions this raised about accountability for medicines matters.

3. The response on medical devices and other matters

The basis for action

6.352 As noted, our interest here was in what were, at the time, unlicensed medical devices. Items to be considered included biological heart valves, bone grafts, disposable products including devices coated with gelatine and heparin, and dressings and adhesives. Even without licensing, the NHS as main purchaser could exert powerful influence on suppliers. This was important because the BSEWG placed tissue implants, open wound dressings, surgical materials and dental and ophthalmic products among the high-risk categories requiring action.

6.353 As noted in Chapter 5, the interest of the relevant DH division, PD/STD, was only belatedly recognised in February 1989. Once that happened those concerned did not allow any grass to grow under their feet. Having read the Southwood Report and collected material on spongiform encephalopathies, they searched their database, reviewed product licences held by the Secretary of State, and decided to mirror the guidance, questionnaires and the letters of the MCA and VMD. Their documents were speedily prepared, and despatched only days after the those of the MCA and VMD. Though only a relatively small number of products and users were involved, none the less the exercise required 330 letters. They also wrote to NHS regional pharmaceutical staff. They are to be commended for this speedy response.

Whose job was it to take action?

6.354 PD/STD showed no reluctance over providing a lead within their triumvirate of pharmacists, doctors and administrators. Miss Duncan, the pharmacist head of Safety and Quality, STD, immediately cleared a line with Dr Metters about action and followed this up. ⁴²

6.355 One of her staff, Mr Will Burton, both advised the NHS on pharmaceutical supplies and did audit work for the Manufacturers' Registration Scheme (MRS) for medical devices. He quickly became the liaison officer between PD and the MCA on BSE, keeping the administrative section informed. We were greatly assisted in our examination of what was done, not only by the statements and documents we received, but also by the careful and detailed support notes supplied by Mr Burton.

Securing action

6.356 It was agreed from the start that the policy line would follow that of Medicines Division (ie, the MCA) as having the overwhelming interest. This affected what followed both in the interpretation of the guidelines and the timing of action.

6.357 As with VMD and the MCA, it proved difficult to secure a 100 per cent response or an accurate one, and PD/STD had to spend months chasing up with letters, telephone calls and successive reminders. However, by 24 November 1989 all the manufacturers had replied. ⁴³

6.358 PD/STD identified two heart valve manufacturers whose products gave particular cause for concern. It met the companies more than once and told us: 'the companies were left in no doubt . . . that their compliance with the guidelines was required.' ⁴⁴ By 26 January 1990 one had complied with the guidelines. The other ceased production at the end of April 1990 because of the expense of alternatives, and at this stage recalled devices on the shelves. ⁴⁵ Thus the timescale for compliance was, in the end, similar to that for sutures.

6.359 We were impressed by PD/STD's administrative approach, as demonstrated by the documentary evidence. In particular, it set a series of deadlines for different activities; it promptly opened up discussions with known users of bovine products and sought to identify other possible users; it chased to get responses; and it set up a database and arranged for audit check results to be placed on it and for it to be continuously updated.

6.360 It also prepared a draft paper on control of harvesting techniques, designed to reduce risk of contamination, and set out how manufacturers should go about obtaining animal material for use in medical devices.

6.361 To coordinate all this action within its sphere of responsibility, it set up an STD BSE working party of officials. Mr Burton described it as a 'project team constituted especially for the purpose from those with the appropriate experience or expertise required to contribute to it'. ⁴⁶ The group met regularly to monitor and progress matters and to share information. Reading the records of matters it discussed suggests it was an efficient arrangement.

6.362 Mr Burton told us that from the time they got involved, he and his colleagues considered that the risk of transmission might be potentially serious. ⁴⁷ From the papers we saw they appeared to have been held back by the tempo of the exercise as a whole and the need to pace themselves with the MCA and advisory committees. ⁴⁸

6.363 None the less, as agreed initially they faithfully followed that lead and modelled their actions accordingly. In doing so they were following what they saw as the prescribed low-key approach.

Our general conclusions on the handling of medical devices

6.364 We recognise that the response required from PD/STD was altogether on a much smaller and more manageable scale than that required of the MCA and VMD. Moreover, the Division did not appear to be labouring under such difficult management and resource problems. None the less, PD/STD's response illustrates an administrative approach that, had it been mirrored by the MCA and VMD, might have led to a brisker momentum in the important task of phasing out suspect products.

4. Our general conclusions on follow-up to the guidelines

What was handled well

6.365 Many things were done well in the follow-up to the guidelines. In particular:

1. The comprehensive questionnaire approach was a heroic venture to make good the deficiencies in both Departments' databanks and to bridge the gap between the different sorts of licence in existence.
2. Despite their perception that the authoritative view now was that the risk from medicines was remote and action purely precautionary, officials worked diligently to carry the follow-up action to its conclusion.
3. The most urgent items were identified and dealt with promptly.
4. They successfully achieved the switch-over voluntarily through their case-by-case approach, despite having no evidence to offer of human risk.
5. They did so while struggling with the legacy of serious past failings in the running of the licensing system that were still in process of being addressed.

Where there was room for improvement

6.366 As we have noted, these endeavours added up to a long-drawn-out process on some items, including some vaccines. There is no means now of finding out whether those products were infective, nor of knowing how many people they were used on. Certainly large numbers of people are vaccinated annually as part of the vaccination programme or prior to overseas travel. Knowing what is now known, a harder line might have been taken, and the window during which people were exposed to potential risk might have been some months or even years shorter.

6.367 One of the main causes of delay was that the Departments believed their own reassuring message. Their overwhelming concern was to avoid a greater public health risk through a vaccine scare. Instead of seeing this as the reason why so reassuring a public line had been taken, they came to believe their own upbeat presentation as a justification for relaxing their efforts. This was only one, but perhaps the most glaring, example throughout the whole of the handling of BSE where the wish to put the best face on things misled the very people whose understanding and efforts were needed to create the necessary conditions of safety.

6.368 Even within the blinkers of the false impression on risk, there was undoubtedly room for improvement in the way the guidelines were followed up. We think it would have been better if:

1. There had been a handling plan that 'managed' the whole process to specific deadlines. This would have required leadership from DH whose priorities determined the overall approach. Ideally this would have happened as soon as the exercise was launched. Alternatively, it might have followed the first meeting of the BSEWG when the criteria were agreed and the measure of the problem was clear. It is a pity that Mr Love's proposals in October for a coordinated approach with clear responsibilities were not followed up. ⁴⁹ This was an opportunity lost.
2. There had been clear expectations about reporting to top management and Ministers. We were struck by how little Ministers were informed, let alone consulted, about the massive administrative exercise of following up the guidelines. Dr Jefferys told us that 'Ministers never provided officials with criteria to apply when considering which matters to refer to Ministers. Officials had to apply their own judgement when deciding what matters to refer to Ministers.' ⁵⁰ We believe that Ministers should take a lively interest in what is being done in their name, and that there should be clear presentation to them of important policy decisions.

5. General conclusions on medicines and BSE

6.369 It was not part of our remit to carry out a review of the question of medicines licensing at the time and the soundness of its principles. In considering some general conclusions, we thought the view of Mr Cunliffe in 1988 when he reviewed the veterinary medicines licensing system provided a useful pointer on how the handling of BSE might be assessed:

The general outline of the UK system ie, a licensing office taking advice from an independent expert body and reporting to the Minister, seems to be correct. The present arrangements allow and, must continue to allow, licensing decisions to be made on science based and defensible judgements about the balance of risk and benefits without undue pressure from industry, politicians, MAFF or Treasury. ⁵¹

6.370 We have commented above on the importance of 'reporting to the Minister'. Mr Cunliffe's assessment also refers to other key elements.

(i.) Science-based judgements and the role of committees

6.371 Mr Cunliffe was of the view that licensing decisions were and should continue to be 'made on science based and defensible judgements about the balance of risk and benefits'. It seemed to us that the way that 'risk and benefit' calculations were done on medicines matters where BSE was concerned often owed much more to judgement than to science. The memorandum which DH supplied on risk assessment reinforced this view. ⁵²

6.372 For BSE it was indeed a matter of exercising judgement given the lack of firm scientific evidence. It is not necessarily a bad thing that expert committees should be asked to perform this task, provided that it is clear that is what they are doing. The discussion on sutures was an interesting example of this. We noted that the BSEWG, like the section 4 committees, took into account not only the technical assessments officials provided, but also more pragmatic considerations. Balancing risks about public concern with scientific risks is effectively making a policy judgement. The earlier advice of Professor Collee to the JCVI that the risk from vaccines had been considered by the HVMBG to be remote and speculative, and very much outweighed by the benefits was another example of a value judgement. It was important that the section 4 committees and subsequently MCA officials should be clear about what was a scientific assessment, and what was a value judgement, so that value judgements were not treated as expert assessments of risk. Who was advising whom? It was for the section 4 committees to advise but for Ministers, sometimes acting through officials, to decide.

6.373 This is a general issue about advisory committees that we discuss further in vol. 1: Findings and Conclusions. It is further complicated by other features we have noted such as the cross-membership of committees and the risk that this can create a hidden decision-taking mechanism.

(ii.) Insulation from pressure versus accountability

6.374 Mr Cunliffe also said that those taking decisions must avoid undue pressure from 'industry, politicians, MAFF or Treasury'. The advisory committee system is one of the devices designed to fulfil that purpose. Another is the deliberate ring-fencing of medicines licensing business from the rest of the work of DH and MAFF. As one witness put it, 'Medicines Division consumes its own smoke.' ⁵³ There are respectable reasons for this. A frequent accusation against MAFF was that it acted in the interests of the food industry or farmers rather than of consumers. It was to help create a visible separation between these interests that Mr Gummer initiated the major restructuring of MAFF commands in 1989. Medicines licensing for animals or humans needed to be seen as dispassionate and striking a fair balance.

6.375 The problem with this ring-fencing is that, coupled with the advisory committee system, it reduces the normal accountability of officials taking decisions on Ministers' behalf. The risk is that those outside the unit concerned may be reluctant to question the competence, speed and judgement of the work of those within it.

6.376 This is exacerbated by the culture of secrecy associated with the provisions of the Medicines Act about non-disclosure of commercially sensitive information. We agree with Mr Cunliffe's comment: 'more openness in factors affecting human safety and animal health would instil greater public confidence.' ⁵⁴

6.377 We commend the moves made by the VPC during this period to put more matters in the public domain by publishing documents. ⁵⁵ However, this was only a partial step in that direction.

6.378 Another factor that appears to have left Ministers and senior management in DH in difficulties about accurately tracing and reviewing past actions was defects and gaps in DH record-keeping, ranging from destruction of ministerial papers to the dismal history of its medicines IT system.

6.379 We think it is important that there should be properly reasoned and recorded decision-taking, and that the criteria being applied are made openly available. It should be made plain by whom decisions are actually taken and the basis for these, both on general policy matters and on individual items. And as we have said, important decisions should be validated by Ministers.

(iii.) Liaison between MAFF and DH on medicines

6.380 We discuss in detail in Chapter 4 the question of liaison between MAFF and DH on BSE and medicines. While we expected to find a degree of inter-departmental remoteness, we were surprised at the distance of the gap on medicines policy matters.

6.381 Topics that might have benefited from structured discussions between the two Licensing Agencies in order to establish consistent policies include the SBO Order; testing of sera and other pharmaceutical products for infectivity; testing of stored BSE cattle organs of the type used for implants; identifying and tracking 'clean' herds and animals for pharmaceutical use; post-mortem testing of such cattle; organ harvesting and avoidance of contamination; gelatine and tallow.

(iv.) Where medical materials come from

6.382 A number of these topics concerned the source of medical materials. One of the matters that clearly emerged from the response of the MCA and its committees to BSE was the absence of even rudimentary knowledge about how pharmaceutical materials were obtained from animals, and techniques to ensure they were not contaminated in any way. Some of the pharmaceutical manufacturers themselves appear to have been equally uninformed, since they relied on intermediaries to provide them with their raw materials. Thus one manufacturer told us:

The sourcing and processing of these materials is the work of suppliers one or more steps 'upstream' from a pharmaceutical company such as [Glaxo Wellcome]. For our company, the details of such activities were traditionally of little concern so long as the substance in question passed regulatory specification tests. ⁵⁶

6.383 Even less appears to have been known by some of those advising on biological products. Professor Campbell, Chairman of the JCVI from 1989 to 1996, told us:

For my own part, I had no detailed knowledge about the way in which vaccines were manufactured. Although I was aware that bovine material was used in the manufacture of vaccines, I had no knowledge of the extent of its usage apart from what I learned at meetings of the BSE Working Group. ⁵⁷

6.384 This was an important knowledge gap among those responding to BSE since the fundamental basis of the UK, and later the European and WHO, approach to both animal and human medicinal products was that clean sources were the only way forward. NIBSC had foreshadowed this in 1988:

If BSE is held to be a problem, the only option is to ensure that bovine materials for manufacture of biological medical products are derived from cattle free from the disease. ⁵⁸

6.385 We noted that concerns about its limited knowledge cropped up repeatedly in the BSEWG. It seems to us that thought should be given to ensuring that those dealing with medicinal products deriving from animals are informed about the sources and collection of materials.

(v.) The legislative framework

6.386 Our review of medicines and BSE highlighted the difference between the legislative framework for medicines and that in other areas.

6.387 Where medicines are concerned, unlike the situation on suspected animal contamination of food, it is not possible to turn off the tap at source by destroying the animal or its products. Hence the SBO ban applied to food but not pharmaceuticals. Instead each manufacturer has to validate the legality and safety of its ingredients. Mr Lawrence recognised this and noted in his briefing material to Ministers in February 1989 that manufacturers would need to secure appropriate assurances from their suppliers. ⁵⁹

6.388 It might have been helpful if the legislative powers available to cut off diseased animals or their contaminated products at source, so that they never entered the food chain, could also have been used to ensure they were not available for medicinal purposes. Manufacturers who purchased material from suppliers might have welcomed such action, which could have saved them many later problems over provenance and certification requirements, in particular for products that were not in their original raw state. It could also have dealt with products that were not covered by the Medicines Act.

6.389 We recognise that there are different considerations in play, and that much is dictated by relevant European legislation. However, the different frameworks make it more difficult to achieve a consistent approach. The most glaringly anomalous outcome was the ban on the use of intestines for food purposes while intestines might still be used for sutures - thought to be a higher-risk route of infection.

6.390 We think the current variety of different powers over animal health, food safety, medicines and other products should be reviewed to ensure that they offer a means of consistent and prompt action in future when an infected product needs urgently to be removed from circulation.