Volume 1: Findings and Conclusions
7. Medicines and cosmetics
Phase 3: implementing the guidelines after March 1989
The context for handling matters
Collecting and analysing the information
The SBO ban and pharmaceuticals
How the BSEWG operated
First meeting of the BSEWG on 6 September 1989
Second meeting of the BSEWG on 10 January 1990
Third meeting of the BSEWG on 4 July 1990
Fourth meeting of the BSEWG on 31 October 1990
Final meeting of the BSEWG in July 1992

937 We look now at the third phase of action and one that has attracted great public interest. When they put the guidelines to the CSM for approval in February, officials had emphasised that they were practicable and capable of being implemented over as short a time period as possible. They now had to ensure this happened. They also had to deal with the matter of existing stocks, on which they had undertaken to come back to the CSM. Were these tasks carried out adequately for both human and veterinary medicines?

The context for handling matters

938 Before we trace the way in which DH and MAFF respectively carried out these tasks over the years that followed, we draw attention to two significant changes that took place in the context in which they were acting.

939 The first was the reorganisation of the administrative arrangements for handling licensing that we have already touched on, in order to create Executive Agencies. Preparatory changes were made in 1989 with the redesignation of MD as the MCA and the appointment of a new head from outside the public sector, Dr Keith Jones. This was paralleled by the appointment of Dr James Rutter as the head of the newly constituted VMD. After a 'shadow' period, during which reporting lines remained much the same, the two Executive Agencies came into formal existence in 1991 and 1990 respectively. The Medical Devices Agency followed in 1994.

940 Although these new arrangements did not alter the way the medicines licensing system worked, they affected how officials were organised, their accounting lines and the performance standards they were expected to meet.

941 The second major change was increasing EU involvement in medicines matters and the handling of BSE risk. European guidelines on BSE and human medicines came into operation in May 1992 and closely similar ones on veterinary products a year later. In addition, the World Health Organisation offered a formal view in November 1991 that the careful sourcing of material was the best way of securing safety from the remote risk in medicinal products. The international dimension to medicines dominated the later years covered by this Report.

Collecting and analysing the information

942 The first step for both Departments was to collect the information asked for in the questionnaires issued in March. The date set for questionnaire returns was 1 May 1989, with a view to discussion at the first meeting of the newly constituted BSEWG in July. Six weeks proved far too short a deadline. It was to take many months of chasing to get in all the responses. The delay in getting returns collected and analysed meant that the first meeting of the BSEWG had to be postponed until September.

943 Meanwhile work continued within the MCA on analysing the responses. The different products were ranked according to risk, and MCA officials were asked to prepare papers on those falling in the three highest risk categories for consideration by the BSEWG when it met. We thought this was a sound approach. The ranking, which was influenced by Dr Kimberlin's views, and was subsequently adopted by the BSEWG, was as follows:

1. Injected products with bovine brain/lymphoid tissue as ingredients.
2. Injected products with bovine ingredients other than the above.
3. Tissue implants, open wound dressings, surgical materials, dental and ophthalmic products with bovine ingredients.
4. Topically administered products with bovine ingredients.
5. Orally administered products with bovine ingredients.
6. Products with other animal/insect/bird ingredients.
7. Products with materials produced from animal material by chemical processes, eg stearic acid, gelatine and lanolin.

The SBO ban and pharmaceuticals

944 Meanwhile, as we described earlier in this volume, action in MAFF was developing on another front. Mr MacGregor's decision to introduce an SBO ban had initially made DH nervous that this would awaken public concerns about pharmaceutical safety and thus threaten the vaccination programme. However, Sir Donald Acheson told us that, apart from this anxiety, DH welcomed the proposed measure as a step to protect human health. When MAFF set about defining the scope of the ban, DH became involved in the process. This was handled mainly by Dr Metters, who was Dr Harris's successor as Deputy Chief Medical Officer, and by Dr Pickles.

945 Dr Pickles quickly spotted that the list of risk tissues included some used for medicines and medical devices, such as intestines, spinal cord and thymus. However, the approach being adopted was that the SBO ban could not and should not apply to material used for pharmaceutical purposes. At a definitive MAFF meeting on 27 September 1989 about the scope of the ban, it was agreed that the Regulations 'were not the correct vehicle' for a ban on non-food items. This was consistent with the existing exemption for unfit meat sent to a manufacturing chemist, in the 1982 Meat (Sterilisation and Staining) Regulations. In November Ministers agreed with the advice put to them that the CSM/VPC guidelines already in place were the appropriate safeguard in relation to the use of SBO in medicines. Manufacturing chemists should therefore continue to be allowed to receive the unsterilised and unstained material.

946 We noted that when the question of this exemption came up again in March 1991, there was a further debate and the position changed. Mr Lawrence saw the exemption as 'rather anomalous' and argued that it should be removed. MAFF Ministers agreed with the proposal and the new Regulations in March 1992 removed the specific exemption for 'manufacturing chemists'. However, bovine material for pharmaceutical use may have continued to fall within the general exemption for premises used for the manufacture of products other than food.

947 This sequence of events highlighted the differences between the legislative frameworks for ensuring the safety of food and medicines.

948 We consider the legislative framework in Chapter 14, and examine there the extent of general statutory powers to ban the use of potentially hazardous bovine tissues for any purpose which might involve a risk to health, or even to destroy them. Differing legislative powers made it difficult to adopt a consistent approach to preventing the use of SBO in food, animal feed, medicines, medical devices and cosmetics.

949 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 in the case of BSE was the ban on the use of intestines for food purposes while they might still be used for sutures - thought to be a higher-risk route of infection.

How the BSEWG operated

950 The BSEWG was set up specifically to advise on the implications of BSE for human medicinal products. Its membership was high-powered. Chaired by Professor Collee, it included the chairmen of the section 4 committees it was advising, together with Dr Tyrrell, Dr Will and Dr Kimberlin of the Spongiform Encephalopathy Advisory Committee (SEAC) and Dr David Taylor of the NPU. Any conclusions it reached were therefore going to have great authority. However, it was purely advisory. It depended on the problematical cases and information about them being brought to its attention by officials, and on officials' subsequent action to follow matters up. Dr A Lee, an official in the VMD, was given the role of MAFF representative on the Working Group to maintain a link with the parallel action by the VMD. Altogether the BSEWG met five times between September 1989 and July 1992. These meetings provide convenient milestones, which we follow below.

First meeting of the BSEWG on 6 September 1989

951 At its first meeting the Working Group considered a list of products identified by officials from questionnaire returns and other data held. It agreed the ranking of risk categories proposed by the MCA and considered that the last four gave no cause for immediate concern. In respect of the first three it made four general recommendations to the effect that:

1. no action was needed where raw materials were sourced outside the British Isles in suitable conditions;
2. the guidelines should apply to material from the British Isles, and companies should be encouraged to comply as soon as possible. The timescale should be agreed for each individual product;
3. no licensing action should be taken at present on non-bovine materials; and
4. the licensing authority should follow scientific progress on BSE so as to be in a position to take future licensing action when necessary.

952 The second of these recommendations depended on officials offering the encouragement and deciding any timescales. One of the papers put to the BSEWG at this meeting gave some indication of their line of thinking about the way the exercise should be handled. It suggested that considerations to be taken into account included 'the findings of the Southwood report in which it was stated that "the risk to man of infection via medicinal products was remote". It is important not to undermine this considered advice by demanding unnecessary assurances and information from manufacturers.'

953 Officials in the VMD appear to have taken a similar view of the Southwood findings. Mr Alastair Kidd told us that manufacturers were advised to change sources of bovine materials as quickly as possible, where necessary, but 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. The VMD told us that this advice was not given generally - the use of existing stocks was considered on a case-by-case basis.

954 At the BSEWG meeting two types of product were identified as needing special consideration. On the first - some homeopathic medicines with Product Licences of Right - it was agreed that more information was needed. The CRM carried this matter forward and decided in November that no action was necessary.

955 On the second, surgical sutures, there was a difference of view within the Working Group. They had a substantial paper prepared by MCA officials before them. Discussions had been taking place for some months with the major UK manufacturer about interim measures that might be adopted while a switch was made to non-UK material. This was not a simple operation as 25 million metres of intestines were used annually. This represented 10 per cent of the annual cattle kill in Australia and nearly a quarter of the New Zealand kill. The upshot of the BSEWG discussion was that, although the company's plans for a general switchover (in the event begun in February 1990 and completed by the summer) were acceptable, a minority thought that the sutures should be excluded forthwith from neurosurgery, on which the company itself had envisaged offering a warning. Professor Collee was one of these.

The follow-up to the first meeting

956 The CDSM opted for the majority view on sutures at its meeting on 20 September, and the CSM at its 28 September meeting endorsed the BSEWG's general recommendations.

957 On 10 October Mr Murray Love, an administrator working in Mr David Hagger's division in MCA, minuted Dr Jefferys and others suggesting a way forward following the BSEWG meeting. The matters he raised were highly pertinent. They included telling firms what the BSEWG had said, timescales for the three high-risk categories, dealing with stockpiled products, and the need for a coordinated licensing authority approach with clear allocation of responsibility. This minute received a lukewarm response from Dr Jefferys, who had discussed it with Mr Hagger, Dr Adams and Dr Purves. Their view was that a meeting of the BSEWG should be arranged for January, and that an in-house procedure for writing to individual companies about products and setting timetables should be agreed. Dr Jefferys told us that the follow-up with companies lay with Mr Hagger's division. Mr Hagger's division, however, was already in the process of being deconstructed as part of the MCA reorganisation.

Second meeting of the BSEWG on 10 January 1990

958 The key issues on this second agenda were the state of play on the 1989 questionnaire and how to deal with products not complying with the guidelines, particularly the remaining four vaccines which by that stage did not comply.

959 Apart from these vaccines, the only products using high-risk materials were some allergens using bovine brain in their preparation, not as an ingredient. The Working Group wanted a tough line on these allergens. The licensing authority should insist on a changeover to Australasian material within a reasonable timescale. It was reported that discussions were still continuing at the time of the next BSEWG meeting in July 1990. In October 1990 officials reported that satisfactory progress had been made. We were unable to ascertain when a final outcome was obtained.

960 On vaccines, Dr Rotblat now had more concrete information than that obtained from her ring-around 11 months earlier. She identified four products, the first three of which were produced by Evans Medical and the fourth by Wellcome:

1. MMR (measles, mumps and rubella) vaccine with stocks to December 1990 - not yet licensed
2. Measles vaccine with stocks to September 1990 - not used much now
3. Tuberculin PPD with stocks to September 1991 - no other source available
4. DTP vaccines (diphtheria, tetanus, pertussis) with unadsorbed stocks to May 1991 and adsorbed to June 1990 - adsorbed used in preference to unadsorbed (not used much now).

961 The meeting decided that 'the benefits accruing from continuance of the vaccine programme outweighed the very remote risk to the population from the use of bovine material in these products'. The minutes go on to say:

It was considered after some discussion that negotiations should take place to ensure that sources are changed as soon as possible and to replace existing stocks with new material whenever feasible. Replacement of Wellcome unadsorbed DTP vaccine, by Wellcome adsorbed vaccine should ensure that the former, which is not much used, is replaced earlier than 1991. In the case of the Tuberculin PPD, no other source is available at present, but the company (Evans) should be asked to move over to the new product and replace stocks as soon as this is feasible.

The follow-up to the second meeting

962 The CDSM, at its meeting on 17 January, praised the speed with which the company making sutures had responded to the BSEWG recommendation: it was to begin the changeover in February to Australasian sources.

963 Concerns about BSE in bovine insulin were raised that spring by the British Diabetic Association. Dr Jefferys told the Association in April 1990 that none was being sourced from the British Isles. Although 42 licensed bovine insulin products had been originally identified for the CSM in 1988, none figured among the items put to the BSEWG in the light of the questionnaire. We infer that they were by then sourced outside the UK.

Third meeting of the BSEWG on 4 July 1990

964 Professor Collee told us that at this meeting the Working Group discussed the safety of foetal calf serum at length. He had sought the advice of Dr Taylor of the NPU and others before the meeting. The Working Group reiterated its view that the risk relating to serum was low. Taken together with the fact that the risk of transmission of BSE was theoretical and the view that the benefit of availability of vaccines outweighed any potential risk from their use, the use of foetal calf serum in the process of manufacture was accepted.

965 The Working Group returned to the issue of the non-complying vaccines. Correspondence with the two companies concerned had produced updated information.

966 The Working Group decided that a licence should not be given to the first product (unlicensed MMR vaccine) unless it complied with the guidelines, and that existing trial batches should not be used.

967 There was still no alternative to the third product (Tuberculin PPD), which used glycerol beef broth during the process of manufacture. Stocks were available up to September 1991. These would be changed over 'as appropriate' as the new supplies, which were peptone-based, came on stream. The Working Group thought that the replacement of stocks should take place as quickly as practicable, but meanwhile, given the low risk from glycerol broth, the danger of having no stocks outweighed the risk from the product.

968 The source of the measles vaccine was being changed to New Zealand and present stocks would be depleted in three months.

969 The company preparing DTP vaccines had changed the source of its bovine media, but meanwhile was still using non-complying material. The Working Group recommended a meeting with the company to discuss bringing forward the time when there was compliance with the guidelines.

970 The safety of topical products was also reviewed at this meeting, in the light of action taken earlier that year on cosmetics. The only two products using bovine material sourced it from West Germany, and it was decided that no further action was needed on licensed topical products.

Fourth meeting of the BSEWG on 31 October 1990

971 This turned out to be the main 'wash-up' meeting of the Working Group. They unanimously decided that the special circumstances of the experimental transmission of BSE to a pig did not warrant a fresh look at porcine material. On allergens, they were told that progress with the company concerned was satisfactory.

972 By now the last of the replies to the questionnaire had been received, some 18 months after they had been sent out, and gave no cause for concern. On the outstanding issue of the stocks of the DTP vaccine, the Working Group was beginning to take a more hawkish line. The stock-out dates for the adsorbed vaccines were now between June and December 1991. Those for the unadsorbed vaccine ran beyond 1991. The Working Group asked its secretariat to explore with the licence holder whether the stocks of the latter could be replaced sooner.

Veterinary products

973 On the veterinary side assurances were still awaited from some companies that appropriate action had been carried through. The BSEWG had received progress reports from Dr Lee at each of its meetings, although this item appears to have been treated as purely for information. The difficulties and delays experienced by the VMD over collecting returns, clarifying obscurities and phasing out certain products had broadly mirrored those on human products. We note that when the VPC had its second and final discussion about the exercise in December 1990, there were at least two companies with considerable stocks of vaccines expected to last another four years. The VMD provided us with a table outlining the 143 products that did not initially comply with the CSM/VPC guidelines and the outcome of compliance measures taken. This indicated that apart from one fish vaccine, all manufacturers had complied with the guidelines, so far as their manufacturing processes were concerned, by 1992.

Final meeting of the BSEWG in July 1992

974 After its meeting in October 1990, the BSEWG lay fallow for almost two years. One or two proposals for a meeting came to nothing. BSE did not figure on either the CSM or BSC agenda. However, in July 1992 what proved to be the final meeting of the BSEWG was held. The Working Group considered the implications of the emergence of BSE overseas for medicines, in particular sutures from France. By now there were European guidelines in place for human medicines. These were in some respects a little looser than the UK guidelines, though based on the same principles. They did not, for example, cover sutures. The BSEWG view was that the UK should treat sutures as if they were covered by the guidelines even though other countries did not do so.

975 Once again, concerns about foetal calf serum were raised, with Professor Collee stressing that continued vigilance was necessary. Besides the unanswered question of whether it could in itself transmit infectivity, there were also concerns about collection methods. These concerns were similar to those raised by Dr Pickles some three years earlier and referred to by Mr Scollen in his report to Mr Cruickshank in February 1989.

976 One item that does not appear to have been raised at the meeting was the safety of gelatine. Dr Minor had suggested shortly before that it might be discussed there. He had been disturbed to learn at a meeting in Heidelberg about the 'shockingly mild' German manufacturing process after 'any old cow bone went into the production vat including spine and skull'. There was a pharmaceutical interest in gelatine because it was used for capsules as well as in some other forms. The matter was in the event followed up by a written opinion being commissioned from Professor Collee. His advice was that the BSE guidelines on sourcing should apply to gelatine. Dr Purves told us that this was taken into account in dealing with product licences subsequently. Problems over gelatine rumbled on thereafter, with British suppliers taking steps to exclude UK material in order to meet increasingly rigorous demands from their overseas customers.