Volume 7: Medicines and Cosmetics
7. The Tyrrell proposals for research into pharmaceuticals
Discussion
How this was approached
Inconsistencies in the approach
Lessons for the future

7.56 Lack of knowledge about whether serum and other bovine blood products could transmit BSE created doubts about the safety of certain vaccines and laboratory materials. Should existing products and stocks continue to be used, in order to maintain the national vaccination programme, if no alternatives were available? What handling precautions were appropriate in laboratories? The need to establish a basis for answering these questions was swiftly recognised.

How this was approached

7.57 We considered in particular the response to the three-star priority Tyrrell recommendation C2a for intracerebral assays in mice of BSA and FCS.

7.58 The second of the proposals made by Tyrrell on pharmaceutical research, C2b, was tentative and unstarred. There was no apparent sponsor. We were not surprised that this proposal was left fallow while the available mouse resources were used for other high-priority work.

7.59 The first proposal, C2a, however, was a different matter. All acknowledged its importance. It raised laboratory safety issues and we have discussed in Volume 6 how those were addressed in respect of transmissible spongiform encephalopathies generally. For the licensing authorities it was directly relevant to the agonising question of how to balance risks in dealing with existing vaccine stocks.

7.60 The NIBSC was responsible for advising on the safety of biological products used in human medicines and had been an early port of call for advice to DH and MAFF on the implications of BSE. Its seminar in May 1988 had indicated that a precautionary strategy meant switching to overseas sourcing. It recommended that research into the infectivity of calf serum be undertaken by the NIBSC and Wellcome Biotechnology, but it appears that no such experiments were undertaken.

7.61 FCS was immediately recognised as a potential risk by the Southwood Working Party. The continuing efforts of Sir Richard to ensure that the CSM was getting to grips with the use of biologicals in medicinal products encompassed this concern. The Tyrrell Committee in its June 1989 Report not surprisingly recommended research studies into serum as a top priority. It had earlier noted manufacturers' concerns over vaccines for both humans and animals.

7.62 To find answers, the first step was to test whether the serum itself carried the BSE agent. This meant using mice as surrogates for cattle and humans and was bound to take years. Meanwhile, money, staff, and in particular sufficient specially bred animals appropriately housed, were all in short supply. Many other cattle and sheep materials urgently needed to be tested in the same way to help establish the safety of food and other products. Which should therefore be done first? As the Tyrrell Report observed:

Nowhere else has the decision on priorities been more difficult. ¹

7.63 However, MAFF and the NPU had not been idle. Prior to the Tyrrell Report, they had already begun to establish a programme of research on tissue and blood testing. Following the three-star rating for tissue studies in recommendation C1, they lost no time in pressing ahead with work at the NPU, concentrating on the aspects identified by Tyrrell as the highest priority. In December 1989, Mr Bradley suggested adding FCS to the priority list. This was confirmed in February 1990.

7.64 As predicted, the NPU work on infectivity took years to complete. When the results were eventually available in 1993, those involving FCS, serum and blood were all negative. As discussed in vol. 2: Science, such experiments cannot provide a 100 per cent guarantee. However, these results, and the fact that vaccines contain no FCS in their highly processed end product, must at least provide some assurances.

7.65 On the face of it, therefore, the necessary research was tackled in a businesslike way. Commendably the FCS studies were carried out promptly by MAFF and the NPU, despite the problems of securing funding and getting a slot in the animal testing programmes.

Inconsistencies in the approach

7.66 However, it seemed to us that this outcome was in some respects achieved through inconsistencies in approach and at a degree of cross-purposes. Four features struck us as having complicated the process:

1. The notion that industry might voluntarily sponsor and share the results of this work.
2. The compartmentalised consideration of the serum testing and other testing work.
3. The detached attitude of the medicines licensing divisions.
4. The divergent perceptions of MAFF, DH and SEAC about the actual work being done and the purposes it would serve.

We comment on each of these.

1. Was it suitable for industry?

7.67 We consider that research of this type and importance was never suitable for leaving to industry itself to carry out. As Dr Shannon had pertinently observed in his minute to Mr Andrews in June 1989, an element of judgement was involved in looking to industry to carry out research work. If findings were for general application in licensing policy and the issue of advice, then Departments needed themselves to promote the research actively, to satisfy themselves about how it was to be done and to get the earliest possible results.

2. Compartmentalised items

7.68 The Tyrrell recommendations gave top priority ratings to both the general tissue studies (item C1) and the studies of serum (item C2), while noting that the latter would depend on titrations of the same kind as the former. Thus, in practice, both needed to be considered together in allocating available resources. As we have noted, the MAFF-sponsored programme of work on tissue titrations speedily took on board the studies needed on serum, assigned it a priority slot and oversaw delivery.

7.69 However, this was not wholly compatible with the administrative line drawn by MAFF in compiling the tables attached to Mr Gummer's letter of 1 August 1989, on the basis of which work was subsequently monitored. This had allocated C1 to MAFF as its sole responsibility in table 1. The serum studies, however, were allocated to table 2, to be financed and carried forward by both MAFF and DH as part of their shared responsibilities for the safety of medicines. DH did not demur and earmarked money in its budget for the work. This separate categorisation contributed to a certain amount of confusion about how the work was carried out thereafter and who was calling the shots.

3. Detached attitude of the MCA and VMD

7.70 The cross-purposes were exacerbated by the detached attitude of the medicines licensing divisions, the MCA and VMD, as customers for the outcome. Licensed medicines were not the only products that used serum. Concern about these other uses led Dr Pickles at the behest of SEAC to carry out her own investigations in July 1990 with the four major suppliers of FCS and BSA. In the event, she satisfied herself that they were all by then obtaining their bovine materials from non-UK sources. We thought this was a commendably practical way of addressing matters that did not fall neatly into the MCA remit.

7.71 However, this did not answer the question of what to do about existing products and stocks, licensed or unlicensed, that had used earlier material. It did not provide information on whether there might already have been extensive exposure to the BSE agent. Nor did it clarify whether in the event of BSE emerging overseas, serum would constitute a continuing source of concern.

7.72 The joint responsibility agreed between MAFF and DH Ministers for work on the safety of serum was specifically linked with their joint responsibilities for safe medication. Dr Metters told Ministers that resources were available and that the C2 studies would be considered once advice had been received from the BSE Working Group in September. However, the BSEWG did not discuss research needs at its September meeting, and Dr Pickles's subsequent minutes and briefing reflected her understanding that the MCA together with the pharmaceutical industry were 'taking care of C2a and b'. This was not in fact the case. On the contrary, as Dr Jefferys made clear in his minute to Dr Barnes in April 1990, the MCA had been giving no consideration to the matter and had no intention of funding any such work. We could find no indication of consultation on the studies and the potential application of their outcome between it and VMD reflecting 'joint responsibilities under the Medicines Act'.

4. Divergent perceptions of MAFF, DH and SEAC

7.73 The main interface between MAFF and DH about the studies, therefore, appears to have been in terms of reports made to SEAC about progress on the Tyrrell recommendations as a whole. We were struck by the apparently divergent perceptions in this process.

7.74 MAFF, as represented by the Central Veterinary Laboratory, had perhaps the simplest and most productive attitude. They decided to fund the serum work at the NPU and gave it a priority slot in their programme in February 1990. They backed it through to its conclusion in 1993.

7.75 DH blew hot and cold. Dr Pickles, after initially supporting the proposal began to swing round to the view that the work was not necessary after all for licensed medicines since they were being tackled through a new sourcing strategy. However, she saw the MCA as being in the lead. By March 1990, only a month after MAFF had taken the work on serum into its programme as a top priority item, and apparently in ignorance of the MAFF action, Dr Pickles was telling Miss Duncan that in her view - though she had 'rather left MCA to look after this item' - it rated lower than other studies for the scarce resources available. This was the DH line thereafter.

7.76 SEAC took a continuing interest in what was happening to the NPU's general clutch of tissues studies under C1a. The findings would be crucial to its assessment of risk. It does not appear to have done other than take note of the successive reports to it about how matters stood on item C2a.

7.77 Its 1992 report set out the reasons why it now thought the C2b studies were of questionable value. After noting the emergence of BSE overseas, it went on to say that, since all the materials now used in the UK were sourced from 'BSE free animals in BSE free herds in BSE free countries', the relevance of the additional pharmaceutical studies was now questionable.

7.78 In the event, the work at the NPU on C1a and C2a transmissions was maintained to its conclusion and became part of the set of scientific benchmarks in the difficult field of assessing risks from BSE.

Lessons for the future

7.79 Given that it was eventually completed, did the cross-purposes surrounding this important piece of work matter? They did not, in our view, constitute grounds for criticism of how matters were handled. However, we thought that the way the project was handled indicated three lessons for the future:

1. It is important that government itself takes a lead in promoting and disseminating research work needed to determine safety regulatory action. While cooperation with industry may be valuable, it seems to us unrealistic to expect private sector companies to be enthusiastic about promoting and publicising research that could be to their financial detriment.
2. As we have seen in other fields, there needs to be a clear policy customer for research work. That lesson, as we have seen, was being increasingly applied by Government Departments during the 1990s. When there is more than one customer, and in particular, more than one customer Department, communication between them and the allocation of lead responsibility is essential.
3. The detachment of the medicines licensing authorities from decision-taking about the Tyrrell studies was striking. We have noted elsewhere that relationships on policy-making and information exchange between the licensing authorities were not close. We think further thought might usefully be given to the arrangements for ensuring their involvement in decision-taking about desirable research on safety matters where animal materials are involved.