Volume 7: Medicines and Cosmetics
4. Initial response on human medicines
Consideration of BSE in Medicines Division from January 1988 to March 1989: a chronological account
January 1988
March 1988
April 1988
May 1988
June 1988
August and September 1988
November 1988

January 1988

Meeting of the CSM/BSC on 6 January 1988

4.20 The product that Mr Sloggem was reviewing was considered by the CSM/BSC four months later, in January 1988. ¹ Mr Sloggem cited in his paper for the meeting recent reports of a slow virus syndrome in cattle. This was the time at which a number of those in Medicines Division learnt of the new disease, and Professor Collee told us that this reference was the first he, too, had seen to what subsequently became known as BSE. ² The BSC recommended that a CTC be refused for a number of reasons, including concern about possible infection with transmissible agents. ³ The BSC considered that spiking experiments with suitable hardy viruses should be carried out. ⁴ This involved contaminating the material in the product with the Hanta virus; if it was eradicated or inactivated by the production process, then 'this was a useful marker for other resistant viruses'. ⁵ In fact, as indicated in vol. 2: Science, later work was to show that the inactivation of such hardy viruses does not guarantee the inactivation of BSE.

March 1988

The Chief Medical Officer's reaction to BSE

4.21 As described in Volume 3, Mr Derek Andrews, Permanent Secretary of MAFF, notified the CMO, Sir Donald Acheson, of the existence of BSE in a letter dated 3 March 1988. ⁶ The CMO called a meeting on 17 March 1988, attended by officials from DH and MAFF, including Mr Alistair Cruickshank, the Under Secretary for Animal Health, and Dr Watson, Director of CVL. ⁷ A subsequent note from Mr Cruickshank to Mr Andrews recorded that while all those present found it difficult to give any clear advice on the subject, they tended towards the view that there was probably no risk in drinking milk or eating the flesh from infected animals. However, the position was far less clear in relation to brains, spleens and other organs, which raised questions about the safety of human vaccines prepared using bovine material. ⁸

4.22 The DH note of the meeting records that concern was expressed over bovine insulin and the use of bovine serum in the manufacture of many vaccines. Dr Harris, DCMO, agreed to speak to the director of the National Institute for Biological Standards and Control (NIBSC) about biological products. ⁹

4.23 Mr Cruickshank's note records that the CMO concluded the meeting by saying that he suspected there was no risk, but that it could take 30-40 years to prove this. He proposed that a group of experts should be set up to provide advice to Agriculture and Health Ministers. The group might be asked as a priority to advise on the use of bovine material in manufacturing vaccines and on the disposal of carcasses of affected animals. ¹⁰

4.24 Following this meeting, on 21 March 1988 Sir Donald Acheson sent a submission to Health Ministers notifying them of the existence of the 'new' disease and seeking agreement to the proposed setting up of an expert group to advise on the human health risks. Sir Donald said:

The condition which was first recognised in 1985 has been brought to my attention in a letter from the Permanent Secretary of MAFF dated 3 March 1988 . . . I have subsequently held a meeting of officials of MAFF, the PHLS ¹¹ and DHSS. Their unanimous view, with which I concur, is that, although a risk to human health through the consumption of milk or meat from infected cattle or through the use of bovine tissue-based biologicals in the pharmaceutical industry is likely to be low, in view of the lethal nature of the virus and its uncertainties, further expert advice is needed as soon as possible. ¹²

4.25 The Ministers agreed with the CMO's proposal, which led to the establishment of the Southwood Working Party. Their establishment and meetings are discussed in detail in vol. 4: The Southwood Working Party, 1988-89. Later in this volume we consider the Working Party's involvement with medicinal products.

April 1988

Medicines Division learns about BSE

4.26 Senior officials in Medicines Division who had not already learnt of the existence of BSE did so through receiving copies of the CMO's submission of 21 March 1988. According to Dr Jefferys, Mr Hagger sent him a copy on 4 April ¹³ and Dr Jones told us that he thinks he saw the minute some time in April. ¹⁴

4.27 On 11 April 1988 Mr Wilson, the Administrative Head of Medicines Division, sent a minute to Dr Jefferys about BSE. It has not been possible to find a copy of that minute, but Dr Jefferys recalled that Mr Wilson asked 'for some immediate comments on the possible implications of the appearance of BSE in cattle for the use of bovine tissue based biologicals in the pharmaceuticals industry'. ¹⁵ Dr Jefferys replied on 13 April 1988:

I would have thought that the risk of infection and the transmission of BSE from 'the use of bovine tissue based biologicals in the pharmaceutical industry' is likely to be less than that from infected food products. I base my views on the facts that much smaller quantities of biological materials are used in pharmaceuticals than would be ingested, and secondly that since the virus particles are resistant to heat, then they will not be inactivated by cooking, etc. For recent products we have taken a very stringent view on the quality control to avoid the risk of transmitting infection. We have demanded 'spiking' studies with hardy viruses (these are rather similar to the scrapie virus).

There are still a significant number of older products which are subject to the review procedure. I understand that these are likely to be reviewed in the next year. It might be worth asking Dr Wood to comment on the approach that will be taken to the review of these products.

Probably the most widely used bovine preparation would be bovine insulin. As you will be aware the current trend is to develop highly purified animal insulins and increasingly to switch patients to recombinant DNA (human) insulin. The purification process should considerably reduce the risks of transmission of any virus for the monocomponent highly purified bovine insulin.

A further final thought is that recently we have required certificates that the animals from which biological products are derived are healthy.

I would be happy to look into this matter further if you wish but my view at present is that we should await the deliberations of the proposed expert group. ¹⁶

4.28 Neither Dr Jefferys nor Dr Jones could recall any particular discussions and meetings over this period, although Dr Jefferys thought the matter must have been discussed at senior management level at one of their monthly Divisional Management Group meetings, co-chaired by Dr Jones and Mr Wilson. Dr Jones and Dr Jefferys agreed that the Divisional view, however arrived at, was to await the deliberations of the Southwood Working Party. ¹⁷

4.29 Mr Wilson wrote a manuscript note to Dr Jones on a copy of Dr Jefferys's minute, on 15 April. He suggested that Dr Jones might want to show the minute to Dr Wood, the head of MB3B, the branch reviewing older medicinal products. Subject to that Mr Wilson would go along with Dr Jefferys's view. ¹⁸

May 1988

A meeting arranged by the NIBSC

4.30 A meeting was convened at the NIBSC on 16 May 1988 to discuss BSE. Dr Schild, the Director of the NIBSC, and Dr Minor, Head of the Division of Virology there, told us that the decision to organise the meeting, drawing on the NIBSC Viral Products Advisory Panel, had arisen out of a discussion between them. ¹⁹ It is not clear what prompted this discussion; it might have been a result of Dr Harris's undertaking on 17 March 1988 to raise the matter of BSE with the NIBSC, or alternatively the communications between Dr Little and his colleagues and the NIBSC in the preceding months. ²⁰ Mr Wilesmith, the CVL epidemiologist, was among those who attended the meeting. Dr Schild told us that the purpose of the meeting was:

to obtain the advice and comments of scientists outside the NIBSC on the nature of the epidemic and its implications for biological medicines. Although questions of licensing are for the MCA (which sets out the conditions under which manufacture of biological substances is permitted) we have an obvious professional interest in the safety and efficacy of biological medicines, and an advisory role in that respect. ²¹

4.31 Dr Minor explained:

The meeting . . . was only ever intended to be a 'one-off' session in which knowledge would be pooled and a paper produced which would offer a synopsis of the state of knowledge on the issue for the benefit of those working on biological medicines. ²²

4.32 The participants, besides Mr Wilesmith, and staff of the NIBSC, were Dr Richard Kimberlin, an expert in TSEs from the NPU; Dr A Beale and Dr A Garland of Wellcome Biotechnology; and Dr R Ridley and Dr H Baker of the Clinical Research Centre. Dr Minor told us that he invited Dr Jefferys, but that he did not attend. ²³ However, Dr Jefferys did not recall receiving such an invitation. He told us it was strange that no formal invitation was sent to Medicines Division, together with a copy of a discussion paper, in the same way as the invitations sent to others. He also indicated that he would have expected to find a written response from himself to any invitation. ²⁴ We have not felt it necessary to seek to resolve this question so many years later.

4.33 Dr Minor produced a report of the meeting, ²⁵ including the following conclusion:

Bovine spongiform encephalopathy presents features suggesting that it is caused by a scrapie like agent although this is not yet unequivocally proven. The incidence varies geographically with a lower incidence in the North. In the absence of data on transmission the properties of the agent are expected to be similar to those of the causative agents of scrapie and Creutzfeldt-Jakob disease, which are, in practical terms, undetectable by existing technology and cannot be selectively destroyed, although they may be removed. If BSE is held to be a problem, the only option is to ensure that bovine materials for manufacture of biological medicinal products are derived from cattle in areas free of the disease.

It is possible that transmission to humans may not be readily effected under existing conditions. This statement is based on experience with scrapie which is unlikely to cause a disease in humans under natural conditions, and in particular has been shown to be epidemiologically unlinked to Creutzfeldt-Jakob disease. There is no evidence for transmission of scrapie to occupational groups such as shepherds and veterinarians which have high exposure to sheep and scrapie infected sheep. This is true for research workers and abattoir workers or butchers, where there may be exposure to brain tissues. The tissue distribution of infectious agents may also act against ease of transmission. In particular serum is a poor source of infectivity in animals affected by scrapie. Vertical transmission of acquired Creutzfeldt-Jakob disease, kuru or BSE has not been demonstrated. Transmission of scrapie from infected ewes to their lambs occurs with relatively high frequency, however, implying possible transplacental spread or transmission via milk. It is thus possible that BSE poses no real threat to human health provided the main exposures are either as a contaminant of food stuffs which will be minimised by inspection of animals, or from products which are not contaminated with nervous tissue. The information on which to base a decision is however extremely sparse. ²⁶

4.34 Those at the meeting recommended that studies should be set up involving NIBSC, Wellcome Biotechnology and other parties to test for the presence of scrapie-like agents in calf serum by inoculation into mice, hamsters and other species. Such experiments would be very lengthy. ²⁷ Dr Minor told us that the studies were actually carried out independently by Wellcome Biotechnology. However, he does not recall actually seeing the research itself and he cannot recall when the results were brought to his attention. ²⁸ The company has told us in correspondence that it can find no record of Wellcome carrying out such experiments. It does, however, note that Dr Minor was involved in a critique of experimental protocols for other experiments being investigated by Wellcome at the time.

4.35 The meeting also recommended that consideration should be given to a survey of licensed products using bovine or ovine material in their manufacture and the origin of these materials. ²⁹

Sir Richard Southwood and Dr Pickles become involved

4.36 On 19 May 1988, a few days after the NIBSC meeting, Sir Richard Southwood met Mr Andrews and the CMO. The CMO suggested that urgent advice on the question of the manufacture of biologicals from cattle material would be needed from Sir Richard's working party. ³⁰

4.37 The next day Dr Pickles sent a minute to Dr Jefferys:

Bovine Spongiform Encephalopathy

I believe you know that there is a joint MAFF-DHSS group looking at this problem. I have now been roped into the secretariat.

We would like to be sure that possible transmission through medicinal products can be ruled out for both humans and animals. Some positive evidence that it appears not to have been so transmitted would be nice. Since we know so little about BSE, we may have to look at scrapie, which is endemic in UK sheep. Is this a problem you should put before biologicals sub-committee?

Questions for them might be:-

- are there any products prepared from bovine or sheep brain which need to be looked at? If rabies vaccine has been made using sheep/goat brain, are there adequate human follow-up data to be sure no viral infections might have been transmitted?

- Can we assume that the 'dose' of any infectious agent administered in non-parenteral medicinal products would have been so small in comparison with doses from food that such products need not be considered further?

- Are there any bovine (or sheep) materials used in production processes of parenterals that might be capable of introducing an infectious agent (eg bovine serum albumin in vaccine production, or bovine insulin)?

We have no evidence that BSE can be a risk to humans. If, however, we could identify a group of people who might have received parenteral 'BSE agent' through medicinal products then they would be a group that might warrant special study.

I note in your minute of 13 April you take some reassurance from recent requirements that animals used in production of biological products should look healthy and be certified as so. With a long-incubation infection (currently thought to be 2 to 6 years) lack of physical signs cannot be taken to signify freedom of disease. So we cannot be sure.

Maybe you would like to discuss this with me. If you do put the problem to Biologicals Sub-Committee, please involve me if you can. ³¹

4.38 The same day Dr Pickles sent a minute to Mrs Alderman, an information scientist in MB1B where the Medicines Division data was kept, asking for information about licensed products for human and veterinary use made from bovine material. ³² Mrs Alderman replied on 23 May 1988 attaching print-outs listing products containing active ingredients or excipients of bovine origin from Medicines Division's NORSK database. Mrs Alderman had compiled the results by searching for constituents containing 'bovine' in their name, which was the only way she could do it. ³³ Following this up in early June Dr Pickles noted that the list had not included any bovine insulins. ³⁴ Mrs Alderman replied the next day with a further list that did include these products. ³⁵

4.39 Dr Jefferys replied to Dr Pickles on 24 May 1988. He said that the CSM/BSC had not formally discussed the matter but had done so informally while assessing an individual application. This appears to be a reference to the January BSC meeting which he had attended. He added: 'For some months now the Sub-Committee have been requiring appropriate "spiking" studies to be undertaken with hardy viruses and these would include bovine products.' Therefore he felt 'reasonably confident about taking appropriate action for the new products'. He thought that the major concern was with the parenteral products. Dr Jefferys continued:

With regard to previously licensed products, then we have no evidence of hazard, but clearly we cannot provide reassurance given the timescale for possible incubation and infection.

As you will be aware from your previous work with the Review, many of the older products are PLRs [Product Licences of Right] (since many of the biological PLRs still have not been reviewed). I am therefore copying this minute to Dr Wood since she will need to take account of this during the review of these products.

Oral Products

As I previously stated, I would have thought that the risk from oral medicinal products must be very small in comparison to the risk from food. I base this on the assumption that the infectious agent is probably not heat-sensitive and therefore will not be removed by normal cooking.

Parenteral Products

I accept that there may be a different consideration of parenteral products. I presume that the major agents would be bovine insulin, and bovine serum albumen in vaccine production. If you were looking for a group of people to study, then I would have thought that those who have received bovine insulin might be the most appropriate group. I suppose it might be possible to undertake a retrospective study comparing those who have received bovine insulin versus those who have received porcine or ideally human insulin. I presume the endpoint would have to be the development of an encephalopathic syndrome. The danger in constructing such a study would be the scientific risks of confounding, etc. and the political risk of worrying large numbers of diabetic patients.

These thoughts are very preliminary ones. It also occurs to me that this is more of a long term issue and that it may well involve William Jenkins since this is rather more an ADR [Adverse Drug Reaction] problem than a New Drugs Group issue. I am therefore copying your minute to him. It may be appropriate for Sue Wood, William and I to have a discussion with you at a mutually convenient time. ³⁶

June 1988

A minute from Dr Pickles

4.40 The Southwood Working Party held its first meeting on 20 June 1988. ³⁷ Following that meeting, Dr Pickles wrote both to Dr Lewis, private secretary to the CMO, ³⁸ and to Dr Jones. ³⁹ Dr Harris, Mr Wilson and Dr Jefferys were among those to whom the latter minute was copied. This seems to us again to have been an important minute, and we set it out in full:

BSE, Spongiform Encephalopathies and Medicinal Products

1. You will have heard of this new disease of British cattle which is thought to be due to scrapie agent, introduced via sheep offal in cattle feeding stuffs. I am part of the secretariat of a working party, chaired by Sir Richard Southwood, which is looking into the implications of this disease. This group had its first meeting yesterday.

2. We are clearly concerned that 'BSE-agent' may be transmitted in medicines. Whilst the epidemiology does not suggest that the current cases in cattle are causally linked with the use of veterinary products, we are concerned about veterinary as well as human medicines in case we facilitate yet more species jumps. Much of the relevant information about ingredients and production processes is not accessible to us so we will look to the section 4 committees (and the Biologicals Sub Committee) to review this problem. All of them, including the VPC and CDSM, might have an interest. Dr Martin is a member of Sir Richard's working party, and might raise the problem informally at a Commission pre-meeting.

3. I have been in correspondence with Dr Jefferys and others about this. I understand the pharmaceutical industry are also concerned: they had been using bovine not sheep products in various processes because scrapie is endemic in British sheep. Now they need to worry about possible dangers to their workers handling bovine materials as well as possible infection in their final products.

4. Questions we might want to have answered are:

- the highest risk would be from parenterals prepared from brain (eg rabies vaccine). Any species in which transmissible spongiform encephalopathies have been described would be suspect ('natural' infections in sheep, goats, cattle, deer, mink, but can be transmitted to hamster, mouse, guinea-pig etc). Are sterilisation processes adequate for the most resistant strain of scrapie agent or for CJD agent? Should companies be asked to include investigation for inclusion of scrapie agent (eg mouse inoculation) in at least some batches?

- If BSE behaves like scrapie, then we might expect other nervous tissue, spleen, lymph nodes and placenta to be contaminated. Infection has been described in other tissues too, eg gut wall, and we cannot be sure blood is free. Do we know what bovine materials are used in which products, both as the active ingredient and in production? Bovine active ingredients in human products include insulin, vasopressin, bone, immune globulins, fibrin, dermal collagen, albumin. Bovine serum albumin and fetal calf serum must be used in preparation of very many products. For each of these products would any 'BSE agent' be destroyed or eliminated in processing? If not, and the product is administered parenterally or topically into an open wound, might there be a risk? (For oral products, there would only be a trivially increased load on top of that taken in food in omnivores/carnivores including man. But for some herbivores, this might allow the agent to be introduced into yet another species).

- Would it be appropriate to arrange for monitoring of cases who have received any of these suspect products in the past? Could studies be undertaken in recipients of bovine insulin without causing alarm? Would recipients of collagen or fibrin implants be another group for study? Perhaps some animal recipients of suspect products should also be studied.

- Should we restrict our concern to products manufactured in the UK, since BSE has not been described elsewhere?

- Should we step up the physical examination of animals involved in medicine production, ensuring a neurological assessment is included and only healthy animals are used?

- Pending results of further investigations, should we insist all ruminants used for the production of human or veterinary products are not fed at any time since birth supplementary animal protein as in meat and bone meal? Should the same rules apply to any other animals involved in production of human or veterinary medicines? This seems to me to be an easy option for the industry (assuming bovine serum albumin can be bought in from countries overseas where such supplementation is not used) and would be a responsible step. It would provide reassurance if, as I suspect, it is not possible to come up with answers to the other questions.

5. Is this a topic you will want to raise with the FDA ⁴⁰ at the forthcoming Tripartite?

6. As you know, BSE is of particular concern to CMO. He has asked me to keep him fully posted as to progress. Following yesterday's meeting of the working party, I have let him know I am writing to you to suggest this potential problem is discussed by your expert committees. Please let me know if there is any further information I could provide for you. I would value the chance to be present as an observer when the issue gets discussed in committee. ⁴¹

4.41 Copying this minute to Mr Lawrence on 21 June 1988, Dr Pickles described it as 'an attempt to galvanise Medicines Division into action'. ⁴²

The response within Medicines Division

4.42 Dr Pickles's minute had the desired effect. It prompted a decision within Medicines Division that the issue of BSE should be referred, in the first place, to the CSM/BSC. Neither Dr Jones nor Dr Jefferys could recall, when we asked them, exactly how this decision came about. ⁴³ Dr Jones thought it likely that he would have discussed Dr Pickles's minute with Dr Jefferys, and that Dr Jefferys would then have met with his staff and pharmaceutical colleagues. When he gave oral evidence, Dr Jefferys thought it was likely that the issue would have been discussed by a team including the three Principal Medical Officers reporting to Dr Jones, the pharmacists and administrative colleagues. He was 'pretty confident' that it would have been discussed at the Divisional Management Group meeting. ⁴⁴ Unfortunately, the minutes of those meetings have not survived.

4.43 In any event, Dr Frances Rotblat, an SMO working to Dr Jefferys, who was medical assessor to the CSM/BSC, and Dr Purves, the pharmaceutical assessor to the CSM/BSC, were asked during the summer of 1988 to prepare a paper on BSE for the Committee. Dr Rotblat told us:

I believe that Dr Jefferys had asked us to prepare this paper. However, I am unable to recall when he first asked us to prepare it. I have some recollection that a decision was taken to prepare the paper so that it could be put before the November meeting of the Biologicals subcommittee and Dr Jefferys probably told Dr Purves and I to work towards completing it in time for that meeting. I believe that when Dr Jefferys asked us to prepare it, he probably told us to prepare it as soon as we could given our existing workloads. I do not believe that Dr Jefferys either told us to drop all our other work and concentrate exclusively on BSE or told us that the paper was a low priority. I imagine that the paper was probably put together over the course of about 3-4 weeks. ⁴⁵

Dr Rotblat said that it appeared the paper was completed by 20 September and referred to her minute to Dr Jefferys of that date. ⁴⁶

4.44 On 11 July 1988, about the time we imagine Dr Rotblat and Dr Purves were asked to prepare their paper, Dr Pickles contacted Dr Minor at the NIBSC in an apparent effort to ensure that prompt consideration was given to BSE by the CSM/BSC. She sent him copies of her minute of 21 June 1988 to Dr Jones and of a note she had prepared for the press office, and said:

As we discussed today on the phone, I have lead responsibility for BSE here in DHSS. For your information, here is a copy of the note I prepared for our press office. Also, in confidence, a note about the implications of BSE for biological products I sent to Dr Jones. You had better not let Medicines Division know you have seen this, but there will be no excuse for not having a proper discussion at the next Biologicals Committee. Perhaps you could let me know if it does not appear on the agenda when you receive the papers. ⁴⁷ [Original emphasis]

4.45 That same day, Dr Minor sent copies of his report of the NIBSC meeting on 16 May to Dr Jefferys. ⁴⁸ As we have noted in the previous chapter, he was also instrumental in Mr Wood's despatch of the draft MAFF guidelines on 12 July to Dr Harris, the DCMO.

August and September 1988

4.46 During August, the CMO corresponded with Mr Andrews and Sir Richard Southwood about the proposed advisory group on BSE-related research (which became the Tyrrell Committee). ⁴⁹ In his letter to the CMO of 30 August 1988 Sir Richard said that he considered serum in pharmacological work the 'only outstanding practical matter' and asked whether something could be done through 'the usual channels' to check the policy of pharmaceutical companies on its use. ⁵⁰ The CMO passed Sir Richard's letter on to Dr Harris, who in turn passed it on to Dr Jones. Dr Jones replied to Sir Richard on 22 September 1988. He told him that the use of bovine serum in pharmaceutical manufacture was one of a number of issues currently being examined by Medicines Division, and promised to let Sir Richard's working party have all the information relating to medicinal products as soon as it became available. ⁵¹

4.47 Meanwhile, when the CSM/BSC met on 7 September 1988, Dr Purves had told them that a paper on BSE was being prepared and would be submitted to them at a later date. ⁵²

4.48 Dr Pickles was not satisfied with Dr Jones's reply to Sir Richard. In a minute to Dr Jones of 26 September 1988 she pointed out that she had been asking for comments from Medicines Division for some months and had several suggestions as to 'pertinent questions' that could be put before the expert committees:

. . . I understand that the topic has only been raised informally at Biologicals. You explained to me that it has lower priority than other work before you at the moment.

The next meeting of Southwood's group is on the 10 November. Will I have something positive to report at that meeting from Medicines Division? ⁵³

4.49 Evidently the CMO asked Dr Jones about the timing of the Medicines Division consideration of BSE. Dr Jones told him on 29 September 1988 that a draft paper had been prepared and would be considered by the CSM, the Committee on Dental and Surgical Materials (CDSM) and various subcommittees in November. A considered view on the whole issue would be available in late November. ⁵⁴ The CMO passed this information on to Sir Richard in early October. ⁵⁵

November 1988

The Rotblat and Purves paper

4.50 The paper on BSE had been completed by Dr Rotblat and Dr Purves by 20 September 1988 ⁵⁶ but was not considered by the CSM/BSC until its meeting on 2 November 1988. Dr Jefferys told us:

In addition to the time actually spent preparing the paper there was and remains about a 3-4 week 'lead period' in that a paper has to be completed more than three weeks before a subcommittee meets so that it can be checked, photocopied, distributed to the members so that they have adequate time to read it and prepare for the meeting. It was the practice to issue papers two weeks before a meeting to committee members. This would have meant that if a paper was to be put to the September meeting of the subcommittees, it would have had to be available no later than the middle of August. ⁵⁷

4.51 Dr Rotblat told us that the two standard principles underlying the paper were, first, ensuring the safety of the raw ingredients, and, second, the use of sterilisation or inactivation procedures in the manufacturing process to minimise any remaining risk. ⁵⁸ Dr Purves told us the purposes of the paper were to:

(1) summarise the current information on BSE;

(2) identify the issues that BSE raised for biological products - to consider the possible risk of transmission of the disease to humans through biological products containing or consisting of bovine materials; and

(3) present draft recommendations for the Committee's consideration. ⁵⁹

4.52 He added:

It was designed to be a discussion paper for the Committee. As was our practice, we presented specific, but draft, recommendations to the Committee to assist in giving focus to the deliberations. Additional recommendations would be included as a result of discussion at committee.

We were very aware that the Southwood Working Group had been set up, given its expert advice in this area and that before implementing industry wide measures, we would need further guidance from our group of experts. However, in the interim we did not hesitate in examining the issue and formulating proposals for action. These could be reviewed in the light of the subsequent recommendations that came from the Southwood Working Party including that Party's assessment of the possible risks associated with biological products. ⁶⁰

4.53 In the paper itself the authors noted that little was known about the disease or the causal agent, although the limited information available indicated that it could be caused by a scrapie-like agent. At the time the total number of reported cases was said to be 510. The paper stated that the lack of hard information made it difficult to see what positive action could be taken by the Division, at least in the short term, but it was thought prudent to consider the following:

1. The animal species from which tissue might be sourced for use in the manufacture of medicinal products.
2. The significance, if any, of the various types of tissue that might be used.
3. The ability of the manufacturing and purification procedures to destroy or remove viral or virus-like agents.
4. The products involved, the type of tissue they contained and the relative risk to the patient on administration of a contaminated product, parenterally, topically and orally. ⁶¹

4.54 In relation to the fourth issue, the paper said:

It is clear there is a need to know which products contain bovine tissues, along with details of the type of tissue used in manufacture, so that a database is available for discussion later. In addition, consideration may need to be given to the risks associated with parenteral, topical and oral administration, should the product be contaminated by the BSE agent . . . Some questions we may wish to ask are:

1. which products include bovine material and, therefore may contain the BSE agent;

2. what follow-up action is required especially in the absence of definitive information on the properties of the BSE agent;

3. what could be asked of companies in answer to concerns about BSE in addition to our current policy, where, in the last year or so, we have been asking for details of the quality of starting materials and the ability of the manufacturing and purification procedures to remove or inactivate hardy viruses. ⁶²

4.55 The second part of the paper set out data from Medicines Division's existing computer records for licensed products. The list showed 53 product licences for preparations containing bovine material, of which 42 were for insulin. It was not clear how complete the computer list was; it did not show material used in the process of manufacture such as bovine serum albumin (BSA) and foetal calf serum (FCS).

4.56 Dr Rotblat and Dr Purves had then divided products into those for oral and parenteral use and those derived from brain, tissue and blood. There were no licensed products derived from bovine brain, but there were three products for parenteral use derived from bovine tissue: insulin, bovine collagen implants and bovine fibrin implants. ⁶³

4.57 They concluded by putting forward the following recommendations for consideration by the BSC:

i. No licensing action should be taken against oral products.

ii. All bovine products should come from cattle from healthy herds, which have not been given food supplements containing material of animal origin. No brain or lymphoid tissue should be used in parenteral products.

iii. Manufacturers of parenteral products should show that their manufacturing processes are capable of inactivating scrapie-like agents.

iv. All licences for new products from bovine material should comply with the above.

v. The Review/CDSM sections should carry out a search for preparations containing bovine material.

vi. There should be an article in MAIL [Medicines Act Information Leaflet] requesting manufacturers to identify bovine preparations used in the manufacturing process. Bovine albumin and foetal calf serum should come from healthy herds.

vii. The ADR [Adverse Drug Reactions] database should be searched for ADRs to bovine products.

viii. The Committee is asked to consider whether to take any action against bovine insulin or whether the risk/benefit ratio is appropriate. ⁶⁴

4.58 Annexed to the paper were a number of documents, including Dr Minor's report of the NIBSC meeting of 16 May 1988 and what appears to be Mr Wood's paper of 6 July, which had been sent to Dr Harris on 12 July. This is annotated 'MAFF Report' and referred to in the cover note as 'suggested action by Ministry of Agriculture'. There is no explanation of its status nor any other reference to it in the paper for the Committee (see Chapter 3).

The CSM/BSC meeting on 2 November 1988

4.59 Professor Collee chaired the CSM/BSC meeting on 2 November 1988; those present included Dr Pickles, Dr Jefferys, Dr Purves, Dr Adams, Dr Schild, Mr Sloggem and Dr Minor. ⁶⁵ No representative of MAFF attended. Professor Collee described to us his thinking, and that of the BSC, at the time:

I recall reading the Purves/Rotblat paper with admiration. I thought that it was balanced and well researched. I recall that my preliminary feeling was that it seemed unlikely that the BSE agent would be transmissible to man, but that the possible consequences of transmission were potentially alarming.

Everyone who attended the Biologicals Sub-Committee meeting on 2nd November was exercised by the issue of BSE. At the meeting, there was a very full discussion of the Purves/Rotblat paper, which was used as a baseline; we then had a wider, general discussion of the issues raised and I would have summarised this discussion. We then went on carefully to discuss each of the recommendations which had been made. It appears that Dr Purves attended the meeting although Dr Rotblat did not. Dr Purves may well have introduced the paper; he certainly answered questions on it. Dr Pickles would almost certainly have contributed to the discussion.

We faced considerable uncertainty at this time. I was aware from my knowledge of other models of infectivity that parenteral delivery of similar agents was likely to be more effective than other potential routes of transmission, such as an oral challenge. I was also aware the infection could 'home onto' particular organs or tissues; that brain was likely to be such an organ and that there might also be risks from the use of nervous tissue. The Purves/Rotblat paper had additionally drawn attention to possible risks from lymphoid tissue; I believe that I was unaware of the possibility of lymphoid tissue posing a particular risk before reading this paper. However, I believe I was alive to the concept of sub-clinical infection. ⁶⁶

4.60 Following its discussions, the CSM/BSC made the following recommendations:

a. No immediate licensing action should be taken against oral products, in which bovine material has been used.

b. All bovine materials should come from cattle from appropriately certified healthy herds, which have not been given food supplements containing material of animal origin. No brain or lymphoid tissue should be used in parenteral products.

c. Manufacturers of parenteral products should show that their manufacturing processes are capable of eliminating scrapie-like agents.

d. All licences for new products from bovine materials should comply with the above.

e. There should be an article in MAIL requesting manufacturers to identify products in which bovine materials had been used. Bovine albumin and foetal calf serum should come from appropriately certified healthy herds.

f. The above should be drawn to the attention of the review/CDSM sections along with the need to search for preparations containing bovine material.

g. The above should be drawn to the attention of the ADR Section and SEAR [respectively that part of Medicines Division and the CSM subcommittee concerned with adverse reactions to medicinal products] along with the need to search the database for reactions to bovine products. ⁶⁷

4.61 Following the meeting of the BSC, Dr Pickles sent a minute to Mr Alan Lawrence, her MAFF counterpart in the Southwood secretariat, enclosing her own summary of the comments and recommendations from the meeting. In respect of information available about licensed products, she recorded:

There is incomplete information on the licensed products potentially affected, as many products with licences of right (PLR's) do not have even active ingredients correctly identified on the computer records. Non-active ingredients/materials of bovine origin may also be missed out. Some collagen implants of bovine origin as used by cosmetic clinics are not even licensed. ⁶⁸

4.62 Dr Pickles also recorded:

The subcommittee's recommendations could form the 'framework' on which specific proposals for specific products could then be formulated by the secretariat and then brought back to the committee. Further information would be sought from MAFF and other experts on how disease-free herds, procedures and countries might be identified. ⁶⁹

4.63 In her covering minute Dr Pickles told Mr Lawrence how matters stood in the other advisory committees (including forthcoming discussions at the SEAR subcommittee and the CSM). She added:

I hope we can persuade Sir Richard that the issue is now being looked at in depth by the appropriate experts who also have the executive power to do something about it. This means that Sir Richard needs only a passing reference in his own report. ⁷⁰

4.64 She said she had seen Mr Wood's draft paper of 6 July and asked Mr Lawrence to find out what was happening with veterinary products in the Veterinary Products Committee (VPC). ⁷¹

4.65 When SEAR considered the issue of BSE two days later, it endorsed the recommendations of the BSC. ⁷²

Sir Richard Southwood's first letter to the CSM

4.66 At their second meeting, on 10 November 1988, the Southwood Working Party were told about the preliminary discussions of the VPC and the CSM/BSC (refer to vol. 4: The Southwood Working Party, 1988-89). This prompted Sir Richard to write to Professor Asscher, the Chairman of the CSM, on 14 November 1988:

I understand that the Committee on Safety of Medicines is shortly to consider whether bovine spongiform encephalopathy presents a hazard in those medicinal products for human use that have been manufactured from bovine sources. At a recent meeting of the expert working party which has been set up by MAFF and DH to consider the implications of this disease, we were informed of the provisional conclusions of the Biologicals Subcommittee.

We were pleased to hear of the detailed consideration that was given to this issue. As you may know, we have already identified the pressing need for more research in this area. We understand that in due course you may be considering whether licensing action of some sort is appropriate in relation to any specific products. We trust that any steps that are thought necessary to safeguard new medicinal products will be applied also to existing products. There are various measures that manufacturers could take to reduce or eliminate the risk of contamination by BSE agent in pharmaceuticals and which could be introduced by agreement with relative ease and with no detriment to the product. Those steps include using material only from healthy herds not fed ruminant-derived protein; avoiding use of brain or lymphoid tissue directly or in culture media; and reducing nervous tissue contamination of serum by ensuring animals are not destroyed by brain-penetrative stunning. You may like to consider whether informal advice on these lines to the pharmaceutical industry might be helpful. Other steps, such as ensuring the manufacturing processes are such as to eliminate any scrapie or similar agent, seem likely to prove more problematic.

We look forward to hearing your considered view when you have completed your deliberations. ⁷³

Consideration by the CDSM and CSM

4.67 The CDSM discussed the recommendations made by the CSM/BSC on 16 November 1988. Of particular interest to the CDSM was the use of sutures derived from bovine intestines. Its view was that at that stage synthetic materials should be used in surgery wherever possible and materials of bovine origin should be used only where essential. It noted it was to be kept informed of further developments. ⁷⁴

4.68 Professor Asscher told us that his first involvement with BSE occurred in the course of preparing for the CSM meeting on 17 November. He added:

The CSM was, however, aware of the issues involving CJD and human growth hormone at this time and of the occurrence of CJD following dura mater implants. They had come to our attention in the course of considering product licences for dura mater. These experiences made us particularly wary of parenteral, as compared to oral, medicinal products. At the time, the fact that scrapie had not transmitted to man also gave us reassurance that BSE was unlikely to be acquired by the oral route. ⁷⁵

4.69 The CSM considered and endorsed the CSM/BSC and SEAR recommendations at its meeting on 17 November 1988. It also noted Sir Richard's letter and agreed that Professor Asscher should write to him 'detailing the view of the Committee and referring to preliminary consideration of this matter by the CRM and CDSM'. ⁷⁶

4.70 Professor Collee was present at the CSM meeting. He recalled that Sir Richard's letter was seen as constructive and that his points guided the further discussion after the CSM meeting over the coming months. ⁷⁷

Further correspondence between Sir Richard Southwood and Professor Asscher

4.71 On 24 November 1988 Professor Asscher replied to Sir Richard's letter. He enclosed the recommendations of the CSM. His letter concluded:

Preliminary discussions have also taken place within the Committee on the Review of Medicines and Committee on Dental and Surgical Materials to consider what action needs to be taken in relation to specific existing products.

I hope you will agree that we now have in progress the appropriate action to safeguard both new medicinal products and existing products. ⁷⁸

4.72 Sir Richard replied to Professor Asscher on 7 December 1988, saying that he would put his letter before the Working Party. He offered two initial comments on the CSM's recommendations:

My colleagues and I are most anxious to ensure that existing products were identified and manufacturers ensured that they conformed to the safety recommendations. The second point is that I believe in practice 'the certification of healthy herds' is going to be more difficult, because as you know, this disease may be present for many years in an asymptomatic condition; thus certification would have to depend on evidence that food supplements containing material of animal origin have not been fed to the herds for as long as six or seven years or the lifetime of the animals concerned. I am not sure what arrangement the Ministry of Agriculture has in mind for certifying herds as healthy from this point of view, but as you will appreciate, the absence of a case of BSE would not be a sufficient condition. ⁷⁹

4.73 We were unsure what Sir Richard meant by existing products. Was it products with existing licences, or was it existing stocks of such products? We asked the Working Party when they gave oral evidence. Sir Richard told us he thought they meant products that were already licensed and stocks of those products. ⁸⁰

4.74 In a letter to Sir Richard on 8 December 1988, Dr Pickles commented that she was not entirely happy with Professor Asscher's reply of 24 November. She saw nothing in the CSM's recommendations that gave her any confidence that it would be taking any necessary action on existing products, or indeed would be taking note of any of the points raised by Sir Richard in his letter. ⁸¹ The Working Party agreed. At their third meeting, on 16 December 1988, it was felt that Professor Asscher's response was 'somewhat complacent, particularly in relation to the problem of existing medicinal products'. It was agreed that a further letter should be sent to Professor Asscher, and that Sir Richard would also write to Dr Little to establish what measures the VPC was adopting. ⁸² The latter correspondence is dealt with in Chapter 5.

4.75 Accordingly, on 23 December 1988 a further letter was sent to Professor Asscher conveying the Working Party's continued concerns. ⁸³ Sir Richard wrote: 'We interpret your recommendations as drafted to mean that conditions that may be impossible in practice will be demanded of new products of bovine origin, and yet, other than for the insulins, we see no firm commitment to look at existing products.' He sought reassurance that appropriate action would be taken against relevant parenteral products other than insulins and heparin. Sir Richard identified a number of other points including:

1. the difficulty, mentioned in his own earlier letter of 7 December, of introducing 'certification of healthy herds' if this meant herds never fed ruminant protein;
2. the problems of ensuring manufacturing processes were capable of eliminating the scrapie agent; and
3. the question whether the exclusion of brain and lymphoid tissue covered only active tissue, or also material used as intermediates and culture media in the manufacturing process.

4.76 Professor Asscher suggested to us that Sir Richard's comments on existing products appeared to be based on a misunderstanding:

the CSM had always intended that its recommendations should be applied to both existing and new products. It was for this reason that the CSM ensured that BSE was also considered by the CRM. ⁸⁴

4.77 It remains unclear to us whether Professor Asscher understood that the Southwood Working Party's concern extended to existing stocks of medicinal products. We consider in Chapter 6 the response to this letter and the action that was taken in relation to existing stocks.

Giving effect to the CSM recommendations

4.78 According to Professor Asscher, following its 17 November meeting the CSM, together with its subcommittees and officials from Medicines Division, worked at formulating an overall policy on the issues raised for human medicinal products by BSE. This work took place alongside the work of the Southwood Working Party. ⁸⁵ Professor Collee told us that this period was one of intense activity with a steep learning curve during which new information and ideas were regularly coming to light. ⁸⁶

4.79 Dr Jefferys said of the period:

All of [the] issues needed to be debated and required considerable technical expertise. They were not questions which admitted of simple straightforward answers; indeed this was leading edge science. It was felt that the guidelines which were eventually to be approved had to be capable of withstanding scientific scrutiny and possible legal challenge. The guidelines would have to be seen to be proportionate. If the eventual guidelines were clearly justifiable and practical the chances of universal compliance would be greatly increased.

A further consideration during this period was that we were all waiting for a sight of the Southwood Report. This was of particular importance not simply because it was felt that it would be the most authoritative consideration of the issues raised by BSE but also because it needs to be remembered that any action taken in respect of individual pharmaceutical products had to be justified on an evidential basis. It was felt that the Southwood Report would provide such a basis and that action taken in advance of a report might well be criticised as premature. ⁸⁷

4.80 One of the points that had emerged at the November 1988 meeting of the CSM was that its recommendations were to be regarded as initial proposals, which might need to be amended in the light of increased knowledge about the disease. The CSM recognised that more advice was needed from officials at MAFF about the veterinary aspects of their proposals, to ensure that there was a consistency of approach towards human and veterinary medicinal products. In particular, in light of the Southwood Working Party's concerns, the concept of a healthy herd and the type of inactivation process likely to be effective had to be addressed. ⁸⁸

4.81 A meeting was therefore held between Dr Adams, Dr Jefferys and Dr Purves of Medicines Division and Dr Little, Mr Kidd and Mr Bradley, from the CVL, on 3 January 1989. Its purpose was to discuss BSE and medicines licensing. ⁸⁹ What transpired at this important meeting and afterwards is considered in Chapter 5.