2008 cases

Précis of Committee meetings held in 2008



Case No. 268. Schering-Plough Animal Health / Pfizer Limited: Promotional material for Spirovac

The issues revolved around whether SPIROVAC was licensed against both strains of L. hardjo – L. hardjo bovis and L. hardjo prajitno.

The words to which complaint was made were contained in advertisements, specifically Cattle Practice, November 2007 (Veterinary Surgeon Journal), and in editorial coverage in Dairy Vet and British Dairying and were:

1. “That Spirovac works against both strains of leptospirosis (L. hardjo bovis and L. hardjo prajitno).” 2. “Licensed against both strains of leptospirosis.”

The Complainant argued that these constituted a breach of Clauses 4.3 and 4.7. These are recited below:

4.3 Information about animal medicines must be accurate, balanced and must not mislead, either directly or by implication, so that critical unbiased judgements and decisions can be made.

4.7 Promotion must not be inconsistent with the SPC, except that a veterinary surgeon or other suitably qualified person employed or engaged by a participating company may in appropriate circumstances give information about off-SPC use in response to a technical enquiry from another veterinary surgeon.

The Complainant maintained that as the SPC provides that protection against the latter had not been demonstrated by challenge, it was not licensed for use against that strain and that the two items of promotion were misleading and intimated a consistency with the SPC, which was not in fact correct.

The Chairman drew attention to the VMD’s correspondence disclosed by the parties which refers to the protection not having been demonstrated by challenge and that in fact no model existed. He took the view that the case, like many others, related to the wording of the promotion.

A discussion ensued regarding the lack of challenge: the fact that no challenge had occurred, reference being drawn particularly to a paper “Immunity to Bovine Leptospirosis” by W A Ellis et al 2000 in which it is stated:-

“This leaves claims of efficacy against hardjo type Prajitno infection unproven for Leptavoid-H or any other Leptospira hardjo vaccine. While it is reasonable to assume that a vaccine, which protects against the heterologous strain, will also protect against the homologous strain, there is one qualification that should be made. That is, if the natural route of infection for hardjo Prajitno is the venereal route then arguments based on a systemic vaccine protecting against systemic infection may not necessarily hold true.”

These important comments followed a statement that the challenge route chosen (super conjunctional) whilst appropriate for hardjo bovis, was clearly inappropriate for hardjo Prajitno studies.

Also noted were the comments in the study regarding CMI (cell mediated immunity) studies, and the relatively slight response to in-vitro antigen stimulation.

The Chairman drew attention to the way the SPC for the product reflected in the item “indications for use” identified only one target strain – the bovis strain. It was only in section 5 further on in the SPC under “Immunological Properties” that reference is made to activity against the strain in-vitro, with the warning as regards the lack of challenge – this reference is repeated under “Further information” in the data sheet, where use against the bovis strain only is given under the “Uses” heading.

The Respondent’s representatives first referred to the nomenclature and the changes in terms (in this précis only the single description “Bovis” and “Prajitno” has been used throughout for simplicity).

They then discussed the science between the two strains which they said was not fully understood.

Under questions from the Chairman, the Respondent’s representatives accepted fully the importance of the Ellis paper and that no model establishing an effective challenge had been able to be created; that protection cannot be proved; and also accepted the differing results from in-vitro application disclosed from the CMI studies.

The Respondent’s Representatives emphasised that they had fully recognised that the product could not be promoted as “protection” against the Prajitno strain, and that they had, therefore, elected to use the words “works” which they felt accurately reflected the SPC wording, in the sense that the product had been shown to be active; in their view the term equated to having “an effect”.

The Respondent’s Representatives were questioned closely by both the Chairman and Members, querying whether readers would not equate “works” with “being effective” and would assume that meant “protection”. The Respondent’s Representatives did not consider this was the case. They never intended to imply any protection from the product against this strain.

The Respondent’s Representatives also explained that their process had been designed to obtain European regulatory approval as well as UK regulatory approval, and that the current impracticality of obtaining a proper challenge model ensured that they could not promote the same effectiveness of Spirovac against both strains. However, they took the view that in producing the product’s Data Sheet, the choice of placement as regard the product’s activity against the Prajitno strain, could have been placed, if they wished, under the Indications for Use paragraph and, therefore, in their view, anything that was contained in the SPC as regards the product’s capabilities constituted a licence. In responding to the enquiry, the Respondent’s Representatives did not consider that the promotion suggested the product was equally effective against both strains. They emphasised their wording was intended to recognise the differences, notwithstanding that they argued that it was licensed against both strains, because that was what was stated in the SPC.

After discussion, the Members were unanimous in their view on the word “works” which was felt to be both misleading and contrary to the SPC.

There was greater discussion on the licensing issue where some Members sympathised with the view expressed by the Respondent and felt that the Respondent was entitled to treat the words in the SPC as amounting to a licence. However, on a vote being taking, the decisions of the Committee were:-

Item 1

The Committee considered that the wording complained of was misleading and was inconsistent with the SPC since it amounted to a claim that Spirovac conferred protection against L. hardjo prajitno when the SPC acknowledges that such protection has not been demonstrated. Accordingly the Committee found a breach of clauses 4.3 and 4.7.

Item 2

The Committee considered that the wording complained of was misleading and (by a majority) was inconsistent with the SPC since it amounted to a claim that Spirovac was licensed for use against both L. hardjo bovis and L. hardjo prajitno when it is only licensed for use against L. hardjo bovis. Accordingly the Committee found a breach of clauses 4.3 and (by a majority) 4.7. It was noted by some Members of the Committee when the Chairman read out the wording of the decision for approval, that it did not specifically refer to the use of the word “works” and it was agreed that the Undertaking sought from the Respondent should specifically refer to the word.

Undertaking

All participants found in breach of the Code are required under Rule 15(i)(a) to give an undertaking that the practice in question (if not already discontinued) will be discontinued.

Pfizer Ltd signed the following undertaking on 14 February 2008:

  1. We acknowledge the decision(s) of the Committee in Case 268/01/2008 as set out in your letter of 5 February 2008.
  2. We accept the decision(s) of the Committee and undertake that the practice(s) in question (if not already discontinued) will be discontinued forthwith, and to that end, we have taken the following steps in relation to any promotion of Spirovac® (until or unless specifically authorised for such treatment by the product’s SPC without any acknowledgement or other qualifying statement to the effect that protection by Spirovac® against L. hardjo prajitno has not been demonstrated):
    1. (a) Forthwith to cease and immediately to suspend any practice which includes any claim that Spirovac® “works” against L. hardjo prajitno, or which by other words, connotations or means, suggests or implies or tends to imply that that product provides protection against that strain; or
    2. (b) Forthwith to cease and immediately to suspend any practice which includes any reference to Spirovac® being licensed for use against L. hardjo prajitno.
  3. We hereby give an assurance that we will take all possible steps to avoid a similar breach, or breaches, of the Code occurring in the future.

On 10 July 2008 the NOAH Board discussed a Report from the NOAH Code of Practice Committee regarding a breach of an Undertaking by Pfizer Animal Health, relating to the promotion of Spirovac®.

Three promotional items issued following the Undertaking were deemed by the Code of Practice Committee to be in breach of this Undertaking, and this decision was then reported to the NOAH Board.

Pfizer was formally reprimanded for their conduct. Pfizer will be writing to all recipients of the offending material to apologise, and to correct any misunderstanding that may have arisen, namely to explain that Spirovac® only has a licensed claim for protection against one of the two strains of bovine leptospirosis, the hardjo bovis strain. Although Spirovac® has been shown to stimulate an antibody response against the second strain, hardjo prajitno, protection against this strain has not been demonstrated by challenge studies and it therefore has no licensed claim against this strain.

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Case No. 270. Merial Animal Health – Intervet/Schering-Plough Animal Health: Promotional material for Equilis Prequenza

This case involved three items of complaint from Merial Animal Health relating to promotional material from Intervet/Schering-Plough in relation to their product Equilis Prequenza®. One promotion was in the Veterinary Times (May 2008 onwards) and the two other promotions were in The Equine Veterinary Journal (September 2008). The complaints were:-

(1) The Veterinary Times

“Contains HA* and NA** …… Reduces viral growth and shedding.”

* ‘HA’ = Hemagglutinin
** ‘NA’ = Neuraminidase

(2) Equine Veterinary Journal

“Does your flu vaccine provide dual protection against emerging strains…? …. Prequenza does”.

(3) Equine Veterinary Journal

“Equilis Prequenza and Equilis Prequenza TE were shown to have high levels of NA activity – giving your clients added piece of mind all year round.”

Merial alleged there was an unsubstantiated assignment of merit given to the Neuraminidase component of Equilis Prequenza which, in the case of the first item, was in breach of Code of Practice Clauses, 4.5, 5.1 and 5.2 and in the case of the second item, was in breach of Clauses 4.3, 5.1 and 5.2 and in the case of the third item, was in breach of Clause 4.3.

The relevant Code of Practice Clauses are recited below:

4.3 Information about animal medicines must be accurate, balanced and must not mislead, either directly or by implication, so that critical unbiased judgements and decisions can be made.

4.5 All information included in promotional material must be capable of substantiation and substantiation must be provided without delay in response to enquiries.

Such substantiation need not be provided, however, in relation to the validity of indications approved in the current marketing authorisation.

5.1 Claims for the usefulness of an animal medicine must be based on an up-to-date evaluation of all the evidence and must reflect this evidence accurately and clearly.

5.2 Exaggerated claims must not be made and all-embracing claims and superlatives avoided. Claims must not imply that an animal medicine, or an active ingredient, has some special merit, quality or property unless this can be substantiated.

It was noteworthy that whilst the Complainant alleged a failure to substantiate the promotion contrary to Clause 4.5 in the case of the first item, no such allegation was made in the case of items 2 and 3.

The formal response supplied by the Respondent was very detailed with many supporting references. Notwithstanding the substantial amount of technical data supplied, however, two references had not been supplied which caused concern to some members of the Committee, especially as there was a lack of challenge data to support the alleged benefit in the NA component.

The Committee was operating the changed procedure brought in to the Rules by the 19th Edition of the Code of Practice Rules and Constitution which took effect in July 2008. Accordingly the Complainant now had two further rights from that previously enjoyed. That is to say, to receive a copy of the Respondent’s formal response and further, if the Complainant so wished, to be represented at the hearing. The Complainant had chosen not to be represented.

The Chairman, having summarised the Case, a discussion ensued.

A Member who indicated he had a knowledge and experience in the equine vaccines referred to, felt that he could give some background information which would be of use. He said within the influenza vaccine market, the issues governing equine protection were similar to those within the human market and that there was always a race to try to cater for the latest strain. He said that he understood the Complainant, Merial’s, own vaccine was limited to the element HA, but involved a more recent strain that the current product in question, which contains both elements HA and NA. One of the effects of influenza is that with annual protection, vaccines will generally give different levels of response and provide cover up to a certain threshold. However, flu viruses shift. Vaccines developed for old strains may still give some extra protection. He gave a description of the various recent strains involving Sydney 207 and others, which sometimes can be expected to follow the same path as earlier strains, but which could never be guaranteed will be the case. Nevertheless, because of the nature of shedding and strain development, the horse that had been the subject of vaccination was likely to get some protection, but how good that protection would be would depend very much in the shift in the strains and which particular strain was involved in the influenza infection in question. He expressed some concern about the description “dual protection”. He accepted the principle that there may well be some protection and thereby immunity utilising both elements, but in his belief, it was unclear whether the Respondent’s product would necessarily give whole protection in the manner implied by the promotion. The other issue which needed to be considered was how much benefit could be attributed to NA. A third point was as to what benefit does it induce – if one looks at two vaccines, one which had HA alone and one which had HA and NA, would there necessarily be a better protection with the latter? The references often say “may”, but he did not feel that it could be said with certainty that in any particular case, that the inclusion of the element NA would necessarily have a benefit. This was particularly the case when one relates the alleged claim to emerging strains which is what is stated in the second promotional piece.

Another Member again expressed surprise at the Respondent not having provided some form of challenge studies which view was supported by another Member, who considered that the main concern was that as there is no challenge study to support the claim, it is impossible to show whether one vaccine against another has the same activity, far less whether it actually created a greater production of antibodies and, therefore, greater protection.

The Chairman suggested that the references indicated some level of protection was given.

Another Member agreed with all the references, but did not feel that they established that there was a high level of protection provided by the inclusion of NA, in that it was impossible to show, from the data that had been supplied, the extent to which NA was providing that protection as opposed to the HA element. Another Member commented on the lack of proof available, bearing in mind that by definition, all challenges would have to involve all strains which was a practical impossibility. Effectively, there was no data, in that Member’s view, to support the promotion. Another Member emphasised how the South African 05 strain may not have related to the Sydney 07 strain, and he was concerned by the promotional reference to emerging strains.

Another Member expressed concern at the misuses of the English language, in his view. Terms such as ‘emerging strains’ and ‘dual protection’ required a considerable degree of education on the part of the reader. If one were to take the wording to its literal limit, it could mean that the product could provide protection for evermore and influenza simply does not work like that. A failure to vaccinate regularly could result in a calamitous situation.

A Member added that the query “does your flu vaccine provide dual protection against emerging strains” of itself was acceptable. It was the provision of the answer “Prequenza does” which created the difficulty in his view.

The Chairman summarised that it was the reference to ‘dual’, ‘protection’ and ‘emerging strains’ within the promotion which constituted the area of greatest concern to the Committee, from Members’ previous comments.

At this point the Representatives of the Respondent were invited into the room, they being Mr Alasdair King and Mr Angus Robinson.

The Chairman expressed concern that it would appear two references, numbered 17 and 18, constituting two recent challenges, had not been provided.

The Respondent’s Representatives apologised for this fact and acknowledged that whilst had one of the studies in question, they did not have both. The Chairman asked them, nevertheless, to give some explanation as to what the two studies showed. In their summary they simply made the point that they did not believe that the Respondent was in breach of the Code of Practice and that whilst there had been a full inter-company discussion on the first piece of promotion, on the second and third items there had been no ability to discuss the matter before the complaint was made to NOAH. It was suggested that there was no disputing the fundamental point that including the NA element within the competence of the vaccine would assist in the overall benefit of that vaccine. Specifically in relation to the first promotion, the fact that their product contains HA and NA is a simple statement of fact, as is the reference to reducing viral growth and shedding. Insofar as the second promotion was concerned, their view was that dual protection did provide protection against emerging strains. Having both elements in the vaccine created an antibody response through dual action. On the third promotion, it was felt that this was simply an extension of the second claim; the inclusion of both NA and HA activity created a dual activity because NA provided the slower response and it provided longer and therefore greater piece of mind to the client. The Representatives emphasised that they did not seek to imply that NA itself had any particular merit by way of measured action in any specific case. It was suggested that the brochure needed to be read as a whole and referred in particular to the graphs on subsequent pages. There were studies as to the dual content with the usual challenge data and it was emphasised that the challenges carried out by or for the Respondent were particularly robust. Nevertheless, however robust they may be and whilst disclosing a clear benefit in having both elements HA and NA, it had not been possible to ascribe any particular merit in relation to NA as against HA. It was suggested that one has to look at the component as a whole. To break that down would be an extremely expensive trial. All the promotion sought to say is that NA has a role to play in immunity. A vaccine with NA was superior to a vaccine with only HA.

Answering a query as to the evidence to support that contention, it was stated that the references showed that NA has some involvement in the protections offered. They were not saying that complete protection was being supplied, as that was not possible. All they were saying is that having NA provided an improvement over not having NA. They said that there was possibly an argument for NOAH to consider whether the term ‘protection’ needed greater regulation, in much the same way as it is not permitted to use the word ‘safe’, but at the present time this was not a requirement and the industry understood that the meaning of “protection” did not imply total protection which was, at the levels of current equine influenza vaccines, not possible.

Answering a query on the age of the strain being used in the production of the vaccine, it was stated that that did not alter the fact that NA was a useful part of the protection process.

It was asked that if there was a comparison using an HA vaccine with no NA content but from a more recent strain than that used in the production of a vaccine with HA and NA, would not the Respondent accept that it might well be the case that the one with only HA would be more effective than the one with both HA and NA. In response the Respondent’s representatives described the form of influenza, which has various strains, splitting like branches of a tree. The recent approach, particularly within the human market, has been to try to “chase” the most current strain in an expectation that future strains would be likely to follow that particular “branch”. However, that is not necessarily what occurs and sometimes the strain that then follows is from a totally different branch, in which event the product that relies on the first strain, will be less effective as against the next strain. However, there will be some protection and the fact that the product then includes NA will ensure that that protection lasts longer than a product that has HA alone.

The Respondent’s representatives were challenged to justify the claim that the inclusion of HA provided protection against emerging strains, and that the degree of protection would depend crucially on the particular strains which were emerging. They stated that there were two provisional ways of managing protection and that whatever strain was involved, vaccination would give some level of protection. No vaccine is going to give complete protection, but the inclusion of NA ensured that such protection that was given would continue longer. They again emphasised that within the industry it was understood that the use of the term ‘protection’ did not imply total or complete protection.

The reference to “high levels of HA and NA” was queried and it was asked to what those high levels related to. In response it was suggested that the product had incredibly high levels, way ahead of the standard range. Accordingly, it was maintained that high levels of activity would arise and with the NA content, this could continue for a longer period.

It was asked whether the inclusion of NA within the vaccine would create a greater level of antibodies. The Respondent Representative’s view was that they were sure that it did, even if it was not possible, at the present time, from the challenge models available, to establish that as a fact. What had been shown was that the inclusion of NA generally appeared to have a beneficial effect for a longer period.

It was asked why there was no mention of NA content within the SPC and it was explained that to get the SPC the parameters now required precise measurement. There was no way of measuring NA. Accordingly, NA content could not be referred to at the present time.

A Member asked if there was any challenge data which compared a vaccine with old HA strains, but including the NA element, as against a new vaccine against a newer HA strain but without the NA element. The Respondent’s representatives maintained that there were several different studies involving different strains over time. That it was impractical to be able to provide a precise challenge model of the nature indicated that would be relevant or material, because of the shedding and changing of strains which would then render the challenge model of little practical relevance. Nevertheless, the inclusion of NA clearly had been shown to inhibit shedding for a longer period than if the vaccine does not contain NA. It was shown that having a horse vaccinated did provide better protection, even in the context of newer strains, than not doing so. It followed, therefore, that vaccination which included the NA element would be likely to last longer and therefore give greater protection than one that did not. It would give a broader level of protection.

Another Member said that he did not have a problem concerning the different components of the flu virus. His concern was the suggestion that there was protection against emerging strains. That would depend entirely on which particular branch the emerging strain came from, as against the strain used within the Respondent’s product. The Respondent’s reply was that with current technology that could be correct, but they would suggest that there would be a stronger likelihood of defence by having the NA included than if it were not. Another Member emphasised the reference to dual protection as against any new strains and suggested that this might imply to a Veterinary Surgeon that there would be no need to repeat vaccinations and secure new vaccinations in the context of emerging strains. The Respondent’s representatives did not believe any Veterinary Surgeon would believe that within current use of industry terms. It was fully accepted that the term “protection” did not imply 100% protection. It was suggested that what they were offering were two different routes to protection by the inclusion of NA.

Another Member suggested that immunity is never absolute, and in answer to that and a further query from a Member, the Respondent’s representatives suggested that no vaccine could ever get to the point where there will, in the context of influenza, be a complete immunity. Nevertheless the fact that a vaccine contains the NA element, provides greater confidence that there will be a longer level of protection. They went on to say that they were suggesting there was a better chance of protection if the vaccine had NA, but accepted that there was no absolute defence. Concentrating on utilising the latest strain based on the HA element, had proved not to provide satisfactory protection in the context of the Newmarket virus, which was one of the few occasions where the influenza virus had killed horses. Nevertheless, the fact was that those horses which had been vaccinated did have a greater level of protection.

Another Member queried reference to ‘dual protection’ when there was no evidence of any level of antibody production resulting from the inclusion of NA. The mere fact that there was activity did not necessarily imply an increase in antibody production. The Respondent’s representatives agreed with this; they were unable to establish precisely the benefit of NA in the context of antibody production, but that nevertheless, there was an overall additional level of protection to protect the horse against future strains.

Finally, another Member expressed concern at the lack of proof being shown by the challenge model, that a vaccine containing HA and NA would necessarily provide a greater level of protection than one without NA. The Respondent’s representatives again confirmed that, in their view, the challenge models clearly showed including NA would give a broader and longer element of protection than not having it. It was not possible, however, to quantify the benefit that NA supplied in any particular case, as against HA.

Following departure of the Respondent’s representatives, who were thanked by the Chairman for their attendance and after further discussion, the Committee’s decisions were as follows:-

Item 1

The Committee considered that the statements complained of were statements of fact which were adequately substantiated. Accordingly the Committee found no breach of any of clauses 4.5, 5.1 or 5.2.

Item 2

The Committee considered that the claim that Prequenza promised “dual protection against emerging strains” was an all-embracing claim and was not substantiated since it had not been demonstrated either that the NA component in Prequenza provided protection or that Prequenza protected against strains which have not yet emerged. Accordingly the Committee found a breach of clauses 4.3 and 5.2.

Item 3

The Committee considered that the claim that the “high levels of NA activity” in Prequenza gave clients “added peace of mind all year round” was not accurate or balanced since it had not been demonstrated that the NA activity resulted in increased protection. Accordingly the Committee found a breach of clause 4.3.

The Secretary asked whether there was any concern about the apparent failure to enter into inter-company discussions on the two elements of promotion over which it has been held there had been a breach, but the Committee’s view was that strictly speaking, although a very short time limit had been imposed, reference had been made concerning the two potential complaints; it did arise following a lengthy discussion, albeit limited to the first promotional element which had discussed the basic issues; and, most important of all, even after the complaint had been made to NOAH, the Respondent chose to dispute that both items of promotion were in breach of the Code, in vigorous terms.

Undertaking

All participants found in breach of the Code are required under Rule 15(i)(a) to give an undertaking that the practice in question (if not already discontinued) will be discontinued.

Intervet/Schering-Plough have been required to sign the following Undertaking:

  1. We acknowledge notification of the decision(s) of the Committee in Case 270/09/08 as set out in your letter of 1 October 2008.
  2. We accept the decisions of the Committee and undertake that the practices in question (if not already discontinued) will be discontinued forthwith, and to that end, we have taken the following steps in relation to any promotion of Equilis Prequenza®:
    1. (a) Forthwith to cease and immediately to suspend any practice which includes any claim that Prequenza promises “dual protection against emerging strains”; and
    2. (b) Forthwith to cease and immediately to suspend any practice which includes any claim that the “high levels of NA activity” in Prequenza gives clients “added peace of mind” for “all year round” or for any period.
  3. We hereby give an assurance that we will take all possible steps to avoid a similar breach, or breaches, of the Code occurring in the future.

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NOAH Ltd
20 November 2008 (to add case 270)