2014 cases

Code of Practice for the Promotion of Animal Medicines

Précis of Committee meetings held in 2014

Case No. 288/11/14. Complaint by Merial Animal Health against MSD Animal Health regarding Equilis Prequenza Vaccine

This complaint centred on the wording in the advertisement:-

“Neuraminidase antibodies provide a degree of protection in the case of HA strain/vaccine mismatch”, which was under a heading:-

“Why have part when you can have it all”, it being suggested by the Complainant, that as a result, the wording wrongly implies that the NA component in an equine influenza vaccine has a relevant influence on immunity (and therefore protection). As a result, the Complainant argued that the advertisement was in breach of the Code Clauses 4.1 (iii) “misleading”; 4.1 (vi) “exaggerated”; 4.1 (vii) “special merit claimed without justification”; 4.2 (i) “inaccurate” and 4.2(ii) “not based on up-to-date evaluations”.

The Chairman emphasised that although referred to in inter-company correspondence and in the letter of complaint, the words also contained in the advertisement “Whole virus vaccines induce a broad immune response due to the presence of the nucleoprotein and RNA”, the Complainant in answer to the Secretary’s query had confirmed that those words did not form part of the wording within the advertisement to which complaint was made.

The Chairman proceeded to draw attention to certain issues which he felt the Committee might properly consider, namely:-

(i) The strapline ‘header’ “Why have part when you can have it all” could provide important context within which to judge the words to which complaint was being made.

(ii) The initial intention by the Respondent to have an academic expert (Professor Andy Durham) was not being proceeded with.

A lengthy discussion ensued, considering the nature of the antigens produced by the whole virus vaccine that comprises Neuraminidase (NA), and whether NA promotes any additional benefit in protecting against emerging strains of equine H3N8 as some research involving the human influenza virus H5N1 had indicated could be the case. It was noted that the Respondent’s product was a whole virus vaccine, whereas the Complainant’s product for equine influenza was a viral vector vaccine containing HA only. The parties’ written arguments with considerable supporting material, was considered in depth.

The Chairman summarised what seemed to be the consensus prior to hearing the parties’ representatives that:-

(a) The hub of the issue was whether there was scientific justification in stating that “Neuraminidase antibodies provide a degree of protection in the case of HA strain/vaccine mismatch” and whether the research into its effects on the human influenza strains could properly be used to justify those promotional words; and

(b) In determining those questions, the question of whether the promotion was intended to be educational to the reader was irrelevant, in that clearly the advertisement did not fall into the criteria of Clause 4.0A of the Code.

The parties’ Representatives were invited to join the Committee and made their presentations which were considered to be excellent.

After introducing himself and the Committee Members to the parties’ Representatives, the Chairman invited the Complainant’s representatives to make their presentation.

That presentation emphasised that the two surface antigens in the influenza virus, Haemagglutinin (HA) and Neuraminidase (NA), classify the type of virus into in this case, H3N8 in the horse and other classifications in humans. It was also emphasised that the antibody linked to immunity that acts to halt virus entry into a cell relates to the HA antigen. Furthermore, it was said that the OIE/ESP (World Organisation for Animal Health’s export surveillance panel) only recommends HA antigen strain inclusion within equine vaccines. The words to which complaint is made relate to research of the human influenza virus, and there is no proven evidence to show that NA provides any additional benefit to emerging strains, or antigenic draft, in the case of horses. As such, the words mislead, exaggerate, maintains a special merit, is inaccurate and is not based on an up-to-date evaluation, in breach of Code of Practice Clauses 4.1(iii); 4.1(vi); 4.1(vii); 4.2(i) and 4.2(ii).

The Representatives for the Complainant added:-

I. In the promotional words to which complaint was being made the word “can” is missing from what is purported to be a research statement;

II. As such, the statement was unsubstantiated; and

III. Remains unsubstantiated notwithstanding vaccination and specifically following injection with the Respondent’s inactivated vaccine ‘Equilis Prequenza’ in horses.

The Respondent’s Representatives then gave their presentation which emphasised the educational intent behind the advertisements.

They emphasised that two of the four commercially available equine vaccines contain the whole inactivated influenza virus, one of these being their product Equilis Prequenza. The other two, in one case a subunit vaccine containing HA and NA, the other (the Complainant’s product) contains HA only. Promotions by manufacturers of subunit vaccines, which over-simplify matters, suggested that the strain of influenza included is the sole consideration to be given when evaluating influenza vaccines, such that older subunit vaccines with outdated strains do not provide for protection. This is contrary to current field experience, where equine influenza continues to circulate at a low level in unvaccinated animals, and that accordingly, current equine vaccines such as Equillis Prequenza promote useful protection despite drift in the HA component away from their vaccine strains. It was suggested that despite understandable and correct focus on Haemagglutinin, it is widely understood that immunological targets other than this came into play in response to influenza infections. The Respondent relied on several academic sources which were cited including Professor Josh Slater, the Professor of Equine Clinical Studies at The Royal Veterinary College; Marcelin et al in a paper of Rev. Med Virol July 2012 “Contribution of antibody protection against neuraminidase to the protection afforded by influenza vaccines”, Palliot in papers 2006; 2010 & 2012; Culliane et al (2013) “Equine Influenza – A Global Perspective”, amongst others.

The Representatives for the Respondent added:-

I. Avian, swine, equine, canine and human influenza are all Influenza A viruses and immunological mechanisms in mammals are similar.

II. The Complainant’s marketing message focussed solely on the HA component and used selected parts of the OIE recommendations regarding appropriate strain in a way which reduces confidence in the current efficacy of competitor vaccines, such as the Respondent’s.

III. The immunity induced by this vaccine is directed against HA proteins that are subject to antigenic drift. Accordingly, the Respondent claimed regular updating of the vaccine will be required to ensure continued efficacy.

IV. The Equilis Prequenza vaccine contains flu strains antigenically distant (with respect to HA) from Richmond 07 flu strain.

V. In a challenge study horses, vaccinated with Equilis Prequenza, had significantly reduced clinical signs and reduced viral shedding when challenged with the influenza strain Richmond/1/2007.

VI. The significance of components other than HA in influenza is emerging from recent evidence.

VII. Challenge and field efficacy studies provide evidence that currently available vaccines continue to offer a significant degree of cross-protection against strains which appear different based on HA, which raises questions of how this might occur.

VIII. The advertisement was designed to show the educated reader how recent relevant research is informing under guidance for the formulation of human and animal influenza vaccines.

IX. The statement sits under the title “Recent Influenza vaccine research demonstrates;”

X. No claim for Equilis Prequenza is made.

XI. Accordingly, the Respondent’s Representatives denied the statement was in breach of the Code of Practice Clauses cited by the Complainant.

It was, therefore, denied that the statement was inaccurate and unbalanced or exaggerated, or thereby, in breach of the Code of Practice.

During the Respondent’s presentation the Chairman sought clarification on:-

(i) Whether the advertisement quoted the Marcelin paper, which was confirmed by the Respondent’s representatives.

(ii) In what part of which paper were the Respondent’s relying specifically to show that there was direct support by actual medical and scientific evidence to justify the promotional words, for example, the Palliot papers supplied, to which reference was made both to Marcelin and Palliott, which references were questioned in detail by the Chairman to establish how the claim was truly so supported as suggested by the Respondent.

(iii) How the leaflet or advertisement could be stated not to be the promotion of their product Equilis Prequenza, given the direct and clear reference to the product and its header “Why have part when you can have it all?”

The Representatives were asked to leave, and a further lengthy discussion ensued, as a result of which the unanimous decision of the Committee was that the phrase “Neuraminidase antibodies provided a degree of protection in the case of HA strain/vaccine mismatch” (“the Item”), when viewed against the context of the advertisement headed ‘Why have part when you can have it all?” was in breach of Code of Practice Clauses 4.1(iii), 4.1(vi) 4.1(vii), 4.2(i) and 4.2(ii).

The Committee, whilst noting that Case 270/09/08 did involve a similar scenario referable to a product with the same Marketing Authorisation (albeit since varied), felt that the decision made by the Committee in that case was of marginal relevance to this Case because the actual words constituting the promotion to which complaint was made were not the same, and because the scientific articles relating to NA have moved on considerably since then.

That said, the Committee made the following unanimous findings:-

The advertisement was promotional and as such had to be subjected to the full rigour of the Code of Practice. It was suggested in the hearing that it was an “educational advertisement”. However, the Code distinguishes clearly between educational leaflets (see Clause 4.0A of the Code of Practice) and Promotions which are dealt with under Clause 4.1 et seq. The requirements of Clause 4.0A are strict and obviously it was inapplicable to the advertisement in which the Item appeared.

Furthermore, the Item appeared with a prominent strap line “Why have part when you can have it all?” and “Equilis Prequenza contains the whole influenza virus”. The Committee considered that it was correct to take into account, when considering the complaint against the Item, that the Item was being used to imply that a whole influenza virus vaccine which contained NA as well as HA was more clinically effective in preventing equine influenza than one which merely contained a HA antigen.

Thus, the central issue was whether vaccines with NA antigens did provide more protection in combating equine influenza than those without NA antigens (‘the Claim“).

In this regard, the Committee considered carefully the scientific papers to determine whether the Claim was substantiated. It came to the view that the Claim was not proven. It took account of the following factors:

  • There was inadequate evidence and clinical trials of equine vaccines with NA antigens as against those without NA antigens to support the Claim.
  • The scientific papers merely canvass the possibility that the inclusion of NA antigen in a vaccine may provide clinical benefits in dealing with the influenza virus.
  • The papers primarily related to humans. Whilst there were papers concerning horses, the findings of those papers were equivocal as to the effectiveness of NA in combating equine influenza.
  • Professor Slater’s statement that there was “little study” of the role of antibody directed against NA in protective immunity but that “extrapolation” from Influenza A virus infections in humans suggests that antibody against NA “may be important” in limiting the severity of clinical signs (which the Committee considered was very equivocal)
  • The Marcelin paper expressly relied upon for substantiating the Item in the advertisement did not concern horses and was tentative in its conclusions.
  • The Committee was mindful of the fact that in the Response, the Respondent merely sought to say that the purpose was “to provide education to the reader that features beyond the HA antigen may have relevance in respect of the immune response to influenza viruses” and that the purpose was to “highlight pertinent research from the influenza literature”. Thus, the Respondent’s primary approach was not to substantiate the Claim but rather to suggest that no claim was being made with regards to whole virus vaccines such as Equilis Prequenza. As said above, the Committee did not accept that it should ignore the fact that the Item was being used in an advertisement and that on a natural reading of it, was intended to promote the clinical benefits of using whole virus vaccines (which have NA antigens) as against those which did not have NA antigens.

In conclusion, the Committee concluded that the Item in the context of the advertisement was intended to mean and did convey the meaning that the inclusion of NA antigens in an equine vaccine gave that vaccine a clinical advantage over vaccines which did not. Such was not substantiated. Accordingly, it was misleading, contained an exaggerated claim, implied it had a special merit which was not substantiated was not accurate and was not based upon an up-to-date evaluation of all the evidence.

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