Code of
Practice for the Promotion of Animal Medicines
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):
(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
(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®:
(a) Forthwith to cease and immediately to suspend any
practice which includes any claim that Prequenza promises "dual
protection against emerging strains"; and
(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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