AUTH/3159/2/19 - Pharmacosmos v Vifor

Promotion of Ferinject

  • Received
    13 February 2019
  • Case number
    AUTH/3159/2/19
  • Applicable Code year
    2016
  • Completed
    13 December 2019
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    No
  • Review
    To be published in the review

Case Summary

Pharmacosmos UK Ltd complained that medical department personnel from Vifor Pharma UK Limited had proactively contacted health professionals to discuss information about Ferinject (ferric carboxymaltose) which was misleading with regard to the Pharmacosmos product, Monofer (iron isomaltoside 1000). Ferinject and Monofer were both indicated for the treatment of iron deficiency when oral iron preparations were ineffective or could not be used.

Pharmacosmos stated that in December 2018 it was contacted by several UK health professionals who were concerned about the way in which safety data about Monofer, from Ehlken et al (2018) had been proactively brought to their attention and discussed by Vifor including members of the Vifor medical team. Ehlken et al evaluated the rates of severe hypersensitivity reactions reported with Ferinject and Monofer in Europe based on data from Eudrovigilance and VigiBase between 2014 and 2017. The study was funded by Vifor.

Pharmacosmos was concerned that this might have occurred in relation to promotional activity by Vifor and opened inter-company dialogue in December 2018 to discuss concerns over the validity, accuracy and quality of the publication being used in this way and to ask for further clarification on the use of Ehlken et al. In its response, Vifor stated that it had not proactively disseminated Ehlken et al, it was not using the paper for promotional activities and its medical teams had not solicited requests for it.

Subsequent to the inter-company exchange, Pharmacosmos received a written statement from a health professional regarding the same article, where he/she had been contacted by Vifor Pharma headquarters, and that the data had been discussed by Vifor Pharma, including by a member of the Vifor medical team. Pharmacosmos submitted that it had received similar verbal reports from other UK health professionals, which also indicated that the article was sent to them by a weblink in an email, without this having been requested by the health professionals.

The health professional in question was a consultant working at an NHS hospital. He/she was emailed by Vifor in the middle of December. The contact was initiated through Vifor Headquarters and was unsolicited. Vifor asked for a telephone meeting to discuss a potential study between Ferinject and Monofer. The health professional understood this was an invitation to participate in a potential future study and accepted the invitation. The Vifor employees that telephoned were not known to the health professional although at least one was believed to be from the medical department. The health professional was surprised to discover that the call was to inform him/her of the results from Ehlken et al. The content of the call described data focussing on a difference between Monofer and Ferinject with regards to hypersensitivity risk. No evidence from other studies was presented. The health professional did not receive an honorarium and no contract was created (so this was not a consultancy arrangement to seek advice on the paper).

Pharmacosmos contended that, based on the evidence provided by the statements, the information provided by Vifor in this case was solicited through proactive contact with health professionals and the topic of discussions was decided upon by Vifor, not in response to any enquiry by the health professionals. The activity was thus promotional.

Pharmacosmos was further concerned about the accuracy of the information provided to health professionals; it did not consider that the information provided was balanced. The article viewed in isolation was fundamentally misleading. Pharmacosmos therefore considered that the matter fell within the scope of the Code.

Given that Vifor had again provided misleading information, unsolicited, to health professionals, that could cast doubt on the safety of Monofer through misleading comparison with Ferinject, it appeared that the same pattern of behaviour had continued despite rulings in two previous cases, Case AUTH/2828/3/16 and Case AUTH/2830/4/16.

Pharmacosmos thus alleged that Vifor had not maintained high standards.

Pharmacosmos alleged that Ehlken et al provided and discussed with the health professionals, contained inappropriate and misleading content.

The study design could not be legitimately used to compare the safety of two products.

The article was not based on an up-to-date evaluation of all the evidence and did not reflect that evidence clearly, and the wider context of the data was not provided in the meetings.

Pharmacosmos alleged that as the article and associated activities could not take the benefit of the exemption from the definition of promotion, they could only be regarded as promotional. The data discussion was led by a member of the medical team and in the context of the delivery in this case, the activity’s promotional nature was disguised. This was highlighted by the health professional’s statement above that the impression given to him/her was that he/she was being asked to discuss potential future studies.

Pharmacosmos stated that Vifor’s letter in response to inter-company dialogue made it clear that Ehlken et al, and associated activities, had not been certified for promotional use. As the health professional statements made clear that this paper was used in a promotional manner, this indicated that Vifor had failed to adhere to Code requirements for certifying promotional materials.

Given the nature of Vifor’s reported activity, the concern that it had raised amongst health professionals, and that Vifor had continued a pattern of behaviour that resulted in multiple clause breaches in two previous cases, Pharmacosmos alleged that the company’s conduct had brought the industry into disrepute, in breach of Clause 2.

The detailed response from Vifor is given below.

The Panel noted that there were differences between and within the parties’ accounts; it was extremely difficult in such cases to know exactly what had transpired. The complainant bore the burden of proof on the balance of probabilities. A judgement had to be made based on the evidence provided by both parties.

The Panel noted that Pharmacosmos provided an unsigned statement which appeared to have been written based on information from a health professional it referred to as HCP1 (health professional 1). Pharmacosmos did not disclose health professional 1’s identity. Vifor identified health professional 1 as there were only two people with whom the Vifor Chief Medical Officer (CMO) discussed his paper. Vifor provided a signed statement from a named Professor referred to as health professional 2.

The Panel noted that the complaint concerned the use of the article by Ehlken et al (2018) which evaluated the rates of severe hypersensitivity reactions reported with Ferinject and Monofer in Europe based on data from EudraVigilance and VigiBase between 2014 and 2017 and was funded by Vifor.

Pharmacosmos alleged that Ehlken et al, which in its view contained inappropriate and misleading content, was being proactively provided to or brought to the intention of several health professionals and was being discussed with them by Vifor.

The Panel noted Vifor’s submission that it had not used Ehlken et al promotionally and had not briefed medical teams either locally or globally to disseminate the publication to any health professionals in the UK. Vifor submitted that its CMO, one of the co-authors of Ehlken et al, contacted three but only spoke to two professors to explain the rationale, results and limitations of the study and answer any questions.

The Panel considered that Pharmacosmos had, on the balance of probabilities, established that the paper in question had been discussed with at least one health professional. Vifor accepted that it had discussed the paper with two health professionals. The first matter to be determined by the Panel was whether the interaction was promotional or non-promotional. The second matter to be determined was whether, on the balance of probabilities, Pharmacosmos had established what was said about the paper in question and if so whether what was said was in breach of the Code.

The Panel noted Vifor’s submission about the importance of peer-to-peer interactions. In the Panel’s view, peer-to-peer interactions between senior company medical employees and senior health professionals were not unacceptable so long as they complied with the Code. Whether such interactions were promotional or non-promotional would depend on a consideration of all the circumstances whilst noting the broad definition of promotion in Clause 1.2. Relevant circumstances would include whether the discussion was an integral and relevant part of an ongoing consultancy. In the Panel’s view, Vifor had submitted conflicting accounts about whether there was a current consultancy at the time of the interaction. It appeared that, according to Vifor, both health professionals were currently consultants in the context of NICE HTA procedures; there was no evidence before the Panel that the paper in question was relevant or integral to that consultancy. The Panel noted that the employee’s statement referred to seeking the health professionals’ scientific advice. The Panel noted Vifor’s submission that the advisory nature of the relationship in relation to the discussions as described by Vifor were not formalised in any consultancy agreement. Given these points the Panel did not consider, on the evidence before it, that the arrangements could be described as an advisory board or similar bearing in mind the requirements of Clause 23.

The Panel noted Vifor’s submission that neither health professional considered the interaction promotional. The Panel noted the broad definition of the term ‘promotion’ at Clause 1.2 of the Code which, in the Panel’s view, was likely to be different to a lay person’s use of that term. A discussion of clinical matters, depending on the circumstances, might fall within the broad definition of promotion in the Code.

Given its comments above, the Panel queried how the proactive discussion of the paper which directly compared two products and appeared to be in favour of Vifor’s product could be anything other than promotional.

The Panel further noted Vifor’s submission that health professional 1 was confused about the initial purpose of the call. Vifor refused to provide details about what the confusion was despite a number of requests nor did the Panel have before it emails etc about the arrangements for the call. Nonetheless, Vifor’s submission about initial confusion was consistent with the evidence from Pharmacosmos that health professional 1 had agreed to be contacted on the assumption that the telephone call was arranged to discuss a potential future study and was surprised that the call was to inform him/her about the results from the recent publication, Ehlken et al. In the Panel’s view, in relation to health professional 1, the promotional nature of the call was, on balance, disguised. A breach of the Code was ruled.

In relation to health professional 2, according to his/her statement, he/she understood that the reason for the call was to discuss the study and referred to both giving advice and the importance of him/her being aware of such data; that such discussions were an important aspect of clinical work; the importance of listening to multiple opinions and the evidence on which they were based to make the best decisions for patients. In the Panel’s view it appeared that health professional 2 was clear that the call in question would involve a discussion of the paper and in that regard the promotional nature of the call was not disguised. No breach of the Code was ruled.

The Panel noted Vifor’s submission that the article and activities had not been certified for promotional use. The Panel noted Vifor’s submission that it did not provide the two health professionals with a copy of the paper, inform them where they could find it or circulate any emails containing links to the paper. It was unclear to the Panel what exactly was discussed during the conversations between Vifor and the two health professionals. Whilst the Panel had some concerns, it considered that Pharmacosmos had not provided evidence that Ehlken et al had been sent unsolicited to any health professional and therefore that it required certification for such use. The Panel, however, further noted Vifor’s submission that there was no brief to the employee, since he would be discussing his own research. In the Panel’s view, in the absence of briefing material Ehlken et al was the basis of the discussion and therefore should have been certified for such use. The Panel therefore ruled a breach of the Code.

The Panel noted that in Ehlken et al information on spontaneously reported severe hypersensitivity reactions was obtained from and analysed separately for two established safety surveillance databases between 2014 and 2017. The Panel noted Pharmacosmos’ submission that the EMA had previously stated that ‘… to conclude that one product is safer than the other, based on numbers of spontaneous suspected adverse reaction reports alone, without consideration of all other relevant data, including clinical trials and epidemiological studies, is in our view ostensibly simplistic, invalid and misleading’.

According to Ehlken et al findings suggest that iron (III) isomaltoside 1000 was associated with higher reporting rates of severe hypersensitivity reactions related to estimated exposure than ferric carboxymaltose in European countries.

The Panel noted that Ehlken et al concluded that further research investigating the occurrence of severe hypersensitivity reactions associated with iv ferric carboxymaltose and iron (III) isomaltoside 1000 was needed to broaden the evidence for benefit-risk assessment. The Panel noted that Pharmacosmos’ specific concerns included that Ferinject entered most markets 3-5 years earlier than Monofer and it was well-known that spontaneous suspected adverse event reporting rates tended to decrease over time and so it was fundamentally biased and misleading to compare the frequencies during the limited time period from 2014 – 2017. In addition, Pharmacosmos noted that several countries where Monofer was not available had been included in Ehlken et al and rather than this leading to over-representation of adverse events for Ferinject, inclusion of selected markets where Ferinject had been long-established and known to have lower than average reporting rates, could lead to artificial lowering of the reported hypersensitivity rates with Ferinject.

The Panel noted that Ehlken et al acknowledged both of these points as limitations including that the reporting of adverse events might be higher directly after launch compared to when products were well-established on the market but stated that in order to overcome the limitation, the 4-year period from 2014-¬2017 was chosen as both products had already been on the European market for several years. Ehlken et al noted that for the majority of countries both products were available. Whilst an impact of differential marketing on the level of the reporting rate could not be ruled out, it was considered to be minor. The Panel noted each companies’ submission about Ehlken et al. Whilst noting the conclusions of Ehlken et al and the limitations discussed by the study authors, the Panel had very little detail before it about precisely what was said about the study during the conversations with the two health professionals. The statement from health professional 2 did not detail what exactly was said about Ehlken et al during the call. The unsigned statement of health professional 1 provided by Pharmacosmos stated that the content of the call described data focussing on a difference between iron isomaltoside and ferric carboxymaltose with regards to hypersensitivity risk. The Panel did not consider that Pharmacosmos had proved, on the balance of probabilities, what was said about Ehlken et al during the conversations with the two health professionals and whether such statements were misleading; no breach was ruled.

The Panel did not consider that Pharmacosmos had established, on the balance of probabilities, that the discussions about Ehlken et al were misleading because they were not based on an up to date evaluation of all of the evidence as alleged. The Panel therefore ruled no breach of the Code in this regard.

The Panel noted its rulings above and did not consider that, based on the narrow allegation, Pharmacosmos had established that Vifor had failed to maintain high standards in relation to the discussion of misleading information with regard to Ehlken et al as alleged and ruled no breach of the Code.

The Panel noted Pharmacosmos’ reference to the rulings in Cases AUTH/2828/3/16 and AUTH/2830/4/16 and its allegation that Vifor was failing to maintain high standards by once again providing misleading information to health professionals that could cast doubt on the safety of Monofer. The Panel noted its comments and rulings above and considered that based on the narrow allegation there was no evidence that Vifor had failed to maintain high standards and no breach was ruled.

The Panel did not consider that the circumstances warranted a ruling of a breach of Clause 2 which was used as a sign of particular censure and reserved for such use and ruled accordingly.