AUTH/2489/3/12 - Merz/Director v Allergan

Breaches of undertaking

  • Received
    02 May 2012
  • Case number
    AUTH/2489/3/12
  • Completed
    15 October 2013
  • No breach Clause(s)
    25
  • Breach Clause(s)
    2 and 25
  • Sanctions applied
    Undertaking received
  • Additional sanctions
    Advertisement
    Public reprimand
    Audit of company’s procedures
  • Appeal
    Appeal by respondent
  • Review
    Published in the November 2013 Review

Case Summary

Merz alleged that, by again making disparaging, misleading and unbalanced claims about the comparative potency/clinical efficacy of its own products Vistabel/Botox (onabotulinumtoxinA) vs that of Bocouture/Xeomin (incobotulinumtoxinA), Allergan had breached undertakings given in previous cases. Merz marketed Bocouture/Xeomin.

The matters were taken up with the Director acting as the complainant as the PMCPA was responsible for ensuring compliance with undertakings.

Merz submitted that the claims at issue were consistent with previous breaches of undertaking, most recently Case AUTH/2460/11/11 together with Cases AUTH/2183/11/08 and AUTH/2346/8/10. These cases clearly demonstrated a flagrant disregard for the Code and associated sanctions. Merz alleged that Allergan's actions in Cases AUTH/2487/3/12 and AUTH/2489/3/12 were covered by the same undertakings as in the previous cases.

In Case AUTH/2487/3/12 the material at issue was an article in Cosmetic News, March 2012. The article 'Dosages for botulinum toxins are not interchangeable says study' was written as if it were an Allergan press release. At issue in Case AUTH/2489/3/12 was a substantially similar article in the International Journal of Aesthetic and Anti- Ageing Medicine (PRIME), a UK-based publication, March 2012, entitled 'BTX-A [botulinum toxin A] Dosing Not Interchangeable'.

The articles summarised Moers-Carpi et al (2011), (a poster presented at a European meeting in September 2011) that was the subject of the breach of undertaking in Case AUTH/2460/11/11. This was a non-peer reviewed poster authored by two Allergan employees and a third author. The articles made claims about the potency of Vistabel compared with Bocouture – a comparison which had been the subject of Cases AUTH/2460/11/11 and AUTH/2346/8/10 – with the intention of implying that Bocouture was less potent than Vistabel.

Merz considered that the design of Moers-Carpi et al was open to significant question; there was no control arm and unmatched doses of each product were used (20 units of Vistabel, 30 units of Bocouture) making potency comparison difficult. In Case AUTH/2460/11/11 the Panel concluded that the use of Moers-Carpi et al data alone did not reflect the balance of evidence and Merz alleged that this was also the case with the two articles in question. The data had not been used in the context of the summaries of product characteristics (SPCs) recommendations for either product of the same starting dose of 20U. Additionally the data was not contextualised, there was no reference to the regulatory approved study data (Sattler et al 2010) which demonstrated non-inferiority between the two medicines at a 1:1 dosing conversion ratio.Merz noted that the articles also did not refer to Carruthers et al (2005) which compared Botox in eighty females with moderate to severe glabellar frown lines at the doses of 10U, 20U, 30U and 40U. The study demonstrated that Botox showed no measurable clinical difference between 20U and 30U; the authors concluded that there 'were no statistically significant differences among the three higher-dose groups'. It was postulated that in most patients 20U was sufficient to saturate the local nerve endings so that additional dosing had little or no incremental clinical effect.

In summary Merz noted that Allergan had been ruled in breach for suggesting that Xeomin (the same pharmaceutical product as Bocouture) was less potent than Botox (the same pharmaceutical product as Vistabel) in Case AUTH/2183/11/08. Following this Allergan gave an undertaking not to use this or similar claims. This undertaking was breached twice in Cases AUTH/2335/7/10 and AUTH/2346/8/10 and Allergan gave yet another undertaking. In Case AUTH/2460/11/11 Allergan was again ruled in breach of an undertaking relating to product potency claims in relation to Bocouture. Within only one month of the outcome of Case AUTH/2460/11/11, Allergan had briefed a third party to promote the same unbalanced data that it was not able to promote directly.

Merz was concerned that Allergan was relentless in its pursuit of the message that the Bocouture and Xeomin units were less potent than the Vistabel and Botox units against all the clinical evidence and the view of the Medicines and Healthcare products Regulatory Agency (MHRA) and the wider European regulators. Furthermore, Merz had been able to comment on an article in the March issue of Cosmetic News up until 23 February which was some time after the ruling for Case AUTH/2460/11/11.

The detailed response from Allergan is given below.

The Panel noted that Allergan had been notified of the outcome of Case AUTH/2460/11/11 on 26 January 2012, four days before it sent a press release about the Moers-Carpi et al (2011) data to Cosmetic News and PRIME; the subsequent articles were published in the March edition of the journals. In Case AUTH/2460/11/11, Allergan was again ruled to have breached undertakings with regard to claims about the relative potency of its botulinum toxin vs that of the Merz product. One of the matters at issue was about the emphasis given to the Moers-Carpi et al results in the relative absence of other data. Allergan accepted the rulings and signed the relevant undertaking on 3 February 2012; there was no reference in the undertaking to any other material already in press. The Panel noted the submission from Merz that it had been given up until 23 February to comment on an articlewhich was to be published in the March editions of Cosmetic News and PRIME. Allergan submitted that after it had sent the press release on 30 January, it had not had any further contact with the journals or been offered the chance to comment on the articles. The Panel noted that Allergan's PR agency had provided the press release following its contact with the editor of Cosmetic News and PRIME (30 January) in the period when Allergan, having received the notification of the Panel's rulings of breaches in Case AUTH/2460/11/11 (26 January) and report to the Code of Practice Appeal Board, would be deciding whether to accept or appeal those rulings (due 3 February). The Panel also noted that the press release was examined and signed on 25 January which was whilst Allergan was awaiting the outcome of Case AUTH/2460/11/11.

The Panel noted that complaints about articles in the press were judged on the information provided by the pharmaceutical company or its agent to the publisher/journalist and not on the content of the article itself. The articles at issue reproduced large sections of Allergan's press release. The press release was headed 'New study provides further evidence that dosing for botulinum toxins are not interchangeable'; the sub-heading read 'Head to head study launched at international aesthetics congress further reinforces need for awareness of the different doses for two botulinum toxin type A products'. The press release ended with a quotation from one of the authors of Moers-Carpi et al, an Allergan employee; 'We are pleased to see further evidence for the efficacy of Vistabel and consider that this study provides further clarity that Vistabel and the Merz unit doses are not interchangeable in clinical practice'.

The Panel noted that in Case AUTH/2460/11/11 both parties had submitted more information than above. The Panel thus noted elements of its rulings in that case.

In addition it noted that in Case AUTH/2346/8/10 Allergan had been ruled in breach of its undertaking given in Case AUTH/2183/11/08 in that an impression was given that Botox was more potent than Xeomin and this was inconsistent with the SPCs and available clinical data. Breaches of the Code including Clause 2 were ruled.

Turning to the cases now at issue, Cases AUTH/2487/3/12 and AUTH/2489/3/12, the Panel noted that the press release in question (Date of preparation Dec 2011) was itself undated. It had been examined by Allergan on 25 January 2012 according to the certificate. The press release was only about the Moers-Carpi et al data. The results of that study had not been set within the context of the recommended doses for Vistabel and Bocouture according to their SPCs, the statement in the Bocouture SPC that comparative clinical study results suggested that Bocouture and the comparator product containing conventional botulinum toxin type A complex (900kD) [Botox/ Vistabel] were of equal potency and the clinical results of Sattler et al which showed that 24 units of Bocouture/Xeomin was non-inferior to 24 units of Botox/Vistabel in the treatment of glabellar lines.

The Panel did not consider that the discussion of Moers-Carpi et al, in isolation, in the press release represented the balance of the evidence with regard to the relative efficacy of Vistabel and Bocouture. In the Panel's view, the press release implied that in order to achieve the same clinical outcome in the treatment of glabellar lines, 20 units of Vistabel was needed vs 30 units of Bocouture, ie unit for unit, Bocouture was less potent than Vistabel. In that regard the Panel considered that the press release was sufficiently similar to the point at issue in Cases AUTH/2346/8/10 and AUTH/2460/11/11 for it to be covered by the undertaking in Case AUTH/2346/8/10. Thus the press release now at issue breached an undertaking previously given. A breach of the Code was ruled in each case. These rulings were appealed by Allergan.

The Panel noted that an undertaking was an important document and that Allergan's successive breaches of undertaking were such as to bring discredit upon and reduce confidence in the pharmaceutical industry. The Panel ruled a breach of Clause 2 which was appealed by Allergan.

The Panel was concerned that Allergan stated that it had reviewed the press release in relation to the outcome of Cases AUTH/2335/7/10 and AUTH/2346/8/10 and that the press release had been sent out when Allergan would be considering whether to appeal yet another breach of undertaking ruled by the Panel in Case AUTH/2460/11/11. Given the seriousness of the situation, the Panel considered that Allergan should have taken urgent action and considered not using the press release until it had decided whether to appeal Case AUTH/2460/11/11, particularly as the form of undertaking required withdrawal of any similar material. Allergan could have contacted the editor of both journals following its provision of the undertaking in Case AUTH/2460/11/11. However, the Panel noted that the press release was used on 30 January and that the undertaking was dated 3 February. Thus Allergan had not breached its undertaking in Case AUTH/2460/11/11 and no breach of the Code was ruled in each case. These rulings were not appealed.

Notwithstanding the fact that in Case AUTH/2460/11/11 Allergan had been reported to the Code of Practice Appeal Board, the Panel once again decided firstly in Case AUTH/2487/3/12 and subsequently in Case AUTH/2489/3/12 to report the company to the Appeal Board in accordance with Paragraph 8.2 of the Constitution and Procedure. The continued breaches of undertaking raised serious questions about the company's procedures and commitment to complying with the Code. The Panel noted that in Case AUTH/2460/11/11 the Appeal Board had required an audit of Allergan's procedures in relation to the Code to be carried out by the Authority and had also decided that the company should be publicly reprimanded for successive breaches of its undertakings.

In considering the appeals the Appeal Board noted that Moers-Carpi et al demonstrated in a head-tohead comparison that 20 units of Vistabel was as effective as 30 units of Bocouture in the treatment of glabellar lines. The Appeal Board noted, however,that the recommended starting dose for both products according to their SPCs was 20 units and it thus queried the choice of doses. The Appeal Board noted Allergan's submission on this point. Moers-Carpi et al did not examine the efficacy of the starting dose of Bocouture and whether this dose would have achieved the same clinical result as 30 units. In that regard the Appeal Board noted that once muscle saturation had occurred, any increase in dose would not produce any increase in effect.

The Appeal Board considered that the press release at issue gave an accurate account of Moers-Carpi et al. Given that both study medicines were botulinum toxins, the Appeal Board considered that many clinicians would assume that the difference in dosing to achieve a similar therapeutic effect meant that Vistabel (20 units) was more potent than Bocouture (30 units). In that regard the Appeal Board noted the following quotation from the press release: 'We are pleased to see further evidence for the efficacy of Vistabel and consider that this study provides further clarity that Vistabel and the Merz unit doses are not interchangeable in clinical practice'.

The Appeal Board noted that the press release did not refer to the relative potency of Vistabel and Bocouture but nonetheless, in its view, the inevitable implication was that Bocouture, unit for unit, was less potent than Vistabel. In the Appeal Board's view, in this particular context, ie a direct comparison of two botulinum toxins dosed in units, clinicians might well take efficacy and potency to mean one and the same. The discussion of Moers- Carpi et al in isolation in the press release did not represent the balance of the evidence with regard to the relative efficacy of Vistabel and Bocouture. Given the implied claim that Bocouture was less potent than Vistabel, the Appeal Board considered that the press release was sufficiently similar to the point at issue in Cases AUTH/2346/8/10 and AUTH/2460/11/11 for it to be covered by the undertaking in Case AUTH/2346/8/10. Thus the press release now at issue breached a previous undertaking. The Appeal Board upheld the Panel's rulings. The Appeal Board further considered that Allergan's successive breaches of undertaking was such as to bring discredit upon and reduce confidence in the pharmaceutical industry. The Appeal Board upheld the Panel's rulings of breaches of Clause 2. The appeals were unsuccessful.

The Appeal Board noted that it was important for the reputation of the pharmaceutical industry that companies understood the importance of their undertakings and took the necessary action to comply with them. The Appeal Board questioned Allergan's conduct and attitude in this regard and decided that the company should be publicly reprimanded for its successive failures to comply with its undertakings. These two cases taken together represented the fourth breach of undertaking. Allergan's conduct was completely unacceptable. The Appeal Board also decided, in accordance with Paragraph 11.3 of the Constitution and Procedure, to require an audit of Allergan's procedures in relation to the Code to be carried out by the Authority. The audit should be conducted at the same time as the re-audit required in CaseAUTH/2460/11/11 which was scheduled to take place in August 2012. On receipt of the audit report the Appeal Board would consider whether further sanctions were necessary including pre-vetting of promotional material.

On receipt of the August 2012 audit report the Appeal Board was disappointed at the lack of progress demonstrated. However the company appeared to have taken action including setting time frames for the bulk of the processes and work to be completed by the end of 2012. The Appeal Board was concerned that the amendments to some of the standard operating procedures (SOPs) had not been finalized. The Appeal Board noted that there were plans to significantly change the company structure and the interim country manager would be replaced in 2013. A UK medical director was due to be appointed. The Appeal Board considered that Allergan should be re-audited in January 2013 at which point it expected there to be significant improvement.

Upon receipt of the January 2013 audit report, the Appeal Board noted that although Allergan had made progress, further improvement was necessary. The Appeal Board noted that one key change in senior personnel would take place shortly and another in due course. Given that further improvement was required, the Appeal Board considered that Allergan should be re-audited in September 2013. Upon receipt of the next audit report, the Appeal Board would decide whether further sanctions were necessary.

Upon receipt of the September audit report, the Appeal Board noted that Allergan had made progress since the re-audit in January. The company had undergone four audits since April 2012. It was important that the progress shown in the September 2013 audit was continued and maintained. Every opportunity should be taken for improvement. The Appeal Board noted that Allergan needed to ensure that it updated its processes in good time to reflect the 2014 Code and that relevant staff were trained on the new Code. Allergan provided details of its plans to implement the recommendations in the audit report. On the basis that this work was completed, the Appeal Board decided that no further action was required.​​​