AUTH/2460/11/11 - Merz/Director v Allergan

Breach of undertaking

  • Received
    25 November 2011
  • Case number
    AUTH/2460/11/11
  • Applicable Code year
    2011
  • Completed
    15 October 2013
  • Breach Clause(s)
    2 (x2), 9.1 (x2), and 25 (x2),
  • Sanctions applied
    Undertaking received
  • Additional sanctions
    Audit of company’s procedures
    Public reprimand
    Advertisement
    Re-audit
  • Appeal
    No appeal. PMCPA Panel report to Appeal Board
  • Review
    November 2013

Case Summary

Merz alleged that at a meeting and through the conduct of one of its representatives, Allergan had continued to misrepresent data relating to the relative potencies of its medicines Vistabel/Botox (botulinum toxin type A (onabotulinumtoxinA)) vs Merz's medicines Bocouture/Xeomin (botulinum toxin type A (incobotulinumtoxinA)). As Merz alleged that Allergan had breached the undertakings given in Cases AUTH/2183/11/08 and AUTH/2346/8/10 this case was taken up by the Director as it was the Authority's responsibility to ensure compliance with undertakings.
 
The detailed response from Allergan is given below.
 
The presentation at issue was given by an Allergan scientific services manager at an aesthetic practitioners meeting. Merz alleged that claims were made about the relative potency of Vistabel vs Bocouture – a comparison which had been the subject of Case AUTH/2346/8/10 – and built the case that the units of potency of the products were not interchangeable and that Bocouture was less potent than Vistabel. The presentation specifically did not reflect the Bocouture summary of product characteristics (SPC) which stated: 'Comparative clinical study results suggest that Bocouture and the comparator product containing conventional Botulinum toxin type A complex (900 kD) are of equal potency'.
 
Merz submitted that in Case AUTH/2346/8/10 the Appeal Board stated that 'both the Bocouture SPC and data on file that support the SPC statement were available to Allergan when the presentation [at issue in that case] was delivered but were nonetheless not included'. Allergan had again presented a discussion about product potency excluding not only the regulator's view but now also that of the Appeal Board. No new independent data to change understanding of relative potencies had been published. In fact since the Appeal Board's ruling a 1:1 conversion ratio between Botox (Vistabel) and Xeomin (Bocouture) had been made even more clear with the publication of the Xeomin 50 unit SPC in May 2011 which stated: 'Comparative clinical study results suggest that Xeomin and the comparator product containing conventional Botulinum toxin type A complex (900 kD) are of equal potency when used with a dosing conversion ratio of 1:1'.
 
Merz alleged that the Allergan presentation referred to non-interchangeability of unit doses directly quoted from the product SPCs yet it again failed to mention the regulatory view of the relative potencies. Merz noted that the botulinum toxin in both Vistabel and Bocouture came from the Hall strain of clostridium botulinum and as such would not be expected to demonstrate different clinical effect.
 
The Allergan speaker then presented data from Moers-Carpi et al (2011) to further develop the impression that Bocouture was less potent than Vistabel. Merz submitted that the design of this study was open to significant question as there was no control arm and unmatched doses of each product were used.
 Merz stated that prior to the publication of this recent data it had been established, and reflected in the SPCs, that the correct starting dose for Vistabel and Bocouture in the treatment of moderate to severe glabellar frown lines was 20 units. Carruthers et al (2005) demonstrated that Botox 20U and 30U showed no measurable clinical difference in the treatment of moderate to severe frown lines and postulated that in most patients a 20U dose was sufficient to saturate the local nerve endings so that additional dosing had little or no incremental clinical effect.
 
The new Allergan study compared 30U of Bocouture with 20U of Vistabel in moderate to severe frown lines. Merz alleged that the crafting of this presentation, the selective use of data, and what could only be a deliberate omission of the established regulatory position to leave the impression of reduced potency of Bocouture to Vistabel was cynical and in breach of previous undertakings made by Allergan.
 
The Panel noted that in Case AUTH/2346/8/10, the Appeal Board considered that a presentation by Allergan had implied that Botox was more potent than Xeomin which was inconsistent with the SPCs and clinical data. Although the material at issue in Case AUTH/2346/8/10 differed from that in Case AUTH/2183/11/08, the Appeal Board considered that the overall effect was sufficiently similar to the point at issue in Case AUTH/2183/11/08 for it to be caught by the undertaking in that case and so breaches of the Code were ruled including a breach of Clause 2.
 
The Panel noted that Bocouture/Xeomin contained the same active constituent as Botox/Vistabel, ie botulinum toxin type A (BONT/A). In all of the products the neurotoxin was derived from an identical strain.
 
The Panel noted that there appeared to be no standard assay method for the two BONT/A preparations. The SPCs for Botox/Vistabel referred to Allergan Units/vial and the Bocouture/Xeomin SPCs referred to LD50 units per vial. The Xeomin SPC stated that due to differences in the LD50 assay, these units were specific to Xeomin and were not interchangeable with other botulinum toxin preparations. All of the SPCs stated that as the botulinum toxin units differed from product to product, doses recommended for one product were not interchangeable with those for another. TheBocouture SPC, however, stated 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. The Xeomin 50 units SPC contained the equivalent statement but added 'when used with a dosing conversion ratio of 1:1'. In this regard the Panel noted that Sattler et al (2010) demonstrated the non-inferiority of 24 units each of Bocouture/Xeomin to Botox/Vistabel in the treatment of frown lines. The SPCs for Bocouture and Vistabel stated identical recommended unit doses for the treatment of moderate to severe frown lines, ie five injections each of 4 units. The Bocouture SPC stated that the dose might be increased to up to 30 units if required by the individual needs of the patient.
 
The title of the presentation at issue was 'Botulinum Toxin Review and Update'. The second slide stated that the most potent of the seven botulinum neurotoxin serotypes was type A, the active constituent of Vistabel and Bocouture. It was also stated that unit doses of botulinum toxin were not interchangeable from one product to another. Slide 14 of the presentation depicted the SPCs for, inter alia, Bocouture and Vistabel and the heading referred to the 'non-interchangeability of units of BONT-A products'. Although the relevant statement in the Bocouture SPC was highlighted, the subsequent statement that comparative clinical study results suggested that Bocouture and Botox/ Vistabel were of equal potency was not and nor was this information given in any other slide.
 
The final section of the presentation headed 'Introduction to Clinical Trials' discussed noninferiority studies in general and the last 19 slides in particular detailed the results of Moers-Carpi et al which compared the efficacy of Vistabel (20 units) vs Bocouture (30 units) in the treatment of patients with moderate/severe glabellar lines. There was no explanation as to why different doses of the two medicines had been chosen despite the doses (in numbers of units) recommended in the respective SPCs being identical. The slide which introduced the study stated that 20 units of Vistabel and 30 units of Bocouture both represented labelled doses. It did not appear, however, that information about the doses chosen in the study had been presented within the context of the SPC recommendations, ie that the starting dose for Bocouture was 20 units which could be increased to up to 30 units if required. The slide headed 'Study Conclusions' stated that Vistabel (20 units) was as effective as Bocouture (30 units) in the treatment of glabellar lines and that the study reinforced the data previously reported by Hunt et al (2010). The Panel noted that there was no reference in the presentation to Sattler et al although the speaker submitted he/she had mentioned that the study had shown that in the same therapy area 24 units of Bocouture was non-inferior to 24 units of Vistabel.
 
The Panel also noted that there was no reference in the presentation to Carruthers et al, the dose ranging study with Botox/Vistabel which had shown that in the treatment of frown lines doses of 30 or40 units did not produce statistically significantly better results than a dose of 20 units and that the majority of patients responded well to 20 units with some needing a higher dose to achieve the same effect. Although this was a Botox/Vistabel study, the Panel considered that it demonstrated an important point which would have helped to provide context to the rest of the presentation. The Panel noted that Allergan had provided a copy of data on file from Merz which it stated
demonstrated a dose response for Bocouture/Xeomin between 10, 20 and 30 units when used to treat frown lines. When determined by the investigator at day 30, the percentage of responders to 20 units and 30 units was 74.5 and 91.7 respectively. It was not stated in the information before the Panel whether this was a statistically significant difference.
 
Overall, the Panel considered that the presentation did not reflect the balance of evidence with regard to the relative potencies and was concerned to note that, as acknowledged by Allergan, it had not been reviewed or approved for use at the meeting. In the Panel's view the presentation implied that Botox/Vistabel was more potent than Bocouture/ Xeomin. In that regard the Panel considered that this was sufficiently similar to the point at issue in Case AUTH/2346/8/10 for it to be covered by the undertaking in that case and to breach undertakings given previously. In that regard high standards had not been maintained. Breaches of the Code were ruled.
 
The Panel noted that an undertaking was an important document and that Allergan's successive breaches of undertaking was such as to bring discredit upon, and reduce confidence in, the pharmaceutical industry. The Panel ruled a breach of Clause 2.
 
Merz stated that an Allergan sales representative, in a visit to a customer who used Bocouture, used the Moers-Carpi et al poster to support the assertion that the potency of Bocouture was inferior to that of Vistabel. The poster directly referred to the Hunt and Clark data that was the subject of the breach of undertaking in Case AUTH/2346/8/10. The customer was clearly left with the message that Bocouture did not possess the same clinical potency per unit as Vistabel.
 
The Panel noted that the Vistabel sales aid provided by Allergan as the only promotional item that referred to Moers-Carpi et al was entitled 'Not all toxins are Vistabel'. The front cover included with the statement 'Vistabel unit doses are not interchangeable with other preparations of botulinum toxins'. One page was headed 'Head to- head data review of glabellar lines' beneath which were a very brief description of Sattler et al and a more detailed description of Moers-Carpi et al. Subsequent pages of the sales aid detailed the results of Moers-Carpi et al with the use of a bar chart and graph. The back page included the claim 'A recently conducted equivalence study confirms that unit doses of Vistabel and Merz toxin are not interchangeable in clinical practice' referenced to Moers-Carpi et al. There was no reference on theback page to Sattler et al. There was no mention of the statement in the Bocouture SPC that clinical data suggested equal potency.
 
There was no complaint about the sales aid. However, the Panel considered it was relevant to the allegation that the customer was left with the message that Bocouture did not possess the same clinical potency per unit as Vistabel.
The Panel noted that the Moers-Carpi et al poster was not available for representatives to distribute; if customers asked for a copy the representatives had to ask medical information to send a copy or receive a copy themselves in a sealed envelope for delivery. Allergan had acknowledged that three customers had asked the representative for a copy of the poster.
 
The Panel noted that it was impossible to know what the representative had said or whether the representative had used the sales aid. However, the Panel considered that, given the content of the sales aid, on the balance of probabilities, the representative had used the Moers-Carpi et al poster to inform the health professional 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.
 
The Panel noted its comments above with regard to the clinical data and the statement in the Bocouture SPC. Noting the content of the sales aid the Panel considered that the arranged provision of the Moers- Carpi et al poster by the representative would, on the balance of probabilities, leave the health professional with the impression that Bocouture did not possess the same clinical potency as Vistabel as alleged. In the Panel's view this breached the undertakings previously given. In that regard high standards had not been maintained. Breaches of the Code were ruled.
 
The Panel noted that an undertaking was an important document and that Allergan's successive breaches of undertaking was such as to bring discredit upon and reduce confidence in the pharmaceutical industry. The Panel ruled a breach of Clause 2.
 
The Panel noted that Allergan had again breached undertakings with regard to claims about the relative potency of its botulinum toxin vs that of the Merz product. In the Panel's view, the repeated and serious nature of such breaches of the Code raised concerns about the company's procedures and warranted consideration by the Appeal Board. In accordance with Paragraph 8.2 of the Constitution and Procedure, the Panel reported the company to the Appeal Board.
 
The Appeal Board noted that Allergan had accepted the breaches of the Code and that it had already undertaken meaningful action to improve its culture and processes to avoid similar errors in the future. Further steps to improve compliance were planned.The Appeal Board considered that the company's comments on the report and presentation revealed a marked lack of insight and objectivity. Given that potency comparisons between Botox and Xeomin had previously resulted in two breaches of undertaking it was vital that Allergan briefed, trained and had systems in place such that its staff did not use material that could result in a further breach of undertaking or the use of unapproved slides. The Appeal Board considered that an undertaking and assurance was an important document and it was extremely concerned that Allergan had now breached its undertaking and assurance on three separate occasions in a short space of time. This was completely unacceptable.
 
The Appeal Board decided that Allergan should be publicly reprimanded for successive breaches of its undertaking. 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 in April 2012. On receipt of the audit report the Appeal Board would consider whether further sanctions were necessary.
 
On receipt of the April 2012 audit report the Appeal Board considered that Allergan's procedures were not satisfactory. The Appeal Board was extremely disappointed that there was insufficient responsibility taken across the company for Code compliance. Company culture did not appear to support compliance with the Code. The Appeal Board noted that it had already publicly reprimanded Allergan.
 
The Appeal Board decided that Allergan should be re-audited in three months' time at which point it expected there to be significant improvement. As part of the usual re-audit process Allergan would be asked to provide an update of its response to the first audit report with actions and timelines. Upon receipt of the report for the re-audit, the Appeal Board would decide whether further sanctions were necessary.
 
The Appeal Board subsequently decided in Cases AUTH/2487/3/12 and AUTH/2489/3/12 to require an audit which would be conducted at the same time as the re-audit required in this case (Case AUTH/2460/11/11). 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.