AUTH/2335/7/10 - Merz/Director v Allergan

Breach of undertaking

  • Received
    21 July 2010
  • Case number
    AUTH/2335/7/10
  • Applicable Code year
    2008
  • Completed
    06 December 2010
  • Breach Clause(s)
    2, 9.1 and 25
  • Sanctions applied
    Undertaking received
  • Additional sanctions
    Advertisement
  • Appeal
    Appeal by complainant
  • Review
    February 2011

Case Summary

Merz alleged that at the FACE (facial aesthetic conference and exhibition) congress, a meeting of aesthetic practitioners held in early July 2010, Allergan had breached the undertaking given in Case AUTH/2183/11/08 by implying that Botox/Vistabel (botulinum toxin) was more potent than Merz's products Xeomin/Bocouture (also botulinum toxin). Bocouture was launched at that meeting and the summary of product characteristics (SPC) was available on Merz's stand from the beginning of the congress.

As the complaint involved an alleged breach of undertaking, it was taken up by the Director as it was the responsibility of the Authority to ensure compliance with undertakings.

Merz explained that the congress organisers had asked Merz, Allergan and Ipsen [all of which marketed forms of botulinum toxin] to deliver a non-promotional presentation entitled 'Scientific Workshop on Pharmacology, Diffusion and Potency of Available Botulinum Toxins'.

 Merz noted that Allergan's presentation, by one of its employees, included a series of efficacy comparisons which favoured the Allergan product, Vistabel (sometimes described as Botox), when compared with the two competitor products and a number of slides showed only the efficacy for Vistabel. The first slide featured a statement that Vistabel prescribing information was available and the last slide was of the prescribing information. All of this together with a misleading presentation of potency data made the presentation promotional; it therefore fell within the scope of the Code.

Data from Hunt et al (2009) was presented on two slides. In the first slide the data was presented next to data from Dressler et al (2008) which demonstrated that Botox and Xeomin had approximately the same potency using the Merz assay for botulinum toxin. The speaker obliquely criticised this assay as being a gelatine-based assay whereas the Botox assay used a more 'clinically relevant diluent' (saline). The speaker then went on to show the data by Hunt et al in a table headed 'Corrected potency units' which implied that these data, in fact, were the correct potency for Xeomin. The speaker described the potency of Xeomin as being 'up to 30% lower' when measured with the Allergan 'standard'. Further data on the potency of Xeomin was boxed in red on the next slide and was again shown as considerably less than 100 units. The data for Botox, as measured by this assay, was not shown. The speaker stated that this demonstrated that different assays gave different results and that it: 'Calls into question any claimsthat the Xeomin unit, or Bocouture unit, is exactly the same as the Botox unit – that they are interchangeable, that they are 1:1 because if they were you would expect to see 100 unit Xeomin coming up on the Botox reference standard'.

When Case AUTH/2183/11/08 was considered the data from Hunt et al had only been presented in poster form however it had now been published as a scientific paper. Merz stated that this was clearly a reference to the extrapolation of this in vitro data to the clinical situation and a promotional message. This went against the ruling in Case AUTH/2183/11/08 in which the Panel ruled that the direct relevance or significance of this data to the clinical situation had not been demonstrated and that this was inconsistent with the SPCs which had similar dosing regimens for the products. In addition, Section 4.2 of the Bocouture SPC (Bocouture was the same product as Xeomin but marketed under a different name for the treatment of glabellar lines) stated that: 'Comparative clinical study results suggest that Bocouture and the comparator product containing conventional Botulinum toxin type A complex (900 kD) are of equal potency'.

At the end of the presentation the chairman of the session asked for the Botox data as a comparator for the Xeomin potency data presented but the presenter did not directly answer this question which further reinforced the argument that this was not a scientific debate as full data was not provided even when requested, or that there was no comparator in the study which raised questions about the study itself and thus made any conclusions even more misleading.

Merz explained that, following the outcome of Case AUTH/2183/11/08, it became aware that the Hunt et al data was still used by Allergan. Following extensive inter-company dialogue, Allergan agreed only to use this data in response to specific requests for information.

Given the inter-company agreement and the undertaking given in the previous case, Merz alleged that the continued use of Hunt et al was likely to bring discredit upon or reduce confidence in the industry in breach of Clause 2.

The detailed response from Allergan is given below.

The Panel noted that an undertaking was an important document. It included an assurance that all possible steps would be taken to avoid similar breaches of the Code in future. It was very important for the reputation of the industry thatcompanies complied with undertakings.

 The Panel noted that the congress organisers had invited speakers from interested companies to present for 20 minutes each at the scientific workshop on pharmacology, diffusion and potency of botulinum toxins. A letter from FACE to Merz referred to presenting on the differences in pharmacology of available toxins. The FACE guidelines for presentation stated the presentation should not be used as an opportunity to market any single product or device.

The Panel considered that it was difficult to view Allergan's presentation as anything other than promotional given its title and its delivery by an employee. It would promote the use of, inter alia, Allergan's medicines. The Panel thus considered that the presentation needed to comply with the Code.

The Panel noted that slide 12 compared the potency of Xeomin and Botox according to results obtained using the Merz 'gelatin-like' LD50 assay. The mean potency of Xeomin was given as 103 and that of Botox as 101.7. Although not entirely clear from the slide, this data was from Dressler et al (poster). The Dressler abstract concluded that the potencies of Xeomin and Botox were equivalent. To the right of the table of data from Dressler et al was another table reporting the results for Xeomin from the Allergan saline-based LD50 assay (Hunt et al). The authors reported the corrected potency of three lots of Xeomin to be 75U/vial, 69U/vial and 78U/vial. No corresponding data was given for Botox. The Panel considered that the audience would inevitably compare the figures from the two tables of data and conclude that Xeomin was less potent than Botox. The following slide (slide 13) also featured a table of data which showed that the potency of Xeomin was less than 100 units (potency reported ranged from 61 to 78 units). Again, no corresponding data for Botox was reported. Although not stated on the slides, both assays (Hunt et al and Dressler et al) were performed in mice.

Slides 25 and 26 demonstrated a clinical advantage for Vistabel vs Xeomin (Moers-Carpi) which delegates might assume was due to the favourable potency data given on slides 12 and 13.

Slide 30 was headed 'Are they [botulinum toxins] all the same' followed by 'They are not interchangeable. Difference in: …….. - clinical performance'.

The Panel noted that in Case AUTH/2183/11/08 Allergan had been ruled in breach of the Code; the Panel referred to its ruling in that case.

Case AUTH/2183/11/08

In the Panel's view the data presented in a product monograph and an objection handler which derived from Hunt et al implied that there was a differencein potencies between Xeomin and Botox in favour of Botox. This was inconsistent with the summaries of product characteristics (SPCs) which showed similar dosing regimens for the two products. The Panel accepted that there was some animal data that possibly showed a difference. However, the supplementary information to the Code was clear that animal data should not be extrapolated to the clinical situation unless there was data to show that it was of direct relevance and significance. This had not been demonstrated. The Panel considered that the comparison could not be substantiated and did not reflect all of the evidence. Breaches of the Code were ruled.

Case AUTH/2335/7/10

The Panel noted that since it had considered Case AUTH/2183/11/08 Merz had launched Bocouture – which was the same as Xeomin but was only indicated for the temporary improvement in the appearance of moderate to severe glabellar frown lines in adults below 65 years when the severity of those lines had an important psychological impact for the patient. The Bocouture SPC stated in Section 4.2 that 'Comparative clinical study results suggest that Bocouture and the comparator product containing conventional Botulinum toxin type A complex (900 kD) [i.e. Botox] are of equal potency'. The Panel noted that Allergan had only recently obtained a copy of the Merz data-on-file document to support the grant of the Bocouture licence and, the Panel assumed, the statement in Section 4.2 of the Bocouture SPC. In contrast to that statement, Allergan had submitted clinical data which demonstrated a statistically significant clinical advantage for Vistabel vs Bocouture (Moers-Carpi).

The Panel considered that the comparative data shown in the presentation was sufficiently different to the material considered in Case AUTH/2183/11/08 for it not to be caught by the undertaking given in that case. The previous material had not referred to Dressler et al or the Moers-Carpi data as shown later in the presentation. The Panel did not consider that the presentation was in breach of the undertaking given in Case AUTH/2183/11/08 and in that regard high standards had been maintained. No breaches of the Code were ruled.

The Panel considered that as there had been no breach of the undertaking there could be no breach of Clause 2. No breach of that clause was ruled.

Upon appeal by Merz the Appeal Board noted that the title of Allergan's presentation was 'Pharmacology, diffusion and potency of Botulinum Toxins'. Slide 1 listed the various botulinum toxins available from the three manufacturers. Slide 3 of the presentation showed a number of vials of different sizes and was headed 'Are they all the same?'. Beneath the picture of the vials was the second question 'Are they non-interchangeable – Structure? Unit potency? Stability? Diffusioncharacteristics? Clinical performance?'. The last slide had the same heading and picture of vials below which was now the statement 'They are non-interchangeable. Differences in: Structure, Unit potency, Stability, Diffusion characteristics, Clinical performance'.

The Appeal Board noted that Merz had drawn attention to slides 12 and 13 of the presentation. These were headed 'Differences in LD50 assays' and 'Xeomin potency'. Slide 10 made it clear that the products were different '… and non-interchangeable potency units are specific'. Slide 11 was headed 'Reasons for potency differences' with the sub headings 'Intrinsic differences in product characteristics' and 'Differences in LD50 assays'.

The Appeal Board noted that the presentation had included data from the small (n=12) Moers-Carpi study which was a split-face comparison of Vistabel and Xeomin in the forehead region of healthy volunteers. The results presented were those which showed a statistically significant advantage for Vistabel [Botox] vs Xeomin when brow position was assessed by digital photography. The results of the patients' own evaluation of therapy, however, were not included; these showed no difference between the products.

The Appeal Board noted that the Bocouture [Xeomin] SPC stated in Section 4.2 that 'Comparative clinical study results suggest that Bocouture and the comparator product containing conventional Botulinum toxin type A complex (900KD) [ie Botox] are of equal potency'. The Appeal Board noted that the relevant data was an unpublished non-inferiority study which Allergan had received from Merz after the meeting in question.

The Appeal Board did not accept Allergan's submission that the inclusion of the Dressler et al and Moers-Carpi studies meant that the presentation was substantially different to the product monograph and objection handler at issue in Case AUTH/2183/11/08.

Overall, the Appeal Board considered that the presentation had implied that Xeomin was less potent than Botox using, inter alia, the same data, ie Hunt et al, as that at issue in Case AUTH/2183/11/08. The Appeal Board considered that the presentation breached the undertaking and in that regard high standards had not been maintained. Breaches of the Code were ruled. The appeal on both points was successful. The Appeal Board noted that an undertaking was an important document. The Appeal Board considered that Allergan's conduct was such as to bring discredit upon and reduce confidence in the pharmaceutical industry. The Appeal Board ruled a breach of Clause 2. The appeal on this point was successful.