AUTH/2496/4/12 - Allergan/PMCPA Director v Merz

Promotion of Xeomin and Bocouture and breach of undertaking

  • Received
    10 April 2012
  • Case number
    AUTH/2496/4/12
  • Applicable Code year
    2011
  • Completed
    09 August 2012
  • Breach Clause(s)
    2, 7.2 (x3), 7.3 (x2), 7.4 (x2), 9.1 and 25 (x2)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
    Advertisement
  • Appeal
    Appeal by complainant
  • Review
    November 2012

Case Summary

​Allergan complained about three advertisements for Xeomin/Bocouture (botulinum neurotoxin type A) issued by Merz. As the complaint involved an alleged breach of undertaking, that part of it was taken up by the Director as it was the Authority's responsibility to ensure compliance with undertakings. Allergan marketed Vistabel/Botox (botulinum neurotoxin type A).

Allergan noted that Merz had used the claims 'Equipotent', 'Equal Potency' and '1:1 Clinical Conversion Ratio' alongside a visual of either a Xeomin or Bocouture vial standing next to a Botox or Vistabel vial. The visual was clearly designed to emphasise a direct 1:1 equivalence/conversion of the two medicines. Some of the material included the phrase 'Clinical studies suggest …'. In addition, less prominently and usually in smaller font, was the Summary of Product Characteristics (SPC) statement 'Unit doses recommended for Bocouture are not interchangeable with those for other preparations of botulinum toxin'.

Allergan alleged that the claims, along with the supporting visuals, were misleading and presented only part of the information in the Bocouture or Xeomin SPC. The overall message was that the products were equally potent and could be converted 1:1.

Allergan noted that the Bocouture SPC stated:

'Unit doses recommended for Bocouture are not interchangeable with those for other preparations of Botulinum toxin.

Comparative clinical study results suggest that Bocouture and the comparator product containing conventional Botulinum toxin type A complex (900 kD) are of equal potency.'

The Xeomin (50U) SPC stated:

'Due to unit differences in the LD50 assay, Xeomin units are specific to Xeomin. Therefore unit doses recommended for Xeomin are not interchangeable with those for other preparations of Botulinum toxin.

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.'

Whilst, the Xeomin (100 units) SPC stated:

 'Unit doses recommended for Xeomin are not interchangeable with those for other preparations of Botulinum toxin.

'The SPCs for Botox 50, 100 and 200 units stated:

'Botulinum toxin units are not interchangeable from one product to another. Doses recommended in Allergan units are different from other botulinum toxin preparations.'

Allergan considered that, in line with the science behind botulinum toxins and over twenty years of regulatory experience, the most prominent and significant statement in the SPCs was that unit doses of the medicines were not interchangeable. This statement was imposed by the Pharmacovigilance Working Party (PhVWP) and in Allergan's view was not 'superseded' by a contradictory statement based upon non-inferiority clinical studies. Non-inferiority studies could not demonstrate equivalence and in that regard Allergan noted the ruling in Case AUTH/2270/10/09 together with Merz's submission in that case that it had no data to support a claim that Xeomin was equivalent to Botox.

Allergan noted that botulinum toxin potency was a laboratory measure and each manufacturer's assay was unique to its own medicine. When Hunt et al (2010) assessed the relative potencies of Bocouture and Vistabel using the Allergan assay, the potency of Merz's Bocouture 50U was found to be, on average, 34 units per vial whereas the average potency of Allergan's Vistabel/Botox 50U was as labelled. Conversely, Dressler et al (2008), using the Merz assay determined that the potencies of Merz's Xeomin and Allergan's Botox were not statistically different. Allergan submitted that as different products were likely to behave differently in different assays these findings were not contradictory since each company used its own proprietary assay.

Allergan submitted that these observed differences in potency and enzymatic activity supported the non-interchangeability of unit doses of botulinum toxins. The optimum dosage and number of injection sites in the treated muscle should be determined individually for each patient. A titration of the dose should be performed. Physicians should consult the appropriate SPC to obtain product specific dosage recommendations.

Allergan alleged that the current Merz campaign and claims at issue were inaccurate, misleading, could not be substantiated and were not based on an upto- date evaluation of all the available evidence. In particular, significant new data (Moers-Carpi et al, 2011) was omitted. These new data from a randomised, double blind, equivalence study (n=220) directly challenged the hypothesis that the products were interchangeable at a 1:1 dose ratio. The basis for this study was the investigators' experience of the relative clinical effectiveness of the differentmedicines, the differences seen in the different reference LD50 assays and the different available dose ranging data. Allergan considered that this new data, while not inconsistent with the findings of the Merz non-inferiority studies, clearly challenged the basis for claims of equivalence and a 1:1 conversion ratio.

Allergan alleged that the claims by Merz for 'Equipotency' and '1:1 Conversion' between Xeomin/Bocouture and Vistabel/Botox was a source of significant concern. No 'dosing conversion' occurred or should be implied from the noninferiority studies conducted by Merz. The direct medical impact was that a significant patient safety risk existed with prescribers encouraged to transfer information from one product to another.

Allergan noted that in Case AUTH/2270/10/09 it was ruled that the results of a non-inferiority study could not be used to claim equivalence. Merz's own submission in that case was that it had no data to support a claim that Xeomin was equivalent to Botox which Allergan believed this was still so. Therefore, Allergan alleged that the claims for 'Equipotency' and '1:1 Conversion' between Xeomin/Bocouture and Vistabel/Botox (ie equivalence) were in breach of the undertaking in Case AUTH/2270/10/09.

The detailed response from Merz is given below.

The Panel considered each advertisement separately. With regard to one Bocouture advertisement, intercompany dialogue had been successful and so the Director decided that only the alleged breach of undertaking would be considered.

The Panel noted that the other Bocouture advertisement featured a photograph of vials of Bocouture and Botox side-by-side. Above the vials was the claim in bold, blue font 'In glabellar frown lines, clinical studies suggest Bocouture vs Botox: Equal Potency 1:1 Clinical Conversion Ratio'. This claim and the photograph took up over half of the advertisement. Below the vials was a thick blue horizontal line beneath which was the statement in smaller black font 'Unit doses recommended for Bocouture are not interchangeable with those for other preparations of botulinum toxin'. This statement and the claim for equal potency were referenced to the Bocouture SPC. The claim for a 1:1 clinical conversion ratio was referenced to Sattler et al (2010).

The Panel noted that in Section 4.2 of the Bocouture SPC, Posology and method of administration, the first statement in bold type read 'Unit doses recommended for Bocouture are not interchangeable with those for other preparations of Botulinum toxins'. A similar bold statement also appeared in the Xeomin SPC. The Panel noted the prominence of these statements in the SPCs and considered that although the Bocouture SPC statement had been included in the advertisement at issue, it was given significantly less prominence than the other claims. Given its position below the thick blue line, it appeared to be separate from the main part of theadvertisement. The prominence given to this statement in the SPC had not been reflected in the advertisement. The Panel considered that the advertisement was misleading in that regard. A breach of the Code was ruled. This ruling was not appealed.

The Panel noted that the claim '…clinical studies suggest… Equal Potency…' was referenced to the Bocouture SPC. The relevant statement in the SPC 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'. The second part of the claim in the advertisement '1:1 Clinical Conversion Ratio', was referenced to Sattler et al, a non-inferiority study which had demonstrated the non-inferiority of 24 units each of Bocouture/Xeomin to Vistabel/Botox in the treatment of glabellar frown lines. The Panel noted that it had previously been established that non-inferiority studies could not be used to imply equivalence.

The Panel considered that the overall impression from the advertisement was that, unit for unit, it had been unequivocally demonstrated that Bocouture and Vistabel were clinically equivalent which was not so. In the Panel's view, the advertisement encouraged prescribers to consider that the unit doses of Bocouture and Botox were interchangeable. The Panel considered that the advertisement was misleading in that regard. The Panel considered that the impression given by the advertisement could not be substantiated. Breaches of the Code were ruled. These rulings were not appealed.

The Xeomin advertisement featured a photograph of vial of Xeomin and Botox side-by-side with a colon (:) between them. The headline claim read 'Clinical studies suggest Xeomin and Botox are equipotent, with a conversation ratio of 1:1 Xeomin SPC'. Below the photograph of the vials on the left-hand side was the statement 'Always prescribe by brand, unit doses are not interchangeable'. This was referenced to the Xeomin 50U SPC. The headline claim and the statement were in a similar prominent white font on a black background.

The Panel noted that Section 4.2 of the Xeomin 50U SPC stated the following:

'Due to unit differences in the LD50 assay, Xeomin units are specific to Xeomin. Therefore unit doses recommended for Xeomin are not interchangeable with those for other preparations of Botulinum toxin.

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'.

The Panel noted the prominence given to the first statement in the SPC and that the order of the two statements in the SPC had been reversed in the advertisement, which resulted in the claim 'Clinical studies suggest…' being used as the headline to theadvertisement. The Panel considered that the relative emphasis on the two SPC statements had not been reflected in the advertisement. In the Panel's view, the advertisement encouraged prescribers to consider the unit doses of Bocouture and Botox were interchangeable. The Panel considered that the advertisement was misleading in this regard. The Panel considered that the impression given by the advertisement could not be substantiated. Breaches of the Code were ruled. These rulings were not appealed.

With regard to the alleged breach of undertaking, the Panel noted that inter-company dialogue was not a pre-requisite and it thus considered that that aspect of the complaint would be considered in relation to all three advertisements at issue.

The Panel noted that in Case AUTH/2270/10/09, Merz had been ruled in breach of the Code for claiming that Xeomin was 'At least as effective as Botox with a similar safety profile'. The Panel considered that the claim implied possible superiority of Xeomin vs Botox which was not supported by the available data. A breach of the Code was ruled which was upheld on appeal.

Turning to the advertisements at issue, the Panel noted that they referred to Xeomin/Bocouture being 'equipotent' or having 'Equal Potency' to Botox/Vistabel. There was no suggestion that Xeomin/Bocouture might be more potent than Botox/Vistabel. In that regard the Panel did not consider that the advertisements breached the undertaking given in Case AUTH/2270/10/09. No breaches of the Code were ruled including Clause 2.

Upon appeal, the Appeal Board noted that the undertaking in Case AUTH/2270/10/09 related to a claim that not only implied equivalence but also possible superiority; its ruling had been made on both aspects. In the current case, Case AUTH/2496/4/12, Allergan's alleged breach of undertaking, the subject of the appeal, related only to claims of equivalence.

The Appeal Board noted that there was still no data to show whether Xeomin/Bocouture was equivalent to Botox/Vistabel. Now, as when the ruling in Case AUTH/2270/10/09 was made, there were only noninferiority studies which showed that the medicines were no worse than each other by a clinically acceptable pre-specified margin.

Turning to Case AUTH/2496/4/12, the Appeal Board considered that the Bocouture advertisement which featured the claim 'In glabellar frown lines, clinical studies suggest' followed by 'Bocouture vs Botox:', 'Equal potency' and '1.1 Clinical Conversion Ratio' together with the visual of a vial of each of the medicines side-by-side, implied that the two products were clinically equivalent and that unit for unit they were interchangeable. The Appeal Board considered that although the claim at issue was not the same as that in Case AUTH/2270/10/09, it was sufficiently similar with regard to a claim for 'equivalence' for it to be covered by the undertaking previously given. The Appeal Board thus ruled abreach of the Code. The appeal on this point was successful.

Similarly the Appeal Board considered that the Xeomin advertisement which featured the claim 'Clinical studies suggest Xeomin and Botox are equipotent, with a conversion ratio of 1:1 Xeomin SmPC' together with a visual of a vial of each medicine side-by-side with a colon between them, also implied that the medicines were clinically equivalent and that unit for unit they were interchangeable. The Appeal Board noted its comments above and thus ruled a breach of the Code. The appeal on this point was successful.

The Appeal Board noted that the Bocouture advertisement included the statement 'Unit doses recommended for Bocouture are not interchangeable with those for other preparations of botulinum toxin' and the Xeomin advertisement similarly included the statement 'Always prescribe by brand, unit doses are not interchangeable'. These statements were referenced to the respective products' SPCs and in both advertisements they appeared in a less prominent position and smaller font than the claims and visuals that implied clinical equivalence. The Appeal Board considered that implying that the products were clinically equivalent and hence interchangeable was contrary to statements in the SPCs. The Appeal Board considered that this raised possible patient safety concerns.

The Appeal Board considered that as Merz had no data on which to base the implied claims of clinical equivalence, and as it had breached its undertaking and assurance in Case AUTH/2270/10/09, it had failed to maintain high standards and had thus brought discredit upon and reduced confidence in the pharmaceutical industry. The Appeal Board ruled breaches of the Code including Clause 2. The appeal on this point was successful.