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AUTH/2721/7/14 - Shire v Genzyme

Case number:AUTH/2721/7/14
Case ref:Shire v Genzyme
Description:Material for an advisory group
No breach:No breaches Clauses 7.2, 7.3, 7.4, 7.6, 7.8, 8.1 and 12.1.
Breach:Breaches Clauses 2, 3.2, 7.2, 7.3, 7.4, 7.6, 7.8, 7.10, 8.1, 9.1 and 14.1. Corrective statement and audits
Appeal:Appeal by respondent
Status:Appeal by respondent
Review:Published in the May 2016 Review
Received:30/06/2014
Completed:17/03/2016
Case Summary:
​​​​Shire Pharmaceuticals complained about material used by Genzyme Therapeutics in relation to a meeting of the Lysosomal Storage Disorders Expert Advisory Group (LSDEAG) on 26 February 2014. The material compared Genzyme’s Fabrazyme (agalsidase beta) with Shire’s Replagal (agalsidase alfa) both of which were indicated for long-term enzyme replacement therapy in patients with confirmed diagnosis of Fabry Disease. 

The detailed response from Genzyme is given below. 

Shire alleged that Genzyme used uncertified, factually incorrect, misleading, inaccurate and promotional information at the LSDEAG meeting. The meeting was instigated by Genzyme and was attended by health professionals, patient group representatives and senior NHS managers. Shire attended the meeting on the understanding that it was a non-promotional scientific exchange. Before the meeting, Genzyme circulated a written narrative, ‘Genzyme proposal to NHS England for major cost savings in low dose maintenance Fabry patients currently treated with Replagal’ and a version of the presentation entitled ‘Fabry enzyme replacement therapy: Clarification of the science and the significant cost savings of our tender proposal’. The presentation given at the meeting contained a significant amendment on Slide 4 although this was not notified or clarified for the audience. 

Genzyme’s presentations 1 (pre-circulated) and 2 (used at the meeting) consisted of twenty two slides with the stated aim being to clarify the science for both Fabrazyme and Replagal. Genzyme stated that the presentation would also show the significant cost savings by a wholesale switch from Replagal to Fabrazyme. 

Shire attended the meeting in response to an unsolicited request from the chairman of the LSDEAG. The request was generated in response to a solicited Genzyme meeting held with the chairman in late 2013. In a letter to Shire dated 27 May 2014, Genzyme stated that Shire was responsible for ‘unfounded and incorrect rumours’ that the low maintenance dose of Fabrazyme was ‘unlicensed’ or even ‘illegal’. As a result of these rumours Genzyme sought to clarify the situation. Shire strongly refuted this unfounded allegation particularly as a basis for Genzyme’s solicitation of the LSDEAG meeting and inappropriate actions during it. 

Shire understood the LSDEAG meeting was intended to be a non-promotional presentation of the publicly available evidence of both Fabrazyme and Replagal. The stated purpose from Genzyme was that its presentation and narrative would clarify the science and the significant cost savings of its proposal in respect of Fabrazyme. Shire stated that in attempting to do this, Genzyme presented misleading and inaccurate information which was inconsistent with the Fabrazyme summary of product characteristics (SPC), promoted actions with the potential to adversely affect patient safety, presented misleading comparisons, made unsubstantiated claims of superiority over Replagal and promoted Fabrazyme in a setting which was intended to be non-promotional, particularly by presenting cost benefits to switch products, leading to disguised promotion and a failure to certify. 

Shire noted that Genzyme repeatedly submitted that the LSDEAG was a ‘national public organisation’ but in reality it was an ‘advisory group’ which did not have a public constitution or a national public remit. The LSDEAG was thus not, in Shire’s view, a ‘national public organisation’ in the sense intended by the Code, particularly as it was not a ‘public’ organisation in the same way that the National Institute for Health and Care Excellence (NICE), the All Wales Medicines Strategy Group (AWMSG) or the Scottish Medicines Consortium (SMC) were. Even if it was, the material could only be exempt from the Code if it was factual, accurate and not misleading; this was not so; Shire also alleged that to present ‘cost benefits’ at such a meeting was promotional. 

The Panel considered that the audience which included clinical experts as well as health professionals from specialised services, including commissioning and patient association representatives would be familiar with the products but this did not negate the need to ensure that materials were sufficiently complete, not misleading and in compliance with the Code. The Panel noted Genzyme’s submission that whilst the clinical experts might be familiar with the studies they might be less familiar with regulatory processes and the specific intricacies related to ultra-rare diseases such as conditional licences and acceptable burdens of proof. The Panel noted that the Code stated, inter alia, that the term promotion did not include: 

• information supplied by pharmaceutical companies to national public organisations, such as the National Institute for Health and Care Excellence (NICE), the All Wales Medicines Strategy Group (AWMSG) and the Scottish Medicines Consortium (SMC) is exempt from the Code provided the information is factual, accurate and not misleading. 

The Panel first had to consider whether the Genzyme material could take advantage of two potential exemptions. In this regard, the Panel had to consider how the meeting arose, the parties understanding about its content and the status of LSDEAG. 

The Panel noted Genzyme’s submission that it had been invited to present scientific evidence at the meeting to address questions and comments regarding the 0.3mg/kg Fabrazyme dose arising following the conclusion of the 2012 tender process; the material would have a direct impact on treatment guidelines that LSDEAG drew up following the tender. The Panel noted that the content of the narrative and presentations appeared to be broader than such matters. As stated by Genzyme, the material covered the differences between the products in relation to dose, price per milligram, the precise regulatory status of various doses and the implications of these points on the cost per patient. The material provided by Genzyme showed that the meeting organiser did not refer to any cost implications of interchanging products whereas cost savings were referred to in the narrative title and included throughout. The Panel had no way of knowing what was discussed during telephone conversations, a pre-meeting or the meeting. The Panel considered that, contrary to Genzyme’s submission, generally the tender process would be considered promotion of the medicine in question. 

The Panel noted that the Code defined promotion as any activity undertaken by a pharmaceutical company or with its authority which promoted the administration, consumption, prescription, purchase, recommendation, sale, supply or use of its medicines. The Panel did not consider that it had been established that the activity amounted to responding to an unsolicited enquiry; Genzyme initiated the sequence of events that led to the meeting and it appeared that the presentations and narrative might have gone beyond the original ambit of the meeting as evidenced by the email from LSDEAG. In any event, any response to an unsolicited enquiry had to be non-promotional and, in this regard, the Panel noted its comments above about the promotional nature of the tendering process. In the Panel’s view, the meeting was inextricably linked to matters arising from the original tender process and the scope and content of the material and the emphasis on comparative costs was such that it appeared to be promotional. In the Panel’s view, Genzyme could not take the benefit of the exemption to the definition of promotion in the Code for responses to unsolicited enquiries. 

The Panel noted the submissions regarding the status of the LSDEAG which was not given as one of the examples of public bodies in the Code. The examples, NICE, AWMSG and SMC all had a role in health technology appraisal. The list was not comprehensive. The Panel queried whether the role of LSDEAG when providing advice at the request of the Specialised Services Commissioning Function (SSCF) to NHS England was sufficiently similar to NICE, AWMSG and SMC. The Panel noted that, according to Genzyme, the minutes of the meeting bore the NHS England logo. The position was unclear. The Panel noted that the exemption in the Code only applied if the information provided to the public body was factual, accurate and not misleading. This latter point would need to be considered in relation to the detailed allegations. 

The Panel noted that even if the material in question could take the benefit of an exemption to the definition of promotion as submitted by Genzyme, the material did not fall outside the scope of the Code. It still had to comply with certain aspects of it. 

The Panel was concerned that Genzyme’s narrative stated that ‘These very similar proteins fall well within regulatory definitions of biosimilar in all preclinical studies’ whereas in its response Genzyme submitted that it was very careful to explain, when introducing the word, in the material that the term was used in its general sense and not to imply that regulatory review had taken place. 

The Panel noted that Shire had made detailed allegations regarding presentation 1 and included references to presentation 2 and the narrative. The meeting organiser had circulated the narrative and presentation 1 to attendees. Genzyme was aware of this when it provided the materials. 

The Panel noted Genzyme’s submission that the scientific presentation was not a comprehensive promotional piece designed to be ‘standalone’ and the detail was clearly laid out in the narrative. The Panel noted that the presentation and narrative should, nonetheless, be capable of standing alone as regards accuracy etc. In general, claims should not be qualified by the use of footnotes and the like. Although the narrative might have assisted understanding, it was not sufficient to qualify the presentations. The Panel considered that it was difficult to argue that Genzyme was not promoting its product at the meeting. 

Upon appeal by Genzyme the Appeal Board first decided that as the material at issue included product claims and information on costs it met the broad definition of promotion. The matter for consideration was whether the material could take the benefit of the exemption to the definition of promotion for information supplied to national public organisations such as NICE, AWMSG and SMC which was factual, accurate and not misleading. The Appeal Board noted the two elements to the exemption. The Appeal Board noted that the material at issue was provided to the LSDEAG not the Specialised Commissioning Team (SCT). Neither the LSDEAG nor the SCT were included in the examples of public bodies listed in the Code. The Appeal Board noted that the list was not exhaustive and that other closely similar bodies might be recognised as national public organisations. Nonetheless, the Appeal Board considered that the exemption should be narrowly construed. The Appeal Board noted that all three bodies listed had a role in health technology assessment. The LSDEAG was established in 2005 to advise the chairman in his role and provide medical input to commissioning. The decisions of the bodies listed in the Code were publicly available and the minutes of the LSDEAG could only be publicly sourced via a freedom of information request. The Appeal Board considered that the LSDEAG/SCT were fundamentally different to those bodies listed in the Code. The Appeal Board noted that unlike the organisations listed in the Code the SCT had commissioning powers. The procurement role of the SCT was an important consideration as was the fact that the meeting was at Genzyme’s request as part of the tender process. The Appeal Board considered all he circumstances and decided that the SCT/LSDEA was not sufficiently similar to the examples cited in the relevant exemption and thus could not take the benefit of that part of the exemption for national public bodies such as NICE etc. 

As set out below, Shire made detailed allegations about many slides. Firstly, Shire made general allegations about biosimilarity and also alleged that the data cited were unable to support the claim of biosimilarity. 

The Panel considered that the term biosimilar would be taken in the regulatory sense rather than in the general sense as submitted by Genzyme. The narrative stated ‘Without exception, direct comparisons of the molecular properties of the two Fabry enzyme replacement therapies (ERT) demonstrate milligram for milligram equivalence (biosimilarity)’, ‘These very similar proteins fall well within regulatory definitions of biosimilar in all pre-clinical studies’ and ‘Despite the biosimilarity, the products have very different standard doses at 1.0mg/kg for Fabrazyme and 0.2mg/kg for Replagal; this strange situation is not replicated by any other biosimilar or generic medicines’. 

The Panel noted the EMEA requirements for authorization of biosimilar medicines; studies needed to be carried out to show that the medicine was similar to the reference medicine and did not have any meaningful quality, safety or efficacy differences from the reference medicine . No such studies for Fabrazyme and Replagal had been performed and it was thus misleading and inaccurate and unsubstantiable to describe the two as ‘biosimilar’. 

With regard to Slide 3, the Panel ruled breaches of the Code which were upheld on appeal by Genzyme as the use of the term ‘biosimilar’ was misleading and thus the comparison was misleading. The Panel considered that its ruling on this point also applied to other slides. The Panel’s rulings of breaches were upheld on appeal from Genzyme.

The Panel did not consider that the lack of information regarding the different methods of production and a complete picture of the information presented in the two products’ EPARs was misleading as alleged. The Panel ruled no breach of the Code in this regard. The Panel noted that whilst the three statements on Slide 3 were not misleading, they did not substantiate the claim of biosimilarity in the heading of the slide as alleged. A breach of the Code was ruled which was upheld on appeal by Genzyme. 

With regard to Slide 4, Shire referred to the differences in wording between the pre-circulated presentation and that presented at the meeting. 

Shire alleged that the statement of ‘Fabrazyme standard dose 1.0mg/kg or reduced maintenance dose of 0.3mg/kg’ was not consistent with the Fabrazyme SPC. 

Shire noted that the Genzyme slide stated that the ‘US licence application unsuccessful again’. This comment related to Shire withdrawing the US licence application on 14 March 2012. These comments were irrelevant to the UK market but were in any event misleading and disparaging as they inferred that the FDA had Replagal withdrawn after multiple attempts by using the word ‘…again’. 

The Panel noted Shire’s allegation that ‘the long term clinical relevance has not been established’ in relation to the reduced maintenance dose of Fabrazyme (0.3mg/kg) was omitted from Slide 4 in presentation 1 which was received by all of the delegates. The revised version which was presented on the day (presentation 2) contained the above phrase, however, it was not circulated as a replacement to presentation 1 and no disclosures were made on the day about the amendment. 

The Panel noted the SPC wording:
‘Posology The recommended dose of Fabrazyme is 1mg/kg body weight administered once every 2 weeks as an intravenous infusion. 

Alternative dosing regimens have been used in clinical studies. In one of these studies, after an initial dose of 1mg/kg every 2 weeks for 6 months, 0.3mg/kg every 2 weeks may maintain clearance of GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings has not been established (see section 5.1).’

The Panel noted that the narrative gave more detail about the differences between the dosing of the products and the original licences which Genzyme stated were granted in exceptional circumstances for both products. The licences included specific obligations to provide data on long-term clinical outcomes. According to Genzyme, these had been fulfilled with Fabrazyme 1mg/kg but not Replagal 0.2mg/kg. Genzyme stated in the narrative that the caveat in respect of Fabrazyme 0.3mg/kg simply mirrored the continued provisional licence status of Replagal 0.2mg/kg ‘in the absence of clinical outcome data approved as sufficient by the regulators’. Fabrazyme’s full European licence following fulfilment of all the original specific obligations including submission of Phase IV data showing reduction of the rate of clinical events which Genzyme stated validated the efficacy of 1mg/kg. The narrative stated that in contrast the failure to meet the specific obligations for Replagal led to the EMA announcement on 25 April that the product was included on the list of products requiring additional monitoring and the need for a black triangle. The Panel noted that Shire’s allegation related to the slides not the narrative. 

The Panel considered that by failing to mention that the long-term clinical relevance of the reduced maintenance dose of 0.3mg/kg had not been established meant that Slide 4, presentation one was misleading, incapable of substantiation and was not sufficiently complete to enable the recipients to form their own opinion of the therapeutic value of the medicine. The Panel thus ruled breaches of the Code which were upheld on appeal by Genzyme. 

In addition, the unqualified statement ‘Fabrazyme standard dose 1.0mg/kg or reduced maintenance dose of 0.3mg/kg’ on Slide 4, presentation 1 was not consistent with the dosage particulars in Section 4.2 and efficacy details at Section 5.1 of the SPC. The Panel ruled a breach of the Code which was upheld on appeal by Genzyme.

The Panel considered the prominent statement ‘US licence application unsuccessful again’ implied that the FDA had rejected the Replagal application again which was misleading, inaccurate and disparaging. The Panel ruled breaches which were upheld on appeal by Genzyme.

Shire noted that on Slides 6 and 22 Genzyme compared the prices of Fabrazyme 1mg/kg, Replagal 0.2mg/kg to Fabrazyme 0.3mg/kg and alleged that this was not consistent with the Fabrazyme SPC. 

The Panel considered that the Fabrazyme SPC was clear that the recommended dose was 1mg/kg body weight. The reference to the use of alternative dosing regimens in clinical studies was in relation to one of these studies when after an initial dose of 1mg/kg every two weeks for 6 months, a dose of 0.3mg/kg every two weeks might maintain clearance of GL-3 in some patients. The Panel further noted the SPC statement that the long-term clinical relevance of these findings had not been established. The Panel noted its comments above at about the 0.3mg/kg dose.

The Panel noted that the only dose cited in the posology section of the Replagal SPC 0.2mg/kg body weight. The Panel considered that the slides implied that Replagal and Fabrazyme at 0.3mg/ kg had similar status according to the respective SPCs and this was not so. Insufficient information about the status of the 0.3mg/kg dose had been given. The Panel considered that the depiction of the 0.3mg/kg dose was inaccurate given the detail in the Fabrazyme SPC. The impression given was misleading and inconsistent with the SPC. The Panel ruled breaches of the Code which were upheld on appeal by Genzyme. 

Slide 7 headed ‘Sakuraba et al: Minimal differences in glycosylation except M6P – the ligand’ reproduced table 1 from Sakuraba et al (2006) which compared the monosaccharide analysis from that study and Lee et al (2003). Data for mannose-6-phosphate (M6P) for Replagal and Fabrazyme were circled. Shire noted that no additional background to the type and purpose of the study eg that it was in vitro. A table taken directly from the publication was modified and only one set of values that differed between the two products were highlighted. Shire alleged that Genzyme had ‘cherry-picked’ the data. Sakuraba et al was not specifically about glycosylation and should not be used independently to substantiate the claims on the slide. No study limitations or caveats were mentioned. 

The Panel considered that the audience would be clear that the data derived from in vitro testing. 

The Panel noted that the table was taken directly from the publication. The only modification by Genzyme was that the data for mannose-6- phosphate was circled as Genzyme submitted this was the specific ligand which enabled cellular internalisation. Values for galactose, fucose, mannose, N-acetylglucosamine and sialic acid although not circled were included. The Panel did not consider that Genzyme had ‘cherry-picked’ data as alleged. The Panel queried Genzyme’s submission that it had attached no significance to the possible differences: there appeared to be no other reason for highlighting and comparing the M6P results. Indeed, such differences were mentioned in the narrative which made the theoretical basis of the discussion clear. The Panel had no way of knowing precisely how the slide was presented. The slide had to be capable of standing alone. The Panel did not consider the slide misleading due to the highlighting of the M6P data. It appeared that Genzyme had a cogent reason for selecting that outcome. No breach of the Code was ruled. The Panel noted that no study limitations or caveats related to the table were given on the slide but did not consider that this necessarily rendered the table misleading as alleged. Shire had not established that the study caveats etc should have been included on the slide. The Panel ruled no breach. The Panel considered that the table was capable of substantiation and ruled no breach. 

Slide 8 was headed ‘Lee et al: Replagal is not more potent’ and showed graphs of resonance units against protein concentration and mean response against activity for both products with regard to M6P binding and fibroblast update. Slide 9 headed ‘Sakuruba [sic] (2006): Any potency differences favoured Fabrazyme’ compared enzyme activities and M6P content for both products and stated that there was no difference in stability in plasma. Animal results favoured Fabrazyme. 

Shire submitted that Genzyme appeared to link the potency claims with a claim of greater cost effectiveness. However, the cost effectiveness claim was itself misleading, meaning that the use of potency claims could not be justified. 

Shire noted that Lee et al (2003) was cited with no additional background information on study design and type. Only two graphs were presented and missed vital context in order to fully interpret the data. The study was not powered to compare potency and the results showed no difference in enzyme activity between Replagal and Fabrazyme which had not been appropriately presented. The study did not substantiate the claim of potency and so was not clinically relevant and was misleading. No study limitations or caveats were mentioned. 

Slide 9 was designed to highlight potency differences in the products but described only limited information about the study. The presentation did not mention that not all animal tests were completed with Replagal due to the limited quantity available to test and therefore did not substantiate the claim that ‘animal results favoured [Fabrazyme]’. 

Shire alleged that these results were ‘cherry-picked’ and Genzyme had omitted data showing the additional differences between the two products. Presenting these data without qualifications was misleading and unbalanced.

The Panel noted that neither Slide 8 nor 9 referred to cost or cost effectiveness; it thus failed to understand Shire’s allegation. Slide 6 showed annual costs but did not mention cost effectiveness. Shire might have been attempting to make a general point that the statements regarding potency and the similarity between the products reinforced Genzyme’s data regarding the cost comparison of Fabrazyme 0.3mg/ kg with 0.2mg/kg Replagal. However, there was no such link on the slides. The narrative discussed potency in relation to the products’ similarity, not their cost-effectiveness. The Panel ruled no breaches of the Code in relation to Slides 8 and 9. 

The Panel considered that Slides 8 and 9 were not designed to evaluate potency per se. Slide 8 did not claim superior potency only that Replagal was not more potent. Slide 9 stated that if there were any potency differences these favoured Fabrazyme. The Panel noted that the final bullet point on Slide 9 stated that ‘animal results favoured [Fabrazyme]’. The Panel queried whether it was sufficiently clear that Slides 8 and 9 related to in vitro data and the clinical effects were not being compared. There was no clinical data to substantiate a claim that Fabrazyme was more potent than Replagal. The slides were misleading in this regard and breaches were ruled which were upheld on appeal by Genzyme. The Panel ruled a breach as the graphs on Slide 8 were not presented in such a way as to give a clear, fair, balanced view of matters which was upheld on appeal by Genzyme. The Panel ruled no breach of the Code with regard to Slide 9 as there was no artwork on that slide. 

The Panel did not consider that either Slide 8 or Slide 9 constituted disguised promotion as alleged and ruled no breach of the Code. 

Slide 11 headed ‘Vedder et al (2007): The only attempted comparison of 0.2mg/kg vs 0.2mg/kg’. The slide included a graph comparing Fabrazyme 0.2mg/kg, Fabrazyme 1mg/kg and Replagal 0.2mg/ kg in relation to decrease of LysoGb3 activity. It also included the quote ‘Although the number of patients is small, it is unlikely that large differences in clinical potency exist at equal dose’ and referred to van Breemen et al (2011). 

Shire stated that Vedder et al was a small head to-head study and included an off-label dose of Fabrazyme 0.2mg/kg. The Panel accepted that the data might be interesting from a scientific view point but considered as it used an unlicensed dose of Fabrazyme it was misleading and inconsistent with the SPC. Thus the Panel ruled breaches of the Code which were upheld on appeal by Genzyme. 

Slide 12 headed ‘Smid et al (2011) supply shortage’ featured a graph which referred to changing Fabrazyme 1mg/kg to Replagal 0.2mg/kg fortnightly or Fabrazyme 0.5mg/kg monthly in relation to LysoGb3. Beside the graph was the statement ‘Consistent with biosimilarity and equivalent pharmacodynamic dose response’. 

Slide 13 headed ‘Switch study after recent FDA Replagal withdrawal’ referred to 15 male patients switched from Replagal 0.2mg/kg to Fabrazyme 1mg/kg in whom LysoGb3 decreased by 39.5% p=0.0002. It also included ‘An increased pharmacodynamic response with an increased dose of biosimilar ERT’ [Enzyme Replacement Therapy]. The slide was referenced to Barranger et al (2014).

Shire noted that neither Smid et al (2011) nor Barranger et al (2014 unpublished) were designed to compare the products to indicate biosimilarity or equivalent pharmacodynamic dose response and were therefore used in a misleading manner. The doses used in Smid et al were inconsistent with the product licence. The graph on Slide 12 was not clear and the results shown were only for male patients, consisting of half the patient population at the start and Genzyme did not provide any study detail or balanced safety information. 

Both slides showed switching studies that were conducted during the Fabrazyme global product shortage. The full detail of potential risk of switching patients to a lower dose of Fabrazyme was not made explicit in the presentation with regard to adverse events. The European Medicines Agency Assessment Report (EMEA/H/C/000370, 9 July 2010), on the consequences of the shortage concluded that as more patients were prescribed lower doses of Fabrazyme, more adverse events were reported, and subsequently patients were moved to Replagal or to 1mg/kg of Fabrazyme. 

Slide 13 included ‘… after recent FDA Replagal withdrawal’; Shire alleged that these comments were misleading and disparaging by inferring that the FDA had Replagal withdrawn. Shire had decided to withdraw the application. 

The Panel noted that Slide 12 presented data following either changes in the dose of Fabrazyme or a switch to Replagal. These changes were a result of a supply shortage of Fabrazyme which according to Smid et al was due to viral contamination at Genzyme’s production facility in June 2009 which led to a world-wide shortage and led to involuntary dose reductions or switch to Replagal. Slide 13 referred to the withdrawal of Replagal by Shire from the FDA approval process. 

The Panel noted that the doses illustrated on Slide 12 were inconsistent with the Fabrazyme SPC. The Panel noted the EMA involvement regarding lowering the dose of Fabrazyme due to the supply shortage. It considered that this did not necessarily override the SPC. The Panel noted the promotional nature of the meeting. The reference to the unlicensed dose of Fabrazyme 0.5mg/kg monthly was inconsistent with the SPC as alleged. A breach was ruled which was upheld on appeal by Genzyme. 

The Panel did not consider it was in itself misleading to show only the male patients. The patient population was 17 patients, 14 males and 3 females. There was no statistically significant difference in LysoGb3 increase after one year for females (p=0.3) whereas there was for males (p=0.001). This data was from a subset of patients. The Panel ruled no breach of the Code on this narrow point. 

With regard to the alleged failure to provide safety data the Panel noted Smid’s comments about that data and the EMA Assessment Report 2010. The Panel noted that the slide had to be capable of standing alone. The Panel considered that as Slide 12 did not provide information on safety, it was not balanced or based on an up-to-date evaluation of all the evidence. A breach of the Code was ruled, which was upheld on appeal by Genzyme. With regard to Slide 13 the Panel noted again no safety data in relation to the consequences of switching. This study, Barranger et al, related to changing Replagal patients to Fabrazyme 1mg/kg. On balance, the Panel decided that Slide 13 was not similar to Slide 12 which referred to switching Fabrazyme 1mg/kg to Replagal 0.2mg/kg fortnightly or Fabrazyme 0.5mg/kg monthly. Shire had not identified the safety consequences in relation to a switch to Fabrazyme 1mg/kg. The Panel therefore ruled no breach of the Code in relation to Slide 13.

The Panel noted its rulings in relation to Slide 12 and considered that consequently the graph failed to satisfy the Code and a breach was ruled which was upheld on appeal by Genzyme. 

The Panel noted that Slide 13 was headed ‘Switch study after recent FDA Replagal withdrawal’ and considered that it was not sufficiently clear that Shire had withdrawn its application. A breach of the Code was ruled. Given the audience and the purpose of the meeting of the Panel also considered that the phrase disparaged Replagal. A breach of the Code was ruled. These rulings were upheld on appeal by Genzyme. 

Slide 15 headed ‘Phase IV study of events ~50% risk reduction (conditional licence commitment)’ compared event rate in the intention to treat population against time for Fabrazyme vs placebo. Shire stated that the graph detailed the number of ‘events’ (not labelled as adverse events) in patients receiving either placebo or Fabrazyme. The study and graph were not referenced, no dose was provided and no information regarding the actual adverse events to allow for an informed, clear and transparent risk assessment. 

The Panel queried whether the impression given by the slide which referred to ‘risk reduction’ and ‘event rate’ would be interpreted by the audience as defined clinical events indicating deterioration of disease as submitted by Genzyme given the absence of any such reference on the slide. 

The Panel ruled that the slide was misleading as insufficient information had been provided to give a clear summary of the data in breach of the Code which was upheld on appeal by Genzyme. No reference had been provided on the slide and the Panel ruled a breach of the Code which was upheld upon appeal by Genzyme. 

Slide 16 was headed ‘Mehta A, Lancet (2009) depicts rates of decline of renal function for enzyme replacement therapies’ Shire stated that a graph from Mehta et al was presented with no clear contextual information. Shire alleged it was misleading not to state that the data was from a Fabry Outcome Survey (observational database) and this omission did not allow the audience to correctly interpret the data. 

A separate Fabrazyme Phase III open label extension study was referenced in the graph using dashed lines. Replagal 0.2mg/kg data was also included but with no reference. The graph presented did not have clear information as to the sources for each bar that were included as part of the original Mehta publication. Shire alleged that this data was therefore ‘cherry-picked’ to show misleading information and unbalanced. 

The Panel ruled a breach as no reference was included on the slide for the Replagal data and this was upheld upon appeal by Genzyme. The Panel considered it would have been helpful to include details about the nature of the data and in this regard the slide was misleading. A breach was ruled which was upheld on appeal by Genzyme. The Panel did not consider that Shire had provided sufficient detail in order to establish that there had been a breach of the Code in relation to its allegation about ‘cherry picking’ data and ruled no breach. 

Shire noted that Slide 17 referred to Fabrazyme 0.2mg/kg/every other week, Replagal 0.4/kg/ every other week and Replagal 0.2mg/kg/weekly which were inconsistent with the Fabrazyme and Replagal SPCs. 

Slides 18 and 19 showed two different graphs which Shire stated were unreferenced, unclear and did not provide clear context. The first showed a change in podocyte GL3-score vs cumulative agalsidase dose. The second graph showed the change in podocyte GL3-score vs the change in albumin-creatinine ratio. Shire alleged that the use of such graphs without context was misleading as the study was not powered to compare the efficacy and safety between Fabrazyme and Replagal. 

Shire alleged that the information provided on Slides 17-19 did not substantiate the conclusions made on Slide 20. The study was not designed to provide the outcomes presented but were only observations made by the authors during the study thus rendering the Genzyme conclusions misleading. 

The Panel ruled that Slide 17 was misleading and inconsistent with the SPC regarding the licensed doses of the two products. Breaches of the Code were ruled which were upheld on appeal by Genzyme other than one of the Panel’s rulings. The Appeal Board considered that as the data was derived verbatim from its cited reference Tondel et al, and without any additional comment, Slide 17 could be substantiated and thus on this very narrow ground it ruled no breach of the Code. The appeal on this point was successful. 

Slides 18 and 19 did not include any context. The Panel noted Genzyme’s submission that the data was used to demonstrate similar milligram to milligram potency. The Panel considered that Slides 18 and 19 were contrary to the licensed doses and misleading. There was no reference on either slide. Each was ruled in breach of the Code and these rulings were upheld upon appeal by Genzyme. 

The Panel noted its rulings above on Slides 18 and 19 and Shire’s allegation that these slides did not substantiate the conclusions on Slide 20. The Panel noted that Slide 20 did not reflect the relevant caveats within the study. The Panel ruled that Slide 20 was misleading as alleged and this ruling was upheld on appeal by Genzyme. 

Slide 21 headed ‘My conclusions are:’ set out a number of conclusions including that the proteins were biosimilar on a mg for mg basis in all published data, that the clinical data and licensed situation was more robust for Fabrazyme 1mg/kg but difficult and incomplete for both. The slide also stated that there were no published data which ‘gainsay biosimilarity’ and that the ‘cost savings of switching low dose patients are compelling’. 

Shire alleged that the claim on Slide 21 that ‘Fabrazyme (0.3mg/kg) provides 50% more protein’ misleadingly implied that Fabrazyme was superior to Replagal. This claim was not clinically relevant, was a hanging comparison, unbalanced and was not referenced. The slide also stated (in a larger font than that used in the rest of the presentation): ‘Cost savings of switching low dose patients are compelling’. 

Shire alleged that Genzyme’s clearly intended to promote Fabrazyme by making unsubstantiated disguised promotional claims that Fabrazyme was more cost effective and to make misleading claims that the Fabrazyme data was more robust than that for Replagal. The assumptions made in an economic evaluation must be clinically appropriate. Shire alleged that the use of such claims in a non promotional setting was in breach of the Code. 

Shire submitted that Genzyme’s assumptions were clinically incorrect and inconsistent with the Fabrazyme licence because the cost comparison was based upon the statement that all patients would be started and maintained on the 0.3mg/kg dose of Fabrazyme. No patients should be started on a 0.3mg/kg dose and this was only acceptable as a maintenance dose for some patients and should not be generalised for all patients. 

Given that the cost comparison was inappropriate and that the comparison between Replagal and the reduced Fabrazyme dose was not capable of substantiation, Shire alleged that the presentations 1 and 2 were misleading, disparaging, inconsistent with the SPC and in breach of the Code. 

The Panel noted the comments previously made regarding the licensed dosage and ruled breaches of the Code in relation to Slide 22. 

The Panel was concerned that the conclusion ‘Cost savings of switching low dose patients are compelling’ on Slide 21 was misleading. This was compounded by Slide 22 headed ‘ERT annual cost per 70kg patient at licensed dose’. The Panel noted that no account had been taken of the need to use 1mg/kg dose of Fabrazyme for six months before any consideration could be given to lowering the dose to 0.3mg/kg in certain patients and that the long-term clinical relevance of these findings had not been established. The Panel considered that Slide 21 was misleading in this regard and ruled breaches of the Code which were upheld on appeal by Genzyme.

The Panel did not consider it was sufficiently clear whether the phrase ‘clinical data and licensed situation are more robust for Fabrazyme 1.0mg/ kg but difficult and incomplete for both’ referred to Fabrazyme 0.3mg/kg or Replagal or both. It noted its previous comments about the use of Fabrazyme 0.3mg/kg. Breaches of the Code were ruled which were upheld on appeal by Genzyme. 

The claim that ‘Fabrazyme 0.3mg/kg provides 50% more protein’ was not clear as to what was being compared as alleged. The Panel ruled breaches of the Code which were upheld on appeal by Genzyme.

The Panel noted the promotional nature of the activity and did not consider that Slide 21 was disguised promotion. No breach of the Code was ruled. 

With regard to the Genzyme narrative, Shire noted the statement that ‘… the pre-clinical and clinical data indicate that patients who are currently stable on low dose ERT (Replagal 0.2mg/kg) may be switched to Fabrazyme at a dose of 0.3mg/kg)’. There were no published data showing the clinical benefits in switching stable patients from Replagal to 0.3mg/kg Fabrazyme. There was no correlation between the dose of different medicines and their clinical effect. Genzyme was not encouraging the rational use of a medicine in proposing that patients stable on Replagal were switched to 0.3mg/kg Fabrazyme. No balance was given by Genzyme to information concerning Fabrazyme’s benefits and the risks associated with its use at this dose. 

The Panel noted its comments about the nature of the meeting. It also considered its rulings above regarding the presentation were relevant to the narrative.

The Panel noted both companies agreed there was no published data on the clinical benefits of switching patients from Replagal to Fabrazyme 0.3mg/kg. The narrative did not include the qualifications given in the SPC. The Panel considered the narrative was misleading and breaches of the Code were ruled which were upheld on appeal by Genzyme. 

The Panel also ruled breaches of the Code due to the lack of clinical data to supporting a switch and as the material did not encourage rational use, which were also upheld on appeal by Genzyme. The Panel noted that Shire had not identified what, in its view, needed to be referenced in the narrative and nor had it provided sufficient detail with regard to an allegation of disparagement. No breach of the Code was ruled. 

Shire stated that Genzyme had solicited a meeting with key stakeholders in sensitive commissioning roles within the NHS; the meeting was intended to be non-promotional. However, under the guise of providing a platform for a scientific debate, Genzyme knowingly promoted Fabrazyme by providing cost information. It also provided incorrect and misleading information which had not been certified. 

Shire submitted that meeting attendees had expected a scientific discussion but instead received promotional information about Fabrazyme and how much cheaper it would be compared with Replagal. The inclusion of direct cost comparisons and switch proposals based upon unfounded biosimilarity claims rendered Genzyme’s actions misleading, inaccurate and disguised promotion. 

Shire alleged that due to the significant breaches outlined above Genzyme had failed to maintain high standards and had discredited the industry. Shire noted that in particular the potential risks posed to patients by promoting the wholesale switch between the products on the basis of inconsistent claims which were not supported by robust clinical or supportive data. Shire alleged a breach of Clause 2. 

The Panel noted its comments above and that as the material was promotional it needed to be certified and this had not happened; high standards had not been maintained. Breaches of the Code were ruled which were upheld on appeal by Genzyme. 

The Panel noted that Clause 2 was reserved for use as a sign of particular censure. The Panel noted the purpose of the meeting, including that it was to clarify information provided during a tender process and that the audience included experts in the field. The Panel was concerned that Genzyme had decided the material was non-promotional. The Panel also noted its rulings above that the material presented and pre-circulated was misleading, inconsistent with the Fabrazyme SPC and disparaging. On balance, the Panel considered that the circumstances brought discredit upon, and reduced confidence in, the pharmaceutical industry and thus ruled a breach of Clause 2. 

Upon appeal by Genzyme the Appeal Board was astonished that Genzyme had considered that material provided subsequent to and directly related to a tender process was non-promotional. The Appeal Board was very concerned that regardless of whether Genzyme thought it could rely upon the exemption in Clause 1.2 for information submitted to national public organisations such as NICE etc, the quality standards in the Code relating to information claims and comparisons had not been applied to the material at issue. Much of Clause 7 applied broadly to all material, including that which was non-promotional rather than being limited to, promotional material as submitted by Genzyme. The Appeal Board noted its rulings above that the material presented and pre-circulated was misleading, inconsistent with the Fabrazyme SPC and disparaging. Genzyme had instigated the meeting. The Appeal Board was extremely concerned that Genzyme’s material had focussed on the cost saving via a simple switch to a 0.3mg/ kg dose of Fabrazyme without including the clear caveats in its SPC and no mention of important patient safety issues such as adverse events. It was also concerned about the conclusion that the cost savings of switching low dose patients were ‘compelling’. The Appeal Board noted that prejudicing patient safety as an example of an activity likely to lead to a breach of Clause 2. The Appeal Board considered that the circumstances brought discredit upon, and reduced confidence in, the pharmaceutical industry and it upheld the Panel’s ruling of a breach of Clause 2. The appeal was unsuccessful. 

The Appeal Board noted that the LSDEAG was the advisory group for the SCT which in effect could decide on commissioning at a national level. The potential gain to Genzyme in promoting a switch to 0.3mg/kg Fabrazyme was significant. The Appeal Board was so concerned about the content of the material at issue, its potential effects and impression given including the disregard for patient safety, that it decided, in accordance with Paragraph 10.6 of the Constitution and Procedure to require Genzyme to issue a corrective statement to all attendees at the LSDEAG meeting and all recipients of the pre-circulated material if they differed. The published case report should be provided. Details of the proposed content and mode and timing of dissemination of the corrective statement must be provided to the Appeal Board for approval prior to use. [The corrective statement appears at the end of the report] 

The Appeal Board also decided that, given all of its concerns above, to require, in accordance with Paragraph 10.4 of the Constitution and Procedure, an audit of Genzyme’s procedures in relation to the Code. The audit would take place as soon as possible. On receipt of the audit report and Genzymes’s comments upon it, the Appeal Board would consider whether further sanctions were necessary. 

Genzyme was audited in February 2015 and upon receipt of the audit report, the Appeal Board was extremely concerned that despite a very critical report which concluded with a number of specific recommendations, Genzyme’s comments upon it were exceptionally brief. Indeed the Appeal Board considered that the brevity of the comments demonstrated a lack of engagement. With regard to the audit report, the Appeal Board was deeply concerned that the information which Genzyme had cascaded to its staff about the outcome of Case AUTH/2721/7/14 was not accurate or balanced; this was unacceptable. The Appeal Board considered that there was an apparent lack of insight and leadership with regard to compliance. 

The Appeal Board requested, inter alia, a more detailed response to the audit report and additionally considered that Genzyme should be re-audited at the end of June 2015; on receipt of the report for that audit it would decide whether further sanctions were necessary. 

On receipt of the more detailed response to the audit report from Genzyme whilst the Appeal Boar had some concerns, it would await the re-audit report before considering this matter further.

Upon receipt of that audit report in July, together with Genzyme’s comments upon it, the Appeal Board noted that although some progress had been made, further improvement was still required The Appeal Board was concerned that some of Genzyme’s anticipated completion dates were long given the action required. Further, Genzyme had not given a completion date for implementation of some of the recommendations. 

The Appeal Board was particularly concerned about some training material and considered that Genzyme needed to develop greater in-house expertise. The Appeal Board noted that Genzyme had plans in that regard and aimed to finalise updated materials by 31 August. It was hoped that updated standard operating procedures etc would be finalised by 30 November. 

Notwithstanding the provision of certain materials in the meantime, the Appeal Board required that Genzyme be re-audited no later than early Decemb 2015; on receipt of the report for that audit it would decide whether further sanctions were necessary. 

Due to major organisational changes Genzyme requested that the re-audit be deferred until Februa 2016. The Appeal Board was reluctant to do so, give its concerns noted above, but it acknowledged the exceptional circumstances and on receipt of updated material from Genzyme, decided that the re-audit could be deferred until February 2016. 

Upon receipt of the report of the audit, together with Genzyme’s (now Sanofi Genzyme) comments upon it, the Appeal Board noted that progress had been made since the audit in June 2015; the company had a new general manager and there had been a change in company structure. The aud report highlighted an improvement in company culture although concerns remained about Code training material that must be addressed. On the basis that this work was completed, the progress shown to date was continued and a company-wide commitment to compliance was maintained, the Appeal Board decided that, on balance, no further action was required.​