AUTH/3366/7/20 - Bayer v Novartis

Promotion of Beovu

  • Received
    17 July 2020
  • Case number
  • Applicable Code year
  • Completed
    17 May 2021
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    Appeal by respondent

Case Summary

Bayer Plc complained about a journal advertisement (ref BRO20-CO22, March 2020) for Beovu (brolucizumab) placed by Novartis Pharmaceuticals UK Ltd in the April 2020 edition of Eye News. The claim at issue was ‘Outperformed aflibercept with superior retinal fluid resolution at Weeks 16 and 48**1’ which appeared as the second of two headline claims in the advertisement, printed in dark pink font.

Beovu was indicated in adults for the treatment of neovascular (wet) age-related macular degeneration (AMD). Bayer marketed Eylea (aflibercept) which was also indicated in adults for the treatment of neovascular (wet) AMD. Eylea and Beovu were biological anti-angiogenic therapies administered by injection into the eye and acted by inhibiting vascular endothelial growth factor (anti-VEGF). Eylea had been approved by the National Institute for Health and Care Excellence (NICE) for use in the treatment of neovascular (wet) AMD.

1 Use of secondary endpoints and footnotes

Bayer stated that the claim ‘Outperformed aflibercept with superior retinal fluid resolution at Weeks 16 and 48**1’ was based on a secondary, exploratory endpoint (resolution of total retinal fluid) of two non-inferiority studies (Dugal et al 2020). Readers had to spot the double asterisk and then read several lines of small print footnotes to begin to appreciate the full context. The fact that this was a secondary endpoint was only revealed by the double asterisk aligned to a statement, in small, black type print, four lines below the claim in question. The primary endpoint in the relevant studies was non-inferiority in mean change in best corrected visual acuity (BCVA) from baseline to week 48. Beovu was found to be non-inferior to aflibercept in both studies. The primary endpoint of the studies (non-inferiority) was only mentioned eight lines below the claim in question, again, in small, bold, black type print.

The footnote clarifying the primary study endpoint did not state the study outcome of non-inferiority having been met. Bayer contended that even if Novartis had included the primary outcome in the advertisement as a similar small type footnote (for example, by stating words to the effect that ‘non-inferiority was met’), that would still be wholly insufficient given such prominent claims of outperformance and superiority in the claim.

Bayer was concerned that Novartis did not agree to stop using footnote qualifiers and state with a similar level of prominence (ie font size, position, colour etc) that the claim was based on an exploratory, secondary endpoint.

The secondary endpoint evidence to support the claim was exploratory, as evidenced in the European Medicines Agency (EMA) European Public Assessment Report (EPAR) for Beovu

Bayer alleged that to claim that Beovu ‘outperformed’ and had ‘superior retinal fluid resolution’ to Eylea without giving sufficient prominence to the primary outcome, and without sufficient prominence to the fact that the claims were based on an exploratory, secondary outcome, was misleading.

In Bayer’s view, a health professional would only read the prominent ‘outperformed’ and ‘superior’ claims in large red typeface, and thus would be likely to miss the small print qualifiers in black font listed separately and at a significant distance below the claim. Bayer alleged that the claim was selected for prominence and had not been properly contextualised in its presentation to allow health professionals to independently assess the therapeutic value of the two medicines discussed. Readers were very likely to be left with the key take-home message that Beovu had overall ‘outperformed’ and was ‘superior’ to Eylea which was not the case. In the context of the EMA’s comments in the EPAR and considering the PMCPA’s previous decisions on such matters, use of terms such as ‘outperformed’ and ‘superior’ in the claim, with qualifying statements appearing in small typeface footnotes below, made the claim a misleading comparison in the context of Clause 7.2.

The Panel noted that both claims in the advertisement related to the secondary endpoints in the pivotal studies (HAWK and HARRIER). Below these two claims were 9 lines of small black footnote text which appeared to be the same font size as the prescribing information which featured immediately below. One sentence, in the seventh and eighth lines of the footnote, was bold and stated: ‘The primary efficacy endpoint in both studies was non-inferiority in mean BCVA [best corrected visual acuity] change from baseline to Week 48 as measured by ETDRS’. The Panel noted that the explanation for the asterisks, **, used after the claim at issue, was given in the fourth line of the footnote text which stated: ‘Secondary endpoint in HAWK and HARRIER, confirmatory analysis in HAWK only (1-sided p values for superiority of Beovu)’.

The Panel noted that the primary objective of both HAWK and HARRIER was to demonstrate that brolucizumab (Beovu: once every 12 weeks/8 weeks) was non-inferior to fixed-dose aflibercept with respect to the change in BCVA from baseline to Week 48. At Week 48, each brolucizumab arm demonstrated non-inferiority to aflibercept in BCVA change from baseline; P < 0.001 for each comparison. The Panel noted that Beovu was found to be non-inferior to aflibercept in both studies. This primary endpoint result was not referred to in the advertisement at issue.

The Panel noted that additional secondary efficacy end points included, inter alia, the status of SRF (subretinal fluid)/IRF (intraretinal fluid) and sub-RPE (retinal pigment epithelium) fluid, and presence of disease activity at Week 16. In both studies, patients received a complete ophthalmic examination (including BCVA and anatomic assessments [IRF/SRF /sub-RPE fluid and CST]) and were evaluated for adverse events every 4 weeks.

The Panel noted that Dugel et al stated that each of the 4 BCVA-related non-inferiority hypotheses of HAWK reached statistical significance (1-sided P < 0.025) and therefore additional confirmatory superiority testing was conducted in HAWK to assess the superiority of brolucizumab regarding, inter alia, presence of IRF and/or SRF. The study authors stated that this additional confirmatory superiority testing of brolucizumab versus aflibercept was prespecified in HAWK (based on HARRIER learnings). Dugel et al stated that superior anatomic outcomes regarding retinal fluid and retinal thickness with brolucizumab 6 mg versus aflibercept could be concluded from HAWK and HARRIER at Weeks 16 and 48 in both studies. Formal demonstration of statistical superiority versus aflibercept was only demonstrated in HAWK.

The Panel considered that it was not necessarily unacceptable to include secondary endpoint data in promotional material without reference to the primary endpoint from a non-inferiority trial so long as such references complied with the Code and were not otherwise misleading.

The Panel noted that section 5.1 of the Beovu SPC referred to the percentage difference in patients with IRF and/or SRF fluid for Beovu versus aflibercept in HAWK and HARRIER at Weeks 16 and 48 as statistically significant. There was no mention in the SPC that this data was secondary endpoint data, however, the secondary endpoint evidence, used to support the claim at issue, was referred to as exploratory in the Beovu EPAR which stated that it could not be the basis for claims in the product information. The Panel considered that the content of the EPAR was relevant, particularly in relation to the requirement in the Code for claims to be balanced and reflect all the evidence. In the Panel’s view, whilst it might not be unacceptable to refer to exploratory analyses in promotional material, the context was an important consideration and it questioned whether such data should be used as the basis for a robust comparison of medicines.

The Panel noted that Beovu was a new product at the time the advertisement was published and in that regard health professionals reading a specialist eye journal would be interested in the outcomes of its key registration studies, HAWK and HARRIER.

The Panel considered the immediate and overall impression to health professionals reading the advertisement. In the Panel’s view, the bold claim at issue including the use of ‘superior’ and ‘outperformed’ would be the take home message and might imply that Beovu was overall clinically superior to aflibercept. The Panel was concerned that the impression of clinical superiority given by the claim was inconsistent with HAWK and HARRIER as reported in Dugel et al which concluded that Beovu was non-inferior to aflibercept in terms of its primary endpoint. The footnote which qualified the claim at issue by stating that it was based on a secondary endpoint was not sufficient to negate this misleading impression. Further the advertisement did not include the study outcome ie that Beovu was found to be non-inferior to aflibercept. The primary efficacy endpoint measure was included in another footnote, headed ‘study design’.

The Panel noted its comments above and considered that the claim in question in the context of the advertisement at issue was misleading and the reader was not provided with sufficient information to properly assess the claim and form his/her own opinion of the therapeutic value of Beovu vs aflibercept. A breach of the Code was ruled.

2 Presentation of emerging clinical and scientific debate

Bayer accepted that Beovu showed a formal statistically significant difference from Eylea (aflibercept) in terms of total retinal fluid resolution in one pivotal study, albeit that this was an exploratory, secondary endpoint. However, the claim ‘Outperformed aflibercept with superior retinal fluid resolution at Weeks 16 and 48**1’ was alleged to be misleading because it implied that total retinal fluid resolution had an accepted clinical relevance, when in fact the differential effect of resolution in different fluid compartments was increasingly considered to be more pertinent.

During inter-company dialogue, Novartis acknowledged that there was ongoing clinical debate on the relative importance of the drying of fluid in different compartments of the retina, but stated that it was not, however, Novartis’ position to tell clinicians how to engage in that debate. That responsibility fell on the prescriber who should decide whether the claims made were relevant to their clinical practice based on current evidence, clinical experience and guidelines.

Bayer stated that prescribers could not decide on relevance if they were not aware of the debate. Bayer contended that the debate was ignored by the prominent broad claim of superiority in respect to total fluid resolution as the drying of total fluid was not presented in the context of the drying of fluid in different retinal compartments. In that regard, the claim did not present the area of emerging scientific opinion in a balanced manner.

Bayer submitted that it was not in question that retinal fluid was important in diagnosing and assessing neovascular AMD and in making associated treatment decisions; however current scientific opinion was split over the clinical relevance of different types of retinal fluid.
When compared with aflibercept, Beovu had not been demonstrated to have a significantly greater impact on drying intra-retinal fluid (Dugal 2019 and Dugal 2017), the compartment that was increasingly recognized by clinical consensus to be the one most closely associated with poor visual outcomes.

Bayer stated that whilst it recognized that this was a complex and controversial area, the debate had not been resolved in favour of one generally accepted viewpoint. The claim presented the increased drying of total retinal fluid by Beovu as a definite clinical benefit in comparison with Eylea, and thereby indicated clinical ‘outperformance’ and ‘superiority’ to Eylea, whereas this had not been proven and was an area where scientific opinion was evolving. Since Novartis had failed to treat the issue of retinal fluid drying in a balanced manner, Bayer alleged the material was misleading.

The Panel considered that as noted in point 1 above the claim ‘Outperformed aflibercept with superior retinal fluid resolution at Weeks 16 and 48’ might incorrectly imply that the results seen in the study directly translated into clinically meaningful benefits for Beovu over Eylea. In the Panel’s view, the advertisement over-simplified the position in that it implied that Beovu clinically outperformed Elyea based on total fluid resolution when there was emerging clinical/scientific opinion on the clinical relevance of the drying of the different compartments of the retina.

The Panel noted its comments above and did not consider that the reader had been provided with sufficient information to properly assess the claim and form his/her own opinion of the therapeutic value of Beovu vs aflibercept in relation to its effect on retinal fluid resolution. A breach of the Code was ruled. This ruling was upheld on appeal by Novartis.

3 Alleged misleading comparison re safety profiles

Bayer alleged that the promotional approach in the advertisement did not provide readers with all the facts necessary to interpret the claim objectively, because it did not discuss the differences between the safety profiles of the two products shown in the same studies. The advertisement not only misleadingly stated that Beovu ‘outperformed’ Eylea (aflibercept) based on an exploratory, secondary endpoint in non-inferiority studies, it also failed to acknowledge that a safety difference was identified during these same studies. The misleading nature of the advertisement was of concern to patient welfare as, when the advertisement was approved, the pivotal studies referenced had shown increased rates of intraocular inflammation and retinal artery occlusion with Beovu compared with Eylea (Dugal 2020). These safety concerns (specifically retinal artery occlusive events) with Beovu were specifically highlighted by the EMA in the summary of the initial CHMP opinion and retinal artery occlusion appeared in the Beovu SPC, but not in the Eylea SPC.

Bayer stated that the clinical importance of that initial observation had been highlighted by further events and details were provided. As a direct result, Beovu was currently subject to investigation of a new safety signal and was in the process of an update to its global prescribing information. In June 2020, some 8 months after first launch, the US label for Beovu was the subject of safety amendments to its label in the US, Australia and Switzerland . Bayer understood discussions were ongoing with the European regulators regarding a similar change to the Beovu SPC.

Whilst Bayer accepted that the safety signal was confirmed only after the advertisement was first approved, the advertisement’s publication in April 2020 occurred after the first emergence of potential post marketing safety concerns in February 2020, and when it was already clear from the pivotal study that adverse events of direct relevance to the new safety signal occurred far more frequently with Beovu compared with Eylea (Dugal 2020). To compare the two products in the advertisement without presenting comparative differences in safety data between them from the pivotal studies, when an advantage based on an exploratory, secondary endpoint from the same studies was claimed, was therefore a misleading comparison by omission.

Bayer also submitted that these safety concerns remained relevant when it came to the general promotional approach for Beovu given that it was a newly launched medicine where post marketing safety experience was still evolving and there remained many uncertainties related to causation, risk factors, incidence and optimal treatment of adverse events. Given the evolving nature of the safety concerns associated with Beovu, Bayer was concerned that Novartis did not agree during inter-company dialogue to present a specific overview of the comparative safety differences between the two products (rather than simply rely on the prescribing information) in the context of making a superiority claim based on an exploratory, secondary endpoint from non-inferiority studies. On that basis, Bayer alleged that the ongoing promotional approach, typified by the advertisement, was neither balanced, nor objective, nor did it reflect a clear and up to date evaluation of all the evidence.

The Panel noted that it was agreed during inter-company dialogue that the emerging safety data was not relevant to the journal advertisement at the time of its publication as it had emerged after and was not reflected in the SPC at the time of the advertisement. Novartis had committed to appropriately representing all safety data as required by the Code in future material. The Panel noted that this matter had thus been settled and therefore it would make no rulings in that regard.

The Panel noted, however, that during inter-company dialogue Bayer had also raised concerns that the claim comparing efficacy should only have been made if a comparison of safety data was also provided. Bayer alleged that not doing so misled as to the overall clinical comparison between the medicines and was the allegation upon which the Panel would make its ruling.

The Panel noted that both medicines would only be administered by ophthalmologists experienced in intravitreal injections; this was a specialist area. Such health professionals, in the Panel’s view, on the balance of probabilities, would not be misled that the claim ‘Outperformed aflibercept with superior retinal fluid resolution at Weeks 16 and 48’ included a comparison of safety profiles.

The Panel did not consider that Bayer had shown, on the balance of probabilities, that presenting efficacy data from HAWK and HARRIER without presenting the comparative differences in safety data between Beovu and aflibercept was misleading by omission as alleged. No breaches of the Code were ruled.