A consultant physician complained about promotion of Toujeo (insulin glargine) by Sanofi. The material at issue presented the outcome of Bailey et al 2016 and claimed that Toujeo provided more stable and more evenly distributed steady-state pharmacokinetic/pharmacodynamic (PK/PD) profiles compared with insulin degludec in type 1 diabetes. The interpretation of this data was that Toujeo in clinical practice would significantly reduce the incidence of hypoglycaemia particularly at night in patients with type 1 diabetes. If true this would be a significant clinical benefit.
The complainant stated that he was concerned that Sanofi had over interpreted the data and so he contacted the author of the study who noted that there were two studies comparing Toujeo and Tresiba (insulin degludec marketed by Novo Nordisk). The Sanofi study (Bailey et al) investigated ‘within-day variability’ the fluctuation of the metabolic effect in a treatment interval of 24 hours which (in absolute terms) was lower at a dose of 0.4U/kg, however, no differences were seen at 0.6U/kg. The other study, Heise et al investigated day-to-day variability and showed a significantly lower day-to-day variability for Tresiba. Heise et al also investigated within-day variability and came to a different conclusion comparing relative withinday variability (fluctuations corrected for the overall metabolic effect) which was higher for Tresiba than for Toujeo.
The author noted that both studies had some limitations however, Heise et al had a considerably higher statistical power as it enrolled more patients and did three clamps with either insulin in each individual. The author stated that further analyses was required to better understand the differences between the two studies.’
From this response the complainant considered that the promotional material at issue was at best, significantly incomplete and at worst, intentionally misleading in that it had only selectively quoted from the data.
The detailed response from Sanofi is given below.
The Panel noted that Bailey et al was a doubleblind cross-over study to compare the steady state pharmacodynamic and pharmacokinetic profiles of Toujeo-300 and degludec-100 with two fixed once-daily dosing regimens (0.4U/kg and 0.6U/ kg) in type 1 diabetics over 24 hours. The study authors concluded that Toujeo-300 resulted in less within day variability of the glucodynamic profile vs degludec-100 at a dose clinically relevant for type 1 diabetics (0.4U/kg/day). At the 0.4U/kg dose 6 hour fractions of glucodynamic activity were more evenly distributed over 24 hours with Toujeo-300 versus degludec-100. An overall more stable and more evenly distributed insulin exposure for Toujeo vs degludec-100 over 24 hours was observed in steady state at both dose levels (0.6U/kg/day and 0.4/kg/ day). The within day variability of the glucodynamic profile with Toujeo-300 at the 0.6U/kg daily dose was not statistically significant vs degludec. The study authors noted that the potential clinical implications of these findings for people on basal insulin therapy should be evaluated in a larger clinical study.
The Panel noted that whether the presentation of data from a clamp study was acceptable under the Code in relation to any implied clinical benefit depended on the individual circumstances of each case. Care should be taken with such data so as not to mislead as to its significance. The Panel noted the study authors’ caveats about the potential clinical implications set out above.
The Panel noted that the data in question was shown to the complainant on an iPad; it was described as the ‘Latest Data app’ and referenced Bailey et al and Bergenstal et al (2017) but that two studies were cited only became apparent on close examination. That claims about the PK and PD profile and a reduction in hypoglycaemia were referenced to different studies was not immediately obvious and in the Panel’s view the design of the page was such that a reader was invited to link the reduction in hypoglycaemic risk with the flatter and more evenly distributed PK and PD profile. Similar concerns applied to the presentation of data throughout the app.
In the Panel’s view, the design and layout of the app was such that readers would associate the findings in Bailey et al with the clinical claims about hypoglycaemia. The Panel considered that the material was misleading in this regard as alleged; it implied that the reduction in hypoglycaemic risk was unequivocally attributable to the product’s PD and PK profile and that was not so and thus not capable of substantiation. Breaches of the Code were ruled.
The Panel also noted the complainant’s allegation that the material was incomplete and misleading as it had selectively quoted from the data. The Panel queried whether the allegation was sufficiently clear: it might be construed as stating that it was not clear that the 0.6U/kg data from Bailey et al was not statistically significant, that the daily variation data from Heise et al was more clinically relevant and ought to have been included or that its secondary endpoint data of within-day variability ought to have been included or indeed that all of the data from Heise et al ought to have been part of the latest data app. The Panel noted that the complainant bore the burden of proof.
The Panel noted the comments made by an author of Bailey et al to the complainant: that while Bailey et al showed that within-day variability was lower for Toujeo at a dose of 0.4U/kg, no differences were seen at a dose of 0.6U/kg and that Heise et al investigated day-to-day variability. According to the complainant the author explained that Heise et al showed a significantly lower day-to-day variability for Tresiba but in relation to within-day variability came to a different conclusion (fluctuations corrected for the overall metabolic effect) which was higher for Tresiba than for Toujeo. The Panel noted the author’s comment to the complainant about the within-day variability data from Heise et al and Bailey et al which the Panel considered appeared to be consistent.*
The Panel noted Sanofi’s detailed submission about the differences between the two studies and why in its view they were not directly comparable. Sanofi had considered that it would not be able do justice to the discussion of the Heise et al study in its promotional material in this instance and could in fact risk confusing readers because in its view Bailey et al and Heise et al were not directly comparable.
The Panel considered that in principle it was not unacceptable to refer to discrete study results so long as the material overall complied with Code. Context including the nature and purpose of the material was relevant. The Panel noted the author’s comment to the complainant about the data in Bailey et al and Heise et al in relation to within-day variability which the Panel considered were similar.* It also noted its comments above about the nature of the allegation. Noting these points, the Panel did not consider the material incomplete or misleading as alleged and ruled no breach of the Code.
The Panel noted its comments and rulings above with regard to the iPad app at issue and links to clinical benefit. The Panel reviewed the accompanying briefing material and training provided to the representative. The training document when referring to Bailey et al stated ‘Understand the clinical information on the variability at duration of action data for Toujeo; translate into customer interactions, to strengthen your in call performance’. The following page listed bullet points under the heading ‘Commercial relevance’ including: ‘What are the 3 claims out of this paper - product features?’ and ‘What are the clinical benefits for your customers and patients? The briefing document presented Bailey et al and Bergenstal et al, side by side without stating that the results of Bailey et al could not be extrapolated to the clinical benefits seen in Bergenstal et al. The Panel noted that it was accepted by Sanofi that the representative in question had linked Bailey et al to a decreased incidence of hypoglycaemia. The Panel considered that encouraging representatives to identify clinical benefits from Bailey et al and failing to instruct them to exercise caution in this regard meant that the material was such that it advocated a course of action likely to breach the Code. A breach of the Code was ruled.The Panel noted its comments and rulings above and considered that Sanofi had failed to maintain high standards. A breach of the Code was ruled.
[* See post publication note at end of case report]