AUTH/3245/9/19 - Anonymous GP (assisted by an Ex Employee) v Novo Nordisk

Promotion of Ozempic      

  • Received
    23 September 2019
  • Case number
  • Applicable Code year
  • Completed
    11 March 2020
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    Appeal by complainant
  • Review
    To be published in the review

Case Summary

An anonymous, contactable individual, who described him/herself as a GP was concerned about claims allegedly made by Novo Nordisk representatives with regard to Ozempic (semaglutide) and weight loss and cardiovascular benefits which he/she alleged was off-label promotion.

Ozempic was indicated for the treatment of certain adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise. It was a once weekly GLP-1 RA (glucagon-like peptide-1 receptor agonist).

The complainant was concerned that Novo Nordisk representatives were making superiority claims regarding the Sustain 6 trial when it was not powered for superiority.

The complainant stated that the reasons for Novo Nordisk promoting semaglutide for weight loss was obvious; many clinics were prescribing it for obese patients without diabetes as it was better than Saxenda but this was not what it was licensed for and the suicide rate was unknown.

The complainant further alleged that the representative was unable to substantiate the claims and give more information and also denigrated dapagliflozin, sitagliptin and canagliflozin.

The detailed response from Novo Nordisk is given below.

The Panel noted that the complainant had the burden of proving his/her complaint on the balance of probabilities. All complaints were judged on the evidence provided by the parties. The complainant had not provided the material at issue which meant that it was difficult for Novo Nordisk to respond. Novo Nordisk provided two leavepieces and an iDetailer for use with health professionals. It also provided a briefing document titled ‘Ozempic Core Launch Guide’.

The Panel noted that Marso et al (the SUSTAIN 6 trial) evaluated cardiovascular outcomes in patients with type 2 diabetes on a standard-care regimen who were randomised to receive once-weekly subcutaneous semaglutide (0.5mg or 1mg) or volume-matched placebo. Patients had to have type 2 diabetes and HbA1c of 7% or above and either had not been treated with an antihyperglycaemic medicine or had been treated with no more than two oral antihyperglycaemic agents, with or without basal or pre-mixed insulin. Key inclusion criteria were an age of 50 or above with established CV disease, chronic heart failure or chronic kidney disease of stage 3 or higher or age 60 or above with at least one CV risk factor.

The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (including silent) or nonfatal stroke. It was powered as a non-inferiority study. The non-inferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. Pre-specified secondary outcomes included the individual components of the primary composite outcome.

The hazard ratio for the composite primary outcome was 0.74; 95% confidence interval 0.58 to 0.95, p<0.001 for non-inferiority and p=0.02 for superiority. The authors stated that the study was not powered to show superiority, so such testing was not pre-specified or adjusted for multiplicity. However, the treatment effect of semaglutide and the accrual of more events than estimated resulted in a significantly lower risk of the primary outcome among patients in the semaglutide group. Patients were followed for a relatively short duration and were at high cardiovascular risk. The application of these findings to other populations and a longer duration of treatment was unknown. It was also unknown to what extent the greater glycated haemoglobin reductions in the semaglutide group contributed to the results. The authors concluded that in patients with type 2 diabetes at high cardiovascular risk, ‘the rate of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke was significantly lower in those receiving semaglutide than in those receiving placebo, which confirmed noninferiority’.

The Ozempic SPC stated that five trials (SUSTAIN 1–5) had the glycaemic efficacy assessment as the primary objective, while one trial (SUSTAIN 6) had cardiovascular outcome as the primary objective. The SPC stated that ‘Treatment with semaglutide demonstrated sustained, statistically superior and clinically meaningful reductions in HbA1c and body weight for up to 2 years compared to placebo and active control treatment (sitagliptin, insulin glargine, exenatide ER and dulaglutide)’. Information about the SUSTAIN trials in the Ozempic SPC included results for primary and secondary endpoints for SUSTAIN 6. The SPC included hazard ratios and confidence intervals but did not mention p values for SUSTAIN 6.

The first page of the 12 page Ozempic leavepiece included the claim ‘Help adults with insufficiently controlled type 2 diabetes’ above the main heading ‘Realise the potential’ followed by claims for superior glycaemic control and superior and sustained weight loss compared to dulaglutide, sitagliptin, exenatide once a week and insulin glargine. There was also a claim for ‘CV benefits’ versus placebo, both in addition to standard of care. The CV benefit claim included an asterisk to a footnote at the bottom of the page which stated, ‘In SUSTAIN 6, Ozempic reduced major adverse CV risk (time to first occurrence of: CV death, non-fatal myocardial infarction, or non-fatal stroke) versus placebo in patients with type 2 diabetes at high CV risk treated with standard of care’. Page 2 referred to patients’ struggle with poor glycaemic control and comorbidities referring to HbA1c, weight and CV disease. Page 3 of the leavepiece claimed that ‘GLP RAs offer meaningful advantages over DPP-4 inhibitors’. This claim was followed by separate claims for Ozempic’s superior glycaemic control and body weight reduction referring to significantly greater weight loss versus sitagliptin. A reference to CV benefits also appeared on the page stating that ‘Ozempic offers CV risk reduction vs placebo, both in addition to standard of care [referenced to SUSTAIN 6] while DPP-4 inhibitors offer no CV risk reduction in their CVOTs [cardiovascular outcomes trials]’. This section was separated from the comparisons for superior glycaemic control and significantly greater weight loss by a vertical red line, however the information appeared beneath the main heading to the page which referred to ‘meaningful advantages’ of GLP-1RAs over DPP-4 inhibitors. The next page gave more detail about the comparison between Ozempic and sitagliptin in HbA1C and was followed by a page giving more detail about the weight loss comparison. The details of the SUSTAIN 6 study were set out on page 6 and the following page claimed that Ozempic significantly reduced the risk of CV events within a 2-year study. Within the graph titled ‘Time to first confirmed major CV event (MACE)’ it stated, in small light grey font, ‘Hazard ratio: 0.74 (95% CI, 0.58-0.95) p<0.001 for non-inferiority’. This was the only reference in the leavepiece to SUSTAIN 6 being a non-inferiority study. Information was provided about the components of the primary composite endpoint including that there was no difference between Ozempic and placebo in relation to non-fatal myocardial infarction and CV death. There was a difference between Ozempic and placebo in relation to non-fatal stroke (p=0.04). The page claimed that when added to standard of care there was a 26% CV risk reduction vs placebo (ARR [absolute risk reduction] 2.3%).

The shorter leavepiece included similar claims. The Panel noted that the word ‘superior’ was not used to describe CV benefits in the leavepieces. The iDetailer had a number of sections including those labelled ‘unmet need’, ‘superior efficacy’ and ‘CVOT’. The ‘CVOT’ section included details about SUSTAIN 6 and CV benefit. The claims were similar to that in the leavepieces. The iDetailer included the same graph as in the leavepieces and the reference to the hazard ratio and non-inferiority result. However, unlike the leavepieces the graph in the iDetailer also included ‘p=0.02 for superiority post hoc’. This reflected the presentation of the data in the graph in the study other than the reference to ‘post hoc’. The Ozempic Core Launch Guide briefing material did not mention that SUSTAIN 6 was powered as a non-inferiority study.

The Panel noted that, overall, the two leavepieces and the iDetailer made a number of superiority claims for Ozempic compared with other therapies. They each included the key messages referring to glycaemic control, weight loss and CV benefits.

The Panel noted that the Code required that the promotion of a medicine must be in accordance with the terms of its marketing authorization and must not be inconsistent with the particulars listed in the SPC.

Section 5.1 of the Ozempic SPC stated that both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality were an integral part of the treatment of type 2 diabetes.

The Panel considered that the complainant had not shown on the balance of probabilities that the claims regarding weight loss and CV outcomes were not presented in the context of the licensed indication for Ozempic ie the treatment of diabetes in certain patients. Information about SUSTAIN 6, CV outcomes and weight loss were included in the SPC. Bearing in mind the limited information provided by the complainant, the Panel considered that in the circumstances the complainant had not shown that Novo Nordisk had promoted Ozempic in a manner which was inconsistent with the particulars listed in its SPC. The Panel therefore ruled no breach of the Code in this regard. This ruling was unsuccessfully appealed by the complainant.

The Panel queried whether the material was sufficiently clear regarding the data for CV outcomes. The only reference to SUSTAIN 6 being a non-inferiority study was in small light grey font included in a graph which appeared on one page of each of the leavepieces in a size similar to the text in the footnote. The iDetailer included similar information as the leavepieces but with the additional reference to ‘p=0.02 for superiority post hoc’. The Panel considered the immediate and overall impression to a health professional. On balance, the Panel considered that the material was not sufficiently clear given the non-inferiority primary endpoint and further in relation to the iDetailer the SUSTAIN 6 authors caution as the study was not powered to show superiority. Nor was the material sufficiently complete to enable the recipient to form their own opinion of the therapeutic value of Ozempic in terms of the claims for CV benefits. A breach of the Code was ruled. The Panel considered that Novo Nordisk had failed to maintain high standards in this regard and a breach of the Code was ruled.

The Panel noted that the complainant had not identified the Novo Nordisk representative who appeared to have discussed the product with him/her and left a leavepiece. The complainant had not clearly set out which claims were of concern to him/her as being incapable of substantiation or denigrated dapagliflozin, sitagliptin and canagliflozin and no details were provided about the alleged failure to respond to the complainant’s request for more information. Nor was any detail provided by the complainant regarding his/her concerns about suicide risk. In the circumstances the complainant had not demonstrated, on the balance of probabilities, that there was a breach of the Code in this regard and the Panel therefore ruled no breach of the Code including Clause 2. The Panel’s ruling of no breach of Clause 2 was unsuccessfully appealed by the complainant.