AUTH/3458/1/21 - Complainant v Napp

Alleged off-licence promotion of Invokana

  • Received
    19 January 2021
  • Case number
    AUTH/3458/1/21
  • Applicable Code year
    2019
  • Completed
    01 October 2021
  • No breach Clause(s)
  • Additional sanctions
  • Appeal
    Respondent appeal

Case Summary

A contactable complainant who described him/herself as a concerned UK health professional complained about the promotion of Invokana (canagliflozin) by Napp Pharmaceuticals Limited. The material at issue was a video hosted on the Diabetes On The Net website entitled ‘CREDENCE: Type 2 Diabetes Management – A New Perspective. Protect the kidney to protect the heart’ (ref UK/INV-20107ab, August 2020). The complainant provided a link to a webpage (ref UK/INV-20107ac, September 2020) which included details about the video in question and a link to it. The video detailed the results from the CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial.

Invokana, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, was indicated for the treatment of certain adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise.

Section 4.1 of the Invokana summary of product characteristics (SPC) (Therapeutic indications) also referred readers to other sections of the SPC for study results on glycaemic control, renal events and cardiovascular events. Section 5.1 stated that improvement in glycaemic control and reduction of cardiovascular and renal morbidity and mortality were integral parts of the treatment of type 2 diabetes.

The complainant alleged that the website did not mention that Invokana was only for adults with type 2 diabetes, not children. The complainant submitted that without providing clarification as to who could be treated, the medicine could be prescribed off-licence.

The complainant did not consider that adequate safety information had been provided, such as how the dose should be reduced or that Invokana should not be used in certain severities of renal failure - which was extremely salient in a website that, given the slogan ‘protect the kidney to protect the heart’, was purporting a reno-protective effect of Invokana and this was not a licenced indication.

The complainant referred to one slide entitled ‘Until recently, licensed renal thresholds for use of SGLT2 [inhibitors] have been based on glycaemic efficacy’. The complainant alleged that the slide misrepresented competitors; the title and body of the text stated one thing, but the small footnote ‘No dose adjustments based on renal function are needed for dapagliflozin, 10mg is the highest recommended dose for dapagliflozin’, meant that it was not true for that medicine.

The complainant submitted that most trial outcomes were not licensed indications and the audience was not made aware that at best these were added benefits, rather than a reason to use the treatment. The complainant referred to a slide which included a number of hazard ratios in favour of canagliflozin vs placebo: these being cardiovascular death or hospitalised heart failure (p=0.0001), hospitalised heart failure (p=0.0003), cardiovascular death, myocardial infarction or stroke (p=0.0121).

The complainant also referred to a slide entitled ‘Use of Canagliflozin in Clinical Practice for Patients with [Type 2 Diabetes]’ which listed canagliflozin as a treatment for three conditions - cardiovascular disease, kidney disease and diabetes. The complainant alleged that this was blatant off-licence promotion – Invokana was only licensed for diabetes, not merely for patients who happened to have type 2 diabetes.

The detailed response from Napp is given below.

The Panel noted that the webpage included the Napp diabetes, Credence trial, and Invokana logos at the top and a link to the Invokana prescribing information. The webpage also included an image of the on demand presentation’s title slide headed ‘CREDENCE: Type 2 Diabetes Management - A New Perspective Protect the kidney to protect the heart’ and included an image of a heart shaped lollipop with kidneys within it. The introduction to the video stated ‘What does the CREDENCE trial mean for the management of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) for specialists?’. It went on to explain that the promotional video which was aimed specifically at renal, diabetes and cardiology specialists, looked at the CREDENCE trial and assessed how Invokana (canagliflozin) might change the management of DKD in type 2 diabetes in the secondary care setting. The video was described as giving a unique insight into the CREDENCE trial design and results from two of the lead investigators; and how the findings of CREDENCE translated into the specialist setting. The Panel noted that the video, which appeared to be aimed at a secondary care audience and lasted just over 1 hour, consisted of three sessions. The Panel noted that the presentation overall explored what the renal results from the CREDENCE trial meant for the management of diabetic kidney disease in adult patients with type 2 diabetes.

It appeared to the Panel that if a reader clicked to view the video from the above webpage, a slide (ref UK/INV-20107p, July 2020) which stated, inter alia, that Invokana was indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise followed by ‘For treatment of diabetic kidney disease (DKD) in adults with T2DM as add-on to standard of care, a dose of 100mg once daily should be used. Please see Invokana SmPC section 4.2 for details about dosing’ was shown before the main presentation began.

With regard to the complainant’s allegation that the website did not mention that Invokana was only for adults with type 2 diabetes, not children, the Panel noted that there was no specific mention or impression given on the webpage in question that Invokana was licensed to treat children with type 2 diabetes. Although it might have been helpful for the indication to have been included on the webpage itself, it was included within the linked prescribing information, the video slide before the presentation began and at additional timepoints within the video. The Panel therefore did not consider that the webpage or video in question was misleading such that it promoted the use of Invokana in children as alleged. No breaches of the Code were ruled.

With regard to a slide entitled ‘Until recently, licensed renal thresholds for use of SGLT2 [inhibitors] have been based on glycaemic efficacy’, .the Panel noted that although it was highly unusual to present out-dated prescribing details, the context in which the side was used and the commentary which accompanied it meant that, in the Panel’s view, the slide was not necessarily unacceptable. The slide followed a discussion of a patient case study and was used to illustrate that until recently, due to his deteriorating kidney function (currently 39ml/min/1.73m2) the patient, who was at high risk of a cardiovascular event, would not have been able to be treated with an SGLT2 inhibitor but that he would have qualified for inclusion in the CREDENCE trial. The slide featured a graphic which showed that for patients with an eGFR of between 60 – 90ml/min/1.73m2, SGLT2 inhibitors could be initiated and titrated up according to glycaemic control. Four SGLT2s were so listed with the starting dose and the maximum dose for titration stated for three of them. The fourth SGLT2 inhibitor listed was dapagliflozin with only a 10mg dose stated. A footnote read, ‘No dose adjustments based on renal function are needed for dapagliflozin, 10mg is the recommended highest dose for dapagliflozin’. The Panel considered that the footnote confirmed the single dose for dapagliflozin as stated in the graphic – it did not qualify it. It was clear from the main body of text that there was only one dose for dapagliflozin compared with the other three SGLT2 inhibitors with doses that could be titrated upwards and so in that regard the Panel did not consider that the information was misleading. No breach of the Code was ruled.

The Panel noted that the complainant alleged that one of the presenters stated that there were benefits to patients’ renal outcomes without mentioning that it was not a licensed indication. The complainant had not provided details of what was said or by whom and the Panel considered that the complainant had not made out his/her allegation in that regard. It was not for the Panel to infer reasons to support a complainant’s allegations. The Panel therefore ruled no breaches of the Code in that regard.

The Panel noted that the complainant alleged that two slides from the video in question, were examples of off-licence promotion. The Panel noted that the first slide included a summary of the cardiovascular trial outcomes including, inter alia, cardiovascular death or hospitalised heart failure; hospitalised heart failure; cardiovascular death, myocardial infarction or stroke. The second slide was titled ‘Use of Canagliflozin in Clinical Practice for Patients With T2DM’ followed by three statements: Canagliflozin as Treatment for Cardiovascular Disease; Canagliflozin as Treatment for Kidney Disease; and Canagliflozin as Treatment for Diabetes. Below these statements were the letter C, K and D. Letter C which was detailed as standing for cardiology and was associated with an image of a heart, K for kidney associated with an image of the kidneys and D for diabetes associated with an image of a pancreas.

The Panel considered that it was not unacceptable for companies to promote the additional benefits that might be afforded from treatment with a particular medicine provided that those benefits were clearly set within the context of the licensed indication. The primary reason to prescribe must be made clear.

The Panel noted from Section 4.1 of the Invokana 100mg SPC that the licensed indication was:

‘for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- as monotherapy when metformin is considered inappropriate due to intolerance
or contraindications

- in addition to other medicinal products for the treatment of diabetes

For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied, see sections 4.4, 4.5 and 5.1.’

Section 5.1 of the SPC stated, below the heading ‘Clinical efficacy and safety’, that improvement in glycaemic control and reduction in cardiovascular and renal morbidity and mortality were integral parts of the treatment of type 2 diabetes.

The Panel noted that section 4.2 (Posology and method of administration) of the Invokana 100mg SPC stated under the heading ‘Renal impairment’ that, inter alia, ‘for treatment of diabetic kidney disease as add on to standard of care (eg ACE-inhibitors or ARBs [angiotensin receptor blockers]), a dose of 100mg canagliflozin once daily should be used’ and further included dose adjustment recommendations depending on the patient’s eGFR or CrCl.

The Panel noted Napp’s submission that renal protection information was included within the Invokana SPC following the outcome data from the CREDENCE trial and that the Invokana 100mg SPC now reflected the extended indication to treat diabetic kidney disease in type 2 diabetes patients as add on to standard of care.

In the Panel’s view, it was thus not necessarily unacceptable to refer to the renal benefits of Invokana in type 2 diabetes patients. Similarly, nor was it necessarily unacceptable to refer to its cardiovascular benefits; both appeared to be an integral part of the treatment of type 2 diabetes.

The Panel considered that although the slide summarising the cardiovascular outcomes did not refer to type 2 diabetes, it noted Napp’s submission that one of the objectives of session 2 ‘CREDENCE: bringing the data to life’, in which the slide at issue appeared was to present the detailed study results including both the renal and cardiovascular endpoints from the study. Further the session began with describing the study and its design including that one of the key inclusion criteria was type 2 diabetes mellitus. The Panel noted that the slide in question followed a slide which discussed the incidence of hospitalised heart failure in clinical trials with SGLT2 inhibitors and the presenter stated that data from the CREDENCE trial showed that people with evidence of kidney damage in the presence of diabetes were not only at increased risk of developing kidney failure but also at the highest risk of developing heart failure too. The Panel further noted that the speaker highlighted that the slide depicting hazard ratios represented a summary of the secondary cardiovascular outcomes from the CREDENCE study. In the Panel’s view, viewers of the video would, therefore, view the cardiovascular outcomes on the slide in question in the context of type 2 diabetes. The Panel did not consider that the complainant had established that the slide at issue promoted Invokana in a manner that was not in accordance with the terms of its marketing authorisation or was inconsistent with the SPC with regards to its cardiovascular benefits in type 2 diabetes patients as alleged; no breach of the Code was ruled. Nor was the slide in the context of the overall presentation misleading in this regard and the Panel ruled no breach of the Code.
The complainant also referred to a slide headed ‘Use of Canagliflozin in Clinical Practice for Patients with [Type 2 Diabetes]’. The slide listed canagliflozin as treatment for cardiovascular disease, kidney disease and diabetes, in that order. Whilst the Panel was concerned that diabetes appeared last in the list and that below this list D(diabetes) with the associated pancreas image also appeared last following C(cardiology) and K(kidney) and the associated heart and kidney image respectively, the Panel noted that the title of the slide clearly referred to the use of canagliflozin in clinical practice for patients with type 2 diabetes. The presenter stated that Invokana had multiple benefits for patients with type 2 diabetes and especially those with evidence of kidney disease. It was stated that the CREDENCE trial had demonstrated that treatment with Invokana resulted in a reduced risk of major cardiovascular events and heart failure, a reduced risk of renal failure and transplantation and that it had a glucose lowering effect. It would be clear to viewers that the treatment of cardiovascular disease and kidney disease was in the context of the treatment of type 2 diabetes patients. The Panel, therefore, did not consider that the complainant had established that the slide at issue promoted Invokana in a manner that was not in accordance with the terms of its marketing authorisation or was inconsistent with its SPC with regards to its renal and cardiovascular benefits in type 2 diabetes patients as alleged; nor was the slide misleading in this regard. The Panel ruled no breaches of the Code.

The Panel noted that the complainant alleged that the webpage which hosted the on demand video claimed that Invokana had a reno-protective effect which was off-licence. In that regard the complainant also referred to the slogan ‘protect the kidney to protect the heart’ which appeared as part of the presentation’s title following ‘CREDENCE: Type 2 Diabetes Management – A New Perspective’. The Panel considered that the complainant bore the burden of proof and had not established, on the balance of probabilities, that either the webpage or the associated video presentation promoted Invokana in a manner that was not in accordance with the terms of its marketing authorisation or was inconsistent with its SPC with regards to its renal benefits in type 2 diabetes patients as alleged, nor was the webpage or the presentation overall misleading in this regard. The Panel ruled no breaches of the Code.

The Panel considered both the webpage advertising the video and the video presentation itself in relation to the complainant’s general concern that not enough safety information had been given on the webpage.

The Panel noted that whilst the webpage referred to the management of diabetic kidney disease in type 2 diabetes mellitus and included the strapline ‘Protect the kidney to protect the heart’, it did not include specific details with regard to treatment of patients with renal impairment with Invokana or provide any specific dosage instructions. The webpage encouraged readers to view the video to find out about what the CREDENCE trial results might mean in practice. Further, the information was included within the Invokana prescribing information linked from the webpage and the agenda for session 3 referred to dosing considerations highlighting that it was a topic that would be covered in the presentation. The Panel noted the secondary care audience and that Invokana had been in use since 2013 when the dosage in renal impairment was more restrictive than currently. The Panel did not consider that, particularly given its purpose and content, the webpage was misleading as alleged. No breach of the Code was ruled.

The Panel noted Napp’s submission that in session 3 of the presentation which discussed how the CREDENCE data translated in a specialist clinical setting, the indication for Invokana was discussed in detail and clearly highlighted the dose adjustments required for Invokana based on renal function as set out in its SPC. The Panel noted, however, that the slide displayed before the presentation began (ref UK/INV-20107p, July 2020), in addition to stating that Invokana was licensed for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise, also stated, with equal prominence and on a separate line, ‘For treatment of diabetic kidney disease (DKD) in adults with [type 2 diabetes] as add-on to standard care, a dose of 100mg once-daily should be used. Please see Invokana SPC section 4.2 for details about dosing’.

The Panel considered that the statement about the treatment of diabetic kidney disease on this slide implied that all adult type 2 diabetes patients with diabetic kidney disease could be given 100mg Invokana which was not so. The Panel noted that a table of dose adjustment recommendations in Section 4.2 of the Invokana SPC showed that although patients with an estimated glomerular filtration rate (eGFR) of more than 30ml/min/1.73m2 could be initiated on Invokana 100mg, those with an eGFR of less than 30ml/min/1.73m2 could not be initiated on Invokana although if they had already started therapy at 100mg then it could be maintained. The Panel further noted that beneath the heading Renal impairment in Section 4.4 of the Invokana SPC, Special warnings and precautions for use, it stated ‘The efficacy of canagliflozin for glycaemic control is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2)’. It further stated that monitoring of renal function was recommended prior to initiation of canagliflozin and at least annually, thereafter (see Sections 4.2, 4.8, 5.1, and 5.2) and before initiation of concomitant medicines that might reduce renal function and periodically thereafter.

The Panel considered that the statement regarding the use of Invokana 100mg in diabetic kidney disease on the slide (ref UK/INV-20107p, July 2020) that displayed before the presentation began was thus misleading. That readers were referred to Section 4.2 of the SPC for details about dosing and a summary of the SPC dose adjustments based on renal function were highlighted towards the end of the presentation in session 3 (starting at 42.50 minutes) was insufficient to negate the immediate misleading impression that all adult type 2 diabetes patients with diabetic kidney disease could be given 100mg Invokana. A breach of the Code was ruled. The Panel considered that high standards had not been maintained and a breach of the Code was ruled. The Panel considered that the claim put type 2 diabetes patients with diabetic kidney disease and an eGFR <30ml/min/1.73m2 at risk of being initiated with Invokana 100mg when the SPC stated that they should not be. The Panel considered that it was potentially prejudicial to patient safety and a breach of Clause 2 was ruled. These rulings were appealed by Napp.

The Panel noted that the Code stated that information and claims about adverse reactions must reflect available evidence or be capable of substantiation by clinical experience. It must not be stated that a product had no adverse reactions, toxic hazards or risks of addiction or dependency. The word ‘safe’ must not be used without qualification. The Panel did not consider that the complainant had raised an allegation in that regard. Nonetheless, the Panel noted Napp’s submission that Session 2 of the video presentation discussed in detail the safety information of Invokana from the CREDENCE trial including the adverse events experienced. The Panel therefore ruled no breach of the Code.

Upon appeal by Napp, the Appeal Board noted the content of the slide at issue which was shown for several seconds before the main presentation of over 1 hour duration began.

The Appeal Board considered that when treating diabetes patients with renal impairment health professionals would be especially cautious and were likely to consult the SPC before prescribing. In that regard the Appeal Board noted the reference on the slide at issue to prescribing information being available at the end of the presentation. In addition, the slide included ‘…Please see Invokana SmPC section 4.2 for details about dosing’. The Appeal Board considered that whilst Napp had chosen to refer prescribers to Section 4.2 on dosing it might have been clearer, given the topic of the presentation, to include a statement summarising the dose adjustment recommendations according to eGFR from Section 4.2 of the SPC. However, the Appeal Board noted that the slide only appeared briefly and that later in the presentation a summary of the SPC dose adjustments based on renal function and that certain patients could continue on Invokana but should not be initiated on the medicine was included. Taking all the circumstances into account the Appeal Board considered that in the context of the video, the slide at issue did not misleadingly imply that all adult type 2 diabetes patients with diabetic kidney disease could be given 100mg Invokana. The Appeal Board ruled no breach of Code. Consequently, the Appeal Board ruled no breach of the Code including Clause 2. The appeal on all points was successful.