AUTH/3202/6/19 - Pharmacist v Napp

Alleged off-licence promotion of Invokana

  • Received
    06 June 2019
  • Case number
    AUTH/3202/6/19
  • Applicable Code year
    2019
  • Completed
    10 June 2020
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    Appeal by respondent

Case Summary

An anonymous and non-contactable individual, who described him/herself as a concerned pharmacist, complained about the promotion of Invokana (canagliflozin) by Napp at a national conference of a diabetes society. Invokana was indicated for the treatment of adults with insufficiently controlled type 2 diabetes as an adjunct to diet and exercise as monotherapy and in combination.

The complainant alleged that the representative on Napp’s exhibition stand explained the new renal outcome data and how Invokana could be the first in therapy for slowing the progression of chronic kidney disease in type 2 diabetes. The representative put forward a valid argument to use Invokana in this patient group but on inspection of the summary of product characteristics (SPC), this was an off-licence indication and under the Code should not have been advocated.

The detailed response from Napp is given below.

The Panel noted that Section 4.1 of the Invokana SPC cross-referred to study results in relation to, inter alia, effects on glycaemic control and cardiovascular events in later sections of the SPC.

The Panel noted that when using a product for its licensed indication there might be other beneficial outcomes for which the product was not licensed. It was not unacceptable to refer to such benefits so long as they were placed clearly within the context of the licenced indication for the product which was the primary reason to prescribe. Napp accepted that renal outcomes were not a licensed indication but described them as an additional benefit.

According to Napp, the representative in question was clear that he/she had presented the CANVAS-R data on renal benefits in line with the SPC and he/she had not answered any questions outside of the licence, referring such questions to the medical team.

The Panel noted that the CANVAS programme was an integrated analysis of two similarly designed trials, CANVAS and CANVAS-R, to assess CV safety and efficacy of Invokana versus placebo in Type 2 diabetics who were at risk of cardiovascular disease. Pre-specified hypotheses testing of secondary outcomes was discontinued as the first secondary outcome hypothesis failed to demonstrate statistical significance. Consequently, all secondary outcomes underwent exploratory analyses and the associated hypothesis tests were not performed. The Panel did not have a copy of either study but noted that the Napp Diabetes Training Hub Module 3 – The Canvas Programme stated that exploratory analyses of renal endpoints suggest that Invokana may reduce the risk of renal events (the progression of albuminuria and the composite renal endpoint of a 40% reduction in eGFR, renal replacement therapy or renal death). P values were not calculated for these exploratory outcomes. Napp stated that the SPC did not refer to the analyses of renal events from the integrated CANVAS programme but did refer to data from the individual CANVAS-R trial in relation to reduction in the progression of albuminuria and reducing the decline of eGFR versus placebo. The Panel noted Napp’s detailed submissions about the Canvas-R data and CREDENCE trials. The Panel noted Napp’s submission that the secondary renal outcomes component to the CANVAS programme demonstrated, inter alia, a significant 47% relative risk reduction for the time to the first adjudicated nephropathy event.

The subsequent CREDENCE trial specifically addressed potential renal protection in type 2 diabetes and was stopped early for clinical efficacy. The Panel did not have a copy of this study. Napp submitted that representatives had been briefed and trained in detail that they could not promote CREDENCE results. The Panel noted a section of the Credence briefing made it clear that when attending third party meetings at an exhibition stand any questions about Credence should be referred to a local MSL or medical information. The section ‘What renal information can be used currently’ advised representatives that they could talk about renal outcomes from CANVAS-R using the sales aid, and when discussing this information to note the disclaimer ‘Improved renal outcomes with Invokana are an additional benefit only and not a licensed indication’. It was also made clear that some patients in Credence were off-licence in that they had eGFR below 60mL/min/1.73m2 and that representatives could not talk reactively or proactively about patients outside of the licence. If asked about CREDENCE, reactive responses were given including that representatives could state that CREDENCE was stopped early for efficacy reasons, and that representatives could not proactively talk about the CREDENCE study, or engage in discussions about the study results or the nature of what these might mean, or encourage health professional discussions that ‘lead’ on CREDENCE. In the Panel’s view, following the briefing about reactive responses might solicit questions about the study results. Representatives were advised to pass requests to medical information or an MSL.

In addition, the Panel noted that the briefing for the meeting in question advised that, if asked a medical question, a medical information request form ‘can be completed’ and that, in addition, a member of the medical team would also be available and should be able to speak to the health professional. Medical question was not defined and yet it appeared to the Panel that the evidence from both parties was that what might be described as medical matters were discussed. The briefing also stated that if asked a question outside of licence the health professional should be put in contact with one of the medical affairs team.

Whilst the complainant did not refer to the sales aid Napp stated that it would have been used at the stand. The Panel noted that whilst it had some concerns about the sales aid, the Renal section featured a banner at the top of each page which read ‘Improvements in renal outcomes with Invokana are additional benefits and not licensed indications’.

The Panel noted that an Invokana leavepiece which, according to Napp, was available from the stand on a page entitled ‘Glucose-Lowering medication in type 2 diabetes: Overall Approach’ included a summary of the ADA/EASD guidelines and stated that ‘Both empagliflozin and canagliflozin have shown reduction in HF and reduction in CKD progression in CVOT’s and recommended Invokana or other SGLT2i with evidence of reducing HF and/or CKD progression in CVOT if eGFR was adequate. The following page entitled ‘Why do the new guidelines favour SGLT2is over DPP4is and SUs?’ included a table showing that Invokana had a positive impact across a number of categories including CKD progression.

The Panel noted that another document available on the stand was entitled ‘Practice Nurse – Beyond Glycaemic Control’ and referred to the CREDENCE trial in a section headed Canagliflozin and renal benefits which described the trial and stated that it had been ended ahead of schedule following positive results suggesting that in future, drugs for diabetes control may also be selected on the basis of proven renal benefits.

The Panel noted that the conference included a Napp sponsored symposium entitled ‘Diabetes and the cardio/renal axis: life changing practice in type 2 diabetes’. The Panel did not know whether the complainant had attended the symposium. Nonetheless, given the symposium and the foreseeable general professional interest in the renal data and the information available on the stand described above, it was not unsurprising that discussion about renal data occurred at the stand. The Panel did not know precisely what occurred including what was said by either party and how the discussion was initiated and there was no way of contacting the complainant for further information. In such circumstances, it was not possible to determine where the truth lay. The complainant bore the burden of proof and had not established, on the balance of probabilities, what was said and whether that discussion promoted Invokana for an unlicensed indication. There was no evidence that the representative had failed to maintain a high standard of ethical conduct in relation to the discussion at the exhibition stand. No breaches of the Code included Clause 2 were ruled.

In relation to the briefing materials, the Panel noted that it was important to be clear in briefing and training materials that in the CANVAS programme the secondary renal results were exploratory and p values had not been calculated. This was especially important given the emphasis attached to renal benefits in the sales materials. The Panel considered that the Diabetes Training Hub Module – The Canvas Programme, on balance, made the status of the secondary renal outcomes clear and in this regard ruled no breach of the Code.

In relation to training on the CREDENCE results, the Panel was concerned that a presentation did not make it clear how the results sat with the licensed indication, including that a sub population of patients sat outside the licensed indication. Nor was it made clear that the training was for educational purposes and did not reflect Napp’s submission that the field force could not proactively talk about CREDENCE. The Panel was particularly concerned about the final page of the presentation which, in its view, bore the appearance of promotional material. It featured a prominent red triangle, divided horizontally into thirds, each third featured a promotional claim in prominent green font. The top third of the triangle read ‘30% Reduction in Death or Dialysis’. A horizontal red arrow adjacent to the claim led to a prominent claim in black font within an irregular yellow star which read ‘FIRST AND ONLY SGLT2i with renal outcome data’. The strap line at the bottom of each slide read ‘Credence to move medicine forward’. The Panel considered that the failure to include the appropriate caveats throughout in relation to the renal data and that the concluding slide contained strong promotional claims about renal outcome data meant that it advocated a course of action that was likely to lead to a breach of the Code. A breach of the code was ruled. This ruling was upheld on appeal by Napp.

The Panel ruled a breach of the Code as it considered that high standards had not been maintained in relation to the briefing material. This ruling was upheld on appeal by Napp. The Panel considered that its concerns about the briefing material were adequately covered and decided to rule no breach of Clause 2 which was reserved to indicate particular censure.