AUTH/2840/4/16 and AUTH/2847/5/16 - Anonymous, non contactable v Novartis and Pfizer

Promotion of Ultibro Breezhaler and Seebri Breezhaler

  • Received
    25 April 2016
  • Case number
    AUTH/2840/4/16 and AUTH/2847/5/16
  • Applicable Code year
    2016
  • Completed
    16 September 2016
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    No appeal
  • Review
    November 2016 Review

Case Summary

An anonymous, non contactable complainant complained about the promotion of long acting beta agonist/long acting muscarinic antagonists (LABA/ LAMA) combination inhalers for the treatment of chronic obstructive pulmonary disease (COPD). The complainant noted that the medicines were licensed for the relief of COPD symptoms but appeared to have been additionally promoted to reduce exacerbations. The complainant stated that some LAMA inhalers had also similarly been promoted off-label. The complainant drew attention to, inter alia, Ultibro Breezhaler (indacaterol (LABA)/ glycopyrronium (LAMA)) and Seebri Breezhaler (glycopyrronium (LAMA)) both co marketed by Novartis Pharmaceuticals UK and Pfizer.

Ultibro Breezhaler and Seebri Breezhaler were both indicated as maintenance bronchodilator treatments to relieve symptoms in adults with COPD.

The complainant noted that the first LABA/LAMA fixed combination to be licensed was Ultibro Breezhaler and stated that it was clear from its European Public Assessment Report (EPAR) that the Committee for Medicinal Products for Human Use (CHMP) turned down an application that included its use to reduce exacerbations, because its effects on such were too small to recommend such use. Ultibro Breezhaler was subsequently licensed only as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD and thus its promotion in relation to COPD exacerbation reduction was off-label. In relation to this case the complainant drew attention to a journal advertisement which stated that 'Ultibro Breezhaler can significantly reduce your patients' rate of moderate to severe exacerbations'. Similarly, the complainant alleged that a leavepiece contained an off-label claim for Seebri Breezhaler namely, '... significantly reduces the risk of first moderate/severe COPD exacerbation by 31%'. Neither contained any other information warning of the off-label aspects to the promoted use of the products.

The complainant stated that his/her colleagues had little awareness that LABA/LAMA combination inhalers or LAMA inhalers were being prescribed in an unlicensed manner. Also, formal recommendations for the use of these medicines in exacerbation reduction were increasingly appearing in local clinical guidelines which suggested that promotion of the medicines had not clearly communicated the off-label nature of this use. The complainant stated that the materials for the various inhalers to which he/she had drawn attention were most probably just the tip of the iceberg; he/she knew of numerous educational meetings/symposia with external speakers where exacerbation reduction data had been presented as part of product promotion.

A potential major concern for the complainant and his/her prescribing colleagues was that they might have unknowingly prescribed LABA/LAMA combination inhalers or LAMA inhalers to numerous COPD patients assuming that they were licensed for exacerbation reduction. The statement from the CHMP which considered exacerbation was therefore a sobering thought especially if COPD patients subsequently suffered exacerbations unexpectedly because their prescribed LABA/LAMA combination inhalers might not be effective enough as intimated by the CHMP assessment of Ultibro Breezhaler. COPD was characterised in part by airway inflammation and the extent of inflammation was progressive leading up to an exacerbation. None of the medicines in question contained an anti inflammatory component. Another very important consideration was that prescribers were unaware from a medico-legal perspective that they would be solely liable for any adverse consequences suffered by patients which might arise.

The detailed response from Novartis and Pfizer is given below.

The Panel noted that both products were indicated as maintenance bronchodilator treatments to relieve symptoms in adult patients with COPD. Section 5.1 of the respective Ultibro Breezhaler and Seebri Breezhaler summaries of product characteristics (SPCs) referred to each medicine's positive impact on exacerbations of COPD. The Panel noted that Section 1.1 of the National Institute for Health and Clinical Excellence (NICE) Guideline on the management of COPD listed the symptoms of the disease which were, inter alia, exertional breathlessness, chronic cough, regular sputum production and wheezing. In Section 1.3 the exacerbation of COPD was described as a sustained worsening of the patient's symptoms from their usual stable state which was beyond normal day-to day variations and was acute in onset. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidance similarly differentiated COPD symptoms and exacerbations. In the Panel's view, there was a difference between COPD symptoms and exacerbation of COPD although it accepted that patients with well controlled symptoms might be less likely to experience an exacerbation than patients with poorly controlled symptoms. In that regard the Panel considered that exacerbations might be referred to in the promotion of COPD maintenance therapy but that there was a difference between promoting a medicine for a licensed indication and promoting the benefits of treating a condition. In the Panel's view, reference to reduced COPD exacerbation must be set within the context of the primary reason to prescribe ie maintenance therapy to relieve symptoms.

The Panel noted that the Ultibro Breezhaler advertisement at issue included the sub-heading 'Ultibro Breezhaler offers benefits beyond current standard COPD maintenance therapies' beneath which were four claims one of which was 'vs salmeterol/fluticasone Ultibro Breezhaler can significantly reduce your patients' rate of moderate or severe exacerbations', referenced to Zhong et al (2015), the LANTERN study. In that regard the Panel considered that the claim for a benefit vs salmeterol/fluticasone appeared to be a consequence of using Ultibro Breezhaler as a maintenance therapy and not the reason to prescribe per se, as alleged. Given the context in which it appeared, the claim was not misleading with regard to the licensed indication for Ultibro Breezhaler. No breaches of the Code were ruled including that high standards had been maintained.

These rulings also applied to the 'Wealth of data' leavepiece and on balance to the sales aid. No breaches of the Code were ruled.

Novartis also provided a copy of a leavepiece, 'What is the right treatment choice for your patients?'. Under a heading of 'Ultibro Breezhaler offers patients effective relief from symptoms of COPD at a price of £32.50' was boxed text entitled 'Reduces exacerbation risk beyond tiotropium (open label) and [salmeterol/fluticasone]' which reported the results from Zhong et al. The leavepiece, however, did not clearly state that Ultibro Breezhaler was a maintenance therapy to relieve COPD symptoms such that the boxed text would be read within the context of the licensed indication. In the Panel's view the leavepiece implied that Ultibro Breezhaler could be prescribed to reduce exacerbations rather than the reduction in exacerbations being a benefit of using the medicine as maintenance therapy. In the Panel's view the leavepiece was inconsistent with the particulars listed in the Ultibro Breezhaler SPC; it misleadingly implied that exacerbation reduction was a primary reason to prescribe Ultibro Breezhaler. Breaches of the Code were ruled including that high standards had not been maintained.

A speaker slide deck, 'Evolving science; Dual bronchodilation', examined the burden of COPD and the challenges of treatment and included an overview of clinical studies for, inter alia, Ultibro Breezhaler. The slide which introduced Ultibro Breezhaler (slide 54) clearly stated that it was indicated as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD. A subsequent section on exacerbations referred to the positive data from the SPARK (vs glycopyrronium and tiotropium) and LANTERN (vs salmeterol/fluticasone (LABA/inhaled corticosteroid (ICS)) studies. Slide 80 within a subsequent section on health-related quality of life, was headed 'Summary: Ultibro Breezhaler significantly improved important patient outcomes vs monotherapies and LABA/ICS' and in that regard listed exacerbations. The second bullet point of the final concluding slide (slide 101) stated 'Once daily Ultibro Breezhaler demonstrated superior efficacy compared with placebo, its monocomponents indacaterol and glycopyrronium, the current standard of care (tiotropium) and LABA/ICS'. It was not stated what the superior efficacy related to. In the Panel's view, given the length of the slide deck and the number of topics discussed, it was possible that, after 101 slides, some viewers would have forgotten exactly what Ultibro Breezhaler was indicated for; some viewers might be left with the impression that Ultibro Breezhaler could be prescribed for the reduction of exacerbations per se which was not consistent with the particulars listed in its SPC. That the presentation implied that Ultibro Breezhaler could be used to reduce COPD exacerbations and was a primary reason to prescribe the product was misleading. Breaches of the Code were ruled including that high standards had not been maintained.

The Panel considered that the training course presentation could have benefitted from a more explicit statement as to the licensed indication for Ultibro Breezhaler and that any reduction in exacerbations was to be discussed as a benefit of maintenance therapy and not as a reason to prescribe per se. Nonetheless, on balance, the Panel did not consider that the material encouraged representatives to promote Ultibro Breezhaler for exacerbation reduction. No breaches were ruled.

The Panel noted that the Seebri Breezhaler leavepiece at issue stated on the front cover that the medicine was indicated as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD. Page 2 of the leavepiece described a typical patient and stated that he 'wants a treatment that will help him breathe better in the morning…and throughout the day'. Page 3 of the leavepiece included the claim that, compared with placebo, Seebri Breezhaler 'Significantly reduces the risk of first moderate/severe COPD exacerbation by 31% (p=0.023)'. The Panel did not consider that the leavepiece promoted Seebri Breezhaler for the reduction of COPD exacerbation as alleged. Preceding claims largely discussed symptom control. The reference to exacerbations had been presented within the context of the licensed indication ie as a benefit of maintenance therapy and not the reason to prescribe per se. The Panel considered that the promotion of Seebri Breezhaler had been consistent with the particulars listed in the SPC. The leavepiece did not imply that exacerbation reduction was a primary reason to prescribe Seebri Breezhaler and so was not misleading in that regard. No breaches of the Code were ruled including that high standards had been maintained.

In response to the complainant's wider concerns about the promotion of Seebri Breezhaler, Novartis provided a copy of two internal training presentation. Overall the Panel considered that the presentations suggested that Seebri Breezhaler could be prescribed per se to reduce COPD exacerbations, for which the medicine was not indicated; both were ruled in breach of the Code including that high standards had not been maintained.

The Seebri Breezhaler sales aid contained a page which was headed 'How can you help delay the time to first moderate to severe COPD exacerbation for your patients' which appeared above a graph comparing the effect of Seebri Breezhaler with that of placebo. The claim at the bottom of the slide read 'Initiate Seebri Breezhaler to reduce your patients' risk of exacerbations'. Finally the Panel noted that although a set of Seebri Breezhaler speaker slides only briefly referred to the positive exacerbation data from Kerwin et al (2012) compared with placebo, those results were not put into context by any statement of the licensed indication for the medicine. The Panel considered that the sales aid and the speaker slides both suggested that Seebri Breezhaler could be prescribed per se to reduce COPD exacerbations, for which the medicine was not indicated; this was inconsistent with the particulars listed in the Seebri Breezhaler SPC. The materials implied that exacerbation reduction was a primary reason to prescribe Seebri Breezhaler. Breaches of the Code were ruled including that high standards had not been maintained.

The Panel noted that a ruling of a breach of Clause 2 was a sign of particular censure and reserved for such. The Panel noted its rulings and comments above but considered that the matters were not such as to bring discredit upon, or reduce confidence in, the industry. No breach of Clause 2 was ruled.