AUTH/2928/1/17 and AUTH/2929/1/17 - Anonymous v Pfizer and Novartis

Pharmacovigilance compliance, promotion of an unlicensed indication and breach of undertaking

  • Received
    04 January 2017
  • Case number
    AUTH/2928/1/17 and AUTH/2929/1/17
  • Applicable Code year
    2016
  • Completed
    06 July 2017
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    No appeal
  • Review
    August 2017 Review

Case Summary

An anonymous, non-contactable complainant, who stated that he/she was a pharmacovigilance (PV) consultant referred to Case AUTH/2847/5/16. The complainant stated that this case contained important PV considerations not previously addressed.

Cases AUTH/2840/4/16 and AUTH/2847/5/16 concerned the promotion of Ultibro Breezhaler (indacaterol (long acting beta agonist (LABA))/ glycopyrronium (long acting muscarinic antagonist (LAMA)) and Seebri Breezhaler (glycopyrronium) by Novartis and Pfzer.

Ultibro Breezhaler and Seebri Breezhaler were both indicated as maintenance bronchodilator treatments to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD).

The complainant stated that in Case AUTH/2847/5/16 Pfzer (although not the marketing authorisation holder for Ultibro Breezhaler) was obliged to collect and record relevant information including off-label use to pass to the marketing authorisation holder, Novartis.

The complainant stated that the current Ultibro Breezhaler campaign was likely to encourage replacement of fxed dose combinations of inhaled corticosteroids (ICS)/LABAs with the aim of modifying or preventing clinically relevant exacerbations. In the event of increased safety reports of clinically relevant exacerbations associated with morbidly and mortality (however likely or unlikely) associated with Ultibro Breezhaler use, this theoretical PV safety signal resulting from a widespread change in prescribing habits/patterns might be missed in terms of being directly linked with Ultibro Breezhaler off-label use. Information on how the current promotional campaign for Ultibro Breezhaler might lead to a widespread change in prescribing habits/patterns was provided.

The complainant stated that Cases AUTH/2840/4/16 and AUTH/2847/5/16 confrmed that Pfzer knew about the alleged off-label nature of promotional activities in April 2016. In the four months that followed the organisation seemed not to have thoroughly considered the PV implications because by September 2016 the extent of off-label promotion was not curbed as expected but actually intensifed as evidenced by the headline, 'Exacerbation risk reduction in your hands' used on an electronic advertisement shown on an exhibition stand at the European Respiratory Society (ERS) congress in London 3-7 September 2016. The copy of the advertisement provided by the complainant referred to both Novartis and Pfzer.

Both companies had failed to identify and clarify what constituted off-label use. It would seem that this failure might have existed for a considerable amount of time which was serious when considering PV obligations. It was likely that potentially thousands of interactions between Pfzer personnel (feld or offce based) and valid reporters regarding the use of Ultibro Breezhaler to reduce exacerbations in COPD patients had taken place.

The complainant alleged that Pfzer and Novartis had previously failed to adequately train personnel to recognise that the use of Ultibro Breezhaler to reduce exacerbations in COPD was off-label resulting in numerous off-label use case reports that had not been collated for PV maintenance obligations.

The complainant alleged that the PMCPA ruling in Cases AUTH/2840/4/16 and AUTH/2847/5/16 was likely to be applicable beyond UK borders such that the number of company interactions where relevant off-label information was not flagged across the whole of Europe would be unacceptably high.

The complainant stated that at the British Thoracic Society (BTS) conference, 7-9 December, Pfzer's campaign for Ultibro Breezhaler included the headline, 'Ultibro Breezhaler, an evidence based solution for patients with COPD with or without a history of exacerbations'.

The clinical development programme for Ultibro Breezhaler included studies where recruited patients had a history of exacerbations (Wedzicha et al 2016 and Zhong et al 2014) and also at least one study where recruited patients did not have a history of exacerbations (Wedzicha et al 2013). The frst half of the headline referred to Ultibro Breezhaler being a 'solution' and projected the perception that it was a solution for patients with exacerbations. The complainant alleged that had Pfzer thoroughly considered the pharmacovigilance implications frst and developed effective corrective and preventative actions (CAPAs) then continuation of off-label promotion was avoidable.

The complainant stated that in order to understand the legitimacy of the FDC-LABA/LAMA class being promoted for exacerbation risk reduction it was important to consult the relevant regulatory framework ie the guideline on clinical investigation of medicines in the treatment of COPD – EMA/ CHMP/700491/2012. The complainant provided detailed comments including that this document primarily covered the maintenance treatment of COPD and not the treatment and management of acute exacerbations and essentially outlined three possible aims of maintenance treatment.

1 Provide symptomatic relief through improvement of airway obstruction

2 Modify or prevent exacerbations

3 Modify the course of the disease or modify disease progression.

Also discussed was the importance of recognising the severity of exacerbations where the document stated that, '... the rate of moderate or severe exacerbations is a clinically relevant endpoint related to the associated morbidity and mortality, and the usually signifcantly increased health-care requirement costs'.

Assessment of risk in terms of the rate of moderate or severe exacerbations was the main requirement for a treatment licensed to be used to modify or prevent exacerbations and had distinctive study criteria to meet before a licence was granted for use in COPD patients.

Meeting two criteria enabled a treatment to be licensed specifcally for use in symptomatic COPD patients despite bronchodilator therapy with a history of exacerbations. The two criteria highlighted were clearly challenging as demonstrated by Ultibro Breezhaler. In 2016 the manufacturer announced that a pivotal study (NCT01946620 – ClinicalTrials.Gov) did not meet the primary endpoint of demonstrating statistically signifcant superiority in the reduction of annualised rates of moderate or severe COPD exacerbations when compared to mono-component LABA treatment alone. The manufacturer indicated that the primary endpoint result would not allow it to make a regulatory fling for the COPD indication in Europe. Had this study (NCT01946620) been successful then specifc wording of the licence indication for COPD would reflect the existence of respective, suitable, supporting data for clinically relevant exacerbations as was the case for other currently licensed FDC-ICS/LABA medicines in COPD.

An obvious dichotomy existed from a regulatory perspective in that Ultibro Breezhaler could not progress towards a licence in COPD after missing the primary endpoint for a study designed in accordance with the two criteria defned and subsequently the manufacturer simply did not promote Ultibro Breezhaler for use in COPD. Whereas, FDC-LABA/LAMAs were granted licences solely for maintenance treatment aimed at symptomatic relief through improvement of airway obstruction; yet without meeting the two defned study criteria, Ultibro Breezhaler was simultaneously being positioned and promoted as a suitable alternative to licensed FDC-ICS/LABAs for exacerbation risk reduction. In effect, regulatory requirements outlined in EMA/CHMP/700491/2012 related to exacerbation risk reduction were being circumvented by promoting Ultibro Breezhaler for exacerbation risk reduction without being granted a licence that reflected the existence of respective, suitable, supporting data for clinically relevant exacerbations.

The complainant alleged that exhibitor activities for Ultibro Breezhaler at the BTS were in breach of the undertaking for Case AUTH/2847/5/16.

The complainant provided an overview of published evidence for Ultibro Breezhaler in terms of alignment with key study criteria for exacerbation risk reduction stated in the guideline on clinical investigation of medicines in the treatment of COPD (EMA/CHMP/700491/2012).

Despite the fact that the study (NCT01946620) involving FDC-fluticasone/formoterol ensured that the clinically relevant primary endpoint – moderate or severe exacerbations was measured and the treatment period was 12 months, progression towards attaining a COPD licence was not possible because the study criteria were challenging and the study eventually missed its primary endpoint. In the case of FDC-LABA/LAMA studies none of the eight Ultibro Breezhaler studies met all three criteria stated, these being clinically relevant primary endpoint for exacerbations, duration of study suffcient to assess exacerbations and above minimal clinically important difference >20% and just one of the eight publications related to Ultibro Breezhaler involved a study where the clinically relevant primary endpoint – moderate or severe exacerbations was measured over a 12 month treatment period (Wedzicha et al 2013) and only a 12% reduction in clinically relevant exacerbations vs the comparator was shown (ie below the threshold of 20%).

The lack of Ultibro Breezhaler studies meeting key study criteria for exacerbation risk reduction stated in the guideline on clinical investigation of medicines in the treatment of COPD (EMA/ CHMP/700491/2012), prompted a broader analysis of other FDC-LABA/LAMAs publications none of the 7 citations involving other FDC-LABA/LAMAs (Buhl et al 2015, Celli et al 2014, Decramer et al 2014, Donohue et al 2013, Donohue et al 2014, D'Urzo et al 2013 and Singh et al 2013) met all three criteria.

Out of nine FDC-LABA/LAMAs publications that had a secondary endpoint measure of exacerbations almost all publications did not defne exacerbations such that it was not clear to the reader that clinically relevant exacerbations were not measured in these studies. Potentially, this might lead to a misunderstanding and exaggeration of clinical beneft.

The complainant stated that the literature review and assessment undertaken confrmed that there was insuffcient evidence to support the use of Ultibro Breezhaler for exacerbation risk reduction. To date, Pfzer and Novartis had simply not undertaken clinical trials in accordance with recommendations in the guideline on clinical investigation of medicines in the treatment of COPD (EMA/CHMP/700491/2012). This was concerning given the continuation of off-label promotion. Pfzer used the recent FLAME study (Wedzicha et al 2016) as the main reference to support the claims appearing in the promotional materials cited by the complainant. It was not entirely clear to the complainant why Novartis, chose not to undertake this study in accordance with recommendations in the guideline on clinical investigation of medicinal products in the treatment of COPD (EMA/CHMP/700491/2012). It made it problematic to adequately assess the results alongside other supporting studies for other medicines that were actually licensed to be used in COPD patients with the aim of modifying or preventing clinically relevant exacerbations (EMA/CHMP/700491/2012).

The complainant stated that the totality of data suggested that the extent of protection from bronchodilation via dual bronchodilators, against the development of clinically relevant exacerbations was insuffcient.

The complainant stated that exhibitor activities for Ultibro Breezhaler at the BTS conference 7/9 December suggested that those on the exhibition stand were specifcally briefed to discuss the medicine in the context of newly issued recommendations within the GOLD 2017 Report.

The updated GOLD Report represented a positive step forward in simplifying the ABCD matrix which previously posed challenges in categorising COPD patients with three different sub-categories possible depending on the presence of either one or both risk factors, namely, FEV1, staging and exacerbations risk. The updated GOLD Report was however concerning from a patient safety perspective as it stated:

• 'Recommendations by the GOLD Committee for use of any medication are based on the best evidence available from published literature and not on labelling directives from government regulators'.

• FDC-LABA/LAMAs were recommended frst line in category D COPD patients and as step up from a LAMA in category C COPD patients. Both of these two recommendations essentially involved use of FDC- LABA/LAMAs in an unlicensed indication or manner.

• 'It should be noted that there is a lack of direct evidence supporting the therapeutic recommendations for patients in groups C and D'.

• FDC-LABA/LAMAs were recommended frst line in category D COPD patients, but there was no evidence that FDC-LABA/LAMAs compared to LAMAs could signifcantly reduce the risk of clinically relevant exacerbations which were associated with morbidity and mortality ie moderate or severe exacerbations.

• Furthermore, although the FLAME study reported that in a secondary endpoint, Ultibro Breezhaler was superior to FDC-fluticasone/ formoterol in terms of clinically relevant moderate or severe exacerbations, this effect was not demonstrated in patients with a history of more than one exacerbation, and category C COPD patients were not included in this study (Wedzicha et al 2016).

The complainant noted that in the GOLD Report there was no ratifed European Pharmacovigilance Risk Assessment Committee (PRAC) recommendation stating a positive risk beneft balance for FDC-ICS/LABAs in COPD (eg the magnitude of beneft in terms of clinically relevant exacerbation reduction observed was as much as ten-fold greater compared to the slight increased risk in terms of pneumonia (Corradi et al 2016)). Yet a major factor cited within the updated GOLD Report for recommending usage of FDC-LABA/ LAMAs in an unlicensed indication or manner was the frequently repeated reference to the risk of pneumonia with use of FDC-ICS/LABAs. This seemed not to be balanced because the respective PRAC recommendations were excluded. Moreover, these risks of pneumonia were not qualifed in the updated GOLD Report, in terms of not translating into a greater risk of mortality (Festic et al 2016).

The complainant alleged that when taking into consideration both Pfzer's continued off label promotion with the revised GOLD Report recommendations that essentially involved recommending use of FDC-LABA/LAMAs in an unlicensed indication or manner, it was clear that there was a underlying move towards circumventing the regulatory requirements outlined in EMA/ CHMP/700491/2012 related to exacerbation risk reduction by promoting/recommending products for exacerbation risk reduction without these medicines being granted licences that reflected the existence of respective, suitable, support data for clinically relevant exacerbations.

The complainant alleged that the regulatory processes in place to protect public health were being marginalised. If the pharmaceutical industry embarked on charting a strategic direction that inadvertently (or otherwise) undermined the very regulatory foundations that were meant to keep patients safe then the industry was entering unwelcomed territory which inevitably would discredit it.

The obvious concern was whilst an unavoidable delay might actually beneft Pfzer commercially. A similar protracted period of time prior to completion of this PV related PMCPA case would not be in the best interest of patient safety. The complainant therefore urged the PMCPA to prioritise completion of this case if possible given the far reaching patient safety implications.

The detailed response from Pfzer and Novartis is given below.

The Panel was extremely concerned that a complaint had been received which included allegations about Novartis' and Pfzer's activities in relation to pharmacovigilance which was vital for patient safety. There were extensive requirements for pharmacovigilance which went beyond the Code. The Panel could only consider allegations in relation to the requirements in the Code.

The Panel noted the complainant's comments about the regulatory requirements outlined in EMA/CHMP/700491/2012 being circumvented by promoting FDC-indacaterol/glycopyrronium for exacerbation risk reduction without being granted a licence that reflected the existence of respective, suitable, supporting data for clinically relevant exacerbations. The Panel was concerned about activities in relation to the Code. It was not for the Panel to determine whether Novartis' and Pfzer's activities including clinical trials were in line with the regulatory requirements per se.

The Code stated that companies must comply with all applicable codes, laws and regulations to which they are subject. The relevant clause had no been raised and the complainant had not provided evidence that the companies had been found in breach of other laws and regulations.

The Panel noted that the complainant had referred to implications across Europe. The Panel could only consider matters which were covered by the UK Code and/or occurred in the UK. The fact that pharmacovigilance reporting in other countries might be lacking was of concern but was not in itse a matter necessarily covered by the ABPI Code.

The Panel noted that both Ultibro Breezhaler and Seebri Breezhaler were indicated as maintenance bronchodilator treatments to relieve symptoms in adult patients with COPD. Section 5.1 of the respective SPCs referred to each medicine's positiv impact on exacerbations of COPD compared to oth medicines. The Ultibro SPC was last revised on 10 November 2016. The Panel noted the companies' comments in relation to changes to the SPC.

The Panel noted its rulings in the previous cases, Cases AUTH/2840/4/16 and AUTH/2847/5/16. In particular that in some of the materials at issue in those cases, for example the claim that 'Ultibro Breezhaler offers benefts beyond current standard COPD maintenance therapies' and 'vs salmeterol/ fluticasone Ultibro Breezhaler can signifcantly reduce your patients' rate of moderate or severe exacerbations' appeared to be a consequence of using Ultibro Breezhaler as a maintenance therapy and not the reason to prescribe per se, as alleged. that regard, no breaches of the Code had been ruled.

Other material was ruled in breach as it did not clearly state that Ultibro Breezhaler was a maintenance therapy to relieve COPD symptoms. For example boxed text in a leavepiece 'Reduces exacerbation risk beyond tiotropium (open label) and [salmeterol/fluticasone]' would not 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 beneft of using the medicine as maintenance therapy. The leavepiece was inconsistent with the particulars listed in the Ultibr Breezhaler SPC. The leavepiece implied that that exacerbation reduction was a primary reason to prescribe Ultibro Breezhaler which was misleading Breaches of the Code had been ruled including that high standards had not been maintained. Similarly a speaker slide deck (ref UK/ULT/16-0025 entitled '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 might give 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 noted that the complaint in Cases AUTH/2840/4/16 and AUTH/2847/5/16 was received in April 2016 and the requisite undertaking was received on 16 September. The ERS congress referred to by the complainant in Cases AUTH/2928/1/17 and AUTH/2929/1/17 took place from 3 – 7 September. This meant that the activities at that meeting were not covered by the requisite undertaking given in Cases AUTH/2840/4/16 and AUTH/2847/5/16. There could be no breach of that undertaking so the Panel ruled no breaches of the Code including Clause 2.

The Panel accepted the companies' submission that the material used at the ERS meeting reiterated topics that had already been considered by the PMCPA and ruled upon in Cases AUTH/2840/4/16 and AUTH/2847/5/16. The Panel decided that these materials were covered by that ruling and thus decided not to make a separate ruling of breaches of the Code in that regard.

The Panel was concerned that given its rulings in Cases AUTH/2840/4/16 and AUTH/2847/5/16 it appeared that the companies had failed in some representative briefng materials to make Ultibro Breezhaler's licensed indication clear. It did not consider that this necessarily meant that the companies had failed to make it clear to staff what constituted off label use of the product as alleged in Cases AUTH/2928/1/17 and AUTH/2929/1/17. Although it was likely that staff might not be clear, the Panel did not consider that the complainant had shown on the balance of probabilities that the companies had failed to adequately train personnel to recognise that the use of FDC-indacaterol/ glycopyrronium to reduce exacerbations in COPD was off label. Further there was no evidence that there would be numerous off label use case reports and if so that these had not been collated for pharmacovigilance maintenance obligations. The Panel therefore ruled no breaches of the Code including Clause 2.

The Panel noted the companies' submission that they were fully committed to protecting and enhancing patient safety and operated extensive, robust scientifc services and pharmacovigilance systems. The Panel did not consider that the companies' failures in Cases AUTH/2840/4/16 and AUTH/2847/5/16 necessarily meant that the relevant staff were not fully conversant with pharmacovigilance requirements relevant to their work nor had the complainant provided evidence in that regard. The Panel therefore ruled no breach of the Code.

With regard to the materials used at the BTS Winter meeting in December 2016, the Panel noted the companies' submission that the material provided by the complainant had not been used at that meeting, it was likely to be a journal advertisement from early 2016 and it preceded the date the undertakings were provided in Cases AUTH/2840/4/16 and AUTH/2847/5/16. The Panel noted, however, that the title of the piece 'Ultibro Breezhaler. An evidence based solution for patients with or without a history of exacerbations' was the same as the current material provided by Pfzer and Novartis.

The Panel considered that the complainant had not shown, on the balance of probabilities, that the companies had used the Ultibro advertisement he/she provided at the British Thoracic Society (BTS) meeting in December 2016 and had therefore promoted Ultibro Breezhaler for an unlicensed indication at that meeting as alleged. The Panel therefore ruled no breaches of the Code. The Panel also considered that in these circumstances there could be no breach of the undertaking given in Cases AUTH/2840/4/16 and AUTH/2847/5/16 and thus ruled no breaches in that regard including Clause 2.

With regard to the allegation that there was a suggestion that staff on the stand were specifcally briefed to discuss Ultibro in the context of the GOLD 2017 Report, the Panel examined the materials available on the stand. These included Wedzicha et al 2016 (FLAME) and various promotional material some of which referred to the GOLD Guidelines including that 'the goal of treatment was to manage symptoms and reduce the risk of exacerbations'.

The Panel noted that Pfzer and Novartis had briefed staff on 18 November 2016 regarding the GOLD 2017 Report. The Panel noted that the companies briefed its staff regarding an important update on materials following the PMCPA ruling in Cases AUTH/2840/4/16 and AUTH/2847/5/16 on 16 September 2016. The briefng stated 'You must ensure that when you are talking about exacerbation data for, inter alia, Ultibro Breezhaler your customers are clear that the reason to prescribe Ultibro Breezhaler is as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. It is acceptable to presen data about exacerbations as long as the customer is not left with the impression that Ultibro is for treating exacerbations or that the primary reason to prescribe is to reduce exacerbations.

The Panel queried why this had not been re iterated to staff at BTS considering Ultibro was to be promoted and the briefng regarding the GOLD 2017 Report which had been issued recently. The briefng summarised key points and listed the main considerations with regard to Ultibro Breezhaler. This included that key defnitions for patient classifcations would be based only on symptoms and exacerbations and that dual bronchodilators such as Ultibro Breezhaler were recommended as frst line treatment regardless of their exacerbation risk and prior to the use of ICS marking a signifcant shift away from ICS containing combination therapies. The instructions also stated that the FLAME study was included as providing evidence for the use of dual bronchodilation; stating that a LAMA/LABA combination was superior to a LABA/ ICS combination in preventing exacerbations and other patient reported outcomes in Group D patients. It was important that Pfzer confdently communicated to clinicians the reference behind this statement in order to position Ultibro Breezhaler as the new standard of care for patients with COPD with or without a history of exacerbations.

The briefng material concluded by stating that as could be seen from the signifcant changes to the GOLD Guidelines which directly impacted Ultibro, treatment decisions were now much more focused on the symptom burden for the patient and LAMA/ LABAs had been given a far more prominent role in the management of COPD. This represented a valuable opportunity for the company to provide prescribers with a simple algorithm to follow which would ensure that patients received the right therapy to manage their COPD and increase their chances of living a healthy, active life.

The briefng material referred to Ultibro as 'the evidence based choice of LAMA/LABA for breathless patients regardless of their exacerbation history' and as 'the new standard of care'. In addition, the Panel queried whether the briefng material was suffciently clear about the need to ensure that any discussion about the reduction in exacerbations should be a beneft of maintenance therapy and not a reason to prescribe per se. The Panel considered, on balance, that the briefng material was not suffciently clear in this regard and thus ruled a breach of the Code.

The Panel did not consider, however, that the complainant had proved, on the balance of probabilities, that based on the exhibitor activities for Ultibro Breezhaler at BTS in December that those on the exhibition stand were specifcally briefed to discuss the medicine within the context of the newly issued recommendations within the revised GOLD Report as alleged. The Panel ruled no breach in that regard.

A slide deck for payors (ref UK/ULTSBR/16-0068(1) 'Supporting the management of COPD' consisted of 68 slides including the burden of COPD on the health system, disease management, the benefts of Ultibro Breezhaler and the future of COPD care. The deck referred to the GOLD guidelines that ICS + LABA was recommended for use only in patients in groups C and D (slide 25). This document included claims that Ultibro Breezhaler was an appropriate steroid free option for the patient for whom LABA/ ICS was considered (eg slide 31) which also included the Ultibro indication making it clear the primary reason for prescribing Ultibro and therefore no breach was ruled. The FLAME study (Wedzicha et al 2016) results were given on slide 32 including a comparison of exacerbation rates of Ultibro and Seretide as well as FEV1 and rescue medication use. The Panel considered the FLAME study results were set within the context of the licensed indication and thus it ruled no breach of the Code.

Material (ref UK/ULTSBR/16-0286) described as 'FLAME Business Card – eprint URL link' promoting the results of FLAME (Wedzicha et al 2016) referred to the exacerbation outcomes and their impact on patients at risk of future exacerbations without setting these in the context of the Ultibro licensed indication. A breach was ruled. In addition, this material implied that the exacerbation reduction was a primary reason to prescribe Ultibro Breezhaler which was misleading. Breaches of the Code were ruled including that high standards had not been maintained. Pfzer and Novartis had failed to comply with their undertakings given in Cases AUTH/2840/4/16 and AUTH/2847/5/16 and a breach of the Code was ruled. The Panel noted the importance of undertakings and considered that failure to comply with the undertakings and assurance previously given in Cases AUTH/2840/4/16 and AUTH/2847/5/16 had brought discredit upon and reduced confdence in the pharmaceutical industry. The Panel thus ruled a breach of Clause 2 of the Code.

The Panel noted that four webinars were conducted in which health professionals were invited to attend a global broadcast about the updated GOLD Report. Representatives were required to show an introductory slide with all obligatory information including Ultibro's licensed indication for an audience of UK health professionals. The Panel noted its comments above regarding the GOLD briefng and the webinars and considered that whilst the GOLD briefng was not suffciently clear, the 'upfront' slide required to be shown to UK health professionals set out the indication and therefore the webinars were clear about Ultibro Breezhaler's licensed indication and in that regard were not in breach of the Code.