AUTH/3501/4/21 - Complainant v Leo

Protopic web page and an alleged breach of undertaking

  • Received
    09 April 2021
  • Case number
    AUTH/3501/4/21
  • Applicable Code year
    2019
  • Completed
    27 January 2022
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    No appeal

Case Summary

An anonymous, contactable complainant alleged that a number of claims about Protopic (tacrolimus) on the 'At a glance' section of the uk.dermaworld.eu website were inaccurate and erroneous. Protopic, was a non-steroid ointment available as 0.1% (for adults and adolescents aged 16 years and over) and 0.03% (for adults, adolescents and children aged 2 years and over) and was indicated for either flare treatment or maintenance treatment in moderate to severe atopic dermatitis in patients who were not responsive to or were intolerant of topical corticosteroids.

The detailed response from Leo is given below.


1 Image used on the webpage

The complainant stated that the image on the webpage was no different to the principle of the image which was ruled in breach of the Code in Case AUTH/2418/7/11. The complainant alleged that as the Protopic summary of product characteristics (SPC) contained a warning around exposure to the sun, it was not appropriate to show a patient who was tanned and in short sleeves. There was no wording at all on the page about the risks of UV exposure. The complainant alleged that the image did not promote Protopic in accordance with the requirements of its SPC and that it breached the undertaking given in Case AUTH/2418/7/11.

The Panel noted the image in question featured, on the left-hand side, a man wearing a long-sleeved shirt and trousers, who appeared to be walking in circles in the rain, holding an open umbrella; the left-hand side of the image appeared to be in dark, stormy conditions. The right-hand side of the image depicted the same man walking out of the rain and into brighter weather, with blue skies and his umbrella closed, and now wearing a short-sleeved shirt and trousers. The man was thus wearing less clothing and consequently exposing more skin than in the left-hand side of the image. The image was overlaid with the Protopic product logo and the claim ‘Protopic Moving beyond topical corticosteroids in moderate to severe atopic dermatitis’.

The Panel noted that Section 4.4 (Special warnings and precautions for use) of the Protopic SPCs stated, inter alia:

‘Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided during use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that are considered to be potentially malignant or pre-malignant.’

The Protopic patient information leaflet stated:

‘If you spend time outdoors after applying Protopic, use a sunscreen and wear loose fitting clothing that protects the skin from the sun. In addition, ask your doctor for advice on other appropriate sun protection methods’.

Whilst the Panel acknowledged that patients treated with Protopic would not entirely avoid being outdoors, it was concerned that there was a clear contrast in the images before and after treatment which showed a man who had changed from a long sleeve to a short sleeve top and had closed his umbrella when walking into better and brighter weather conditions; the Panel considered that this implied that the patient did not have to be concerned about exposure to sunlight whilst on treatment and that was not so. The Panel considered that this was inconsistent with the particulars listed in the Protopic SPC and high standards had not been maintained. Breaches of the Code were ruled.

The image on the right did not show the model as ‘demonstrably tanned compared to the picture of him on the left-hand side’ as alleged and therefore the Panel did not consider that the image was misleading on the narrow point alleged; no breach of the Code was ruled.

The Panel noted in Case AUTH/2418/7/11, Astellas was ruled in breach of the Code as the front cover of a Protopic leavepiece, which depicted a woman wearing less clothing and consequently exposing more skin than those around her, implied that the patient did not have to be concerned about exposure to sun which was not so and was inconsistent with the particulars listed in the Protopic SPC, which was upheld on appeal. Astellas’ undertaking was signed in 2011 which was prior to Protopic being divested to Leo Pharma in 2018.

The Panel considered that Leo, following the divestment, in addition to its general responsibility for complying with the Code might have a responsibility to ensure that similar breaches of the Code in relation to Protopic were avoided. Whilst the Panel considered that the matter was sufficiently similar to that which had been ruled in breach in Case AUTH/2418/7/11, on balance, the Panel decided that the requirement in the Code applied to the company concerned and thus ruled no breaches of the Code including Clause 2 as that undertaking was given by Astellas and not Leo. The Panel considered, however, that the similar nature of the breaches meant that high standards had not been maintained and thus ruled a breach of the Code in that regard.


2 ‘Protopic Moving beyond topical corticosteroids in moderate to severe atopic dermatitis’

The complainant alleged that the statement was misleading and the promotion was inconsistent with the SPC as the phrase ‘moving beyond’ implied that Protopic was more efficacious or advanced than topical corticosteroids, yet the SPC did not support that claim. The claim had not been referenced so the information was not sufficiently complete to enable the reader to assess its credibility.
The Panel considered that the expression ‘moving beyond’ was ambiguous. However, the claim did not imply that Protopic was more efficacious or advanced compared to topical corticosteroids as alleged. The complainant had not discharged his/her burden of proof that the claim was inconsistent with the SPC, misleading or incapable of substantiation as alleged and thus based on the narrow allegation the Panel ruled no breaches of the Code.

The Panel considered that the complainant had not discharged his/her burden of proof that the statement needed to be referenced to a published study, nor that Leo had failed to maintain high standards. No breaches of the Code were ruled including Clause 2.


3 'Protopic is designed for moderate to severe [atopic dermatitis]'

The complainant alleged that the claim was inconsistent with the SPC which stated that Protopic could be used for flare treatment in adults and adolescents in the treatment of moderate to severe atopic dermatitis who were not adequately responsive to or intolerant of conventional therapies such as topical corticosteroids. Therefore, Protopic should not be promoted or used as a first-line agent in moderate to severe atopic dermatitis as suggested and was only suitable for a particular population at a certain dosage for a particular length of time. The complainant alleged that this broad claim was misleading and prejudiced patient safety.

The Panel noted that the Protopic indication was not stated on the ‘at a glance’ webpage at issue but the indication for flare treatment was stated on the preceding webpage which provided the link to the ‘at a glance’ webpage.

It appeared to the Panel that health professionals would likely access the ‘at a glance’ webpage from the ‘treatments’ page, which included Protopic’s indication, and therefore would not be misled that the claim at issue incorrectly implied that Protopic could be used as a first-line agent as alleged. Although it would have been helpful if the full indication for Protopic was stated on the ‘at a glance’ webpage, the Panel considered that the complainant had not established that the claim ‘Protopic is designed for moderate to severe AD [atopic dermatitis]’ in the context of the webpage and website was inconsistent with the SPC or misleading as alleged. The Panel ruled no breaches of the Code including Clause 2.


4 'Protopic targets inflammation + Protopic supports repair of skin barrier'

The complainant stated that for the claim that Protopic targeted inflammation, the data in the SPC was limited to in vitro human cells and animal models and could not be extrapolated to the clinical setting. The claim was not consistent with the SPC.

The complainant alleged that the SPC wording did not support that Protopic targeted inflammation in a clinical setting, was misleading and not capable of substantiation.

For the second half of the claim, the complainant stated that the reference, Xhauflaire-Uhodae et al (2007) was not powered to support such a claim nor did it conclude that Protopic supported skin barrier repair. The complainant alleged that the claim was unfair, misleading and not capable of substantiation.

The claim ‘Protopic targets inflammation’ was referenced to the Protopic SPC. The Panel noted Leo’s submission that as per the SPC, the efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus ointment in Phase I to Phase III clinical trials and that several of those trials included as a primary end-point, response rate defined as the proportion of patients with at least 60% improvement in the modified Eczema Area and Severity Index between baseline and a specified time point. The Panel further noted Leo’s submission that based on the modified Eczema Area and Severity Index 60 response rate, which included a measure of inflammation, Protopic had demonstrated clinical evidence as to its effect on inflammation.

The Panel considered that the complainant had not discharged his/her burden of proof that the claim ‘Protopic targets inflammation’ was inconsistent with the SPC, misleading or incapable of substantiation as alleged and the Panel therefore ruled no breaches of the Code.

The claim ‘Protopic supports repair of skin barrier’ was referenced to Xhauflaire-UhodaE et al, a double-blind randomised study which compared tacrolimus and betamethasone valerate and stated that during treatment, both compounds yielded a similar improvement in skin barrier function. The Panel further noted that Danby et al (2014) compared the effects of betamethasone valerate 0.1% cream and tacrolimus 0.1% ointment and concluded that tacrolimus 0.1% ointment improved the condition of the skin barrier.

The Panel noted that the claim was not comparing Protopic to any other treatment. On the evidence before it, the complainant had not discharged his/her burden of proof that the claim ‘Protopic supports repair of skin barrier’ was misleading or incapable of substantiation as alleged and the Panel therefore ruled no breaches of the Code including Clause 2.


5 'Help patients know what to expect when they start treatment with Protopic'
and patient ‘before and after’ photographs

The complainant alleged that the statement implied that the page should be used by a health professional in a patient consultation as a visual aid and should therefore have contained the mandatory wording for patients using a medicine as per the Code. Such information for use with patients should not be a part of a promotional webpage which in turn promoted the product to the public.

The images were labelled as being taken at baseline and ‘After 4 weeks’ but there was no information as to whether the patient was treated with Protopic for an initial flare or for maintenance therapy as the posology varied accordingly. The complainant alleged that the information was ambiguous and incomplete.

For flare treatment, the SPC recommended that if no signs of improvement were seen after two weeks of treatment, further treatment options should be considered. The complainant alleged that the inclusion of a baseline and 4 week image suggested that Protopic should be used for 4 weeks and then assessed, which was misleading. The incomplete and selective information prejudiced patient safety and the images did not promote the rational use of a medicine as patients might be left on Protopic unnecessarily and for longer than appropriate.

In the Panel’s view, the photographs were for health professionals to understand what to expect following treatment so that they could explain this to their patients. Consequently, the Panel did not consider that the images promoted a prescription only medicine to the public or were for viewing by the public and therefore no breaches of the Code were ruled including Clause 2.

The Panel did not consider that the complainant had established that photographs depicting results after 4 weeks of treatment, in the material at issue, meant that Protopic had been promoted in a manner inconsistent with its SPC as alleged. Nor did the Panel consider that the photographs were misleading or did not promote the rational use of the medicine as alleged. No breaches of the Code were ruled including Clause 2.


6 Lack of warning regarding sun protection methods

The complainant noted that under the heading ‘Preparing your patients for their Protopic 0.1% treatment’ was a mention of skin irritation, burning sensation and pruritis to the left of an outline sketch of a woman in a short sleeveless dress with exposed arms, legs and neck; but there was no wording to reflect the warning from Section 4.4 of the SPC. The complainant alleged that the image together with the lack of information on precautions around UV exposure did not give an accurate presentation of Protopic; it prejudiced patient safety and was misleading.

The Panel noted that the website contained a link to the prescribing information; it did not have a copy and Leo had made no submission in that regard. Whether a special warning or precaution also needed to be highlighted in another section of the promotional material depended on a consideration of all of the circumstances including the nature of the warning/precaution and the content, layout, audience and intended use of the material.

The Panel noted that next to the sketch of a lady in a short sleeveless dress and beneath the heading ‘Preparing your patients for their Protopic 0.1% treatment’, it stated:

‘1 in 2 patients experienced some type of skin irritation at the site of application.

Burning sensation and pruritus were very common and tended to resolve within one week of starting treatment.’

The Panel noted that the sketch was very basic and considered that it was difficult to tell if the individual was indoors or outdoors. In the Panel’s view, this section of the material appeared to focus on application site reactions. The Panel did not consider that the sketch implied that there were no concerns with sun exposure. Whilst it might have been helpful within this section of the material to include the special warning and precaution for use regarding minimising exposure of the skin to sunlight etc, the Panel did not consider that the complainant had established that its omission rendered the material misleading as alleged. The Panel ruled no breaches of the Code including Clause 2.


7 ‘Protopic 0.1% delays time to next flare when used proactively’ and associated graph

The complainant stated that the study design and primary endpoint in the study had not been included to put the claim in context as the results were in a sub-population.

The complainant alleged that the claim and graph around delaying time to the next flare was misleading as it did not take into consideration the time taken to undergo ‘reactive’ management (6 weeks in this study) and before ‘proactive’ management could start.

The complainant alleged that although the graph stated that it had been adapted from the Protopic SPC, it exaggerated the efficacy of Protopic, was misleading, incompatible with the SPC and not capable of substantiation. The artwork itself was misleading as it showed only one flare for Protopic over 1 year when more than one flare would be expected.

The Panel noted that Section 4.1 of the Protopic 0.1% ointment SPC stated that it was indicated in adults and adolescents (16 years of age and above) for:

Flare treatment
Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.

Maintenance treatment
Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (ie occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).

The Panel noted the lack of information about the study design on the webpage in question; the webpage made no reference to the fact that patients in this study had had previous treatment with tacrolimus twice daily until clear, almost clear or mild disease for a maximum of 6 weeks before being randomised to receive either tacrolimus or vehicle, once a day twice weekly. The misleading impression given was compounded by the fact that the indication for Protopic 0.1% as a maintenance treatment had not been stated on the webpage in question or the preceding webpage and therefore it was not clear to health professionals reading the material that Protopic was only to be used as a maintenance therapy in patients who had had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected). Furthermore, the webpage did not make clear the dosing frequency (once a day twice weekly) for which the results presented were based upon. The Panel considered that the webpage had insufficient information about the study design to put the claim ‘Protopic 0.1% delays time to next flare when used proactively’ into context and a breach of the Code was ruled.

The Panel noted that the graph in the material in question stated that the median time to first disease exacerbation was 15 days for vehicle and 142 days for Protopic 0.1% when in fact the SPC stated that it was 14 days vs 123 days, respectively. Leo submitted that this was an error. The error in the graph misleadingly implied that Protopic 0.1% delayed time to disease exacerbation for a longer period than the study had reported. Further the graph was inconsistent with the study data in section 5.1 of the SPC and was incapable of substantiation; breaches of the Code were ruled. High standards had not been maintained and a further breach of the Code was ruled.

The Panel considered that the graph implied that patients taking Protopic 0.1% in the study had a median of 1 flare during the 12 month study period vs 6.8 flares for those patients taking the vehicle; the SPC stated that the median number of disease exacerbations adjusted for time at risk was 1.0 for tacrolimus 0.1% vs 6.8 for vehicle. The Panel considered that the complainant had not established that the data regarding number of flares in the graph was misleading as alleged and no breach of the Code was ruled.

The Panel noted its rulings of breaches of the Code above which it considered covered the matter and no breach of Clause 2 was ruled.


8 Use of 0.1% Protopic

The complainant alleged that Leo only presented information on the higher strength of tacrolimus and its claims and clinical images would suggest it was encouraging long-term use of the product, ie proactive management of flares. There was no information to reflect the SPC recommendation to use the lowest strength and frequency for the shortest duration necessary, as determined by the physician’s evaluation of the clinical condition; it was likely to prejudice patient safety.

The Panel considered that the complainant had not established that the material encouraged use of Protopic 0.1% long term. Reference to its use proactively did not, in the Panel’s view, imply that the medicine should be used indefinitely. The SPC and material stated that Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis. In the Panel’s view, whilst it would have been helpful to have stated on the webpage the information from the SPC that in relation to maintenance treatment, after 12 months, a review of the patient should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data beyond 12 months, the Panel did not consider that the omission of this information on the webpage misleadingly implied that Protopic 0.1% should be used long-term as alleged or that promotion was inconsistent with the particulars in the SPC. No breaches of the Code were ruled including no breach of Clause 2.


9 Date of the SPC used as a reference

The complainant noted that the web page in question used the Protopic SPC as a reference without a date of last revision. The date of the page was May 2019 and the SPC for Protopic was updated in August 2020. The complainant stated that it appeared that the content of the web page was not reviewed after that update and the reference used was not clear.

The Panel noted Leo’s submission that the changes made to the SPC in August 2020 had no bearing on the existing content of the material in question apart from the prescribing information which had been amended and separately certified in September 2020. The Panel did not have a copy of this prescribing information.

The Panel did not consider that the complainant had established that reference to the Protopic SPC on the webpage, without providing the SPC date of revision, in itself, was misleading as alleged nor failed to maintain high standards and no breaches of the Code was ruled including Clause 2 on this narrow point.

Overall

The Panel considered that its rulings adequately covered each matter and that further rulings in relation to the overall case were not warranted in relation to the requirement to maintain high standards and Clause 2; no further breaches were ruled in that regard.