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AUTH/2961/6/17 - Indivior v Martindale

Case number:AUTH/2961/6/17
Case ref:Indivior v Martindale
Description:Promotion of Espranor and information to the public
No breach:No Breach Clauses 7.2, 7.3, 7.4, 7.6 and 9.1
Breach:Breach Clauses 2, 7.2, 7.3, 7.4, 7.9, 9.1, 26.1 and 26.2
Appeal:No appeal
Status:Breach ruled, case report pending
Review:Published in the May Review 2018
Received:26/06/2017
Completed:27/06/2017
Case Summary:

Indivior complained about the promotion of Espranor oral lyophilisate (buprenorphine) by Martindale Pharmaceuticals. The materials at issue were two detail aids, a patient leaflet and a website. Indivior marketed Subutex (buprenorphine sublingual tablets). Both Espranor and Subutex were indicated for substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. 

The detailed response from Martindale is given below. 

Indivior noted that the landing page to the Espranor website included the claim ‘Espranor is a novel formulation of buprenorphine which allows instant disintegration and rapid dissolution when placed on the tongue. It is licensed as a substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment’. The claim was directly visible to all visitors ie patients and health professionals worldwide. At the bottom of the homepage, the options to enter the website as ‘a UK health professional’ or ‘not a health professional’ were visible. The ‘not a health professional’ option opened a new page which appeared to be a general page for patients whether taking Espranor or not. Indivior was concerned that the website was promotional and encouraged patients to request Espranor and that important safety information from the summary of product characteristics (SPC) with regard to Espranor not being directly interchangeable with other buprenorphine products, was not addressed. 

The Panel noted that the patient section of the website stated that it was for ‘patients interested in opioid substitution therapy (OST) and Espranor’ and considered that its audience was therefore wider than just patients who had been prescribed the product as submitted by Martindale. The website was open access and the homepage would potentially be seen by a broad audience. This was not unacceptable so long as the website complied with the Code and relevant parts were suitable for the general public. The Panel noted that the website was directed at not only health professionals and those who had been prescribed the medicine but also the general public. Irrespective of the intended audience, the open access homepage should be suitable for the general public. The Panel noted that the claim in question ‘Espranor is a novel formulation of buprenorphine which allows instant disintegration and rapid dissolution when placed on the tongue. It is licensed as a substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment’ would be seen by this wide audience and considered that it promoted a prescription-only medicine to, inter alia, members of the public and encouraged them to ask their doctor to prescribe it. Breaches of the Code were ruled. 

The Panel noted that the part of the website which stated that it was for patients interested in OST and Espranor, contained information about Espranor and a link to the patient leaflet, rather than general information about OST and all relevant treatments. In the Panel’s view, this section of the website might be generally suitable for patients for whom Espranor had been prescribed, rather than the general public and it encouraged the general public to seek a prescription for it. A breach of the Code was ruled. 

The Panel noted Indivior’s concern that the section of the website for patients interested in OST and Espranor’ did not include important safety information, identified in the SPC, such as ‘Espranor is not directly interchangeable with other buprenorphine products’. The Panel noted that the webpage in question gave top line information about Espranor and stated that readers should speak to their doctor if they had any specific questions about their treatment. A reference to the Yellow Card Scheme appeared at the bottom of the page. A link to the patient information leaflet (PIL) was provided and this included the warning ‘Espranor is not interchangeable with other oral buprenorphine products and the dose of Espranor may differ from the dose of other buprenorphine products’. The Panel noted its comments above about the unclear nature of the intended audience and its rulings of breaches of the Code. The page in question described Espranor as a new wafer form of buprenorphine and referred to its use as a substitute for opiate drugs such as morphine or heroin. The Panel noted Martindale’s submission about the vulnerable nature of those being treated for opioid dependence and that any change to medication would cause anxiety. The Panel considered that the statements about Espranor might encourage patients to consider interchangeability. The Panel considered that the web page should stand alone as regards the medicine’s risk/benefit profile and compliance with the Code and could not rely on the PIL in that regard. Readers would not necessarily click on the link. In addition, the Panel noted the emphasis in the EU Risk Minimisation Plan for Espranor that it should not be swapped for sublingual buprenorphine, or vice versa, without health professional advice. Given the prominence given to the interchangeability warning in the PIL, that the webpage appeared to be directed at, inter alia, patients and the points raised above including the vulnerable nature of such patients, the Panel considered the omission of such information meant that this section was not presented in a balanced way. A breach of the Code was ruled. 

Indivior noted that the claim ‘This renders the buprenorphine dose impossible to remove from the mouth once administered’ appeared in one detail aid and ‘No delay, No diversion, No nonsense buprenorphine’ appeared in the other.

Indivior stated that misuse (intentional and inappropriate use not in accordance with the authorised product information which could be accompanied by harmful physical or psychological effects) and diversion (the unsanctioned supply of regulated medicines from legal sources to the illicit drug market, or to a user for whom the drugs were not intended) of medicines used in opioid use disorder was a well-known and accepted adverse event that occurred with opioid agonists, including buprenorphine. 

Indivior noted that in response to a query related to the claim’ ‘impossible to remove from the mouth once administered’ Martindale referred to the SPC which stated: ‘Removal of Espranor from the mouth following supervised administration is virtually impossible due to its rapid dispersal on the tongue’. Indivior alleged that the claim was exaggerated, misleading, inaccurate and not supported by the evidence provided; it was harmful to prescribers and patients as it created the illusion that it was not possible to remove the medication once on the tongue. 

The Panel noted that it had asked both parties to define, inter alia, ‘dispersal’, ‘dissolution’, ‘disintegrate’ and ‘dissolve’. The parties’ definitions were not wholly dissimilar. However, the Panel queried whether Martindale had applied sufficient rigour to the consistent application of the terms throughout the materials such that their meanings were clear. The Panel noted that this matter was further complicated as the use of certain terms also appeared to be inconsistent in the various studies and public documents. 

The Panel noted that the claims at issue ‘This renders the buprenorphine dose impossible to remove from the mouth once administered’ and ‘No delay, No diversion, No nonsense buprenorphine’ implied that there was absolutely no possibility that a dose could be removed from the mouth following supervised administration (diversion) which was not so. The Espranor SPC stated ‘Removal of Espranor from the mouth following supervised administration is virtually impossible due to its rapid dispersal on the tongue’ (emphasis added) which implied that that there was a potential for the dose to be removed from the mouth following its supervised administration. The Panel further noted clinical data (Strang et al 2017) regarding the disintegration time of Espranor ie that time when ‘the tablet could no longer be removed intact’. 96.3% of Espranor administrations achieved partial disintegration on the tongue in ≤ 15 seconds’ and ‘the median time for complete [Espranor] tablet disintegration was 2 minutes ...’. This meant that 3.7% of administrations took longer than 15 seconds to achieve partial disintegration leaving potential for the dose to be removed. By 2 minutes, Espranor had completely disintegrated in 58% of administrations. In four recordings either partial or complete disintegration was noted at 15 minutes. 

The Panel noted the qualified statement in a clinical study that a benefit of the reduced time to disintegration with Espranor was ‘the reduced potential for concealment and diversion’ (emphasis added). The Panel considered that the claims in question ‘No diversion.’ and ‘This renders the buprenorphine dose impossible to remove from the mouth once administered’ were too dogmatic and implied there was absolutely no possibility of diversion, however small, and that was not so. This implication was compounded in relation to the latter claim as it appeared beneath the unqualified heading ‘Espranor prevents the most common route of diversion’ (emphasis added). The Panel considered that the claims in question were misleading and could not be substantiated, breaches of the Code were ruled. 

The Panel further noted Indivior’s allegation that the information about adverse events (in this case misuse and diversion of buprenorphine) did not reflect the available evidence. The Panel considered that the claims in question might potentially be harmful to patients as doctors might assume that it was absolutely impossible for patients to remove the dose which was not necessarily so. However, the clause cited by Indivior related to the requirement that claims about adverse reactions must reflect available evidence and not state that there were no adverse reactions, toxic hazards or risks of addiction or dependency. The Panel noted Indivior’s submission that, inter alia, diversion was a well-known and accepted adverse event with opioid agonists including buprenorphine. The Panel noted diversion was not listed in Section 4.8, Undesirable effects, of the Espranor SPC. In the Panel’s view, the claims in question did not fall within the remit of the cited clause and so it ruled no breach of that clause. 

Indivior stated that Martindale had been unable to provide data to support a number of claims that Espranor instantly disintegrated when placed on the tongue eg ‘…buprenorphine that instantly disintegrates on the tongue …’. In fact, the evidence it provided showed that this was not the case. Indivior noted that conflicting claims were presented side-by-side in the PIL which stated ‘Instant Disintegration’, followed by ‘Average time to complete disintegration (median): 2 minutes’, further confusing patients. Indivior alleged that the claims were inaccurate, misleading and misrepresented the data which was unsubstantiated by the published evidence. Indivior further noted that the SPC stated ‘The oral lyophilisate should be taken from the blister unit with dry fingers, and placed whole on the tongue until dispersed, which usually occurs within 15 seconds’. 

The Panel noted its general comments above about the definition and inconsistent use of, inter alia, ‘disintegration’. It considered its comments above about diversion were relevant to the claims now at issue about instant disintegration. 

The Panel considered that most of the claims made for instant disintegration were too dogmatic and implied that the tablets completely disintegrated instantly on every administration which was not so. Context was important. Further information should be given about disintegration times, the meaning of the term and clinical study results so that readers could properly assess the claims. In the Panel’s view, 5 of the 6 claims in question were each misleading and could not be substantiated; breaches of the Code were ruled. 

The Panel noted that further information about partial disintegration time and dissolution time vs sublingual buprenorphine was provided alongside the claim ‘Instant disintegration’ on page 3 of the one of the detail aids. In that regard the Panel considered that the context was such that this claim was materially different to the others at issue. However, on balance, the Panel considered that the prominent claim ‘Instant disintegration’ was misleading insofar as it gave the immediate visual impression that tablets completely disintegrated instantly on each administration and that was not necessarily so. This immediate impression was not capable of substantiation. Breaches of the Code were ruled. Indivior noted that it had highlighted above the importance of misuse and diversion in patients receiving OST. Martindale had not provided evidence to support claims that Espranor eliminated or prevented the opportunity for removal of the medicine. A video on the Espranor website showed that the product remained on the tongue and available for removal for at least the eight seconds; the product was shown largely unchanged on the tongue. The SPC stated: ‘Removal of Espranor from the mouth following supervised administration is virtually impossible due to its rapid dispersal on the tongue’ (emphasis added). Indivior did not accept that this statement could be converted into the claim that the product ‘eliminates’ the opportunity for diversion. Indivior alleged that such claims were inaccurate, misleading and not substantiated. 

The Panel noted its general comments and rulings above in relation to instant disintegration and diversion claims. The Panel noted that it might be difficult for a patient to remove Espranor from the mouth once administered but considered that it was misleading to state that Espranor and its ‘instant disintegration’ completely eliminated the opportunity for such removal. The Panel considered that such claims were too dogmatic. Insufficient information was given to enable a reader to assess the data. The Panel further noted the SPC statements above and considered that the claims at issue were misleading and not capable of substantiation; breaches of the Code were ruled. Indivior referred to the claims ‘Espranor is not interchangeable with other buprenorphine products’ which appeared on the website and ‘Espranor was not directly interchangeable with other forms of buprenorphine’ which appeared in each of the detail aids. Indivior stated that efficacy data confirmed that ‘Espranor is not interchangeable with other buprenorphine products’. This was prominently featured on the packaging the SPC and PIL (either in bold, or in a boxed warning) and so should be similarly displayed on all materials to enable prescribers and patients to make informed choices. Indivior did not consider that Martindale had not gone to sufficient lengths to highlight that Espranor was not interchangeable with other buprenorphines used in OST; the text was not sufficiently prominent and this important information was not provided early enough in all of the materials in question and was not in the patient leaflet at all. Indivior alleged that Martindale had brought discredit upon the industry by underplaying a key prescribing issue and thus misleading prescribers. 

The Panel noted that a boxed warning that Espranor was not interchangeable with other buprenorphine products was included in Section 4.2 of the SPC. A boxed warning appeared at the beginning of Section 2 (What you need to know before you take Espranor) of the PIL which read ‘Espranor is not interchangeable with other oral buprenorphine products and the dose of Espranor may differ from the dose of other buprenorphine products’. This latter boxed warning was also part of the labelling on the product packaging as referred to in the PAR. The Panel noted that the EU Risk Management Plan discussed the prevention of error due to the wrong medication and noted the higher bioavailability of buprenorphine from Espranor than from Subutex. Medication errors were listed as an important potential risk in the summary of safety concerns. 

The Panel disagreed with Indivior’s contention that the warning in question should make it clearer that Espranor was not interchangeable with other buprenorphines used in OST. The Panel noted that some other buprenorphine products were licensed to treat, inter alia, moderate to severe cancer pain and severe pain which did not respond to nonopioid analgesics. The Panel noted Espranor’s licensed indication, substitution treatment for opioid dependence, and that each item at issue was either promotional material for the product or for patients who had been prescribed it and discussed its licensed use. The Panel thus did not consider that the non-interchangeability warning at issue needed to qualify the reference to buprenorphines by stating that it applied to those used in OST. High standards had been maintained on this point. No breach of the Code was ruled. 

The Panel disagreed with Martindale’s submission that the warning in one of the detail aids, ‘Espranor is not directly interchangeable with other forms of buprenorphine’, stood out as the header because it was highlighted in blue. The Panel noted that all five subheadings on the page were in the same pale blue font. Two main headings were in purple font and the text was otherwise black. The Panel considered that the pale blue font colour and the overall design of the page, including the position of the warning in question as the subheading to the final paragraph at the bottom of the page, meant that it was not sufficiently prominent. Although, as submitted by Martindale, the warning in the Espranor SPC was in the same size as the rest of the text on that page, it was also within a box and ‘Not interchangeable with other buprenorphine products’ was emboldened. The Panel considered that the warning should have been made more prominent given the therapy area, the vulnerable nature of the patients and its prominence in the SPC. A breach of the Code was ruled. 

The Panel noted that the warning ‘Espranor is not directly interchangeable with other buprenorphine products’ was in the other detail aid followed by the prescribing information. Despite the use of emboldened font within the warning, the Panel considered that it should have been presented earlier in the detail aid given that the preceding pages discussed how Espranor delivered buprenorphine in OST more effectively than hard, compressed, sublingual formulations and compared its dissolution time to that of Subutex. The Panel considered that its comments above about the need for the warning to be more prominent were relevant here. High standards had not been maintained. A breach of the Code was ruled. 

With regard to the Espranor website, the Panel noted that although the warning in the SPC had been reproduced in full and was within an outlined box, it was only presented towards the end of the health professional section. As above the Panel considered that it should have been presented earlier; high standards had not been maintained and a breach of the Code was ruled. 

The Panel noted that Indivior had also alleged that the warning was not sufficiently prominent on page 15 of the website which comprised prescribing information. In this regard, the Panel noted that the prescribing information did not include the SPC. The Code dictated the content of prescribing information which included precautions and contraindications and warnings issued by, inter alia, the licensing authority which were required to be in advertisements and it also required prescribing information to be provided in a clear and legible manner. There was no reference in the relevant clauses about prominence of particular elements of the prescribing information. The Panel noted that the warning, ‘Espranor is not interchangeable with other buprenorphine products’ was in the same font size as the rest of the prescribing information within the Dosage and administration section. It was underlined as were 10 other phrases or sentences in the first column of prescribing information. It was not prominent such that it caught the reader’s eye. Although the Panel considered that it would have been helpful if the warning had been visually more prominent in the absence of a specific direction or requirement of the Code, on balance, it did not consider that the company had failed to maintain high standards. No breach of the Code was ruled. 

The Panel noted that the absence of the warning on the patient section of the website was covered by its ruling above. 

With regard to the patient leaflet the Panel noted its relevant comments above including the content of the EU Risk Minimisation Plan and in particular noted the vulnerability of the patients and considered that in these particular circumstances it was important to ensure that all relevant information was made available. The Panel considered that the failure to include the verbatim warning (or similar) in the patient information leaflet was such that high standards had not been maintained. A breach of the Code was ruled. 

The Panel noted the vulnerability of the patient population and that the highlighted warning was a prominent part of the SPC, PIL and the product pack. The Panel noted its comments above on the lack of prominence given to the warning across several materials and that it was not on the patient materials at issue at all. The Panel noted that prejudicing patient safety was given as an example of an activity likely to be in breach of Clause 2 of the Code. A breach of that clause was ruled. 

Indivior alleged that Martindale misrepresented dissolution and disintegration data for Subutex when comparing it with Espranor, implying that there were greater differences in dissolution time to that shown by the head-to-head data. According to Indivior, Martindale also suggested that the difference was clinically important without providing any supportive evidence. Indivior referred to the SPC and clinical data and stated that dissolution and disintegration were not comparable nor interchangeable in this context. Indivior alleged that Martindale was misleading with this comparison; it had distorted the data, exaggerated and given undue emphasis to the benefits of Espranor compared with Subutex. 

The Panel noted Indivior’s submission that the SPC for Subutex stated ‘The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes’. The Espranor SPC stated that ‘The oral lyophilisate should be … placed whole on the tongue until dispersed, which usually occurred within 15 seconds, and then absorbed through the oromucosa. Swallowing should be avoided for 2 minutes ... Patients should not consume food or drink for 5 minutes after administration’. The SPC further noted that physicians must advise patients that the oromucosal route of administration was the only effective and safe route of administration for Espranor. If the oral lyophilisate or saliva containing buprenorphine were swallowed, the buprenorphine would be metabolised and excreted and have minimal effect. The Panel noted its comments above about the clinical data regarding disintegration and diversion. 

In relation to the website claim ‘Unlike conventional hard compressed buprenorphine sublingual tablets which take up to 10 minutes to dissolve, Espranor instantly disintegrates within 15 seconds of being placed on the tongue resulting in rapid dissolution (median time 2 minutes)’, the Panel noted that the latter part of the claim ‘resulting in rapid dissolution (median time 2 minutes)’ appeared at the top of the following page on the version provided by the complainant. The Panel noted its ruling of a breach of the Code in relation to a claim about instant disintegration within 15 seconds above. The Panel noted the reference to 5-10 minutes in the Subutex SPC and considered that readers would probably compare the stated ‘instant disintegration’ of Espranor with the stated ‘up to 10 minutes’ dissolution time for the comparator. The Panel noted Indivior’s submission that dissolution and disintegration were not comparable in this context and noted the parties’ definition of terms. The Panel queried whether ‘up to 10 minutes’ was a fair reflection of the Subutex SPC. Those readers who saw the entire claim, which concluded on page 4, might compare Espranor’s median dissolution time of 2 minutes with ‘up to 10 minutes’ for Subutex. The Panel considered that the claim in question ‘Unlike conventional hard compressed buprenorphine sublingual tablets which take up to 10 minutes to dissolve, Espranor instantly disintegrates within 15 seconds of being placed on the tongue resulting in rapid dissolution (median time 2 minutes)’ exaggerated the differences between the products and was misleading in this regard. The claim could not be substantiated. Breaches of the Code were ruled. 

In relation to the website claim ‘Buprenorphine is currently only available as hard compressed sublingual tablets which take up to 10 minutes to dissolve,’ the Panel noted that whilst the claim itself did not refer to Espranor, the preceding paragraphs discussed Espranor and referred to its ‘rapid dissolution’ and ‘Instant disintegration ...’. Closely similar claims about instant disintegration had been ruled in breach of the Code above. The Panel noted its comments above about the Subutex SPC and the phrase ‘up to 10 minutes’. In the Panel’s view, readers were invited to compare the stated ‘up to’ 10 minutes’ dissolution time of the comparator with the stated instant disintegration of Espranor which were misleading and exaggerated the differences between the products. This comparison was incapable of substantiation. A breach of the Code ruled. 

The Panel noted that the claim ‘Conventional, hard, compressed, sublingual buprenorphine tablets take up to 10 minutes to dissolve’ on the front page of one of the detail aid immediately followed the claim ‘Espranor oral lyophillsate has been specifically designed to disintegrate instantly and dissolve rapidly when placed on the tongue’. This preceding claim, including the phrase ‘disintegrate instantly’, had been ruled in breach of the Code above. The emboldened unqualified claims on the front page of the detail aid included ‘No delay. No diversion’. The Panel noted its comments above about the Subutex SPC and the phrase ‘up to 10 minutes’. The Panel considered readers were invited to compare the stated ‘up to’ 10 minute dissolution time for Subutex with the stated instant disintegration of Espranor which gave a misleading and exaggerated comparison of the two which could not be substantiated. Breaches of the Code were ruled. The Panel noted that the claim ‘In the UK, licensed buprenorphine is currently only available as hardcompressed sublingual tablets, which take up to 10 minutes to dissolve and may compromise supervised administration’ was in the introductory section of one of the detail aids that discussed barriers to buprenorphine use (page 3). Whilst the preceding page and subsequent sections on the page in question discussed Espranor, the Panel noted that the only relevant statement in relation to Espranor across both pages was the first bullet point at the top of page 2 which read ‘Espranor oral lyophilisate is a novel freeze dried wafer formulation of buprenorphine which disintegrates instantly and rapidly when placed on the tongue’. As noted above, claims about instant disintegration had been ruled in breach of the Code. The Panel noted the detailed information given across pages 2 and 3 of the A4 detail aid. Other than the aforementioned bullet point, there was no other mention of disintegration and dissolution. Visually no prominence was given to the aforementioned bullet point at the top of page 2 such that the Panel considered, on the balance of probabilities, that the claim in question on page 3, ‘In the UK, licensed buprenorphine is currently only available as hard-compressed sublingual tablets, which take up to 10 minutes to dissolve and may compromise supervised administration’ would not be read in light of the first bullet point on the preceding page and thus not a comparison with it. The design of the page was relevant. The Panel ruled no breach of the Code. 

In relation to the allegation about the comparison on page 3 of the other detail aid, the Panel noted the page was prominently headed ‘Espranor: rapid by design’. Beneath the left-hand column and the prominent subheading ‘Instant disintegration’ a clock face depicted that 96% of Espranor patients vs 72% with Subutex (p=0.0002) had partial disintegration (no longer removable from the mouth) at ≥15 seconds. The figure of 96% was prominent and in the same purple font as the claims ‘rapid by design and instant disintegration’. The right-hand column was headed ‘Rapid dissolution’ beneath which the average time to complete disintegration (median) was visually depicted showing Espranor as 2 minutes and Subutex as 10 minutes, p<0.0001. The data was referenced to the Espranor SPC and Strang et al (2015). The Panel noted its comments on this page above. The Panel noted its comments above on the wording in the Subutex SPC. The Panel noted that the bar chart did not reflect the range of 5-10 minutes within which Subutex usually dissolved as stated in its SPC. The Panel noted that there were differences between the products in relation to disintegration and dissolution in favour of Espranor. The prominent subheading ‘Instant disintegration’ had previously been ruled in breach of the Code. The Panel noted that more comparative data was given on this page than for the claims at issue above. Nonetheless, the Panel considered that the failure to fairly reflect the Subutex SPC in conjunction with the prominent claim ‘instant disintegration’ meant that the comparison was misleading and exaggerated the differences between the products. The comparison was not capable of substantiation. Breaches of the Code were ruled.

The Panel noted the allegation that Martindale suggested that the above comparisons were clinically relevant which was not supported by the data. However, the Panel noted that whilst claims had to be capable of substantiation, the burden was on Indivior to show that, on the balance of probabilities, such claims were not clinically relevant. It had not identified any data and Martindale had not responded to this point. The Panel noted that the studies before it in relation to different matters in this case included discussion of supervision times. In the Panel’s view, Indivior had not discharged the burden of proof. The Panel ruled no breach of the Code.

Indivior noted claims regarding the reduced supervision time afforded by Espranor and that in support of such claims Martindale had referred to an excerpt of its clinical study report which was a key reference for multiple claims in its materials, but this had not been provided in a full enough form to confirm or deny the claim. It surmised: ‘The faster speed of disintegration with [Espranor] will reduce the supervision time required compared to [sub-lingual buprenorphine], providing a greater convenience for both the patient and clinician, and the potential for reduced supervision costs in both the healthcare and prison systems’ (emphasis added). Indivior did not consider that there was evidence to support the claims and again noted that the Espranor SPC stated ‘… Swallowing should be avoided for 2 minutes … Patients should not consume food or drink for 5 minutes after administration’ which increased the required supervision time to at least 5 minutes. 

The Panel noted Indivior’s reasoning that, given wording in the Espranor SPC, supervision time should be at least 5 minutes. In the Panel’s view, the aim of supervision was to ensure that the patient did not remove a dose for diversion. It was well-known that patients removed doses of buprenorphine from supervised consumption in creative ways. 

The Panel considered that its comments above about the time taken to achieve partial and complete disintegration and diversion were relevant here. 

The Panel noted Martindale’s submission that there was no statement in the SPC to suggest supervision for 5 minutes to ensure that food was not consumed after taking Espranor; the only reference to supervision was during the initiation of treatment. Daily supervision of dosing was recommended to ensure proper placement of the dose on the tongue and to observe patient response to treatment as a guide to effective dose titration according to clinical effect. 

The Panel noted that Strang et al (2017) concluded that ‘Espranor’s rapid disintegration and consequent greater ease of supervised dosing may increase the feasibility of buprenorphine treatment in busy community and custodial settings when supervised dosing is considered important. This now needs to be explored clinically’. The authors subsequently stated that ‘hopefully rapid-dissolving variants of buprenorphine may increase the range of settings in which buprenorphine can safely be delivered such as settings where it is unrealistic to expect full supervision of dosing over several minutes’. These contexts would warrant attention in future studies. The Panel noted that the page of the clinical study report that had previously been disclosed to Indivior was more dogmatic, it stated ‘The faster speed of disintegration with [Espranor] will reduce the supervision time required compared to the comparator, providing a greater convenience for both the patient and clinician, and the potential for reduced supervision costs in both the healthcare and prison systems’. 

The Panel noted that there were differences between the products which were relevant to supervision time. The Panel considered that the phrase ‘reduces the time required.’ had to be considered in the context in which it was used. 

The Panel noted that the website claim ‘Rapid dissolution reduces the time required for supervised administration’ was one of two bullet points and appeared immediately above the claim ‘Instant disintegration eliminates the opportunity for removal from the mouth once administered’ which was ruled in breach of the Code above in relation to the elimination claim. In addition, the phrase ‘instant disintegration’ was closely similar to matters ruled in breach of the Code above. In the Panel’s view, the context including the unqualified claim about instant disintegration and elimination implied that the reduction in time required for supervision would be greater than it in fact was. In this regard, the claim ‘Rapid dissolution reduces the time required for supervised administration’ was misleading and incapable of substantiation. Breaches of the Code were ruled. 

In relation to the claim ‘Instant disintegration of Espranor reduces the time required by pharmacists for supervised self-administration of buprenorphine’ in one of the detail aids, the Panel considered that its comments in relation to the first claim above applied here. ‘Instant disintegration’ was part of the claim at issue. Breaches of the Code were ruled. 

The Panel noted that the third claim ‘Minimises supervision time and reduces potential diversion for misuse.’ was a prominent claim at the bottom of page 3 of the other detail aid on the same page as matters ruled in breach of the Code above in relation to comparative dissolution times and the claim ‘Instant disintegration’. The Panel considered that the term ‘minimises’ was different to the term ‘reduces’. It implied reduction to an almost irreducible amount. In the Panel’s view, this implication was compounded by the other claims ruled in breach on the page. Overall, the Panel considered the claim misleading and incapable of substantiation. Breaches of the Code were ruled. 

Indivior referred to the claim ‘Equivalent safety and efficacy to sublingual buprenorphine’ which appeared on page 8 of one of the detail aids and to ‘Clinical trials show that Espranor is as effective as conventional compressed sublingual forms of buprenorphine at treating opioid dependence with a comparable safety profile’ which appeared on the website. Indivior submitted that these claims were in contrast to the statement ‘56.5% of patients reported mild AEs [adverse events] with Espranor compared with 7.7% of patients taking [sublingual buprenorphine]’ found in both detail aids. Indivior also noted that Strang et al (2017) stated ‘… more AEs and Treatment-Emergent AEs with [Espranor] (mostly “mild”)’ and ‘However, a greater proportion of [Espranor] subjects experienced at least one AE and similarly for TEAE (73.9 and 69.6%, respectively) compared to the [sublingual buprenorphine] group’. Indivior was concerned that Martindale had misrepresented the safety data on its website. It also noted that Martindale had additional risk minimisation measures stipulated in its risk management plan, as stipulated in the Public Assessment Report (PAR). Martindale did not address these in any of the materials Indivior had seen. Indivior further noted that there was no safety information in the patient leaflet. 

The Panel noted that the first claim at issue was a subheading and read ‘Equivalent safety and efficacy to sublingual buprenorphine’. It appeared on page 8 of one of the detail aids. The Panel noted Martindale’s submission that the key safety concern facing any new formulation of buprenorphine was respiratory depression and the Espranor safety study which aimed to investigate this concern stated that whilst administration of Espranor did not result in a higher risk of respiratory depression when compared to sublingual buprenorphine a higher number of mild treatment-emergent adverse events (TEAEs) were reported in the Espranor group. Strang et al (2017) stated that a greater proportion of Espranor subjects experienced at least one AE and similarly for TEAE (73.0 and 69.6% respectively). 

The Panel noted that although information about the greater incidence of mild adverse events with Espranor vs Subutex appeared on page 6 of the detail aid, the claim at issue ‘Equivalent safety and efficacy to sublingual buprenorphine’ appeared on page 8. The Panel considered that the claims and data on page 8 had to be able to stand alone in relation to the requirements of the Code and, in this regard, considered that the phrase ‘Equivalent safety ...’ was not a fair overall reflection of the adverse event data given the difference in the incidence in mild adverse events and was misleading in this regard. The claim was incapable of substantiation and did not reflect the available evidence. Breaches of the Code were ruled. 

The second claim at issue on page 7 of the website read ‘Clinical trials show that Espranor is as effective as conventional compressed sublingual forms of buprenorphine at treating opioid dependence with a comparable safety profile’ and was referenced to Strang et al (2015). There was no further discussion of the products’ adverse event profiles. The Panel considered that its comments immediately above about the adverse event data applied here. The Panel considered that the claim at issue was not a fair reflection of the adverse event data in relation to mild adverse events. The claim was incapable of substantiation and did not reflect the available evidence. Breaches of the Code were ruled. 

The Panel noted Martindale’s submission that the patient leaflet was for those prescribed Espranor as a ‘how to administer’ guide and provided details of how to report side-effects. The patient would also have the Espranor patient information leaflet with the full list of adverse events. The Panel noted that the leaflet had to be able to stand alone with regard to the requirements of the Code. It was headed ‘This leaflet is intended for patients that have been prescribed Espranor’. No information about the product was given other than a diagrammatic illustration of its administration and information on how to report side effects. Given its limited circulation to patients for whom the product had been prescribed and specific purpose to illustrate administration, the Panel, on balance, did not consider that it was necessary to include safety data as alleged. No breach of the Code was ruled. 

Indivior presumed that Martindale chose to use its clinical study report to reference significant claims in its materials because Strang et al (2017) was not available at the time. Indivior asked a number of times for fully marked up references to support the claims. Martindale subsequently sent 6 out of at least 123 pages of the study report, which did not support the claims referenced, around 5 weeks later. Indivior was concerned that some claims were taken from extracts of the preamble of the study report and not from any data itself, and that other claims supported by the study report would require verification. Indivior had not seen the full report and was concerned at the length of time taken to receive final comments from Martindale. 

Indivior was very concerned at the strength of some of the claims given that they appeared to be based on opinion and summation rather than data or peerreviewed evidence. 

The Panel noted that the Code required that substantiation for any information, claim or comparison must be provided as soon as possible, and certainly within ten working days, at the request of members of the health professions or other relevant decision makers. The Panel noted that the relevant clause had not been raised and so Martindale not been asked to comment on it and the Panel could make no rulings in that regard. 

The Panel noted Indivior’s concern with regard to the strength of some claims but also noted that Indivior had not identified the claims at issue; it was not for the Panel to identify the claims. In the Panel’s view, it did not have a valid complaint to consider and thus ruled no breach of the Code. 

Overall, Indivior alleged that high standards had not been maintained with regard to the launch campaign for Espranor. Indivior submitted that the alleged breaches were overall very serious and some in particular brought discredit upon, and reduced confidence in, the pharmaceutical industry. With regard to dependency therapy the NHS was under significant resource constraints, making it particularly important for the pharmaceutical industry to provide credible evidence based information to prescribers and patients alike about its products. Indivior alleged a breach of Clause 2. 

The Panel noted its comments and rulings above and considered that Martindale had failed to maintain high standards; a breach of Clause 2 had also been ruled above. 

The Panel noted that a ruling of a breach of Clause 2 was a sign of particular censure and was reserved for such circumstances. Examples of activities that were likely to be in breach of Clause 2 included, inter alia, prejudicing patient safety and/or public health. 

The Panel noted its rulings of breaches and comments above. The Panel noted the vulnerability of the patient population and the therapy area. The Panel noted Indivior’s reference to the need for evidence-based information and, in this regard, noted the difficulties of undertaking studies in this patient population. The Panel noted the small study size, Espranor n=23 and sublingual buprenorphine, n=13 and that it was unblinded. The Panel considered that further information about the study should have been provided in the materials to enable the reader to assess the data. This was particularly so given the strong unqualified nature of some of the claims at issue. In addition, the Panel considered that the cumulative effect of advertising Espranor to the public and encouraging patients to ask for it, implying that there was absolutely no possibility of diversion, and claims in relation to reduced supervision time due to the instant disintegration of Espranor, which was not so, prejudiced patient safety and a further breach of Clause 2 was ruled.