Janssen-Cilag complained about a Jardiance (empagliﬂozin) letter distributed by Boehringer Ingelheim and Eli Lilly and Company (the Alliance) representatives which was stapled to a copy of Zinman et al (2015), (the EMPA-REG study) and a one sided A4 sheet of prescribing information. The letter referred to cardiovascular outcome data.
Janssen explained that Jardiance was a sodium glucose transporter 2 (SGLT2) inhibitor indicated to improve glycaemic control in type 2 diabetic adults either as monotherapy or combination therapy. The only reference to any cardiovascular outcomes in the Jardiance summary of product characteristics (SPC) was in Section 5.1 as follows:
‘Cardiovascular safety In a prospective, pre-specified meta-analysis of independently adjudicated cardiovascular events from 12 phase 2 and 3 clinical studies involving 10,036 patients with type 2 diabetes, empagliﬂozin did not increase cardiovascular risk.’
Janssen stated that the US Food and Drug Administration (FDA) mandated that all new glucose-lowering agents should include a meta analysis of the cardiovascular safety outcome studies to be carried out by the market authorization holder on new molecules licensed after July 2008, to demonstrate that the therapy would not result in an unacceptable increase in cardiovascular risk in patients with type 2 diabetes. Hence the above SPC wording. In addition, the Alliance initiated The EMPA-REG study which was listed in the risk management plan for Jardiance.
Zinman et al (2014) and Zinman et al (2015) described in detail the rationale, design and baseline characteristics of the EMPA-REG study together with the following caveat regarding the results:
‘The results may not be generalizable (e.g., to patients with type 2 diabetes without cardiovascular disease), the risk–benefit profile for this drug class will need further elucidation (particularly for adverse events), and the ultimate position of empagliﬂozin among multiple drugs in the clinical management of type 2 diabetes will still need to be defined. Thus, it will be important to confirm these results with findings from other ongoing trials of SGLT2 inhibitors’ (Ingelfinger and Rosen 2016).’
In view of the EMPA-REG study results the Alliance applied for a new indication for the prevention of cardiovascular events to be included in Section 4.1 of the Jardiance SPC. No decision had been made by the Committee for Medicinal Products for Human Use (CHMP) as yet.
Janssen noted that the letter at issue, dated January 2016, was designed to inform health professionals about the results of the EMPA-REG study. A large part of the letter described the cardiovascular risk reduction seen with Jardiance. By proactively disseminating this letter, via its sales force, the Alliance had promoted the use of Jardiance to reduce cardiovascular risk ahead of an approval of the licensed indication. Although a statement ‘Jardiance is not indicated for the treatment of weight loss, blood pressure control or cardiovascular risk reduction’ was in the section describing the posology of Jardiance, this restriction was not clear from the outset as it appeared on page 2 of the letter and was not prominently displayed.
Janssen also alleged that the promotional letter closely, and inappropriately, resembled a ‘Dear Doctor’ letter, which was reserved for special communication to health professionals of important events such as safety alerts, and so was misleading in this regard. Moreover, the letter was signed by senior medical employees of the Alliance who held overall responsibility for compliance with the Code.
A number of breaches of the Code were alleged.
The detailed response from the Alliance is given below.
The Panel noted that page 1 of the letter bore no company name, logo or address and no prominent name or logo of a medicine. The envelope was plain. It was not immediately obvious who the letter was from or what it was about. In that regard the Panel noted that the material had been handed out to a health professional after a 1:1 Jardiance call with an Alliance representative and whilst the recipient would have had the benefit of that interaction, anyone else picking up the material might not realise where it had come from. The briefing material regarding the use of the material (dated 12 January 2016) stated that the EMPA REG study represented a significant milestone in the treatment of diabetes but that the company was unable to discuss it in detail until the relevant authorization and training was provided. With regard to ‘the relevant authorization’, the Panel noted that the CHMP agenda for its February 2016 meeting showed that an application for a licence extension for Jardiance to include prevention of cardiovascular events based on the EMPA-REG study results had been submitted. The briefing material stated that the EMPA-REG study should only be given out until 30 June 2016 but without any discussion other than the following mandatory verbatim:
‘You may be aware of the regulatory requirement to conduct cardiovascular outcome studies for all new antidiabetic agents. The cardiovascular outcome study for Jardiance was published in the New England Journal of Medicine in September 2015. In this folder you will find a reprint of the paper. The study forms part of a potential SPC update and I am unable to discuss it further with you. However, the folder includes an accompanying letter from our Medical Directors which indicates how further information may be obtained together with Jardiance prescribing information.’
‘You may be aware of the regulatory requirement to conduct cardiovascular outcome studies for all new antidiabetic agents. The cardiovascular outcome study for Jardiance was published in the New England Journal of Medicine in September 2015.
In this folder you will find a reprint of the paper. The study forms part of a potential SPC update and I am unable to discuss it further with you. However, the folder includes an accompanying letter from our Medical Directors which indicates how further information may be obtained together with Jardiance prescribing information.’
The letter was addressed ‘Dear UK Healthcare Professional’. The second of the first two very short introductory paragraphs stated that Jardiance was a glucose-lowering agent for the treatment of adults with type 2 diabetes; it was not stated, as in the SPC, that it was indicated solely to improve glycaemic control. The most prominent section on page 1 was headed ‘Recent Cardiovascular Outcomes Data’ and took up the rest (approximately 75%) of the page. In that regard the Panel noted that, due to concerns that glucose lowering medicines might be associated with adverse cardiovascular outcomes (type 2 diabetes was itself a major risk factor for cardiovascular disease), the EMPA-REG study was a cardiovascular safety study mandated by the regulators; it was designed to address long-term (median 3.1 years) safety concerns, not to generate efficacy data for a possible new indication. Four bullet points detailed the main results from Zinman et al (2015) including that Jardiance significantly reduced the relative risk of the combined primary endpoint, of cardiovascular death, non-fatal heart attack or non-fatal stroke by 14% vs placebo. This was in contrast to the Jardiance SPC which stated that Jardiance did not increase cardiovascular risk. Page 2 of the letter stated the licensed indication for Jardiance (to improve glycaemic control in type 2 diabetes) and that the medicine was not indicated for, inter alia, cardiovascular risk reduction. It was further stated that if the reader had any questions or would like to discuss the EMPA-REG study with an Alliance medical advisor, this could be arranged by contacting the medical information department. The letter appeared to have been jointly sent from a medical director from each company.
In the Panel’s view it was clear from the briefing given to the representatives that Zinman et al (2015) would form the basis of a proposed change to the SPC and in that regard representatives were instructed not to proactively or reactively discuss the study. By proactively distributing the material at issue, however, the Alliance was knowingly using its representatives to solicit queries about the study, the results of which it knew were inconsistent with the Jardiance SPC. The Panel noted that although the Code did not prevent the legitimate exchange of medical and scientific information during the development of a medicine, provided that such information or activity did not constitute promotion, representatives distributing the material at issue after a 1:1 Jardiance call, clearly constituted the promotion of Jardiance.
The Panel considered that the prominence given within the letter to the cardiovascular outcome data from the EMPA-REG study promoted Jardiance for cardiovascular risk reduction for which it was not licensed. The results of the study went beyond the SPC statement that Jardiance did not increase cardiovascular risk. The results were not presented in the context of the safety profile for Jardiance. The statement on page 2 that Jardiance was not indicated for cardiovascular risk reduction was insufficient to mitigate the otherwise misleading and primary impression given by page 1 and the reference to outcomes data. In the Panel’s view, the material was preparing the market for an anticipated licence extension. A breach of the Code was ruled which was upheld on appeal.
The Panel noted the allegation that the letter resembled a ‘Dear Doctor’ letter and was therefore disguised promotion. The Panel assumed that the ‘Dear Doctor’ letters referred to were those sent by companies to convey important product safety information at the request of the MHRA. The Panel considered that given the very bland and not obviously promotional appearance of the letter, some recipients might assume that it was important safety information, or other non promotional information, even if it had been handed to them by a representative. In the Panel’s view, not all recipients would be so familiar with ‘Dear Doctor’ letters such that they would immediately recognise any difference. In the Panel’s view the representatives’ mandatory verbatim was not sufficiently clear about the status of the material; in any event the letter should be able to stand alone with regard to compliance with the Code. In the Panel’s view, despite the material being distributed by representatives, its promotional intent was not immediately obvious and in that regard it was disguised. A breach of the Code was ruled which was upheld on appeal.
The Panel noted that the Code required companies to appoint a senior employee to be responsible for ensuring that the company met the requirements of the Code. The Alliance met these requirements and so no breach of the Code was ruled.
The Panel considered that high standards had not been maintained. A breach of the Code was ruled which was upheld on appeal. The Panel was further concerned that the Alliance appeared to have knowingly distributed material which was inconsistent with the Jardiance SPC and which it would use to support a licence extension for a currently unlicensed indication. A breach of Clause 2, a sign of particular censure, was ruled and upheld on appeal.
The Panel noted its reasons for ruling breaches of the Code as set out above. In addition, the Panel was extremely concerned that the Alliance had given its representatives material to distribute to health professionals which it knew they could not discuss with those health professionals. In the Panel’s view this gave a wholly inappropriate signal to the representatives regarding compliance and was completely unacceptable; it compromised the representatives’ position and demonstrated a very poor understanding of the Code on behalf of the signatories. In that regard, and in accordance with Paragraph 8.2 of the Constitution and Procedure, the Panel decided to report the Alliance to the Appeal Board for it to consider whether further sanctions were appropriate.
The Appeal Board noted its comments and rulings of breaches of the Code including a breach of Clause 2. The Appeal Board considered that the Alliance’s actions either showed a disregard for, or a fundamental lack of understanding of, the requirements of the Code. The amount of time the companies had spent discussing the position before issuing the letter implied they were aware of the risks involved. The Appeal Board did not accept, as submitted by the Alliance, that the issues in this case were due to a grey area of the Code. It appeared that the Alliance had decided to put commercial gain before compliance. This was totally unacceptable.
The Appeal Board was very concerned that health professionals had been provided with material which promoted Jardiance for an unlicensed indication. This was unacceptable. Consequently, the Appeal Board decided, in accordance with Paragraph 11.3 of the Constitution and Procedure, to require the Alliance to issue a corrective statement to all recipients and to take steps to recover the material. (The corrective statement, which was agreed by the Appeal Board prior to use, appears at the end of this report).
The Appeal Board also decided that, given its concerns set out above, to require, in accordance with Paragraph 11.3, an audit of both Lilly and Boehringer Ingelheim’s procedures in relation to the Code with an emphasis on the activities of the Alliance. The audits would take place as soon as possible. On receipt of the audit reports, the Appeal Board would consider whether further sanctions were necessary.
Boehringer Ingelheim and Lilly were audited in July 2016 and the audit reports were considered by the Appeal Board in September.
The Appeal Board noted from both audit reports concerns about the governance of the Alliance although it was pleased to note a greater involvement of the compliance function on the senior governance committee.
The Appeal Board noted from the Boehringer Ingelheim audit report that, inter alia, there were concerns about the company’s standard operating procedures (SOPs), staff training and control of advisory boards. The Appeal Board considered that staff throughout the company needed to urgently improve and demonstrate their knowledge and understanding of the Code and commitment to compliance.
The Appeal Board noted that Boehringer Ingelheim had completed some of the work on its compliance action plan but it still had much to do. The Appeal Board noted its comments above and considered that Boehringer Ingelheim should be re-audited in March 2017 when it would expect the company’s action plan to be complete and the company able to demonstrate considerable improvement in compliance culture and process.
The Appeal Board noted from the Lilly audit report that compliance and ethics were highly valued at the company and its staff had understood and genuinely regretted the failings in this case. However, the audit report highlighted concerns about the company’s SOPs, its approval process and governance of advisory boards.
The Appeal Board noted that some work on Lilly’s compliance plan was already complete and that all actions were due to be completed by the end of October 2016. The Appeal Board considered that Lilly should be re-audited around the same time as Boehringer Ingelheim. On receipt of the report for the March 2017 re-audit in relation to Boehringer Ingelheim and the company’s response to subsequent questions raised by the Appeal Board, the Appeal Board decided that no further action was required.
On receipt of the report for the March 2017 re-audit in relation to Lilly and the company’s responses to subsequent questions raised by the Authority and points raised by a whistleblower the Appeal Board decided that, on balance, no further action was required.