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AUTH/2327/6/10 - MHRA v Grünenthal

Case number:AUTH/2327/6/10
Case ref:MHRA v Grünenthal
Description:Promotion of tapentadol
Breach:Breaches Clauses 2, 3.1 and 9.1. Audits, public reprimand.
Appeal:No appeal
Status:Breach ruled, Audit
Review:Published in the May 2012 Review
Received:25/06/2010
Completed:22/03/2012
Case Summary:

​ The Medicines and Healthcare products Regulatory Agency (MHRA) advised the Authority that it was concerned that Grünenthal was promoting its unlicensed medicine, tapentadol, to health professionals. The matter was taken up as a complaint under the Code.

The MHRA explained that it had received an allegation that suggested that Grünenthal had promoted its unlicensed product, tapentadol, to health professionals. The MHRA knew from previous correspondence with the company that its team of health economic liaison managers (HELMs) contacted 3,000 health professionals about the product’s budgetary implications in advance of the grant of a marketing authorization. The MHRA deemed this activity to be promotional and provided advice on compliance with the law. A report of the case was provided.

The anonymous source alleged that the company had continued to target health professionals and it set call rates for this and had supporting materials, including slides, to use in proactive discussions with NHS staff.

The MHRA would take a very serious view of any further promotion of tapentadol in advance of the grant of a marketing authorization since Grünenthal had already been censured by the MHRA for the previous case. In addition the MHRA had asked to vet all promotional and related materials for the product, including any proactive materials for use by HELMs.

In the absence of any evidence of actual promotion from a recipient, the MHRA did not consider it appropriate to take forward a legal investigation for breach of the regulations. Instead it asked the Authority to investigate Grünenthal’s actions to ensure that it had not promoted tapentadol and that it had appropriate procedures and controls in place for its HELMs and any other staff that might discuss unlicensed medicines with health professionals.

The detailed response from Grünenthal is given below.

The Panel noted that the complaint from an anonymous source to the MHRA was that Grünenthal continued to promote tapentadol prior to the grant of a marketing authorization. The MHRA had received a complaint about the matter in November 2009 and had agreed action with Grünenthal in January 2010. The Panel noted that the MHRA had considered the activities in relation to the Advertising Regulations and the Blue Guide. The Panel considered that it was limited to considering Grünenthal’s activities after January 2010 in relation to the Code.

The Panel noted Grünenthal’s comments about the anonymous source of the complaint to the MHRA and the burden of proof. The Panel noted, as set out in the introduction to the Constitution and Procedure, that complainants had the burden of proving their complaint on the balance of probabilities. Anonymous complaints were accepted and like all complaints judged on the evidence provided by the parties.

The Panel noted that Grünenthal had begun an advance notification process for tapentadol in November 2009 ie only 10 months before it anticipated having a marketing authorization for the medicine. In that regard, the Panel queried whether the information had been supplied early enough such that budget holders etc could be reasonably expected to act upon it. Information could only be supplied if the product had a significant budgetary implication. The Panel queried whether this was so but did not consider this was relevant to the complaint before it.

It appeared, that, in compliance with a request from the MHRA, that whilst HELMs were not given any printed material regarding tapentadol, they could still talk about it. The Panel considered that this approach was wholly unacceptable. The HELMS were given, inter alia, information about tapentadol some of which was headed ‘not approved for distribution’. Some of this material showed an advantage for tapentadol vs oxycodone. In the Panel’s view, the more information the HELMs were given about tapentadol the more likely they were to use it with their customers for commercial advantage.

The Panel noted Grünenthal’s submission that the HELMs had not engaged in any proactive advance notification for tapentadol following an agreement with the MHRA in January. It appeared that since then the HELMs had undertaken a formulary mapping exercise to gain an understanding of how a new medicine would be introduced into the local health economy. This exercise required the HELMs to seek answers to a number of key business questions. Some of those questions were detailed in a briefing presentation, 2 March, and included the following: ‘Identify attitudes to [controlled drugs] and tapentadol in nociceptive neuropathic and specifically back pain’; ‘Where do they see tapentadol on the analgesic ladder?’; ‘Where does the customer see a new pain drug adding most value?’ and ‘Does [drug and therapeutics] need to be achieved before a new pain drug can be used?’. The Panel noted Grünenthal’s submission that following dialogue with the MHRA in April 2010, HELMs were briefed to discuss the process issues in relation to new products in general. Further formulary mapping questions appeared in a presentation dated 28 April 2010.

The Panel noted that the HELMs visited individuals responsible for the approval and purchase of medicines within the NHS; they also visited those who had to gain approval for the use of medicines in local health economies. The HELMs proactively saw both types of customers in relation to Grünenthal’s licensed products all of which were for pain relief. The Panel considered that in this regard customers would see the HELMs as medical representatives. To have that same group of people then asking questions about tapentadol or a ‘new pain drug’ would be seen as promotional.

The Panel disagreed with Grünenthal’s submission that the HELM position was a non-promotional role. Their activities were not limited to a fact finding role as the nature of the questions they were to ask would raise interest and awareness in the new product and solicit questions about it. The slides presented to the HELMs about tapentadol reinforced the promotional aspect of their activity. The HELMs were expected to have selling skills and they visited the same people to tell them about licensed medicines and to ask them questions about tapentadol and/or ‘a new pain drug’. In the Panel’s view asking such questions amounted to the promotion of tapentadol before the grant of its marketing authorization. Thus a breach of the Code was ruled. The Panel considered that high standards had not been maintained. A breach of the Code was ruled.

The Panel considered that to brief a team, employed for its selling skills, to raise the profile of tapentadol and/or ‘a new pain drug’ just weeks before the expected grant of a marketing authorization was unacceptable. The Panel was very concerned about the failure to provide the HELMs with clear written instruction and this was a particularly serious omission given the concerns raised by the MHRA about the activity. The Panel considered that the activity amounted to a softening of the market. Such activity brought discredit upon and reduced confidence in the pharmaceutical industry. A breach of the Code was ruled.

The Panel was extremely concerned about Grünenthal’s activities with regard to the advanced notification of tapentadol. The MHRA had provided advice to the company following a mailing about tapentadol to 3,000 people. Since being in correspondence with the MHRA, Grünenthal had used a team of HELMs to gather information about, inter alia, attitudes to tapentadol and how to get ‘a new pain drug’ on to a formulary. The HELMs were expected to have selling skills and saw some of the same people about licensed and unlicensed medicines. The HELMs were expected to work closely with the sales team. Briefings to HELMs about this matter after the intervention of the MHRA were inadequate. Overall the Panel considered that Grünenthal’s activity amounted to the promotion of tapentadol prior to the grant of its licence. In the Panel’s view the HELMs’ activities did not constitute the advance notification of tapentadol as no information was being supplied that showed that the product would have a significant budgetary effect. The Panel considered that overallGrünenthal’s actions were unacceptable. The Panel decided to report the company to the Code of Practice Appeal Board in accordance with Paragraph 8.2 of the Constitution and Procedure. The Panel noted Grünenthal’s submission that on receipt of this complaint it had suspended all formulary mapping activities.

The Appeal Board noted from the company representatives that Grünenthal had originally set up a market access team to try to limit the extensive off-label use of Versatis and to gain market access for its portfolio of licensed pain medicines. Part of the HELMs’ role was to promote Grünenthal’s medicines. The company had then used this same team, with the same job description, to work on the advance notification of tapentadol. The Appeal Board was very concerned about the conduct of Grünenthal. The prohibition on the promotion of a medicine prior to the receipt of its marketing authorization should have been well understood. It appeared that Grünenthal had not taken the opportunity to thoroughly review the HELMs’ role and responsibilities when the MHRA had determined that, in providing advance notification, they had infact promoted tapentadol prior to the grant of its marketing authorization. Although changes had been made to the way the HELMs worked at this point, in that they had no role in relation to advance notification, the account mapping and other activities which they carried out were considered by the Panel to still amount to the promotion of a medicine prior to the grant of its marketing authorization. This was unacceptable.

The Appeal Board was very concerned to learn that the market access team had generated presentations and briefing materials for the HELMs which had not been certified. In that regard the Appeal Board queried whether the senior management team had exercised sufficient control over the market access team especially considering it was newly appointed, had responsibilities for an unlicensed medicine and the MHRA’s involvement in the matter.

The Appeal Board decided in accordance with Paragraph 11.3 of the Constitution and Procedure to require an audit of Grünenthal’s procedures in relation to the Code to be carried out by the Authority. The audit should be conducted as soon as possible. On receipt of the audit report the Appeal Board would consider whether further sanctions were necessary.

Upon receipt of the audit report (October 2010) the Appeal Board noted that Grünenthal had agreed compliance plans which would address all the areas recommended for attention and this was already being implemented.

The Appeal Board decided that a second audit should be carried out in February 2011 when it would expect the recommendations in the audit report to be implemented. On receipt of that audit report the Appeal Board would consider whether further sanctions were necessary.

Upon receipt of the second audit report (delayed until March 2011) the Appeal Board was encouraged by Grünenthal’s progress since October but considered that the company still needed to demonstrate that it understood the importance of compliance. The Code and its requirements needed to become embedded into all levels of the company.

The Appeal Board decided that a third audit should be carried out in September when it would expect the recommendations in the audit report to be implemented. On receipt of that audit report the Appeal Board would consider whether further sanctions were necessary.

Upon consideration of the third audit the Appeal Board was concerned that it still appeared that the company had not really understood the seriousness of the situation. The Appeal Board was extremely concerned to note errors in the response from Grünenthal to the recommendations from the March 2011 audit (part of the preparation for the September 2011 audit). This was unacceptable. It was hard to believe, given the recommendation in March that the company should be confident that all the Versatis material was clear regarding the licensed indication, that the company had not been precise about what had been done. Senior employees had not taken decisive action to implement the recommendation. The failure of senior employees to respond in full to questions at the audit about that recommendation led the Appeal Board to question the company’s stated commitment to compliance.

The Appeal Board decided that Grünenthal should be publicly reprimanded in relation to the misinformation in its response to the Authority. Prior to the third audit the Appeal Board was extremely concerned about the apparent lack of demonstrated change in the company culture. It noted that some activities had been started and these might improve the situation. A new general manager was appointed in October. The Appeal Board decided that a fourth audit of Grünenthal should take place by mid February 2012. Upon receipt of the report for that audit, it would decide whether further action was needed.

Upon consideration of the forth audit report (February 2012) the Appeal Board noted that Grünenthal had undergone changes in senior staff including a new general manager. There appeared to be a different culture in the company and a more positive attitude to compliance. The Appeal Board considered that there had been encouraging progress since the last audit. On the basis that the company adopted an approach of continual improvement the Appeal Board considered that no further action was required.