AUTH/3041/6/18 and AUTH/3042/6/18 - Employee v Otsuka Europe and Otsuka UK

Updating prescribing information

  • Received
    01 June 2018
  • Case number
    AUTH/3041/6/18 and AUTH/3042/6/18
  • Applicable Code year
    2016
  • Completed
    25 June 2020
  • Additional sanctions
    Audit of company’s procedures
    Re-audit
    Public reprimand
  • Appeal
    No appeal
  • Review
    Public reprimand for Otsuka Europe published in May 2020

Case Summary

This is an interim case report because the final report will be delayed due to the Code of Practice Appeal Board’s requirement for audits of Otsuka Pharmaceuticals Europe Ltd and Otsuka Pharmaceuticals Ltd’s procedures in relation to the Code (Paragraph 11.3 of the Constitution and Procedure refers).

An Otsuka employee complained about the company’s procedures for updating the summary of product characteristics (SPC) and prescribing information for Jinarc (tolvaptan, used in chronic kidney disease), Samsca (tolvaptan, used in hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion) and Abilify (aripiprazole, used in schizophrenia).  Abilify Maintena was a prolonged-release injectable formulation of aripiprazole.

The complainant alleged that due to a lack of process, changes to the SPC and prescribing information had not been communicated to affiliates or third parties on time.  The complainant, who referred to updates from 2017 for Jinarc, Samsca and Abilify, considered that patient safety had been placed at risk.

The detailed responses from Otsuka UK and Otsuka Europe are given below.

The Panel noted that Otsuka Europe was the marketing authorisation holder for Jinarc, Samsca and Abilify which were supplied in the UK by Otsuka UK.  Otsuka Europe was also the marketing authorisation holder for Abilify Maintena which was supplied in the UK by Otsuka UK and Lundbeck under a co-promotion agreement.  It appeared from the various standard operating procedures that Otsuka Europe Development and Commercialisation was responsible for notifying Otsuka Europe of any changes to the SPCs.  The Panel considered that it was unclear whether it was Otsuka Europe or Otsuka Europe Commercialisation and Development that was ultimately responsible for communicating the SPC and PIL changes to Otsuka UK.  Historically, affiliates were responsible for implementing the changes including updating prescribing information; going forward Otsuka Europe would be responsible for prescribing information updates.

Otsuka UK was responsible for updating the eMC.  The Panel noted Otsuka’s submission that Otsuka UK and Otsuka Europe each produced and certified the material it used.

Case AUTH/3042/6/18 – Otsuka UK

1        Jinarc

The Panel noted that following a telephone call with the European Medicines Agency (EMA) on 6 January 2017, Otsuka Europe Development and Commercialisation communicated the update to include anuria as a new contraindication in Section 4.3 of the Jinarc SPC to Otsuka Europe and Otsuka UK on 9 January 2017.  Otsuka treated this as the start date of formal approval for implementation of the update.  Otsuka UK implemented the SPC update but did not send the revised SPC to the eMC until 3 February 2017.  The Panel considered that the delay in sending the updated SPC to the eMC meant that Otsuka UK had failed to maintain high standards and a breach of the Code was ruled.

Otsuka UK prepared updated prescribing information on 17 February 2017.  The Panel disagreed with Otsuka’s submission that this SPC update was not regarded as constituting important safety information requiring adoption of the accelerated prescribing information amendment under the relevant SOP. 

The Panel noted Otsuka’s submission that new promotional material incorporating the revised prescribing information was issued from 1 March 2017.  However, it was of concern that existing promotional material which pre-dated the SPC update was only withdrawn on 29 March 2017 as a routine withdrawal, rather than to ensure compliance with the Code after the SPC update.  The Panel noted that the Code listed the components of prescribing information which had to be provided including, inter alia, contraindications relevant to the promoted indication.  Failure to provide the required information in the prescribing information would be a breach of the Code.  The Panel considered that all promotional material that was not withdrawn until 29 March and contained prescribing information that omitted the anuria contraindication and was, therefore, inconsistent with the SPC current at that time, was not up-to-date and was therefore in breach of the Code.  The Panel considered that the delay in updating the prescribing information and withdrawing material with out-of-date prescribing information meant that Otsuka UK had failed to maintain high standards and a breach of the Code was ruled.

The Panel noted Otsuka’s submission that in April 2018, Otsuka UK discovered that anuria as a contraindication had not been included in certain educational materials required under a risk minimisation plan (RMP).  The Panel was concerned to note that the educational material implementing the RMP had still not been updated and submitted to the MHRA for approval at the time of Otsuka’s response to this complaint (June 2018).  The Panel considered that Otsuka UK had failed to maintain high standards by not promptly updating educational material required under the RMP and a breach of the Code was ruled.  The Panel considered that such failures had potential patient safety implications and noted its comments on Clause 2 and ruling on this matter below.

The Panel noted that the CHMP issued a positive opinion on 6 July 2017 to update Section 5.1 of the Jinarc SPC to include clinical trial results from the post-authorisation study, an extension to the TEMPO trial, which evaluated the effects of tolvaptan on, inter alia, safety.  Otsuka Europe Development and Commercialisation communicated the SPC update to Otsuka Europe and Otsuka UK the same day.  The Panel noted Otsuka’s submission that the communication was, however, not received by Otsuka UK until November 2017 and Otsuka sent the revised SPC to the eMC on 29 November 2017.  The Panel considered that the substantial and unexplained delay in Otsuka UK implementing the SPC change and updating the eMC meant that high standards had not been maintained.  A breach of the Code was ruled.

The Panel noted the content of prescribing information and that some changes to an SPC might not need to be reflected in the prescribing information.  The Panel noted Otsuka’s view that this SPC revision had not necessitated a change to the prescribing information.  The complainant bore the burden of proof and, in the Panel’s view, he/she had not established that the SPC update necessitated a change to the prescribing information.  The Panel therefore ruled no breach of the Code.

The Panel noted that whilst fluconazole had been listed as a moderate CYP3A inhibitor in Section 4.5 of the Jinarc SPC since marketing authorisation was granted in May 2015, the CHMP issued a positive opinion on 12 April 2018 to include additional information regarding the co-administration of tolvaptan and fluconazole.  Otsuka Europe Development and Commercialisation communicated the SPC change to Otsuka Europe and Otsuka UK on 16 April 2018.  Otsuka UK implemented the update and sent the revised SPC to eMC on 25 April 2018.  The Panel did not consider that Otsuka UK had failed to maintain high standards in this regard and no breach of the Code was ruled.

The complainant bore the burden of proof and, in the Panel’s view, he/she had not established that the SPC update necessitated a change to the prescribing information.  The Panel therefore ruled no breach of the Code.

The Panel noted Otsuka’s submission that, upon review of its materials, a number of Jinarc RMP training materials and health professional guides did not contain the dose adjustment required as a result of the Jinarc SPC update in relation to the interaction with fluconazole.  The Panel further noted, with concern, that on its examination of the SPCs, the Jinarc dose reduction recommendation for patients taking moderate CYP3A inhibitors, including fluconazole, appeared to have been in the SPC since the grant of the marketing authorisation in May 2015, rather than April 2018 as implied by Otsuka, and thus the company’s submission on this point was incorrect.  The Panel was concerned to note Otsuka’s submission that the RMP material had yet to be updated and submitted to the MHRA at the time of Otsuka’s response to this complaint and considered that Otsuka had failed to maintain high standards by not promptly updating educational material required under the RMP.  A breach of the Code was ruled.  The Panel considered that such failures had potential patient safety implications and noted its comments on Clause 2 and ruling on this matter below.

2        Samsca

The Panel noted Otsuka’s submission that the European Commission decision to update the Samsca SPC to include the 7.5mg dosage form and update the undesirable effects, posology and method of administration was adopted on 18 September 2017.  The update included the change in incidence of an adverse event, rapid correction of hyponatraemia (RCHN) from common to very common and a recommendation to use a lower dose in patients susceptible to RCHN. 

Otsuka Europe Development and Commercialisation communicated the update to Otsuka Europe and Otsuka UK on 20 September 2017.  The Panel noted Otsuka’s submission that the notification was sent to the incorrect person at Otsuka UK and was therefore not received.  The communication was re-sent to Otsuka UK on 21 November 2017.  Otsuka UK implemented the SPC update but did not send the revised SPC to the eMC until 8 January 2018.  The Panel considered that the delay in implementing this SPC update and sending it to the eMC meant that high standards had not been maintained.  A breach of the Code was ruled.  The Panel noted the nature of the SPC update and considered that such failures had potential patient safety implications.  The Panel noted its comments on Clause 2 and ruling on this matter below.

The Panel was concerned to note Otsuka’s submission that existing promotional material, which pre-dated the SPC update, was only withdrawn on 4 December 2017.  The Panel noted, however, Otsuka’s submission that no promotional activity took place between the end of September 2017 and February 2018 and so, in Otsuka’s view, there was no requirement to revise the prescribing information when the SPC was updated.  The Panel queried why, if the material was not being used, it was not withdrawn sooner.  The Panel noted that Otsuka had not commented on any applicable online promotional materials such as those available on websites.  The Panel noted Otsuka’s submission that the prescribing information was ultimately revised on 9 January 2018, before promotion started in February 2018 and promotional material incorporating changes following the SPC update was first issued on 18 March 2018.

Whilst the Panel had concerns, it noted that there was no evidence before it that material with out-of-date prescribing information had been distributed or was available online.  The complainant had provided insufficient evidence to discharge the burden of proof on the balance of probabilities; no breach of the Code was ruled.  The Panel considered, however, that failure to withdraw such material to ensure it could not be used meant that Otsuka had failed to maintain high standards and a breach of the Code was ruled.

3        Abilify and Abilify Maintena

The Panel noted Otsuka’s submission that the CHMP issued a positive opinion on 26 October 2017 and recommended approval of an SPC update for Abilify and Abilify Maintena to add specific warnings related to impulse control disorder, binge eating, compulsive shopping and poriomania. 

The Panel noted Otsuka’s submission that the date the linguistic review ended (4 December 2017) was the SPC update implementation date and Otsuka Europe Development and Commercialisation communicated the SPC update to Otsuka Europe and Otsuka UK on 7 December 2017.  The revised SPCs for the various Abilify formulations were sent to the eMC between 25 January 2018 and 5 February 2018.  The Panel considered that the delay in updating the eMC with the SPC change, which included additional information in Section 4.4 (special warnings and precautions for use) and the addition of new adverse drug reactions to Section 4.8 meant that high standards had not been maintained and a breach of the Code was ruled.  The Panel considered that such failures had potential patient safety implications and noted its comments on Clause 2 and ruling on this matter below.

The Panel was concerned to note Otsuka’s submission that this SPC update would generally have prompted update of promotional material in line with standard SOP timelines (within 6 months of formal approval and not later than implementation of updated PIL in finished product packs).  Revision was carried out in accordance with accelerated timelines only because review of the prescribing information indicated that improvement was needed irrespective of the SPC update. 

The Panel noted that the general principle was that prescribing information must be up-to-date, must comply with the Code and must be consistent with the SPC.

The Panel noted, however, Otsuka’s submission that existing promotional material, which pre-dated the SPC update, was withdrawn on 28 November 2017.  No promotional material was issued between 4 December 2017 (date SPC update approved) and 11 December 2017 (date prescribing information revised).  The Panel, therefore, ruled no breach of the Code.

The Panel noted that there was an update to Section 6.1 of the Abilify oral solution SPC regarding a change of flavour.  The Panel noted Otsuka’s submission that the update did not require European Commission approval; EMA confirmed the validity of the submission and issued a positive opinion on 26 March 2018.

Otsuka Europe Development and Commercialisation communicated the SPC update to Otsuka Europe and Otsuka UK on 28 March.  The update was, however, sent to an individual Otsuka UK employee who was on annual leave at the time rather than to the designated UK regulatory inbox.

Otsuka UK sent the revised SPC to the eMC on 24 April 2018.  The Panel was particularly concerned to note that this delay occurred despite Otsuka’s submission that a task force to implement corrective and preventative measures was put in place in February 2018, after an Otsuka UK employee had raised concerns about the company process in November 2017.  The Panel considered that high standards had not been maintained and ruled a breach of the Code.

The Panel noted that the complainant had not established that the SPC update necessitated a change to the prescribing information.  No breach of the Code was ruled.

The Panel noted Otsuka’s submission that it had reviewed Otsuka UK Jinarc, Samsca, Abilify and Abilify Maintena materials certified from 1 January 2017 and had identified materials that did not contain the latest version of prescribing information and materials that were missing prescribing information.  The Panel noted that Otsuka might have been referring to what it considered to be the latest version of the prescribing information; given its ruling above the Panel considered that what Otsuka considered to be the latest version of prescribing information might not have met the requirements of the Code.  The Panel further queried whether the search criteria adopted by Otsuka captured all affected materials in scope of the complaint.  In relation to the materials that Otsuka submitted did not contain the latest version of prescribing information the Panel considered that in relation to Jinarc its ruling above appeared to cover this matter and it made no further ruling.  In relation to Abilify Maintena materials that Otsuka submitted did not contain the latest version of prescribing information the Panel ruled a breach of the Code.  A breach of the Code was ruled in relation to each of the materials noted above that Otsuka submitted were missing prescribing information.  High standards had not been maintained and a breach of the Code was ruled.  The Panel considered that such failures had potential patient safety implications and noted its comments on Clause 2 and ruling on this matter below.

The Panel noted that it was crucial that health professionals and others could rely upon the industry for up-to-date and accurate information about medicines.  The Panel was concerned to note Otsuka UK’s failures to implement SPC changes and to promptly: update the eMC website; update prescribing information; withdraw materials including promotional material with out-of-date prescribing information; and update and submit material required under the RMP to the MHRA.  The Panel noted its comments above with regard to materials with potential patient safety implications as a result of such failures.

The Panel was particularly concerned about the volume of educational material required under the Jinarc RMP that had not been updated and submitted to the MHRA for approval at the time of Otsuka’s response to this complaint.  The Panel was concerned that Otsuka only appeared to have become aware of this when responding to this complaint and was further concerned that its submission about when the Jinarc dose adjustment for patients taking fluconazole first appeared in the SPC was incorrect.  It was important, and fundamental to self-regulation, that companies submitted accurate information when responding to complaints.

The Panel considered that such failures brought discredit upon, and reduced confidence in, the pharmaceutical industry.  It was crucial that health professionals and others could rely completely upon the industry for up-to-date and accurate information about their medicines particularly new information, the omission of which could potentially impact patient safety.  A breach of Clause 2 was ruled.

The Panel noted that Otsuka was trying to address the issues in question.  Despite such efforts, it was clear that governance issues remained.  The Panel noted the breadth and depth of the company’s compliance difficulties.  In the Panel’s view, it was likely that the compliance issues went beyond matters that arose from the narrow set of materials identified by Otsuka in response to this complaint and beyond matters raised by the complainant.  The Panel noted that its brief review of the company’s SOPs raised further concerns in relation to governance.  In addition, the Panel noted that some Jinarc RMP materials appeared to contain incorrect information.  The Panel considered that its concerns in relation to this case and broader concerns about the company’s governance warranted reporting Otsuka UK to the Appeal Board under Paragraph 8.2 of the Constitution and Procedure for the Appeal Board to consider in relation to Paragraph 11.3 of the Constitution and Procedure.

*     *     *     *     *

Case AUTH/3041/6/18 Otsuka Europe

The Panel noted that Otsuka Europe’s headquarters were based in the UK.  Otsuka Europe was a member of the ABPI and thus obliged to comply with the Code. 

The Panel noted that it was unclear from Otsuka’s submission what actions Otsuka Europe had taken when notified of each SPC update by Otsuka Europe Development and Commercialisation.  It was of concern that no information was given about withdrawal of materials by Otsuka Europe. 

The Panel noted Otsuka’s submission that Otsuka Europe produced and certified the materials it used.  The Panel noted Otsuka’s submission that upon review of all Jinarc, Samsca, Abilify and Abilify Maintena materials certified from 1 January 2017 that required prescribing information and were issued by Otsuka Europe and used in the UK and/or with UK health professionals it identified 7 Jinarc promotional materials issued by Otsuka Europe related to a website that did not contain the latest version of the prescribing information.  The Panel ruled breaches of the Code in relation to each of these materials. 

The Panel noted the complainant bore the burden of proof and had not established that any Samsca material issued by Otsuka Europe since 1 January 2017 contained out-of-date prescribing information.  The Panel thus ruled no breach of the Code.

The Panel noted Otsuka’s submission that it had not identified any Abilify or Abilify Maintena materials issued by Otsuka Europe that did not contain the latest version of prescribing information, however, it had identified two Abilify Maintena materials that were missing prescribing information and a breach of the Code  was ruled in relation to each. 

In the Panel’s view, and noting its rulings above, governance of materials at Otsuka Europe had fallen below acceptable standards.  The Panel considered that high standards had not been maintained and a breach of the Code was ruled.

The Panel noted instances where Otsuka UK had not received prompt communication from Otsuka Europe regarding an SPC update because the notification was sent to the incorrect person or to an individual who was on leave rather than to a designated UK regulatory inbox.  The Panel noted its comments and rulings above in Case AUTH/3042/6/18.  The Panel also considered that certain comments above at Case AUTH/3042/6/18 were relevant in relation to poor governance by Otsuka Europe.  The Panel considered that the failures had potential patient safety implications as noted in Case AUTH/3042/6/18.  It was crucial that health professionals and others could rely completely upon the industry for up-to-date and accurate information about medicines.  The Panel considered on balance that the cumulative effect of its rulings and comments above brought discredit upon and reduced confidence in the pharmaceutical industry and warranted a ruling of a breach of Clause 2 and ruled accordingly.

The Panel considered that, in general, and noting its comments and rulings above, Otsuka Europe’s overall governance in relation to its processes and materials above appeared to be poor.  The Panel noted Otsuka’s submission that processes fell short of expected high standards and the time for remediation was too long.  The Panel was concerned that confirmation of implementation of SPC and PIL updates was apparently not recorded prior to June 2018.

Although it appeared from its submission that Otsuka Europe was trying to address some of the issues in question, the Panel considered that its concerns in relation to this case warranted reporting Otsuka Europe to the Appeal Board under Paragraph 8.2 of the Constitution and Procedure for the Appeal Board to consider in relation to Paragraph 11.3 of the Constitution and Procedure.

The Appeal Board noted the Panel’s comments and rulings of breaches of Clauses of the Code in Cases AUTH/3041/6/18 and AUTH/3042/6/18, including its decision to report Otsuka Europe and Otsuka UK to the Appeal Board.  The Appeal Board noted that Otsuka Europe and Otsuka UK had provided detailed information about their compliance difficulties and they had apologised.

The Appeal Board noted the timelines provided showing European remediation to date from March 2018.  It appeared from questioning the company representatives that little activity had taken place following the internal audit in September 2016 and when the issue was raised internally in November 2017.  It was only after the complaint was made to the PMCPA in June 2018 that action was taken.  This raised concerns about how seriously the company took the issue, its impact on patient safety and the culture at Otsuka.  The company representatives stated that the delay was due to a lack of understanding of the seriousness and importance of the process.  There was a lack of communication across the company.  Senior leaders had apologised to employees.  Speak-up processes had been introduced and more was shared about reporting incidents.

The Appeal Board noted the company’s submission that it recently had another internal audit of its end-to-end processes and it was awaiting that report.  The company representatives referred to the CORE programme which started in February 2019 led by the UK.  The CORE programme had 4 elements; culture and compliance, one organisation, ready for audit and everybody was responsible for compliance.  The company representatives also referred briefly to other issues identified mentioning meetings and congresses.  These would be prioritised.  Otsuka UK referred to a new meetings process.

The Appeal Board was very concerned that an overall failure of governance in relation to Otsuka Europe and Otsuka UK’s processes in implementing SPC changes, updating prescribing information, updating and withdrawing promotional materials, and the update and submission to the MHRA of its risk minimisation materials in a timely manner had potential patient safety implications.  It was crucial that health professionals and others could rely completely upon the industry for up-to-date and accurate information about its medicines.  The Appeal Board noted Otsuka UK and Otsuka Europe’s submission that they were now putting systems and processes in place to address these issues.  The Appeal Board noted the scale of the task but queried whether this was being done sufficiently quickly given the seriousness of the matter.

The Appeal Board decided that in accordance with Paragraph 11.3 of the Constitution and Procedure, Otsuka Europe and Otsuka UK should be publicly reprimanded for the failures to implement SPC changes and update impacted materials in a timely manner which had potential to impact patient safety.  The Appeal Board also decided to require audits of Otsuka Europe and Otsuka UKs’ procedures in relation to the Code in Cases AUTH/3041/6/18 and AUTH/3042/6/18.  These audits should take place by mid July 2019.  The audits would take place at the same time as that required in Case AUTH/3123/11/18.  On receipt of the report of the audits, the Appeal Board would consider whether further sanctions were necessary.

On receipt of the report for the July 2019 audits the Appeal Board was very concerned to note the extent of the companies’ failings including that there was a systemic lack of governance shown by the failure to take action in these cases. Leadership and communication needed to be improved urgently. The governance from Japan to Europe and from Europe to UK needed huge improvement. There appeared to be longstanding failures in this regard, particularly in relation to holding senior individuals to account.

The Appeal Board noted that the report of the audits highlighted a number of concerns including that existing senior staff needed to improve their knowledge and leadership on compliance matters, engage with and ensure that all staff understood its importance. Staff should be helped and encouraged to improve their skills in relation to matters covered by the Code. Significant commitment was required to address the issues.

The Appeal Board noted from the report of the audits that Otsuka Europe had not provided accurate information about the training of the SOPs to the Appeal Board in March 2019 when the reports from the Panel were considered. The Appeal Board noted that self-regulation relied upon, inter alia, the provision of complete and accurate information from pharmaceutical companies. The Appeal Board decided that in accordance with Paragraph 11.3 of the Constitution and Procedure, Otsuka Europe should be publicly reprimanded for providing inaccurate information to the Appeal Board.

The Appeal Board noted Otsuka’s compliance plan and decided that Otsuka should provide a detailed written account of its progress by the end of November 2019. It was vital that swift comprehensive action was taken and noting the failure to take appropriate action over a long period of time, the Appeal Board considered that given the exceptional circumstances of this matter, including the scale and seriousness of the difficulties at Otsuka, it would be helpful if Otsuka representatives attended the December 2019 meeting of the Appeal Board to discuss the progress and future plans. The Appeal Board noted that both Otsuka Europe and Otsuka UK had set themselves a number of compliance objectives and considered that sufficient time would be needed for these to be completed in order for any meaningful progress to be assessed. The Appeal Board decided that both Otsuka Europe and Otsuka UK should be re-audited in early 2020. At its meeting in December the Appeal Board would decide the timing of the re-audits and on receipt of the report for the re-audits it would decide whether further sanctions were necessary.

At its meeting in December 2019 representatives from Otsuka Europe and Otsuka UK attended to discuss the progress and future plans. The companies welcomed the opportunity to provide the Appeal Board and PMCPA with a written account of the activities conducted and progress made since receipt of the report of the audits. The Appeal Board noted that whilst there was a lot of work to be done, a number of activities and actions were completed, planned and/or in process. On the information before it the Appeal Board decided that the re-audits should take place in April 2020 at which point it expected substantial improvements. On receipt of the report for the re-audits it would decide whether further sanctions were necessary.