AUTH/2747/1/15 - Anonymous health professional v Astellas Pharma Europe

Case Summary

​​​An anonymous, non-contactable health professional complained about the arrangements for a meeting organised by Astellas Pharma Europe, in Milan, February 2014. 

The complainant noted that Astellas had invited him/her and colleagues to a meeting in Milan, to obtain advice about prostate cancer. More than 100 other clinicians were at this large advisory board meeting and Astellas presented the benefits of its medicine an unlicensed indication for enzalutamide. The complainant alleged that Astellas was not truthful as to why delegates had been invited to the meeting and the company promoted something it should not have done. 

The detailed response from Astellas Europe is given below. 

The Panel noted that Astellas Europe's submission that the most practical, effective and expedient way to quickly gather a group of advising urologists, oncologists and uro-oncologists from a number of countries with the two expert speakers was to hold the advisory board meetings in one European location, rather than to organise separate advisory boards in individual countries. The Panel considered that holding multiple simultaneous local advisory board meetings overseas, in one central location would not necessarily be unacceptable providing all the aspects complied with the Code. There had to be valid and cogent reasons for holding meetings at venues outside the UK. In this regard, the Panel noted that the UK health professionals were not otherwise attending an international meeting or other event in Milan. The Panel queried whether the availability of the two speakers was an adequate justification given the nature of the meeting and that local experts on the data were available for each advisory board. 

The Panel noted this was the third such meeting held by Astellas. The previous two meetings had taken place before and immediately after the initial marketing authorization of Xtandi in the treatment of adult men with metastatic castration-resistant prostate cancer whose disease had progressed on or after docetaxel therapy. The meeting at issue was held prior to the grant of the marketing authorization for a new indication for the treatment of men with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy was not yet clinically indicated. 

The Panel queried whether the contents of the two previous meetings held in 2012 and 2013 were as distinct as submitted by Astellas. Whilst one advisory board was in the post-chemotherapy indication, the objectives were, nonetheless, similar to the advisory board at issue. Given the advice previously received, the Panel queried whether there remained a bona fide need for advice such as to justify the meeting in question. 

The Panel noted the criteria and process for the selection of experts. The Panel noted that participants at advisory board meetings would reasonably be expected to have sufficient expertise and experience in the relevant disease area that their contribution would be beyond that of simply having experience of treating patients for that particular disease and certainly be relevant to the advice sought by the company. The Panel considered that the number of local experts identified seemed quite large and queried whether participation was driven by who could attend as opposed to who should attend to provide Astellas with appropriate advice. 

Participants were not required to do any prereading or other preparation. The meeting had two distinct sections; the first section lasted just over 2 hours and included presentations from the two speakers on 'The role of the androgen receptor signalling pathway in mCRPC [metastatic castration resistant​ prostate cancer]' and 'Enzalutamide in mCRPC'. Astellas submitted these ensured a common understanding of new treatment options and the Phase 3 data. Both presentations were followed by 25 minute Q&A sessions. The second section of the meeting lasted for 2 hours and 25 minutes. Attendees were split into their respective country/regional advisory board meetings where over 2 hours, 10 minutes they completed two exercises. Firstly, to differentiate enzalutamide from competitors in the proposed target patient population and secondly, to look at current prescribing practice across the patient pathway in mCRPC including where enzalutamide might fit into that pathway now and in the future. 

The Panel noted Astellas' submission that two thirds of the total time was dedicated to seeking advice. This included the two Q&A sessions, which the Panel considered were for the attendees to ask questions such that they were equipped to participate in the advisory boards rather than a means of providing advice to the company. The time allocated for the provision of advice was therefore less than fifty percent of the total meeting time. 

The Panel considered that it would have been helpful if the data could have been sent in advance as pre-reading so that participants could have come prepared to provide advice at the outset. The Panel further noted that Astellas' company attendees included, a data expert for each national advisory board meeting and noted its comments above in this regard about the availability of the speakers. The Panel accepted that it was important that participants understood the data and this might be particularly relevant given the different approaches to treating prostate cancer be that by urologists or oncologists. It was concerned that this was listed as one of the three objectives for the meeting. The Panel noted, however, that the sole purpose of advisory board meetings should be to gain advice from the participants; the presentation of current data should not be the primary reason to attend. 

The Panel examined the meeting report and was concerned to note that 75 questions were raised following the presentations and many of these did not appear to be related to Astellas' submission of the need for a common understanding of the data. Further, the plenary session was rated as the most useful/valuable aspect of the meeting by 38.8% of health professional respondents with the panel discussion scoring 27.1% and the discussion with colleagues from the same country scoring 34.1%. The audience was asked to suggest interesting topics that could be the focus of future meetings. Company feedback included 'ideal opportunity to be with KOLs', '… the advisers provided useful insights', 'they … want to know more relevant information about enzalutamide and research with it' and 'working groups are not always well accepted'. The feedback from both groups included a comment about sending material for pre-reading and further time for discussion. 

The Panel noted that the provision of advice related to the completion of the two exercises. The information provided to each group for the first exercise consisted of a document entitled 'Differentiating enzalutamide in mCRPC' below the heading was the sentence 'Please see below statements, based on the PREVAIL data, to be used as reference during the ranking exercise'. The Panel was concerned about the universally positive nature of the statements in relation to enzalutamide. It appeared that participants were only assessing the impact of potential promotional claims. The second exercise was another group workmat based exercise. The workmat was headed 'Place in patient pathway: Progression on ADT, chemotherapy naïve'. A workmat was to be completed for four treatments. At the end of each exercise the facilitator was instructed to ask whether any other features of enzalutamide that had not been covered were particularly relevant to the UK. There was no mention on any of the materials submitted for the national meeting that the information provided or the data was for an unlicensed indication. 

The Panel considered that as the exercises were to be completed by the UK attendees as a group, consensus would have to be reached to complete the workmats. As such, the views of some of the participants might not be documented or taken into consideration. Further, the Panel noted the exercises could perhaps be carried out individually or prepared individually prior to a joint discussion. Given its comments above, the Panel did not consider that attending the presentations constituted a valid and cogent reason for holding the meeting outside the UK. The Panel was concerned that the time spent obtaining advice was low, less than 50% of the total meeting time and further no preparation was needed. The attendees worked as a group to provide one view. The Panel noted its comments above about the arrangements, content and feedback for the meeting. The Panel did not consider that the arrangements were such that the UK health professionals had attended a genuine advisory board meeting and therefore ruled a breach of the Code. 

The Panel considered that, as it had ruled the arrangements did not meet the criteria for advisory boards, UK health professionals had been paid to attend a meeting where an unlicensed indication was promoted. As Xtandi was licensed in the UK the Panel considered that the arrangements constituted promotion of an unlicensed indication and not promotion of an unlicensed medicine. It therefore ruled no breach of the Code in this regard. It could not make a ruling regarding the promotion of an unlicensed indication as the relevant clause had not been cited by the case preparation manager. 

The Panel noted that UK health professionals had received payment to attend a meeting which the Panel considered promoted the medicine and a breach of the Code was ruled. The Panel considered that the requirement that promotional material and activities must not be disguised had not been met and ruled a breach of the Code. High standards had not been maintained and the Panel ruled a breach of the Code. 

The Panel noted that Clause 2 was reserved for use as a sign of particular censure. The health professionals had attended the meeting believing it was a legitimate advisory board meeting, which was not so. In addition, they had received a payment for attending a promotional meeting for an indication which at the time did not have marketing authorization. The Panel noted that unacceptable payments was listed in the supplementary information to Clause 2 as an example of an activity likely to be in breach of that clause. The Panel considered that the arrangements brought discredit upon and reduced confidence in the pharmaceutical industry. A breach of Clause 2 was ruled. 

The Panel noted its comments and rulings above and considered that its concerns about the arrangements and the company's procedures warranted consideration by the Appeal Board. The Panel thus reported Astellas Europe to the Appeal Board in accordance with Paragraph 8.2 of the Constitution and Procedure. 

The Appeal Board noted the Panel's ruling that the Astellas Europe's Pan-European Uro-oncology Advisory Board Meeting was not a genuine advisory board meeting. The Appeal Board noted that the meeting clearly promoted Xtandi for an unlicensed indication to UK health professionals. In response to a question Astellas Europe stated that the meeting at issue had been held within a few days of the first presentation of the data at a conference. Astellas Europe accepted that the meeting had not met the criteria for advisory boards as required by the Code or its own standard operating procedures (SOPs), and in that regard the Appeal Board was very concerned that either the company's SOPs were not sufficiently clear or had not been followed. The arrangements and material had been certified by Astellas Europe rather than the UK affiliate and in that regard the Appeal Board questioned the rigour of the company's processes and procedures. Improvements needed to be made and should be a priority. The Appeal Board noted that the representatives from Astellas Europe referred on a number of occasions to recognising, with hindsight that its activities could be seen as promotional. The Appeal Board noted Astellas Europe's submission that it had undertaken a number of measures to address the issues. The Appeal Board also noted that the company had accepted all the Panel's rulings of breaches of the Code including Clause 2. 

The Appeal Board was concerned that the UK health professionals had attended the meeting on the understanding that it was an advisory board and had been paid to do so. This was unacceptable. Consequently, the Appeal Board decided, in accordance with Paragraph 11.3 of the Constitution and Procedure to require Astellas Europe to issue a corrective statement to all the UK attendees at the meeting. The corrective statement should refer to the case report. Under Paragraph 11.3 details of the proposed content and mode and timing of dissemination of the corrective statement must be provided to the Appeal Board for approval prior to use.​

CASE AUTH/2747/1/15  ANONYMOUS HEALTH PROFESSIONAL v ASTELLAS PHARMA EUROPE

Arrangements for a meeting

An anonymous, non-contactable health professional complained about the arrangements for a meeting organised by Astellas Pharma Europe, in Milan, February 2014.

The complainant noted that Astellas had invited him/her and colleagues to a meeting in Milan, to obtain advice about prostate cancer.  More than 100 other clinicians were at this large advisory board meeting and Astellas presented the benefits of its medicine an unlicensed indication for enzalutamide.  The complainant alleged that Astellas was not truthful as to why delegates had been invited to the meeting and the company promoted something it should not have done.

The detailed response from Astellas Europe is given below.

The Panel noted that Astellas Europe’s submission that the most practical, effective and expedient way to quickly gather a group of advising urologists, oncologists and uro-oncologists from a number of countries with the two expert speakers was to hold the advisory board meetings in one European location, rather than to organise separate advisory boards in individual countries.  The Panel considered that holding multiple simultaneous local advisory board meetings overseas, in one central location would not necessarily be unacceptable providing all the aspects complied with the Code.  There had to be valid and cogent reasons for holding meetings at venues outside the UK.  In this regard, the Panel noted that the UK health professionals were not otherwise attending an international meeting or other event in Milan.  The Panel queried whether the availability of the two speakers was an adequate justification given the nature of the meeting and that local experts on the data were available for each advisory board. 

The Panel noted this was the third such meeting held by Astellas.  The previous two meetings had taken place before and immediately after the initial marketing authorization of Xtandi in the treatment of adult men with metastatic castration-resistant prostate cancer whose disease had progressed on or after docetaxel therapy.  The meeting at issue was held prior to the grant of the marketing authorization for a new indication for the treatment of men with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy was not yet clinically indicated.

The Panel queried whether the contents of the two previous meetings held in 2012 and 2013 were as distinct as submitted by Astellas.  Whilst one advisory board was in the post-chemotherapy indication, the objectives were, nonetheless, similar to the advisory board at issue.  Given the advice previously received, the Panel queried whether there remained a bona fide need for advice such as to justify the meeting in question.

The Panel noted the criteria and process for the selection of experts.  The Panel noted that participants at advisory board meetings would reasonably be expected to have sufficient expertise and experience in the relevant disease area that their contribution would be beyond that of simply having experience of treating patients for that particular disease and certainly be relevant to the advice sought by the company.  The Panel considered that the number of local experts identified seemed quite large and queried whether participation was driven by who could attend as opposed to who should attend to provide Astellas with appropriate advice.

Participants were not required to do any pre-reading or other preparation.  The meeting had two distinct sections; the first section lasted just over 2 hours and included presentations from the two speakers on ‘The role of the androgen receptor signalling pathway in mCRPC [metastatic castration resistant prostate cancer]’ and ‘Enzalutamide in mCRPC’.  Astellas submitted these ensured a common understanding of new treatment options and the Phase 3 data.  Both presentations were followed by 25 minute Q&A sessions.  The second section of the meeting lasted for 2 hours and 25 minutes.  Attendees were split into their respective country/regional advisory board meetings where over 2 hours, 10 minutes they completed two exercises.  Firstly, to differentiate enzalutamide from competitors in the proposed target patient population and secondly, to look at current prescribing practice across the patient pathway in mCRPC including where enzalutamide might fit into that pathway now and in the future. 

The Panel noted Astellas’ submission that two thirds of the total time was dedicated to seeking advice.  This included the two Q&A sessions, which the Panel considered were for the attendees to ask questions such that they were equipped to participate in the advisory boards rather than a means of providing advice to the company.  The time allocated for the provision of advice was therefore less than fifty percent of the total meeting time. 

The Panel considered that it would have been helpful if the data could have been sent in advance as pre-reading so that participants could have come prepared to provide advice at the outset.  The Panel further noted that Astellas’ company attendees included, a data expert for each national advisory board meeting and noted its comments above in this regard about the availability of the speakers.  The Panel accepted that it was important that participants understood the data and this might be particularly relevant given the different approaches to treating prostate cancer be that by urologists or oncologists.  It was concerned that this was listed as one of the three objectives for the meeting.  The Panel noted, however, that the sole purpose of advisory board meetings should be to gain advice from the participants; the presentation of current data should not be the primary reason to attend.

The Panel examined the meeting report and was concerned to note that 75 questions were raised following the presentations and many of these did not appear to be related to Astellas’ submission of the need for a common understanding of the data.  Further, the plenary session was rated as the most useful/valuable aspect of the meeting by 38.8% of health professional respondents with the panel discussion scoring 27.1% and the discussion with colleagues from the same country scoring 34.1%.  The audience was asked to suggest interesting topics that could be the focus of future meetings.  Company feedback included ‘ideal opportunity to be with KOLs’, ‘… the advisers provided useful insights’, ‘they … want to know more relevant information about enzalutamide and research with it’ and ‘working groups are not always well accepted’.  The feedback from both groups included a comment about sending material for pre-reading and further time for discussion.

The Panel noted that the provision of advice related to the completion of the two exercises.  The information provided to each group for the first exercise consisted of a document entitled ‘Differentiating enzalutamide in mCRPC’ below the heading was the sentence ‘Please see below statements, based on the PREVAIL data, to be used as reference during the ranking exercise’.  The Panel was concerned about the universally positive nature of the statements in relation to enzalutamide.  It appeared that participants were only assessing the impact of potential promotional claims.  The second exercise was another group workmat based exercise.  The workmat was headed ‘Place in patient pathway: Progression on ADT, chemotherapy naïve’.  A workmat was to be completed for four treatments.  At the end of each exercise the facilitator was instructed to ask whether any other features of enzalutamide that had not been covered were particularly relevant to the UK.  There was no mention on any of the materials submitted for the national meeting that the information provided or the data was for an unlicensed indication.

The Panel considered that as the exercises were to be completed by the UK attendees as a group, consensus would have to be reached to complete the workmats.  As such, the views of some of the participants might not be documented or taken into consideration.  Further, the Panel noted the exercises could perhaps be carried out individually or prepared individually prior to a joint discussion.

Given its comments above, the Panel did not consider that attending the presentations constituted a valid and cogent reason for holding the meeting outside the UK.  The Panel was concerned that the time spent obtaining advice was low, less than 50% of the total meeting time and further no preparation was needed.  The attendees worked as a group to provide one view.  The Panel noted its comments above about the arrangements, content and feedback for the meeting.  The Panel did not consider that the arrangements were such that the UK health professionals had attended a genuine advisory board meeting and therefore ruled a breach of the Code.

The Panel considered that, as it had ruled the arrangements did not meet the criteria for advisory boards, UK health professionals had been paid to attend a meeting where an unlicensed indication was promoted.  As Xtandi was licensed in the UK the Panel considered that the arrangements constituted promotion of an unlicensed indication and not promotion of an unlicensed medicine.  It therefore ruled no breach of the Code in this regard.  It could not make a ruling regarding the promotion of an unlicensed indication as the relevant clause had not been cited by the case preparation manager.

The Panel noted that UK health professionals had received payment to attend a meeting which the Panel considered promoted the medicine and a breach of the Code was ruled.  The Panel considered that the requirement that promotional material and activities must not be disguised had not been met and ruled a breach of the Code.

High standards had not been maintained and the Panel ruled a breach of the Code.

The Panel noted that Clause 2 was reserved for use as a sign of particular censure.  The health professionals had attended the meeting believing it was a legitimate advisory board meeting, which was not so.  In addition, they had received a payment for attending a promotional meeting for an indication which at the time did not have marketing authorization.  The Panel noted that unacceptable payments was listed in the supplementary information to Clause 2 as an example of an activity likely to be in breach of that clause.  The Panel considered that the arrangements brought discredit upon and reduced confidence in the pharmaceutical industry.  A breach of Clause 2 was ruled.

The Panel noted its comments and rulings above and considered that its concerns about the arrangements and the company’s procedures warranted consideration by the Appeal Board.  The Panel thus reported Astellas Europe to the Appeal Board in accordance with Paragraph 8.2 of the Constitution and Procedure.

The Appeal Board noted the Panel’s ruling that the Astellas Europe’s Pan-European Uro-oncology Advisory Board Meeting was not a genuine advisory board meeting.  The Appeal Board noted that the meeting clearly promoted Xtandi for an unlicensed indication to UK health professionals.  In response to a question Astellas Europe stated that the meeting at issue had been held within a few days of the first presentation of the data at a conference.  Astellas Europe accepted that the meeting had not met the criteria for advisory boards as required by the Code or its own standard operating procedures (SOPs), and in that regard the Appeal Board was very concerned that either the company’s SOPs were not sufficiently clear or had not been followed.  The arrangements and material had been certified by Astellas Europe rather than the UK affiliate and in that regard the Appeal Board questioned the rigour of the company’s processes and procedures.  Improvements needed to be made and should be a priority.  The Appeal Board noted that the representatives from Astellas Europe referred on a number of occasions to recognising, with hindsight that its activities could be seen as promotional.  The Appeal Board noted Astellas Europe’s submission that it had undertaken a number of measures to address the issues.  The Appeal Board also noted that the company had accepted all the Panel’s rulings of breaches of the Code including Clause 2. 

The Appeal Board was concerned that the UK health professionals had attended the meeting on the understanding that it was an advisory board and had been paid to do so.  This was unacceptable.  Consequently, the Appeal Board decided, in accordance with Paragraph 11.3 of the Constitution and Procedure to require Astellas Europe to issue a corrective statement to all the UK attendees at the meeting.  The corrective statement should refer to the case report.  Under Paragraph 11.3 details of the proposed content and mode and timing of dissemination of the corrective statement must be provided to the Appeal Board for approval prior to use. 

An anonymous, non-contactable health professional complained about the arrangements for a meeting organised by Astellas Pharma Europe, in Milan, in February 2014.

COMPLAINT

The complainant stated that he/she worked with a number of pharmaceutical companies and wished for all of them to act honestly and ethically and in the interests of patients not only profit.  He/she understood that pharmaceutical companies should not promote a medicine before they had full goahead from the regulators with a licence to operate.

The complainant noted that Astellas had invited him/her and his/her colleagues to a meeting at an airport hotel in Milan, Italy on 28 and 29 February 2014 to get their advice at an advisory meeting about prostate cancer.  More than 100 other clinicians were at this large meeting and crucially, Astellas presented the benefits of its new medicine enzalutamide in pre-chemotherapy indication.  The complainant stated that the medicine was not licensed yet by the European Medicines Agency (EMA).

The complainant alleged that with regard to the meeting, Astellas was not truthful as to why delegates had been invited and also the company promoted something it should not have done.

When writing to Astellas, the Authority asked it to consider the requirements of Clauses 2, 3.1, 9.1, 12.1, 18.1 and 20 of the 2014 Code.

RESPONSE

Astellas explained that the meeting at issue was the Pan-European Uro-oncology Advisory Board Meeting.  It was arranged and conducted by Astellas Pharma Europe Ltd which was the regional organisation of Astellas and covered countries in Europe, Middle East and Africa (EMEA).  The European organisation was located on the same site as the UK organisation.  The companies operated as separate legal entities and the response to this complaint was provided by the European organisation.

Astellas Europe stated that it took its commitments with regard to the Code very seriously, and was disappointed that a health professional had complained.  Astellas Europe was committed to addressing all aspects of the complaint and in cooperating fully with the PMCPA to resolve the matter.

The meeting at issue was held on 27/28 February 2014 rather than 28/29 and was the Pan-European Uro-oncology Advisory Board Meeting which consisted of an introductory session and 16 national advisory board meetings.  An agenda was provided.

1            Regulatory status

Astellas Europe submitted that it held the marketing authorization for enzalutamide (Xtandi) which was approved for the treatment of adult men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy in the EU, 21 June 2013, based on the results of the AFFIRM study.  This indication was licensed via the EMA centralised procedure when the invitations were issued and when the meeting took place.

The role of enzalutamide had since been evaluated earlier in the natural history of prostate cancer in the PREVAIL study and results were first reported at the American Society of Clinical Oncology Genitourinary (ASCO-GU) meeting January 2014 in the USA.  These results led to a Type II variation to include an additional indication which was granted a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) on 23 October 2014 and approved by the European Commission on 2 December 2014, ‘… for the treatment of adult men with metastatic castration-resistant prostate cancer who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated’.  The meeting at issue took place after the publication of the PREVAIL results and within the anticipated 6-month window in which the Type II variation adding the chemo-naive indication for enzalutamide was expected to be approved.

The summary of product characteristics (SPC) current when the invitations were issued and the meeting held was provided.  The current SPC was also provided.

2            Objectives of the advisory board meetings

Astellas Europe stated that the objectives of the advisory board meetings were to:

• Present data on enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) in the context of other available and emerging therapies, in order to ensure the experts at the meeting had a consistent level of knowledge of the data and thus could provide Astellas with advice, insight and feedback
• Provide Astellas with further insight into the current and likely future clinical management of mCRPC at a Pan-European level
• Seek expert insight and feedback regarding the potential opportunities and challenges facing enzalutamide as a therapeutic option for mCRPC in a complex market environment in Europe with fundamental questions in each country.

To achieve these objectives the advisory board meetings were set up with a preceding introductory data presentation so that all advisors had a common understanding of new treatment options followed by national advisory boards to enable indepth understanding of country and sub-national differences.

3 Arrangements and logistics

The meeting took place at an airport hotel in Milan, on 27/28 February 2014.  Milan airport was chosen because it was a central location within a short flight time for the majority of European countries.  The 4 star airport hotel helped ensure ease of access for the majority of advisors, as opposed to travelling to an inner city hotel; the meeting facilities and capacity available at the hotel were essential to meet the logistical requirements of the meeting.

As stated previously, enzalutamide was already licensed in Europe for a sub-group of men with prostate cancer when the advisory board meetings took place, based on the AFFIRM study.  Following the results of the PREVAIL study, Astellas had around 6 months in which to gather expert advice with regard to local market access for the additional indication before this indication would likely be approved.  Treatment of prostate cancer was complex with the recent or impending introduction of a number of new therapies and expanded licences which made treatment pathways in each country uncertain.  Astellas invited the European principal investigator of the PREVAIL study and another European expert to present data to the advisors from each country.  Both speakers were global experts with busy schedules and limited availability.

The most practical, effective and expedient way to quickly gather a group of advising urologists, oncologists and uro-oncologists from a number of countries with the two expert speakers was to hold the advisory board meetings in one European location, rather than to organise separate advisory boards in individual countries.  It would not have been logistically viable to have separate meetings with the same expert speakers within the required timeframe.  The arrangements of these advisory board meetings allowed Astellas to ensure the availability of the independent expert speakers.  The arrangements also reduced the burden on the speakers and their clinical commitments by allowing them to make one presentation to each country as part of the introductory session as opposed to attending separate meetings in each country.  Astellas realised that conducting multiple, simultaneous advisory boards was innovative and complex and that any such new approach might attract comment.

The advisory board meetings started on the 28 February with registration from 7:30am and the introductory session commenced at 8:45am.  To avoid the risk of travel disruption and to ensure all advisors were present at the start of the meeting, advisors travelled to arrive by 27 February.  Economy flights were offered to advisors as required, with the exception of those from South Africa who were offered premium economy due to the long travel time.  One expert speaker travelled business class and the other travelled economy in accordance with local compliance requirements.  Train travel was provided as necessary to a few Italian advisors and some Italian and Slovenian advisors travelled by car.  Accommodation was provided for all advisors and speakers in the 4 star venue as necessary to meet travel arrangements.

Dinner (€60/head) for the advisors on 27 February was preceded by a 15 minute introduction to Astellas in order to prepare them for the next day.  This was held in a private room at a restaurant, and they were seated in advisory board/country tables so that the advisors could meet their respective peers and country facilitators.  Arrangements were reviewed and approved locally by each affiliate’s local compliance reviewer.

4 Participants

Astellas Europe stated that two hundred and eighty two advisors received a ‘save the date’ email and of these, 143 received the invitation letter (including the speakers).  The 16 national advisory board meetings were attended by 108 advisors (including speakers) from 23 countries (including 5 UK advisors).  Each advisor was identified by the local affiliate.

Countries outside the EU, in which Astellas Europe affiliates operated and that were involved in the meeting, included Turkey, Russia and South Africa.  These countries were included because all were considering fast track approval options, encompassing the AFFIRM and PREVAIL data.

Affiliates were asked to identify 30 local experts with personal experience of treating patients with mCRPC, and the names of these were grouped based on their clinical expertise into first 10 (15 for Nordic and South East Europe affiliates that cover more than one country), second 10 and third 10 advisors.

• First 10 invitees for each country (15 for Nordic and South East Europe affiliates that cover more than one country) were sent the ‘save the date’ email.
• For each decline, the next name from the list was sent the ‘save the date’ email until 10 potential invitees registered interest in participating in the meetings.
• 10 potential invitees were each sent an invitation Ietter and a copy of the draft agenda for the meetings. The emailed invitation clearly stated the objectives of the meetings and the requirements of their participation.
• When experts confirmed their participation, each had to sign a written contract, clearly outlining the requirements of their participation. A copy of a signed advisory board agreement with a UK health professional was provided.

Astellas Europe provided details of the number of potential invitees, actual recipients of the ‘save the date’ email/ invitation and the actual number of attendees by country.

All advisors were paid €1,000 with the exception of those from South East Europe who were paid €500.  These amounts were commensurate with fair market value assessment by country, following approval by the local compliance reviewer and in accordance with the level of advice and contribution required.  The two expert speakers were each paid €1,500 which included preparation time and the delivery of the services at the advisory board meetings.

The Astellas attendees were from Astellas Europe, Astellas Pharma Global Development (APGD) and the local country affiliates.  Details were provided of Astellas attendees and their respective roles at the event.

Each advisory board meeting was attended by no more than 10 advisors and no more than 3 Astellas employees which consisted of; a facilitator from the relevant affiliate, a data expert and a support person from Astellas, where appropriate and feasible.  The local country affiliate attendees facilitated the individual national groups in their local language.  The data experts provided input concerning the new data on enzalutamide, where requested.  The additional Astellas Europe attendees were present to provide clarification if needed.

5 Content of the advisory board meetings

On the evening of 27 February 2014, a brief introduction to Astellas was presented to prepare the advisors for the next day.  A copy of the presentation was provided.

The advisory board meetings on 28 February 2014 consisted of two key parts, an introductory session and national advisory board meetings.

The introductory session welcomed the advisors and presented the objectives of the meeting.  As stated above, there were two speaker presentations in which data, relevant to the treatment of mCRPC was presented for the purpose of contextualisation so each advisor could provide informed advice in his/ her national advisory board meeting.

The first presentation, ‘Enzalutamide: The role of the androgen receptor signalling in mCRPC’ gave an overview of the mechanism and the importance of the androgen receptor in mCRPC, as well as current and future therapeutic options for CRPC.  The second presentation, ‘Enzalutamide in mCRPC’ covered the epidemiology and natural history of CRPC, the evolution of treatment over time and the current and future treatments available; including enzalutamide (PREVAIL data).  Copies of the presentations were provided.

The data presentations by the speakers were followed by a question and answer session to allow for clarification.  Tablet computers were provided as part of the introductory session in order to facilitate the question and answer session and feedback at the end of the event.  These tablets were restricted and no access was provided to any applications or the Internet and they were returned at the end of the meeting.

The introductory session concluded with a short break before the 16 individual advisory board meetings which accommodated all countries, as well as multi-country groups where appropriate eg countries in South East Europe were grouped where geographically appropriate (Romania, Croatia, Slovenia, Serbia, Bosnia/Herzegovina) and as would normally happen with an advisory board conducted in that region.

In the individual national advisory board meetings, two workmats were provided to facilitate the collection of advice.  There were clear objectives for the advisory board meetings and these were detailed in the staff briefing slides (copy provided) as below:

Session 1 (differentiating enzalutamide in mCRPC):

• To gain advice on key clinical features and evidence differentiating enzalutamide from competitors in the proposed target patient population

Session 2 (mCRPC patient journey and profiles):

• To determine current treatment prescribing practice across the patient pathway in mCRPC
• To identify where enzalutamide might fit into that pathway, now and in the future.

These were essential outputs of these advisory board meetings and advisors would not have been paid without active participation.

The programme on 28 February consisted of 5 hours in total (including a break of 30 minutes).  Presentation time was 1 hour, 30 minutes and advice seeking/discussion time was 3 hours.  Two thirds of the total time (excluding break) was dedicated to seeking advice.

The meeting closed at 1:45pm which allowed the advisors to return home in good time to be back at work as soon as possible in order to limit the burden on their workload and patient care responsibilities.

6 Response to complaint

Astellas Europe noted that the complaint had been submitted almost a year after the non-promotional advisory board meetings and outlined four areas of concern:

-             ‘... to act in an honest and ethical way and in the interests of patients not only profit ...’

-             ‘... that pharmaceutical companies should not promote a medicine before they have full goahead from the regulators with a licence to operate’.

-             The arrangements of the meeting were inappropriate.

-             The invitation was misleading ‘... Astellas was not truthful as to why delegates had been invited and also the company promoted something it should not have done’.

Clause 3.1 – A medicine must not be promoted prior to the grant of the marketing authorization which permits its sale or supply

Astellas Europe submitted that the advisory board meetings were non-promotional, scientific/medicalled meetings with an agenda focussed on legitimate scientific exchange about the treatment of mCRPC.

The rationale and objectives for the advisory board meetings were outlined above.  The advice gained was critical given the dynamic nature of mCRPC with recent approval of three new treatments, representing three different treatment modalities namely a chemotherapeutic agent, an androgensynthesis inhibitor and a radio-pharmaceutical agent.  The meeting approval form for the advisory board meetings and the agenda confirmed the intent and purpose of the meetings, namely scientific exchange prior to the pending additional indication of enzalutamide.  This exchange was essential given the variation in the management of prostate cancer across Europe, the Middle East and Africa eg in Germany the care was led by urologists, whereas in other countries such as the UK, guidelines advocated close cooperation between urologists and oncologists as part of multi-disciplinary teams.  The AFFIRM study was an oncologist-led study whereas

PREVAIL was a urologist-led study.  It behoved Astellas, as the marketing authorization holder, to understand the clinical practice patterns across countries and be guided as how to responsibly engage with the lead clinicians and ensure seamless patient transition from urologists to oncologists as appropriate to the stage of the disease.

As stated above, clinical data on enzalutamide and other treatments (abiraterone, radium-223, docetaxel) was provided in the introductory session for the purpose of contextualisation so each advisor could provide informed advice in the individual national advisory board meetings.  This was essential in order to achieve the objectives of the national advisory board meetings.

The meetings structure and medical leadership were further evidence that this was not, and should not be perceived as a promotional meeting.  The workshop materials and outputs (copies provided) were examples of the input/advice gathered from the advisors.

For the reasons stated above Astellas Europe denied a breach of Clause 3.1.

Clause 12.1 – Promotional material and activities must not be disguised

Astellas Europe submitted that the meeting invitation was clear in terms of intention, and outlined the objectives of the advisory board meetings which were non-promotional.  The advice given was captured and was the basis for the fee for service.  The scientific exchange at the advisory board meetings was essential, given the variation in the management of prostate cancer across the EMEA region.

The format consisted of 16 separate national advisory board meetings, which provided answers unique to practices within each country regarding the treatment of mCRPC and market access needs.  Each advisory board was held in a separate room with no more than 10 advisors.

As stated above, the most practical, effective and expedient way to quickly gather a group of urologists, oncologists and uro-oncologists from a number countries with the two expert speakers was to hold the advisory board meetings in one European location, rather than organise separate advisory boards in individual countries.  The arrangements were reviewed and approved by the affiliate local compliance reviewers.

On 27 February 2014 a brief historical overview of Astellas and its background, structure, therapy areas and products was provided to the participants.  This also continued on 28 February with ‘Welcome, Objectives and Agenda’ from Astellas.

Both presentations made by the speakers on 28 February were based on bona fide medical and scientific subject matter and were accurate, balanced, fair and objective for the purpose of the advisory boards.  The clinical data presented was essential to meet the stated objectives of the advisory board meetings and was thus acceptable in this setting.

For the reasons stated above, Astellas Europe submitted that the advisory board meetings were not in breach of Clause 12.1.

Clause 18.1 – Payments to individuals and Clause 20 – The Use of Consultants

Astellas Europe submitted that the advisory board meetings were a bona fide non-promotional activity as explained under Clause 12.1 above and each advisor was paid a fee commensurate with fair market value within their local country.  The fees were based on the time to perform services, the technical complexity of services and responsibility assumed by the advisors.  The services provided were preparing for and attending the advisory board, performing the duties of an advisory board member such as to actively participate in the discussion during the advisory board meeting and periodic and ancillary consultancy as required for clarification following the event.

Each advisor had a written contract and was selected based on the criteria outlined above.  There was a legitimate need for the advisors’ services based on the objectives of the advisory board meetings and above.

The format consisted of 16 separate national advisory board meetings which provided answers unique to practices within each country regarding the treatment of mCRPC and market access needs.  Each advisory board meeting was held in a separate room with no more than 10 advisors.

The country affiliate facilitators wrote reports following the individual advisory boards to inform their market access plans and local treatment pathways and options by considering how the data from the enzalutamide, abiraterone and radium-223 Phase III trials could impact everyday clinical practice decisions.  At a regional level the reports highlighted differences across countries (eg treating physician and pathway, treatment options and clinical definition of progression, market access conditions) which assisted in customising regional support to the local affiliates (eg provision of supporting medical materials, answers to frequently asked questions).

Astellas Europe thus submitted that the advisory board meetings were not an inducement to prescribe and they met the requirements of Clause 20 and thus were not in breach of Clauses 18.1 or 20.

Clause 9.1 – High standards must be maintained at all times and

Clause 2 – Discredit to and reduction of confidence in the Industry

Based on the above, Astellas Europe submitted that high standards had been maintained.  The advisory board meetings were not an inducement to prescribe, nor were they promotion prior to the grant of a marketing authorization.  Astellas thus denied a breach of Clauses 9.1 or 2.

Summary

Astellas Europe recognised that as with any innovation, there might be areas open to interpretation.  However, it strove for continuous improvement in order to ensure that its business operations were carried out in a robust, efficient and compliant manner.

The company’s intention was to achieve a pragmatic approach to a complex challenge, to seek and obtain high quality advice in a complicated and rapidly changing clinical environment across a number of European and a few key non-EU countries as efficiently as possible, given the estimated regulatory timelines.  It believed that it achieved this in a compliant manner and it was disappointing to receive a complaint.  Astellas Europe took

its responsibilities with regard to the Code very seriously and it hoped that the Panel agreed that it had not breached any of the stated clauses of the Code.

Astellas Europe responded to a request for further information as follows.

1            What preparation work was required of the attendees prior to the meeting?

Astellas Europe stated it was expected that the advisors would review the objectives outlined in the invitation and come to the meeting prepared to participate and contribute to the meeting with advice pertinent to the practice in their country.  On this occasion, no preparatory materials were provided and advisors were compensated in consideration for their participation and contribution to the meeting.  The amounts were commensurate with fair market value assessment by country, following approval by the local compliance reviewer and in accordance with the level of advice and contribution required.

The expert speakers prepared slides and presented at the meeting.  In addition, they both participated in their respective national advisory board meetings.  The expert speakers were compensated in consideration for their preparation time, participation and contribution to the meeting.  The amounts were commensurate with fair market value assessment by country, following approval by the local compliance reviewer and in accordance with the level of advice and contribution required.

2            Information about the objective, content, arrangements and attendees of the two meetings previously held, Barcelona, November 2012 and Frankfurt July 2013

Astellas Europe stated it in-licensed enzalutamide in October 2009 and tivozanib in February 2011.  These products were Astellas’ first products launched in oncology.

The Astellas Europe EMEA regional oncology business unit was formed in May 2011 and the organisation was building capabilities in anticipation of these two new in-licensed products being launched in 2014.  The oncology organisation in the local affiliates was being scaled-up in line with the anticipated original approval and launch timescale.  Original assumptions were for approval and then launches starting in Q2 2014 for enzalutamide in the post-chemotherapy indication.  Tivozanib was estimated for approval in Q4 2013.  Based on statistically significant improvement in overall survival shown in the interim results of the enzalutamide AFFIRM phase III study in November 2011, the independent data monitoring committee recommended the study be stopped early.  This allowed Astellas to apply for regulatory approval of the post-chemotherapy indication earlier than anticipated.  A schematic showing the outline of timings related to enzalutamide and tivozanib was provided.

Astellas Europe submitted it took a pragmatic and efficient approach in leading the preparation across the EMEA region to seek advice through these innovative advisory board meetings in a consistent and compliant way, as mentioned above the affiliates were being scaled up.

The comment on a briefing slide that this was the third meeting of this type related to the fact that this was the third time this framework (namely introductory expert presentations followed by parallel individual advisory boards) had been used and not that there were three meetings with identical content.  The topics for each meeting were different and summarised as follows:

Meeting November 2012 – to seek advice on best practice in clinical management of advanced renal cell carcinoma (RCC) and castrate resistant prostate cancer relating to tivozanib and enzalutamide respectively.

Meeting July 2013 – to seek advice on enzalutamide in metastatic castrate resistant prostate cancer following the first approval of enzalutamide in the post-chemotherapy indication and how enzalutamide could be introduced into clinical practice in the light of the changing treatment landscape.

Meeting February 2014 – to seek advice on enzalutamide in metastatic castrate resistant prostate cancer relating to the additional chemonaive indication.  This meeting was the subject of the complaint.

These were distinct and separate meetings with a common format.  The objectives, content and attendees were different and further details were provided.  The overall intention of Astellas was to act in a responsible manner in the best interests of physicians and patients.

1. a) Pan-European Uro-oncology Advisory Board - 15 November 2012, Barcelona

Astellas Europe stated that this advisory board covered renal cell carcinoma (RCC) and prostate cancer with the objective to receive initial advice regarding the challenges facing tivozanib and enzalutamide in Europe in the run up to and immediately post launch.  This advice was critical at that time as these products would be Astellas’ first products launched to the oncology healthcare community and Astellas needed to understand the impact of these alongside currently available and new therapies in the major countries in Europe. 

Objectives

• To help Astellas put data on enzalutamide in castrate-resistant prostate cancer (CRPC) and tivozanib in advanced renal cell carcinoma in

context of other available and emerging therapies

 

• To help Astellas gain further insight into the current and likely future clinical management of CRPC and advanced RCC at a European level
• To receive advice regarding the challenges facing enzalutamide and tivozanib in Europe in the run up to and immediately post launch.

Arrangements

The meeting was held in Barcelona, Spain, in a 4 star hotel, which was one of the congress hotels for the European Multidisciplinary Meeting on Urological Cancers (EMUC) congress which took place in Barcelona immediately following this meeting.  The meeting ran from 5pm to 9pm followed by a dinner.  Accommodation and subsistence were provided.

Economy flights, or train travel were provided, with the exception of one speaker who flew business class from Germany.

Introductory session expert speakers were paid a fee for service of €1750 each, whilst the advisors received fees of €1000, with the exception of the UK advisors who received €750.  In the cases where there was a co-chair in the individual country advisory boards, these received a fee of €1500, with the exception of the UK who received €1000.  The fees were commensurate with country fair market value and approved by local compliance reviewers.

Attendees

The expert speakers were named.  A total of 53 advisors attended from UK, Germany, Italy, France and Spain.  These were oncologists, uro-oncologists and clinical researchers.  These advisors were selected from countries that represented Astellas’ five major European affiliates.

Astellas attendees were from the UK, Germany, Italy, France and Spain affiliates and Astellas Europe.  Astellas Europe attendees did not participate in the affiliate advisory boards.  

Content

The subject of the meeting was RCC and metastatic CRPC, and the country working group advisors attended an introductory session with presentations on two different pipeline products in the therapy areas stated above, prior to country-specific workshops in their local language led by the local Astellas affiliate and a local expert co-chair.

The workshops covered both cancer types and were designed for the advisors to provide advice on the key issues and challenges Astellas would face in launching these two products in oncology, both from a product perspective and as a company new to this area.  

The meeting consisted of a total duration of 240 minutes, including a break of 20 minutes, with an introductory session and individual country workshop sessions.   

The introductory session consisted of a welcome and agenda overview, an introduction to Astellas and two external speaker presentations, one on enzalutamide in CRPC in the post-chemotherapy indication based on the results of the AFFIRM study, and the other on tivozanib in advanced RCC, plus two short Q&A sessions for clarification on the presentations.

The national workshop sessions consisted of 5 separate individual country-specific workshops consisting of a short introduction and objectives prior to seeking advice on the above topics.

1. b) Pan-European Uro-oncology Expert Meeting - 3-4 July 2013, Frankfurt

Astellas Europe stated that this advisory board was conducted in order to receive advice specifically regarding the potential opportunities and challenges facing enzalutamide in Europe following first EMA approval in June 2013 for the treatment of adult men with metastatic castration-resistant prostate cancer whose disease had progressed on or after docetaxel therapy (the post-chemotherapy indication based on the results of the AFFIRM study).

Objectives

• To enable Astellas to frame the data on enzalutamide in CRPC in the context of other available and emerging therapies
• To provide Astellas with further insight into the current and likely future clinical management of CRPC at a European level
• To receive advice regarding the potential opportunities and challenges facing enzalutamide in Europe following EMA approval.

Arrangements

The meeting was held at a 4 star Frankfurt Airport Hotel, due to the city’s central location and the hotel’s proximity to the airport, to help ensure ease of access for the advisors.  Overnight accommodation and subsistence were provided.

The advisors arrived on 3 July in order to avoid the risk of travel disruption and to ensure all advisors were present at the start of the meeting.  The meeting on 4 July started at 8.40am following registration and collection of iPads (for Q&A sessions) and closed at 1:30pm.

Economy flights, or train travel were provided, with the exception of the two speakers who travelled business class.

The introductory session speakers were paid a fee for service of €1500 each, whilst the advisors received fees of €1000.  These fees were commensurate with country fair market value and approved by local compliance reviewers.

Attendees

The expert speakers were named.  A total of 61 advisors attended from Austria, Czech Republic & Slovakia, Germany, Greece/Cyprus, Ireland, Netherlands, Nordics, Poland, Switzerland and UK. 

These advisors were oncologists and uro-oncologists and were selected for their expertise in prostate cancer from the countries that would be first to launch enzalutamide in the post-chemotherapy setting.

Astellas attendees were from the affiliates in Austria, Czech Republic & Slovakia, Germany, Greece, Netherlands, Nordics, Poland, Switzerland, UK and Astellas Europe.

Content

The meeting consisted of a total duration of 290 minutes, including a break of 15 minutes, with an introductory session and international working group sessions.  

The introductory session consisted of a welcome and agenda, an introduction to Astellas and two external speaker presentations, one on the biology of androgen receptor signalling (‘CRPC: the rationale for targeting the androgen receptor’) and the other on ‘Enzalutamide: directly targeting the androgen receptor in mCRPC’, plus two Q&A sessions for clarification on the presentations.

There were 5 international working group sessions, each consisting of a selection of advisors from Austria, Czech Republic & Slovakia, Germany, Greece/Cyprus, Ireland, Netherlands, Nordics, Poland, Switzerland and UK, seeking advice on the above topics.

The international working group sessions began with a short introduction and objectives prior to the advisors carrying out an analysis for enzalutamide in the post-chemotherapy setting and providing an understanding of the differences and similarities across multiple European countries.  This was followed by an exercise where the advisors were asked to consolidate this analysis and decide which of the components listed were most important and should be taken through to the implementation exercise.  This exercise sought advice on practical activities/programmes that Astellas could use to support the launch of enzalutamide across Europe taking into consideration the opportunities and challenges identified previously.

3            Briefing materials for one of the speakers at the meeting in        question

Astellas Europe stated that one of the speakers was provided with a verbal briefing similar to the slide deck presented to the other speaker. 

4            How did attendees from South Africa contribute to the opportunities and challenges within Europe?

APEL, the regional headquarters organisation of Astellas, covered countries in Europe, Middle East and Africa (EMEA).  Countries outside the EU, in which Astellas EMEA affiliates operated and that were involved in the meeting, included South Africa.  The rationale for including South Africa was because the country was considering fast track approval options, encompassing the AFFIRM (post chemotherapy) and PREVAIL (chemo-naïve) data.  Launch timings of enzalutamide in South Africa had the potential to be accelerated by approximately 2 years based on a new electronic regulatory submission process.  Astellas therefore required the same considerations and advice from South African health professionals as from its other European advisors at that time.

At a regional level the final report highlighted differences across countries (eg treating physician and pathway, treatment options and clinical definition of progression, market access conditions) which assisted in customising regional support to the local affiliates (eg provision of supporting medical materials, answers to frequently asked questions) including South Africa.

5            Was a summary or outputs provided to the attendees following the meeting?

Astellas Europe stated that no meeting summary or outputs were provided to the advisors.

PANEL RULING

The Panel noted that the complainant was anonymous and non-contactable.  As stated in the introduction to the Constitution and Procedures such complaints were accepted and like all complaints, judged on the evidence provided by the parties.  Complainants had the burden of proving their complaint on the balance of probabilities.

The Panel noted that it was acceptable for companies to pay health professionals and others for relevant advice.  Nonetheless, the arrangements for such meetings had to comply with the Code, particularly Clause 20.  To be considered a legitimate advisory board the choice and number of participants should stand up to independent scrutiny; each should be chosen according to their expertise such that they would be able to contribute meaningfully to the purpose and expected outcomes of the advisory board.  The number of participants should be limited so as to allow active participation by all.  The agenda should allow adequate time for discussion.  The number of meetings and the number of participants should be driven by need and not the invitees’ willingness to attend.  Invitations to participate should state the purpose of the advisory board meeting, the expected advisory role and the amount of work to be undertaken.  If an honorarium was offered it should be made clear that it was a payment for such work and advice.  Honoraria must be reasonable and reflect the fair market value of the time and effort involved.

The Panel noted the complainant alleged that he/ she had been invited to attend an advisory board meeting on prostate cancer however, the advisory board was attended by more than 100 other clinicians and was more like a large meeting than an advisory board.  Astellas Europe submitted that the most practical, effective and expedient way to quickly gather a group of advising urologists, oncologists and uro-oncologists from a number of countries with the two expert speakers was to hold the advisory board meetings in one European location, rather than to organise separate advisory boards in individual countries.  Astellas stated that it would not have been logistically viable to have separate meetings with the same expert speakers within the required timeframe.  Astellas stated that the arrangements allowed it to ensure the availability of the expert speakers and reduce the burden on them.  The Panel considered that holding multiple simultaneous local advisory board meetings overseas, in one central location would not necessarily be unacceptable providing all the aspects complied with the Code.  As stated in the supplementary information to Clause 19, Meetings and Hospitality, there had to be valid and cogent reasons for holding meetings at venues outside the UK.  In this regard, the Panel noted that the UK health professionals were not otherwise attending an international meeting or other event in Milan.  In the particular circumstances of this case, the Panel queried whether the availability of the two speakers was an adequate justification given the nature of the meeting and that local experts on the data were available for each advisory board.  The Panel was only considering the overall acceptability of the arrangements for the meeting in February 2014 in relation to UK health professionals.

The Panel noted this was the third such meeting held by Astellas.  The previous two meetings had taken place before and immediately after the initial marketing authorization of Xtandi in the treatment of adult men with metastatic castration-resistant prostate cancer whose disease had progressed on or after docetaxel therapy.  The meeting at issue was held prior to the grant of the marketing authorization for a new indication for the treatment of adult men with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy was not yet clinically indicated.

The Panel queried whether the contents of the two previous meetings held in 2012 and 2013 were as distinct as submitted by Astellas.  The objectives of both included enabling Astellas to frame data on enzalutamide in CRPC in the context of other available and emerging therapies and to provide insight into the current and likely future clinical management of CRPC at a European level and advice on the potential European opportunities and challenges.  Whilst one advisory board was in the post-chemotherapy indication, the objectives were, nonetheless, similar to the advisory board at issue.  Given the advice previously received, the Panel queried whether there remained a bona fide need for advice such as to justify the meeting in question.

The Panel noted the criteria and process for the selection of experts.  Affiliates were asked to identify 30 local experts with personal experience of treating patients with mCRPC, and the names of these were grouped, based on their clinical expertise.  The first 10 participants for each country (15 for Nordic and South East Europe affiliates that covered more than one country) were sent a ‘save the date’ email.  For each decline, the next name on the list for the respective country was invited until 10 participants registered interest in attending from each country who were each sent an email invitation letter, including information on the honorarium and a copy of the draft agenda.  Upon confirmation each advisor was required to sign a contract which stated that advisors were required to actively participate in the discussion during the advisory board meeting.  The Panel noted that participants at advisory board meetings would reasonably be expected to have sufficient expertise and experience in the relevant disease area that their contribution would be beyond that of simply having experience of treating patients for that particular disease and certainly be relevant to the advice sought by the company.  The Panel considered that the number of local experts identified seemed quite large and queried whether participation was driven by who could attend as opposed to who should attend to provide Astellas with appropriate advice.

The Panel examined the agenda.  Participants were not required to do any pre-reading or other preparation.  The meeting had two distinct sections; the first section lasted just over 2 hours and included presentations from the two speakers on ‘The role of the androgen receptor signalling pathway in mCRPC’ and ‘Enzalutamide in mCRPC’.  Astellas submitted these ensured all advisors had a common understanding of new treatment options and the Phase 3 data for enzalutamide.  Both presentations were followed by 25 minute Q&A sessions.  The second section of the meeting lasted for 2 hours and 25 minutes.  Attendees were split into their respective country/regional advisory board meetings where they completed two exercises.  Firstly, to differentiate enzalutamide from competitors in the proposed target patient population and secondly, to look at current prescribing practice across the patient pathway in mCRPC including where enzalutamide might fit into that pathway now and in the future.  The total time allowed for the two exercises was 2 hours and 10 minutes.

The Panel noted Astellas’ submission that two thirds of the total time (excluding breaks) was dedicated to seeking advice.  This included the two Q&A sessions, which followed the presentations.  The Panel considered that the Q&A sessions were for the attendees to ask questions such that they were equipped to participate in the advisory boards rather than a means of providing advice to the company.  The time allocated for the attendees to provide advice was therefore less than fifty percent of the total meeting time. 

The Panel considered that it would have been helpful if the data, or a summary thereof, could have been sent in advance as pre-reading so that participants could have come prepared to provide advice at the outset.  The Panel further noted that Astellas’ company attendees included, inter alia, a data expert for each national advisory board meeting and noted its comments above in this regard about the availability of the speakers.  The Panel accepted that it was important that participants understood the data and this might be particularly relevant given the different approaches to treating prostate cancer be that by urologists or oncologists.  It was concerned that this was listed as one of the three objectives for the meeting.  The Panel noted, however, that the sole purpose of advisory board meetings should be to gain advice from the participants; the presentation of current data by eminent speakers should not be the primary reason participants wanted to attend.

The Panel noted that all attendees were asked to complete a survey evaluating the meeting.  The Panel examined the meeting report and was concerned to note that 75 questions were raised following the presentations and many of these did not appear to be related to Astellas’ submission of the need for a common understanding of the data.  Further, the plenary session was rated as the most useful/valuable aspect of the meeting by 38.8% of health professional respondents with the panel discussion scoring 27.1% and the discussion with colleagues from the same country scoring 34.1%.  The audience was asked to suggest interesting topics that could be the focus of future meetings.  Company feedback included ‘ideal opportunity to be with KOLs’, ‘… the advisers provided useful insights’, ‘they … want to know more relevant information about enzalutamide and research with it’ and ‘working groups are not always well accepted’.  The feedback from both groups included a comment about sending material for pre-reading and further time for discussion.

The Panel noted that the provision of advice related to the completion of the two exercises.  The information provided to each group for the first exercise consisted of a document entitled ‘Differentiating enzalutamide in mCRPC’ below the heading was the sentence ‘Please see below statements, based on the PREVAIL data, to be used as reference during the ranking exercise’.  A table was provided with ten categories; these being Mechanism of action, Overall survival, Radiographic

Progression-Free Survival (PFS), Time to Prostate-Specific Antigen (PSA) progression, ProstateSpecific Antigen response, Objective soft tissue response, Quality of life, Adverse events, Time to chemotherapy and Convenience.  For each of the categories a positive statement for enzalutamide, based on the PREVAIL study, was provided.  The participants were to complete group workmats ranking each of the categories and associated statements as having high, moderate or low impact to differentiate enzalutamide from competitors in the proposed target population.  The Panel was concerned about the universally positive nature of the statements.  It appeared that participants were only assessing the impact of potential promotional claims.

The second exercise was another group workmat based exercise.  The workmat was headed ‘Place in patient pathway: Progression on ADT, chemotherapy naïve’.  A workmat was to be completed for each of the following treatments (in the following order), docetaxel/cabazitaxel, enzalutamide, abiraterone and radium-223 (if time allowed).  The workmat consisted of five sections: patient factors that would make them a candidate for the treatment, disease factors; factors concerning the patient’s disease state that would make them a candidate for this treatment.  Both of these sections also required the group to rank the factors given.  The other three sections were: exclusions; factors which would exclude a patient from treatment with this agent if the above criteria were met, and two sections for competitor considerations; to add two factors which would preclude this alternative treatment from being used in the patient described above.  At the end of each exercise the facilitator was instructed to ask whether any other features of enzalutamide that had not been covered were particularly relevant to the UK healthcare system.  The Panel noted there was no mention on any of the materials submitted for the national advisory board meetings that the information provided or the data was for an unlicensed indication.

The Panel considered that as the exercises were to be completed by the UK attendees as a group, consensus would have to be reached to complete the workmats.  As such, the views of some of the participants might not be documented or taken into consideration.  Further, the Panel noted the exercises could perhaps be carried out individually or prepared individually prior to a joint discussion.

The meeting for UK health professionals was held outside the UK and, as noted above, there had to be valid and cogent reasons for holding such meetings outside the UK.  Given its comments above, the Panel did not consider that attending the presentations constituted a valid and cogent reason for holding the meeting outside the UK.  The Panel was concerned that the time spent obtaining advice was low, less than 50% of the total meeting time and further no preparation was needed.  The attendees worked as a group to provide one view.  The Panel noted its comments above about the arrangements, content and feedback for the meeting.  Taking all the factors into account the Panel did not consider that the arrangements were such that the UK health professionals had attended a genuine advisory board meeting.  It therefore ruled a breach of Clause 20.1.

The Panel considered that, as it had ruled the arrangements did not meet the criteria for advisory boards, UK health professionals had been paid to attend a meeting where an unlicensed indication was promoted.  As Xtandi was licensed in the UK the Panel considered that the arrangements constituted promotion of an unlicensed indication and not promotion of an unlicensed medicine.  It therefore ruled no breach of Clause 3.1.  It could not make a ruling regarding Clause 3.2 which prohibited promotion of an unlicensed indication as this had not been cited by the case preparation manager.

The Panel noted that UK health professionals had received payment to attend a meeting which the Panel considered promoted the medicine.  This was contrary to requirements of Clause 18.1 and a breach of that Clause was ruled.  The Panel considered that the requirement that promotional material and activities must not be disguised had not been met and ruled a breach of Clause 12.1.

The Panel considered that, overall, high standards had not been maintained and a breach of Clause 9.1 was ruled.

The Panel noted that Clause 2 was reserved for use as a sign of particular censure.  The health professionals had attended the meeting believing it was a legitimate advisory board meeting, which was not so.  In addition, they had received a payment for attending a promotional meeting for an indication which at the time did not have marketing authorization.  The Panel noted that unacceptable payments was listed in the supplementary information to Clause 2 as an example of an activity likely to be in breach of that Clause.  The Panel considered that the arrangements brought discredit upon and reduced confidence in the pharmaceutical industry.  A breach of Clause 2 was ruled.

The Panel noted its comments and rulings above and considered that its concerns about the arrangements and the company’s procedures warranted consideration by the Appeal Board.  The Panel thus reported Astellas Europe to the Appeal Board in accordance with Paragraph 8.2 of the Constitution and Procedure.

COMMENTS FROM ASTELLAS EUROPE ON THE REPORT FROM THE PANEL

At the consideration of the report the representatives from Astellas Europe stated that the company recognised that the execution of the Pan-European Advisory Board should have been conducted to a higher standard and it did not meet the criteria for advisory boards, as required by the Code and documented in its standard operating procedures (SOPs).  Astellas Europe accepted the Panel’s rulings of breaches of the Code and deeply regretted that it had brought disrepute on the pharmaceutical industry.

The company stated that it had already undertaken a number of measures and gave details of its key compliance activities since 2014.  These included the move of healthcare compliance to the legal department to become the Legal and Compliance Department; growth of the compliance team; updated/new regional policies and procedures including advisory boards; rollout of a global policy for review of materials used to promote to health professionals; Legal and Compliance day; quarterly compliance updates; final signatory training; in-house PMCPA seminar; 2015 Code update; revised ZINC process and system training; regional Healthcare Compliance and reporting workshop; face-to-face/on-line training on new regional policies and SOPs; internal monitoring of compliance review and approval process; communication cascade of the Panel’s ruling including the affiliate teams; further case review at quarterly compliance updates; planned training on advisory boards including details of this case including the UK affiliate and the agencies involved in the meeting at issue.  Astellas Europe stated it was committed to continual improvement of compliance activities and standards.

APPEAL BOARD CONSIDERATION OF THE REPORT FROM THE PANEL

The Appeal Board noted the Panel’s ruling that the Astellas Europe’s Pan-European Uro-oncology Advisory Board Meeting was not a genuine advisory board meeting.  The Appeal Board noted that the meeting clearly promoted Xtandi for an unlicensed indication to UK health professionals.  In response to a question the representatives from Astellas Europe stated that the meeting at issue had been held within a few days of the first presentation of the data at a conference.  Astellas Europe accepted that the meeting had not met the criteria for advisory boards as required by the Code or its own SOPs, and in that regard the Appeal Board was very concerned that either the company’s SOPs were not sufficiently clear or had not been followed.  The arrangements and material had been certified by Astellas Europe rather than the UK affiliate and in that regard the Appeal Board questioned the rigour of the company’s processes and procedures.  Improvements needed to be made and should be a priority.  The Appeal Board noted that the representatives from Astellas Europe referred on a number of occasions to recognising, with hindsight that its activities could be seen as promotional.  The Appeal Board noted Astellas Europe’s submission that it had undertaken a number of measures to address the issues.  The Appeal Board also noted that the company had accepted all the Panel’s rulings of breaches of the Code including Clause 2. 

The Appeal Board was concerned that the UK health professionals had attended the meeting on the understanding that it was an advisory board and had been paid to do so.  This was unacceptable.  Consequently, the Appeal Board decided, in accordance with Paragraph 11.3 of the Constitution and Procedure, to require Astellas Europe to issue a corrective statement to all the UK attendees at the meeting.  The corrective statement should refer to the case report.  Under Paragraph 11.3 details of the proposed content and mode and timing of dissemination of the corrective statement must be provided to the Appeal Board for approval prior to use. 

Complaint received                      14 January 2015

Undertaking received                  14 April 2015

Appeal Board consideration       14 May 2015

Corrective statement issued      1 July 2015

Case completed                            14 May 2015