Case title: How the European Medicines Agency (EMA) organised a re-examination of an application for a marketing authorisation of a medicinal product for treating age-related macular degeneration

Date: Monday, 10 July 2023

Remote inspection arrangements

Conference call during which the EMA representatives presented the documents that had been identified as forming part of its response to an alert received from the complainant. No copies of these documents were shared with the Ombudsman.

Present

European Medicines Agency:

Head of Litigation Office

Legal Administrator, Litigation Office

Scientific Administrator, Meeting Secretariat Office

European Ombudsman

Jennifer King, Legal Expert

Koen Roovers, Inquiries Officer

Purpose of the inspection meeting

The purpose of the meeting was for the Ombudsman’s inquiry team to inspect any documents EMA holds on:

I. How it followed up on the alert it received from the complainant concerning an alleged undeclared interest of one of the Ad Hoc Advisory Group (AHEG) members, including EMA's assessment of the interest in question;

II. Its assessment as regards the breach of trust procedure in the context of the interest in question;

III. The AHEG’s response to sub-question 3 of the list of questions to the Committee for Medicinal Products for Human Use (CHMP), in addition to any voting records.

Introduction and procedural information

The Ombudsman inquiry team introduced themselves, thanked EMA representatives for meeting with them and set out the purpose of the meeting. They outlined the legal framework that applies to meetings held by the Ombudsman, in particular, that the Ombudsman would not disclose any information identified by EMA as confidential, neither to the complainant nor to any other person outside the Ombudsman’s Office, without EMA’s prior consent.^[1]

The inquiry team explained that they would draw up a draft report on the meeting to be sent to EMA to ensure that the contents were factually accurate and complete. The meeting report would then be finalised, included in the file and provided to the complainant. No confidential information would be included in the report or otherwise provided to the complainant or any third party.

Documents inspected 

The EMA representatives stated at the outset that they consider the personal data in the documents to be inspected as being sensitive and therefore confidential but not classified information under the EUCI rules. As a result EMA considers that it is not appropriate to disclose the personal data in the inspected documents.

The documents were shared and viewed remotely in the order of the bullet points set out in the inspection letter of the European Ombudsman of 23 June 2023 to EMA[2].

• Documents EMA holds as regards how it followed up on the alert it received from the complainant concerning an alleged undeclared interest of one of the Ad Hoc Advisory Group (AHEG) members

In response to the first point of the inspection letter, EMA identified and made available for inspection the following (sets of) documents:

i. The initial complaint (or alert) by the complainant to EMA concerning the alleged existence of a conflict of interest on the part of an AHEG member. The alert was sent by email from the complainant to the EMA Secretariat on 21 February 2022 (at 10:20 CET).

(The emails which are referred to as documents (ii) – (iv) were presented as one document during the inspection meeting.)

ii. An email from the EMA Secretariat that was sent to the expert (who is referred to as the “concerned expert” under this bullet point), on 21 February 2022 (at 11:08 CET). In the context of that email, the EMA Secretariat requested clarifications concerning the alleged undeclared interest that was described in the alert.

iii. An email from the concerned expert to the EMA Secretariat sent on 21 February 2022 (at 21:57 CET). In the context of that email, the concerned expert confirmed that he had no interests in the pharmaceutical sector.

iv. An internal exchange of emails within EMA comprising EMA’s assessment of the complainant’s alert and the response of the concerned expert, which culminated in the finding  (as sent to internal colleagues) on 22 February 2022 (at 19:02 CET) that the concerned expert was not considered to be conflicted within the meaning of EMA’s Policy on the handling of competing interests. In that connection, it was also noted that the concerned expert did not need to have declared the interest described in the complainant’s alert.

v. A follow-up complaint by the complainant concerning, amongst others, the alleged existence of a conflict of interest on the part of the concerned expert, that was sent by the complainant to the Executive Director of EMA on 31 March 2022 via EMA’s online enquiry form. (The complaint bore the date of 28 March 2022 but was submitted to EMA on 31 March 2022.) In addition, the document (v) included a record of the (paper) version of the (same) complaint which was sent via post mail to EMA and was received on 4 April 2022. Finally, the document (v) also contained the corresponding acknowledgement of receipt in respect of the complaint, which was sent by the EMA Secretariat to the complainant on 4 April 2022.

vi. EMA’s reply of 20 April 2022 to the complainant which confirmed, amongst other matters, that it had not identified a conflict of interest on the part of the concerned expert at the time of the AHEG group. (EMA’s reply is included in the case file of the inquiry team: namely, pages 53-57 of the complaint to the European Ombudsman.)

• The second point of the inspection letter which pertains to any documents EMA holds on “[i]ts assessment as regards the breach of trust procedure in the context of the interest in question”

In response to the second point of the inspection letter, EMA cross-referred to documents (iv) and (vi), as described above. 

• The third point of the inspection letter which pertains to any documents EMA holds on “[s]ub-question 3 of the list of questions for the AHEG of the Committee for Medicinal Products for Human Use (CHMP), in addition to the AHEG's Answers and Comments to the CHMP, including possible voting records” or possible “details on which experts held the minority and majority views”

In response to the third point of the inspection letter, EMA identified and made available for inspection the following sets of documents:

i. An email which was sent by one of the three (non-restricted) experts of the AHEG to the EMA Secretariat on 20 February 2022 (at 23.23 CET). In the context of that email, that expert confirmed that he had no comments in respect of the draft minutes of the AHEG meeting and that “the minutes have summarised the discussion very well”.

ii. An email which was sent by one of the three (non-restricted) experts of the AHEG, to the EMA Secretariat on 21 February 2022 (at 12:10 CET). In the context of that email, the expert enclosed a two-page document which outlined his comments in respect of the AHEG meeting.

iii. An email which was sent by the Chairperson (who also served as one of the three (non-restricted) experts) of the AHEG to the EMA Secretariat on 21 February (at 19:27 CET). In the context of that email, the Chairperson proposed certain clarifications to the recording of the minutes in respect of the answer to the third sub-question of the CHMP.

iv. An internal exchange of emails within the EMA Secretariat on 21 February 2022 concerning the request by one of the non-restricted experts for a phone call to discuss the AHEG meeting; and a summary of the outcome of that discussion based on that phone call.

v. An email from the EMA Secretariat to the Chairperson of the AHEG which was sent on 21 February 2022 (at 14:21 CET). In the context of that email, it was confirmed that the minutes had been amended in order to reflect more precisely the comments of the expert who provided comments.

Information exchanged

The EMA representatives furthermore provided the following information:

- The other companies that were mentioned in the alert of the complainant were well-known for only producing medical devices.

- EMA explained that they draw a distinction between experts who are employed by pharmaceutical companies and those who are or were engaged as consultants and that this distinction is reflected in the EMA policy on the handling of competing interests of scientific committees’ members and experts. EMA explained that this is important as a consultant may only have been engaged for a single project, related to a medical device and not a medicinal product and may have provided their input some time ago.

- EMA indicated that, in accordance with the rules set out under the policy on the handling of competing interests of scientific committees’ members and experts (as applicable at the time of the evaluation of x), AHEG experts were required to declare interests only in the pharmaceutical sector and not in the medical device sector. In that regard, the EMA Secretariat assessed interests in the pharmaceutical sector that could be considered to affect the impartiality of experts within the meaning of that policy. According to the express letter of the EMA policy on the handling of competing interests of scientific committees’ members and experts (as applicable at the time of the evaluation of x), only members and alternates of the EMA Committee for Advanced Therapies needed to declare interests in the medical device sector that could affect their impartiality.

- It was further clarified that, under the current policy (which took effect as of January 2023), experts are required to declare interests in the medical device sector. However, as far as concerns SAG/AHEG experts, possible interests in the medical device sector will not result in restrictions to EMA’s activities under its rules. The EMA representatives expressed the view that its policy on competing interests seeks to strike an appropriate balance between guarding against risks of conflicts of interest and having a sufficiently broad pool of potential experts available. (This position was endorsed by the Court of Justice in its judgment of 22 June 2023 in Germany and Estonia v Pharma Mar and Commission, Joined Cases C-6/21 P and C-16/21 P, EU:C:2023:502, paragraphs 61, 67 and 72.) In other words, EMA’s objectives are that it obtains the expertise it needs, and that the expertise on which it relies is impartial.

- The inquiry team asked whether the company with which the expert in question had a consultancy interest in a medical device was developing a (allegedly) competing medicinal product to the complainant’s medicinal product that was under re-examination. EMA confirmed that that the activity in question was not a declarable interest under its policy (which was applicable at the material time). As there was no requirement for the expert to declare an interest in the medical device sector, it was therefore not considered as a competing interest.

- The expert in question was new to EMA and his declaration of interest did not disclose any competing interests, which had recently been checked in an ex ante assessment and also prior to the start of the AHEG meeting. Following those checks, no restrictions had been imposed on the expert’s involvement in the AHEG meeting.

- In general, EMA trusts that experts provide a full and sincere account of their interests when they complete and sign an EMA declaration of interests. Experts are required to update their declaration of interests as needed and when any (declarable) interest arises. At the start of every scientific meeting, such as the AHEG meeting, the chair asks the experts to declare any interest which was not declared at the time when they submitted their declaration of interest and which could potentially conflict with the agenda items.

- The EMA representatives agreed that where the onus is on experts to accurately declare interests, it is important that the guidance on how to complete the declaration of interest is clear and unambiguous. In the present case, the EMA representatives consider that the EMA policy on the handling of competing interests of scientific committees’ members and experts (as applicable at the time of the evaluation of x) was very clear as to the absence of any requirement for EMA experts (other than members and alternates and EMA’s Committee for Advanced Therapies) to declare any interests in the medical device sector.

- Declarations of interest are assessed at the time a new expert registers in the Experts Management Tool; and they are also assessed prior to the involvement of an expert in an EMA activity (such as an AHEG meeting). EMA does not have the resources to do an in-depth verification of each of the individual declarations of interests that are submitted to it, nor does it have criteria for conducting such a verification. EMA’s representatives explained that there are over 5,500 experts registered in their Experts Management Tool and of those more than 2,200 are actively involved in EMA’s activities.

- EMA only conducts an independent verification of a declaration of interest when there is an indication that the concerned declaration might be incomplete or inaccurate, for example such as here where an alert is received. To that end, EMA will take the appropriate steps in order to verify the completeness and/or accuracy of the concerned expert’s declared interest(s). EMA will investigate the information contained in the alert received and verify it against publicly available information, as needed. EMA may contact the concerned expert to obtain information or clarifications on the existence of any alleged conflict of interests, as needed. In the present case, EMA reviewed the alert which had been brought to its attention by the complainant (namely, a published article journal). Further to the review of that published article, EMA contacted the (allegedly) conflicted expert for the purpose of clarifying whether the article referred solely to activities in medical devices or also activities in medicinal products. (The expert explained that the article related only to activities in medical devices.) The Ombudsman inquiry team notes that, based on the inspection meeting, the alert that is the subject in this inquiry was not checked more broadly against other possible sources of publicly available information.

- EMA also has a system of ex post controls, whereby it takes a sample of experts involved in an activity to see if the declarations of interests and curriculum vitae are accurate. In this context, EMA takes account of whether the declaration of interests has been the subject of an evaluation for involvement in the activity concerned to determine if the application of restrictions is required and if so, if the outcome of that evaluation was recorded correctly in the respective meeting minutes of the concerned EMA activity. More information on this mechanism is set out in the EMA’s annual report on independence[3]. EMA also clarified that their ex post control is carried out by two individuals so that if either was involved in performing the expert’s declaration of interests’ evaluation initially, the other colleague would carry out the ex post review. 

- In response to a question from the Ombudsman, as to whether it would have been possible to have postponed the AHEG meeting to enable a greater number of experts to participate, the EMA representatives explained that the organisation of AHEGs, as well as their meetings, are organised under time pressure. This stems from the fact that there are several internal milestones involved before EMA’s scientific committee adopts an opinion within strict legal deadlines.[4]  In the case of x, it was noted that a number of potential experts that the EMA had initially contacted were unavailable rather than conflicted. There is however no room for delay.

- Alerts, such as the one made by complainant, are received by EMA approximately once or twice per year.

- EMA representatives clarified and confirmed during the meeting that the curriculum vitae of the expert concerned was taken into account in determining whether there is a conflict of interest. A review of the CV did not identify any particular element that required further clarification.

- As regards the breach of trust procedure, EMA confirmed that based on the outcome of its assessment of the alert, which concluded that the interest identified was not declarable, there was no requirement to launch a breach of trust procedure in this case.

- In relation to the recording of the positions of the three non-conflicted experts, the EMA representatives confirmed that, under the applicable rules of procedure, there are no formal voting procedures for AHEGs as these groups perform an advisory role only and do not adopt opinions. It was also confirmed that a divergent position expressed by an expert is recorded in the minutes of the meeting; however, the applicable rules of procedure for SAGs/AHEGs do not require the names of an individual supporting a divergent position to be recorded. The approval of the minutes takes the form of a series of emails between the experts who were entitled to express their views during the meeting. The EMA representatives confirmed that the expert concerned expressed the minority view in the meeting, which was reflected in the minutes and presented by the Chair of the AHEG to the CHMP.

Conclusion of the inspection of documents / meeting

The inquiry team thanked the EMA representatives for their time and for the explanations provided, and the meeting ended.

 

Brussels, 10 July 2023

Jennifer King                                                                                                                                                  Koen Roovers

Legal Expert                                                                                                                                                   Inquiries Officer

 

[1] Article 4.8 of the European Ombudsman’s Implementing Provisions.

[2] See: https://www.ombudsman.europa.eu/en/doc/correspondence/en/171611.

[3] See: https://www.ema.europa.eu/en/documents/report/2022-european-medicines-agency-annual-report-independence_en.pdf.

[4] In the case of the procedure for the re-examination of a marketing authorisation application (such as the case of x), the timeline for the procedure is set out under Article 9(2), second subparagraph, of Regulation (EC) No 726/2004.