The European Medicines Agency (EMA)—Europe’s counterpart to the U.S. Food and Drug Administration (FDA)—recently issued several guidance documents regarding conflicts of interest at the agency. The new policies and procedures went into effect on April 3, 2012.
European Medicines Agency policy on the handling of conflicts of interests of the Management Board
Members of the Management Board are prohibited from having financial or other interests in the pharmaceutical industry which could affect their impartiality. Members must act in the public interest and in an independent manner, and must make an annual declaration of their financial interests. All indirect interests, which could relate to this industry, must be entered in a register held by the Agency, which is accessible to the public, on request, at the Agency’s offices. This policy applies to all Members and observers of the Management Board, including all Members of the Management Board sub-committees.
The Agency’s Code of conduct provides practical guidance on direct and indirect interests and the necessity to declare them in order to avoid potential conflicts of interests.
The Management Board adopted the Policy on the handling of conflicts of interests of the Management Board members in 2006. Taking into account the experience accumulated to date and the revised policy for handling of conflicts of interests of scientific committee members and experts adopted in 2010, the Board decided to review and update the policy applicable to its members. This policy is specific for the Board and differs from the policy for the Agency’s scientific committees (see below) as the Management Board takes strategic decisions and oversees corporate activities of the Agency as opposed to scientific or product specific matters.
Definitions
The definitions which are set out in the Policy on the handling of conflicts of interests of Scientific Committee members and experts apply to this policy.
Direct interest in pharmaceutical industry are:
- Employment with a company
- Consultancy for a company
- Strategic advisory role for a company
- Financial interests
- Ownership of a patent: relates to a patent for a medicinal product/competitor product owned by the individual or the individual’s Institution, and the individual is a beneficiary.
Consultancy for a company: an activity where the concerned member provided advice or services (including training on a one to one basis) to a pharmaceutical company regardless of contractual arrangements or any form of remuneration. It should be noted that scientific advice provided by the NCA of a Member State is not considered a consultancy activity.
Strategic advisory role for a company: participation (with a right to vote on/influence the outputs) in a (Scientific) Advisory Board/Steering Committee with the role of providing advice/expressing opinions on the (future) strategy, direction and development activities of a pharmaceutical company, either in terms of general strategy or product related strategy, regardless of contractual arrangements or any form of remuneration. It should be noted that:
- Data Monitoring Committees (composed of independent external experts reviewing un-blinded clinical trial data independently of the sponsor/pharmaceutical company) fall outside the scope of this definition.
- Members who participated in these forums are considered in the same way as principal investigators.
- Involvement of a member in research work for a pharmaceutical company is considered an indirect interest.
Financial interests relate to:
- Holding of shares of a pharmaceutical company with the exclusion of independently managed investment funds/pension schemes that are not exclusively based on the pharmaceutical sector.
- Compensation, fees, honoraria, salaries paid directly by a pharmaceutical company to the individual, other than payment for expenses incurred with research work or re-imbursement of reasonable expenses incurred in relation to conference/seminar attendance as a speaker, panellist or in a similar role (i.e. accommodation and travel costs).
Ownership of a patent: relates to a patent for a medicinal product/competitor product owned by the individual or the individual’s Institution, and the individual is a beneficiary. Competitor product: is defined as a medicinal product that targets a similar patient population with the same clinical objective (i.e. to treat, prevent or diagnose a particular condition), hence constituting a potential commercial competition.
Expert Witness: is an expert whose role is limited to testify and give specialist advice on a specific issue by providing information and replying to any questions only. Such Expert Witness can be invited to participate at Scientific Committee, Working Party, SAG or Ad-Hoc Expert Group meetings.
Household member: is a spouse, partner or child living at the same address as the individual. Pharmaceutical company: also includes supply or service companies which contribute to the research, development, production and maintenance of a medicinal product.
Indirect interests in pharmaceutical industry are:
- Principal investigator
- Investigator
- Individual’s institution/organization receives a grant or other funding
Principal investigator: is the investigator with the responsibility for the coordination of investigators at different centres participating in a multicentre pharmaceutical industry instigated/sponsored trial or the leading investigator of a monocentre pharmaceutical industry instigated/sponsored trial, or the coordinating (principal) investigator signing the clinical study report.
Investigator: is an investigator involved in a clinical pharmaceutical industry instigated/sponsored trial at a specific trial site who can be the responsible lead investigator of the trial at that specific site or a member of the clinical trial team who performs critical trial related procedures and makes important trial related decisions.
Grant or other funding (other than compensation for services requested by National Competent Authorities): two situations need to be considered:
- Individual’s department of an academic institution receives a grant or other funding (e.g. sponsoring of a Chair at the University department) from a pharmaceutical company for research work and the individual receives no personal gain;
- Organization (e.g. Patient organization) receives a grant or other funding from a pharmaceutical company for non-research work and the individual (irrespective if the individual is employed by the organization or is a volunteer and acts as a representative) receives no personal gain.
- Pharmaceutical company: also includes supply or service companies, which contribute to the research, development, production and maintenance of a medicinal product.
- Household member: is a spouse, partner or child living at the same address as the individual.
EMA noted that these definitions can not address all the various scenarios which may exist. Therefore, in order to determine if a particular situation is covered by the definition the Agency’s DIAG will evaluate on a case-by-case basis.
Policies
Members of the Board must declare all interests that could be prejudicial to their independence, whether of direct or indirect nature. The declaration forms used for scientific committees will also be used to declare interests by members of the Board. The Management Board secretariat must put in place necessary procedures to implement the policy. Involvement of the individual in activities of the Board may be restricted taking into account:
- The nature of the declared interest,
- The timeframe during which the interest occurred.
- The type of a member’s role in the Board (chair, vice-chair, a member).
Current direct interest (employment, strategic advisory role, consultancy, financial interests) in pharmaceutical industry are incompatible with involvement in the activities of the Board. The requirements are stricter for chair / vice-chair. The timeframe to be considered for the declared direct or indirect interest is either:
- current (i.e. at any time point during the term of the mandate of a member), or
- within the past 2 years, or
- within the past 2 to 5 years.
Interests need to be declared up to 5 years after which the interest ceases to exist. However, individuals can declare any interests beyond the 5 years timeframe. They can also restrict on their own initiative their involvement as a result of such declaration.
Members update their declarations annually or as soon as their interests change, informing the Chair and Executive Director of any changes to their declared interest without undue delay. Declarations should cover interests that occurred within the five years before the date of the declaration.
If a member intends to be engaged (either solicited or not) in occupational activities with a pharmaceutical company (such as employment) during the term of the mandate, the member must immediately inform the Agency and refrain from any activities which may have an impact on the pharmaceutical company concerned and must comply with any additional conditions or limitations which the Agency may consider appropriate to impose.
Members will be asked to declare interests which can be considered prejudicial to their independence with respect to the items on the agenda at the beginning of each Management Board meeting and any declared interests will be recorded in the minutes. These declarations must be made available to the public.
In addition to interests related to pharmaceutical industry, consideration should also be given to any possible interest with non-pharmaceutical companies that may have interaction with the Agency in other areas such as procurement procedures (e.g. in the are of information technology, office refurbishment, other services). These interests must be entered in the declaration of interests.
The obligation for the individual to declare interest in relation to the activities of his/her institution/organisation is subject to the extent that the individual has knowledge of the institution’s/organisation’s activities. When declaring interests members should also declare current direct interest of (a) household member(s) (i.e. spouse, partner and children living at the same address as the individual).
Involvement in academic trials and in publicly funded research/development initiatives, as well as membership of an Ethics Committee should be declared. This will not result in the Agency restricting involvement in EMA activities, unless a specific conflict is identified. In case, where, following the expiry of a declaration of interest, a member is late to provide a new declaration, meeting documents and correspondence will not be sent to the member or alternate and their support staff until the Declaration of Interests is received.
The Chair and/or the Vice-Chair will be informed on the declared interests of Management Board members recorded in the conflicts of interests’ register of the Management Board, in order to identify if there are any interests that could present a conflict with regard to the work of the Management Board and/or its sub groups including the Management Board Telematics Committee (MBTC).
The Management Board, as a whole, will be informed at start of each meeting of interests declared by members that pose conflict with specific items on the meeting agenda. This information will be recorded in the minutes. All members (including non-Board members) serving on Management Board subcommittees must not have specific interests related to the topics dealt with by the subcommittees. If a declared interest poses factual or perceived conflict of interest, members should refrain from participation in related discussions and decision-making.
In order to check the correctness of the information contained in the declarations of interests the Agency applies a system of ex-post control checks.
Members of the Management Board: Interests that are not allowed
Current direct interests (as defined above) are not allowed at any time during the term of the mandate
Interests which impose certain restrictions
Direct interest allowed with restrictions if greater than 0 and less than 5 years for Employment; Consultancy; and Strategic advisory role.
Indirect interest allowed with restrictions if current and less than 5 years include Principle investigator and Grant or other funding to institution. Current direct interest of (a) household member(s) also are included. These restrictions mean that depending on the nature of specific interests declared and the length of the interest members will:
- Withdraw from discussions and decisions or as topic coordinators on certain topics if the interest(s) is 2 years old.
- Withdraw from decisions on certain topics if the interest(s) is greater than 2 but less than 5 years old. Members may join in the discussion and act as topic coordinators.
- Withdraw from discussions and decisions or as topic coordinators on certain topics in case of current direct interests of (a) household member(s)
The topics within which restrictions will apply include (the list is not exhaustive):
- Long term strategy (Road Map) (strategic direction of EMA – possible impact on industry)
- Fee regulation implementing rules (direct impact on industry)
- Policy for support to veterinary companies in the area of minor uses and minor species (direct impact on industry)
Chair and vice-chair of the Management Board: Interests that are not allowed
Direct interests are not allowed within previous 5 years and at any time point during the term of the mandate for Employment; Consultancy; and Strategic advisory role. Current direct interests are not allowed at any time point during the term of the mandate including Financial interests and Patent ownership.
Indirect interests are not allowed within previous 5 years and at any time point during the term of the mandate: Principle investigator; Investigator; and Grant or other funding to institution. Current direct interest(s) of any household member(s) is not allowed.
This policy describes the arrangements put in place by the European Medicines Agency (EMA) to manage declared conflicts of interests (CoIs) of Scientific Committees’ members and experts. In order to further strengthen the robustness of the Agency’s handling of CoIs a breach of trust procedure has been developed.
In accordance with the EMA Policy on CoIs, prior to any involvement in EMA activities, EMA Scientific Committees’ members and experts need to be nominated and included in the EMA experts database. Such inclusion is only possible once the following documents have been submitted to the EMA: Nomination Form, Declaration of Interests and confidentiality undertaking form, and Curriculum Vitae.
The Nominating Authority has to ensure, in close collaboration with the nominated member/expert, that all relevant material necessary for the Agency’s review of the declared CoIs has been made available to the EMA prior to the member’s/expert’s involvement in any activity of the EMA.
The EMA Breach of Trust Procedure on CoIs applies to Scientific Committees’ members and experts. The scope of the EMA Breach of Trust Procedure on CoIs concerns any incomplete and/or incorrect eDoIs. Failure to fill in the eDoI in a complete and/or correct manner may be considered as a prima facie breach of trust towards the EMA. Because of that failure, appropriate actions, including the exclusion of the concerned person from the EMA activit(y)ies, may be taken by the Agency.
Procedure
1. In case the EMA has knowledge of information that is not consistent with the information included in the electronic Declaration of Interests (eDoI), and such information should have been declared, the EMA Executive Director will inform the expert in writing, asking the expert to clarify the situation, in particular by providing the rationale for the absence of the information to be declared, and to complete the eDoI with the missing information. The Nominating Authority will also be informed.
2. In the meantime, awaiting the expert’s reply, the expert’s involvement in EMA activities may be suspended until the aforementioned information has been received and assessed by the EMA. The expert as well as the Nominating Authority will be notified of this suspension.
3. Once the aforementioned information has been received, the EMA must start an internal procedure and assess this information in order to establish whether the omission of the expert needs to be considered as a breach of trust vis-à-vis the Agency if it is found that: (a) the information missing from the eDoI is a declarable interest according to the EMA Policy and guidance, and (b) the expert did not declare the missing information intentionally or through gross negligence or he/she failed otherwise to meet his/her obligations under the EMA Policy on the handling of CoIs.
4. The expert must be notified of the opening of the procedure and of the possible consequences of this procedure.
5. The expert must be invited to a hearing in order to gather his/her views on the facts in question. The hearing must be organised before any decision is taken. During the hearing, he/she must have the possibility of expressing his/her point of view. The EMA must take account of any comments or documents submitted before and during the hearing.
6. The EMA Executive Director must take a decision having due regard to all information provided.
7. The expert is given the possibility to appeal the decision. Following the receipt of the reasoned decision the expert can appeal within fourteen calendar days as of the day of notification of the decision, providing all the supporting documents and information. The Agency will subsequently assess all submitted documents and information before reaching a final decision.
8. If the final decision of the Agency is that there is a breach of trust:
- For a member of any of the Scientific Committees the EMA Executive Director must consult the Management Board (where relevant through written procedure) on the EMA Executive Director’s decision to exclude the person from the membership of the concerned Scientific Committee and any other EMA activity.
- For any other expert the EMA Executive Director must take the decision and inform the expert and the Nominating Authority of the exclusion of the expert from the membership of the concerned scientific forum (e.g. Working Party, Scientific Advisory Group) and/or any (other) EMA activity. The Nominating Authority must be invited to replace the membership.
9. Following the consultation with the Management Board in case the breach of trust relates to a member of any of the Scientific Committees the EMA Executive Director must inform the member and the Nominating Authority of the exclusion of the person from the membership and any other EMA activity. The Nominating Authority must be invited to replace the membership.
10. In case of a breach of trust the EMA Executive Director reserves the right to make this information public.
11. Whenever a breach of trust will reveal a case of suspected fraud the EMA will inform the European Antifraud Office (OLAF) without delay.
Integrity of the Scientific Review
Irrespective of the outcome of the Breach of Trust procedure a decision will be taken by the EMA Executive Director to initiate a checking of the integrity of the scientific review. In such situation the EMA Executive Director must ask the concerned operational Unit(s), in liaison with the Senior Medical Officer and the Legal Service, to carry-out a checking of the scientific outputs adopted by the scientific fora to which the member/expert was providing his/her input in order to ensure the integrity of the scientific review process. Where considered necessary, the EMA can involve external expertise.
The concerned operational Unit(s) will be asked to prepare a report within a timeline specified by the EMA Executive Director. Upon receipt of this report the EMA Executive Director must decide if any further remedial action is necessary, e.g. a scientific re-evaluation by the concerned Scientific Committee with regard to the medicinal products whose assessment may have been affected. The Management Board and the Audit Advisory Committee will be informed on the outcome and any remedial action taken.
EU legislation clearly states that the members of the Scientific Committees and experts must not have financial or other interests in the pharmaceutical industry that could affect their impartiality. They must make an annual declaration of their financial interests. In addition, all indirect interests, which could relate to the pharmaceutical industry must be entered in a register held by the EMA, which is accessible to the public, on request.
The Agency’s Code of Conduct, provides guidance on several aspects related to conflicts of interests. Information is made available about what should be declared by whom and at what moment in time. In addition, clarification about some operational aspects is given by stating the tasks of the Agency’s Secretariat, the obligations of the individuals concerned and the meeting proceedings.
A Policy on the handling of conflicts of interests for the Scientific Committee members and experts was established in March 2004 and subsequently reviewed and updated in December 2005 in the light of experience gained over the first year of use.
Since 2006 further experience has been obtained. The two main findings have been demands by the wider community for the Agency to strengthen its handling of conflicts of interests, as well as requests from stakeholders for the Agency to ensure that the best scientific expertise is involved in the assessment process.
This has resulted in an in-depth review of the Policy in place, and a revised Policy was endorsed by the Management Board at its 7 October 2010 meeting, becoming effective on 29 September 2011. A 6 months’ analysis of the implementation of the revised Policy was performed in February 2012 and further amendments to the Policy, taking into account such analysis, were endorsed at the March 2012 Management Board meeting. The Policy must be reviewed within 3 years or at an earlier stage if considered necessary.
The scope of the Policy relates to the handling of conflicts of interests of Scientific Committee (i.e. the CHMP, CVMP, COMP, HMPC, PDCO, CAT and PRAC) members (including, where relevant, alternates) and experts involved in activities at the level of the Agency. Involvement in the Agency’s activities means all activities carried out at the Agency in the context of the authorisation and surveillance of medicinal products for human and veterinary use.
This includes meeting attendance, involvement in the scientific assessment and guidance development, as well as participation in inspections. The scope of this Policy does not relate to staff and experts at the level of the NCAs participating in the (evaluation) work (with respect to the authorisation and surveillance of medicinal products) at national level for services provided to the Agency. This is in line with the MoU4 concluded between the NCAs and the Agency.
The main objective of the Policy is to ensure that the Scientific Committee members and the experts participating in the Agency’s activities have no interests in the pharmaceutical industry which could affect their impartiality, as per the requirements of EU legislation. This has to be balanced with the need to secure the best (specialist) scientific expertise for the evaluation and surveillance of medicinal products for human and veterinary use.
In order to achieve this objective and to strike the aforementioned balance the Policy focuses on three important pillars, i.e.: robustness, efficiency, and transparency of the process for the handling of conflicts of interests of Scientific Committee members and experts.
The focus is on direct interests in pharmaceutical industry, leading to the highest risk level (level 3) with a more restricted involvement in the Agency’s activities. Indirect interests in pharmaceutical industry lead to an intermediate risk level (level 2) with mitigating actions to reach the best possible balance between limiting the involvement in the Agency’s activities and the need for the availability of the best (specialist) scientific expertise.
The obligation for the individual to declare interests in relation to the activities of his/her Institution/Organization is subject to the extent that the individual has knowledge of the Institution’s/Organization’s activities. Restrictions will apply in case the individual acts as a Scientific Committee chair/vice-chair, rapporteur (or equivalent leading/coordinating role) or as a peer reviewer.
In these situations the individual either needs to be replaced (Scientific Committee chair/vice-chair) for the discussions, final deliberations and voting as appropriate, or can not act as rapporteur (or equivalent leading/coordinating role) or as a peer reviewer, in relation to any medicinal product from the pharmaceutical company giving a grant or other funding to the Institution (either individual’s NCA or the individual’s department of an academic Institution)/ individual’s Organisation (e.g. Patient Organization).
Individuals are requested to declare current direct interests of (a) household member(s). Such interests will result in an intermediate risk level (level 2). Restrictions will apply in case the individual acts as a Scientific Committee chair/vice-chair, rapporteur (or equivalent leading/coordinating role) or as a peer reviewer. In these situations the individual either needs to be replaced (Scientific Committee chair/vice-chair) for the discussions, final deliberations and voting as appropriate, or can not act as rapporteur (or equivalent leading/coordinating role) or as a peer reviewer, in relation to any medicinal product from the pharmaceutical company for which current direct interests of (a) household member(s) have been declared.
Involvement in academic trials and in publicly funded research/development initiatives, as well as membership of an Ethics Committee should be declared. This will not result in the Agency restricting involvement in EMA activities, unless a specific conflict of interest is identified.
Restricting involvement in the Agency’s activities
Involvement of the individual in the Agency’s activities is restricted taking into account the nature of the declared interest, the timeframe during which such interest occurred, as well as the type of activity. As a general rule, current employment with a pharmaceutical company or current financial interests in pharmaceutical industry are incompatible with involvement in the activities of the Agency.
One exception to this general rule applies to the concept of Expert Witness. Current financial interests are compatible with such concept. Furthermore, if a Scientific Committee/Working Party/SAG/Ad-hoc Expert Group member intends to be engaged (either solicited or not) in occupational activities with a pharmaceutical company (such as employment) during the term of the mandate, the member must immediately inform the Agency and refrain from any activities which may have an impact on the pharmaceutical company concerned and must comply with any additional conditions or limitations which the Agency may consider appropriate to impose.
The requirements for membership of decision-making bodies (i.e. Scientific Committees) are stricter than for advisory bodies (i.e. SAGs and Ad-Hoc Expert Groups). The requirements are also stricter for chairpersons / vice-chairpersons of the Scientific Committees compared to the chairpersons / vice-chairpersons of other fora and compared to the members of the Scientific Committees and the other fora. Likewise the requirements are stricter for rapporteurs (or equivalent leading / co-ordinating role) and formally appointed peer reviewers compared to the other members of the scientific fora.
The timeframe to be considered for the declared direct or indirect interest is either current (i.e. at any time point during the term of the mandate of a member or at the time of involvement of an individual in a specific Agency activity), or within the past 2 years, or within the past 2 to 5 years. Interests need to be declared up to 5 years after the interest ceases to exist. However, individuals can declare any interests beyond the 5 years timeframe. They can also restrict on their own initiative their involvement in the Agency’s activities as a result of such declaration.
Achieving an Efficient Process
Conflicts of interests are classified into 3 categories, i.e. direct versus indirect versus no interests declared. Direct interests are assigned the highest risk level (level 3), indirect interests an intermediate risk level (level 2), and in case no interests are declared a risk level 1 is assigned.
A two step procedure applies: following receipt of the DoI a risk level is automatically assigned according to the above classification. Subsequently the level of participation in the Agency’s activities is determined by the Agency’s secretariat taking into account the assigned risk level and the restrictions which apply to participation in the various activities of the Agency.
A proactive approach is envisaged as regards the possible identification of conflicts of interests through an obligatory screening by the Agency of the declared conflicts of interests of Scientific Committee members prior to any formal nomination by the Competent Authority. The Agency will provide feedback to the Nominating Authority on the outcome of the pre-screening for subsequent consideration by the Nominating Authority when launching the formal nomination process. Likewise, the possibility of pre-screening of any expert prior to involvement in the Agency’s activities is offered to the Nominating Authority.
A proactive approach is also applied with respect to the search for alternative experts in the field, making the best use of the established relationships with academia and learned societies. In addition, for the establishment of a new SAG or the renewal of the mandate of an existing SAG a public call for expression of interests is launched by the Agency.
Achieving a Transparent Process
Introduction of transparency on declared conflicts of interests throughout the whole scientific review process, starting with the (Co)-Rapporteur assessment reports (or the assessment reports from equivalent leading / co-ordinating individuals) to the minutes of the various fora up to a specific section in EPARs (or equivalent public documents) on all conflicts of interests declared throughout the scientific review.
Publication of the DoIs and Curricula Vitae on the Agency’s website of all experts, whilst ensuring that personal data legislation is adhered to, as well as publication on the Agency’s website of the assigned risk levels (level 1, 2 or 3).
Before any work can be undertaken by the Agency on the checking of conflicts of interests, members of the Scientific Committee and experts first need to be nominated after which they need to be included in the Agency’s expert database. The roles and the responsibilities of both the Nominating Authority and the Agency are summarised in the aforementioned MoU.
Nomination Process
Scientific Committee members (and, where relevant, alternates) are nominated by Member States for a term of three years, which may be renewed. The Management Board is consulted on nominations prior to the appointment of CHMP, CVMP and PRAC members. Scientific Committee members must be chosen by reason of their role and experience in the evaluation of medicinal products for human and veterinary use, as appropriate, and must represent their Competent Authorities.
For experts, member States must transmit to the Agency a list of experts with proven experience in the evaluation of medicinal products in order to serve on Working Parties or SAGs, or to act as additional experts to Scientific Committees, Working Parties or SAGs. Nominations should be accompanied by a description of the experts’ qualifications and their specific areas of expertise.
In addition, situations can arise where the need for additional expertise, not covered by nominations made by the Member States, is identified at the level of the Scientific Committees. In such circumstances, the nomination of the identified expertise is undertaken by the Agency.
Inclusion in the Agency’s Expert Database
All Scientific Committee members and experts must be included in the Agency’s experts database prior to the first appointment resulting in involvement in activities at the level of the Agency (meeting attendance, scientific evaluation, inspections, guidance development, etc.). Such inclusion is only possible once the following documents have been submitted to the Agency: Nomination form; Public declaration of interests and confidentiality undertaking form; and Curriculum Vitae.
The Nominating Authority has to ensure, in close collaboration with the nominated member/expert, that all relevant material necessary for the Agency’s review has been made available prior to the member’s/expert’s involvement in any activity of the Agency.
The list of experts is published on the Agency’s website. In addition, it should be noted that the declarations of interests submitted by members and experts are publicly available.
Whereas, in accordance with the requirements of EU legislation, the declarations of interests of experts can be consulted, upon request and in person, at the Agency’s offices in London, the Agency has decided, in order to further increase its transparency, to make the declarations of interests of the chairpersons, members and alternates (where such alternates are nominated) of the Scientific Committees, as well as all experts available on the Agency’s website.