. 2021 Sep 15;44(11):1193–1208. doi: 10.1007/s40264-021-01111-w

Table 5.

Analysis of iconic cases of pharmacovigilance engagement at the European Medicines Agency applying the International Risk Governance Council Framework

IRGC risk scenario type	Safety concern subject to assessment at EMA and outcome of engagement for the regulatory decision	Characterisation of the engagement event at EMA and comparison with IRGC engagement recommendation for given risk type
Complex risk	Risk of VTE with CHCs [17, 18]: Although the causality of VTE with CHCs had been well-established over decades, there was remaining complexity due to questions about differential risk quantifications between (newer) CHC products depending on their progestogen components. In 2013, this required EMA’s PRAC to decide on updated risk estimates and risk minimisation measures, while evidence on CHC prescribing practices in EU Member States was limited. Being conscious of the need for clear risk communication and of the challenges of communication to effectively manage risk, an ad hoc stakeholder meeting was organised prior to regulatory decision making Engagement outcome: The dedicated meeting resulted in communication that included risk presentation with a person-number rather than a person-time denominator, a table for patients in the package leaflet and a graphic for healthcare professionals in the summary of product characteristics to facilitate understanding of differential risks, and deletion of VTE risk with pregnancy as comparator in the package leaflet	Engagement mechanism: Dedicated meeting Scope: Obtaining input on product tolerability, safety and risk management, including communication preferences, for the regulatory decision on product information and other communication materials to healthcare professionals and patients Breadth: Healthcare professional representatives and one patient representative from the EIWH (further patient representatives contributed in writing) Depth: Consultation Texture: The communication in 2013 differed from the communication after the previous regulatory procedure for CHCs in 2001 by taking into account communication preferences of patients and healthcare professionals [18]. This shows that the input from patients and healthcare professionals motivated a change in the practice of regulators, which was probably satisfying for stakeholders and building their trust that their input would also be taken seriously by regulators in the future Discourse type: Epistemological discourse, in accordance with IRGC recommendations
Uncertain risk	Risk of lipodystrophy with medicines used for HAART [19–24]: Observant and networking patients suspected that HAART, which combines products authorised in the EU as of 1996 for treating HIV infection, may cause symptoms of lipodystrophy after use for 18 months or longer; they brought this to the attention of the regulatory authorities and maintained personal interactions with the authorities. EMA reacted upon this uncertainty with precautionary warnings and a multistakeholder research project set up in 1999. Engagement outcome: The reporting of new suspected adverse reactions to regulatory authorities directly from patients led to patient representatives becoming part of the multistakeholder Oversight Committee on Metabolic Disorders with HAART, which reported regularly to the scientific committees at EMA and provided evidence for updating the product information	Engagement mechanism: Dedicated meeting Scope: Overseeing research on adverse effects after long-term medicines use for providing evidence for regulatory decisions on updating product information Breadth: Patient and healthcare professional representatives, researchers and marketing authorisation holders Depth: Participation (however not in regulatory decision making) Texture: Following the success of HIV patients’ campaigns in accelerating the development of medicines and the introduction of fast regulatory authorisation procedures [25], the detection and reporting of adverse effects of anti-HIV medicines by patients themselves in the 1990s was a new experience and a further recognition of the capacity patients can have as active contributors to medical progress as well as regulation and surveillance of medicines [24]. The subsequent participation of patient representatives in research oversight was a novum and established a partnership with patients based on an equal footing with shared values and agreed rationales Discourse type: Reflective discourse, in accordance with IRGC recommendations
Potential risk of carcinogenicity with contaminated nelfinavir-containing products [20, 26]: The detection of a possibly severe genotoxic and carcinogenic contamination of nelfinavir-containing medicinal products in 2007 prompted an immediate batch recall by the marketing authorisation holder and subsequent precautionary suspension of the EU marketing authorisation until investigations and risk assessment at EMA could be completed and demonstrate that the exposure of patients had been below the toxic threshold. The quality defect notification from the marketing authorisation holder triggered EMA’s immediate outreach to the relevant patient organisation as soon as investigations had been started. Engagement outcome: Through this engagement, appropriate treatment management while investigations of the safety concern and product suspension were ongoing could be facilitated to avoid negative health outcomes of undue interruption of treatment	Engagement mechanism: Tele-communication with a relevant stakeholder organisation Scope: Providing immediate and updated information to a patient representative to reassure patients that investigations had been started promptly and were taken seriously, and to motivate patients to seek appropriate treatment management while investigations and precautionary actions were ongoing Breadth: One patient representative from the European AIDS Treatment Group Depth: Information Texture: The immediate and sustained contact of a widely known, well-respected and trusted member of the HIV-patient community by EMA enabled this patient representative to act as a facilitator within the patient community, as an interface with healthcare professionals and as a spokesperson for the patients and their right to high-quality medicines vis-à-vis EMA. In particular, he could reassure patients that EMA, together with the authorities in EU Member States, took the matter seriously, dedicated appropriate resources, worked as speedy as possible and kept him up to date with honest information. Patients were generally satisfied with this diligent involvement of their trusted representative by EMA, which was also paralleled at national level, for example in France [26] Discourse type: Reflective discourse, in accordance with IRGC recommendations
Ambiguous risk	Risk of teratogenicity with thalidomide [27, 28]: The causality between birth defects and use of thalidomide against sleep disorders and morning sickness in pregnancy had been established in the 1960s, but ambiguity emerged in 2007 during the assessment for re-authorising thalidomide in the EU against multiple myeloma. The ambiguity emerged from divergent perspectives of persons affected by the severe teratogenic effects (victims) in the 1950/1960s and multiple myeloma patients. Therefore, a stakeholder meeting was convened by EMA Engagement outcome: The dedicated meeting organised by EMA brought together thalidomide victims and multiple myeloma patients, and their input and convergence on the package leaflet, the labelling of the outer packaging and further comprehensive actions for risk management enabled EMA’s scientific committee to recommend re-authorising thalidomide in 2008	Engagement mechanism: Dedicated meeting Scope: Obtaining input on a risk management plan and the possibility of a marketing authorisation acceptable to victims Breadth: Victim and patient representatives Depth: Consultation Texture: The dedicated meeting at EMA provided a forum where an open dialogue and mutual understanding between thalidomide victims facing severe challenges every day of their lives and multiple myeloma patients hoping for a new cure could actually happen and convergence could be achieved. Given the trauma of the thalidomide disaster, this convergence on a risk management plan with risk minimisation measures that were acceptable to, and did not compromise, the different expectations of both affected populations was needed for EMA’s scientific committee recommending re-authorisation in an accountable manner [28] Discourse type: Participative discourse, in accordance with IRGC recommendations, however not in the public domain, as at the time public hearings were not yet a legal option (although the meeting was announced in the public domain)
Risk of PML with natalizumab [29–31]: Natalizumab was authorised in the EU in June 2006, i.e. the same month the US FDA allowed this medicine to re-enter the US market following risk assessment with patient advocate involvement [2]. Furthermore, prior to the EU marketing authorisation, views from patient representatives had been solicited, who were in favour of a clear restriction of natalizumab to patients “that are really in need of such a therapy” [32]. In September 2008, new PML case reports were assessed by EMA’s scientific committee. Given the seriousness of PML and patient appreciation of the treatment benefit, a SAG meeting was convened with patient and healthcare representatives Engagement outcome: Taking into account the considerations of the SAG meeting, the regulatory decision resulted in strengthening the product information in the sections on warnings and adverse reactions and considered that the evaluation of the risk–benefit balance of the medicine remained positive	Engagement mechanism: Scientific Advisory Group (SAG) meeting Scope: Obtaining input on preferred diagnostic procedures, risk minimisation measures and the overall risk-benefit balance for the regulatory decision on product information Breadth: Healthcare professional specialists and one patient representative Depth: Consultation Texture: The patient views allowed maintaining the marketing authorisation with acceptance of the PML risk for the regulatory conclusion on a positive risk–benefit balance on the basis of strengthened warnings in the product information [29, 32] Discourse type: Participative discourse, in accordance with IRGC recommendations, however not in the public domain, as at the time public hearings were not yet a legal option (although there were public statements and direct healthcare professional communication before and after the committee meeting)
Risk of teratogenicity and developmental disorders with valproate [33, 34]: The risk of birth defects and developmental disorders later in life of children exposed to valproate in utero had been established over time, with several assessments resulting in regulatory risk minimisation measures. Following the measures imposed by PRAC in 2014, ambiguity emerged during a new assessment by PRAC in 2017 initiated because of some lack of implementation and effectiveness of the 2014 measures. Ambiguity emerged from the medical imperatives to give any patient the most beneficial treatment, in particular given fatal risks of epilepsy, and to protect children from teratogenic effects. Additional complexity arose from the fact that children of pregnant women whose epilepsy is not well-treated have health risks also Engagement outcome: The input from patient and healthcare professionals at the public hearing and subsequent dedicated meeting resulted in regulatory decisions on restrictions in indications and a new programme for risk minimisation and prevention of pregnancy during treatment, including a visual warning on the teratogenic risk on the outer packaging and focus on counselling of female patients, in order to address feedback, requests and suggestions from patients and healthcare professionals	Engagement mechanism: Public hearing Scope: Obtaining input on the risk of taking valproate during pregnancy and potential effects on the child, on the 2014 risk minimisation measures and the need for further measures for supporting regulatory decisions Breadth: Patient representative speakers from four European Union (EU) Member States (Belgium, France, Ireland and the UK) and one international organisation, healthcare professional representatives from European umbrella and UK organisations and one marketing authorisation holder Depth: Consultation Texture: This first public hearing was a major positive experience for external stakeholders and PRAC alike, all expressing feelings that it “would make a difference” to the PRAC outcome. EMA concluded that the hearing improved the quality of the assessment and was instrumental to the decision making on new risk minimisation measures [35]. During the hearing, aspects critical for the implementation of risk minimisation measures in healthcare emerged, including aspects of an ethical nature that considered the needs for protecting children but at the same time not depriving anybody from necessary treatment. There was overall convergence of all stakeholders on the need for informed therapeutic decision making and free choice of the concerned women, which is reflected in the risk minimisation programme with a focus on counselling of female patients. Overall, the public hearing provided for a high degree of texture due to the very humane, respectful and professional style of the face-to-face interactions [34] Discourse type: Participative discourse in the public domain, in accordance with IRGC recommendations

IRGC risk scenario type

Safety concern subject to assessment at EMA and outcome of engagement for the regulatory decision

Characterisation of the engagement event at EMA and comparison with IRGC engagement recommendation for given risk type

Complex risk

Risk of VTE with CHCs [17, 18]: Although the causality of VTE with CHCs had been well-established over decades, there was remaining complexity due to questions about differential risk quantifications between (newer) CHC products depending on their progestogen components. In 2013, this required EMA’s PRAC to decide on updated risk estimates and risk minimisation measures, while evidence on CHC prescribing practices in EU Member States was limited. Being conscious of the need for clear risk communication and of the challenges of communication to effectively manage risk, an ad hoc stakeholder meeting was organised prior to regulatory decision making

Engagement outcome: The dedicated meeting resulted in communication that included risk presentation with a person-number rather than a person-time denominator, a table for patients in the package leaflet and a graphic for healthcare professionals in the summary of product characteristics to facilitate understanding of differential risks, and deletion of VTE risk with pregnancy as comparator in the package leaflet

Engagement mechanism: Dedicated meeting

Scope: Obtaining input on product tolerability, safety and risk management, including communication preferences, for the regulatory decision on product information and other communication materials to healthcare professionals and patients

Breadth: Healthcare professional representatives and one patient representative from the EIWH (further patient representatives contributed in writing)

Depth: Consultation

Texture: The communication in 2013 differed from the communication after the previous regulatory procedure for CHCs in 2001 by taking into account communication preferences of patients and healthcare professionals [18]. This shows that the input from patients and healthcare professionals motivated a change in the practice of regulators, which was probably satisfying for stakeholders and building their trust that their input would also be taken seriously by regulators in the future

Discourse type: Epistemological discourse, in accordance with IRGC recommendations

Uncertain risk

Risk of lipodystrophy with medicines used for HAART [19–24]: Observant and networking patients suspected that HAART, which combines products authorised in the EU as of 1996 for treating HIV infection, may cause symptoms of lipodystrophy after use for 18 months or longer; they brought this to the attention of the regulatory authorities and maintained personal interactions with the authorities. EMA reacted upon this uncertainty with precautionary warnings and a multistakeholder research project set up in 1999.

Engagement outcome: The reporting of new suspected adverse reactions to regulatory authorities directly from patients led to patient representatives becoming part of the multistakeholder Oversight Committee on Metabolic Disorders with HAART, which reported regularly to the scientific committees at EMA and provided evidence for updating the product information

Engagement mechanism: Dedicated meeting

Scope: Overseeing research on adverse effects after long-term medicines use for providing evidence for regulatory decisions on updating product information

Breadth: Patient and healthcare professional representatives, researchers and marketing authorisation holders

Depth: Participation (however not in regulatory decision making)

Texture: Following the success of HIV patients’ campaigns in accelerating the development of medicines and the introduction of fast regulatory authorisation procedures [25], the detection and reporting of adverse effects of anti-HIV medicines by patients themselves in the 1990s was a new experience and a further recognition of the capacity patients can have as active contributors to medical progress as well as regulation and surveillance of medicines [24]. The subsequent participation of patient representatives in research oversight was a novum and established a partnership with patients based on an equal footing with shared values and agreed rationales

Discourse type: Reflective discourse, in accordance with IRGC recommendations

Potential risk of carcinogenicity with contaminated nelfinavir-containing products [20, 26]: The detection of a possibly severe genotoxic and carcinogenic contamination of nelfinavir-containing medicinal products in 2007 prompted an immediate batch recall by the marketing authorisation holder and subsequent precautionary suspension of the EU marketing authorisation until investigations and risk assessment at EMA could be completed and demonstrate that the exposure of patients had been below the toxic threshold. The quality defect notification from the marketing authorisation holder triggered EMA’s immediate outreach to the relevant patient organisation as soon as investigations had been started.

Engagement outcome: Through this engagement, appropriate treatment management while investigations of the safety concern and product suspension were ongoing could be facilitated to avoid negative health outcomes of undue interruption of treatment

Engagement mechanism: Tele-communication with a relevant stakeholder organisation

Scope: Providing immediate and updated information to a patient representative to reassure patients that investigations had been started promptly and were taken seriously, and to motivate patients to seek appropriate treatment management while investigations and precautionary actions were ongoing

Breadth: One patient representative from the European AIDS Treatment Group

Depth: Information

Texture: The immediate and sustained contact of a widely known, well-respected and trusted member of the HIV-patient community by EMA enabled this patient representative to act as a facilitator within the patient community, as an interface with healthcare professionals and as a spokesperson for the patients and their right to high-quality medicines vis-à-vis EMA. In particular, he could reassure patients that EMA, together with the authorities in EU Member States, took the matter seriously, dedicated appropriate resources, worked as speedy as possible and kept him up to date with honest information. Patients were generally satisfied with this diligent involvement of their trusted representative by EMA, which was also paralleled at national level, for example in France [26]

Discourse type: Reflective discourse, in accordance with IRGC recommendations

Ambiguous risk

Risk of teratogenicity with thalidomide [27, 28]: The causality between birth defects and use of thalidomide against sleep disorders and morning sickness in pregnancy had been established in the 1960s, but ambiguity emerged in 2007 during the assessment for re-authorising thalidomide in the EU against multiple myeloma. The ambiguity emerged from divergent perspectives of persons affected by the severe teratogenic effects (victims) in the 1950/1960s and multiple myeloma patients. Therefore, a stakeholder meeting was convened by EMA

Engagement outcome: The dedicated meeting organised by EMA brought together thalidomide victims and multiple myeloma patients, and their input and convergence on the package leaflet, the labelling of the outer packaging and further comprehensive actions for risk management enabled EMA’s scientific committee to recommend re-authorising thalidomide in 2008

Engagement mechanism: Dedicated meeting

Scope: Obtaining input on a risk management plan and the possibility of a marketing authorisation acceptable to victims

Breadth: Victim and patient representatives

Depth: Consultation

Texture: The dedicated meeting at EMA provided a forum where an open dialogue and mutual understanding between thalidomide victims facing severe challenges every day of their lives and multiple myeloma patients hoping for a new cure could actually happen and convergence could be achieved. Given the trauma of the thalidomide disaster, this convergence on a risk management plan with risk minimisation measures that were acceptable to, and did not compromise, the different expectations of both affected populations was needed for EMA’s scientific committee recommending re-authorisation in an accountable manner [28]

Discourse type: Participative discourse, in accordance with IRGC recommendations, however not in the public domain, as at the time public hearings were not yet a legal option (although the meeting was announced in the public domain)

Risk of PML with natalizumab [29–31]: Natalizumab was authorised in the EU in June 2006, i.e. the same month the US FDA allowed this medicine to re-enter the US market following risk assessment with patient advocate involvement [2]. Furthermore, prior to the EU marketing authorisation, views from patient representatives had been solicited, who were in favour of a clear restriction of natalizumab to patients “that are really in need of such a therapy” [32]. In September 2008, new PML case reports were assessed by EMA’s scientific committee. Given the seriousness of PML and patient appreciation of the treatment benefit, a SAG meeting was convened with patient and healthcare representatives

Engagement outcome: Taking into account the considerations of the SAG meeting, the regulatory decision resulted in strengthening the product information in the sections on warnings and adverse reactions and considered that the evaluation of the risk–benefit balance of the medicine remained positive

Engagement mechanism: Scientific Advisory Group (SAG) meeting

Scope: Obtaining input on preferred diagnostic procedures, risk minimisation measures and the overall risk-benefit balance for the regulatory decision on product information

Breadth: Healthcare professional specialists and one patient representative

Depth: Consultation

Texture: The patient views allowed maintaining the marketing authorisation with acceptance of the PML risk for the regulatory conclusion on a positive risk–benefit balance on the basis of strengthened warnings in the product information [29, 32]

Risk of teratogenicity and developmental disorders with valproate [33, 34]: The risk of birth defects and developmental disorders later in life of children exposed to valproate in utero had been established over time, with several assessments resulting in regulatory risk minimisation measures. Following the measures imposed by PRAC in 2014, ambiguity emerged during a new assessment by PRAC in 2017 initiated because of some lack of implementation and effectiveness of the 2014 measures. Ambiguity emerged from the medical imperatives to give any patient the most beneficial treatment, in particular given fatal risks of epilepsy, and to protect children from teratogenic effects. Additional complexity arose from the fact that children of pregnant women whose epilepsy is not well-treated have health risks also

Engagement outcome: The input from patient and healthcare professionals at the public hearing and subsequent dedicated meeting resulted in regulatory decisions on restrictions in indications and a new programme for risk minimisation and prevention of pregnancy during treatment, including a visual warning on the teratogenic risk on the outer packaging and focus on counselling of female patients, in order to address feedback, requests and suggestions from patients and healthcare professionals

Engagement mechanism: Public hearing

Scope: Obtaining input on the risk of taking valproate during pregnancy and potential effects on the child, on the 2014 risk minimisation measures and the need for further measures for supporting regulatory decisions

Breadth: Patient representative speakers from four European Union (EU) Member States (Belgium, France, Ireland and the UK) and one international organisation, healthcare professional representatives from European umbrella and UK organisations and one marketing authorisation holder

Depth: Consultation

Texture: This first public hearing was a major positive experience for external stakeholders and PRAC alike, all expressing feelings that it “would make a difference” to the PRAC outcome. EMA concluded that the hearing improved the quality of the assessment and was instrumental to the decision making on new risk minimisation measures [35]. During the hearing, aspects critical for the implementation of risk minimisation measures in healthcare emerged, including aspects of an ethical nature that considered the needs for protecting children but at the same time not depriving anybody from necessary treatment. There was overall convergence of all stakeholders on the need for informed therapeutic decision making and free choice of the concerned women, which is reflected in the risk minimisation programme with a focus on counselling of female patients. Overall, the public hearing provided for a high degree of texture due to the very humane, respectful and professional style of the face-to-face interactions [34]

Discourse type: Participative discourse in the public domain, in accordance with IRGC recommendations

EMA European Medicines Agency, IRGC International Risk Governance Council, VTE venous thromboembolism, CHCs combined hormonal contraceptives, PRAC Pharmacovigilance Risk Assessment Committee, EU European Union, EIWH European Institute of Women’s Health, HAART highly active antiretroviral therapy, HIV human immunodeficiency virus, AIDS acquired immune deficiency syndrome, PML progressive multifocal leukoencephalopathy, SAG Scientific Advisory Group