Annexes to COM(2019)591 - National and European Medicines Agency experience regarding the list of medicines for human use subject to additional monitoring - Main contents
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| dossier | COM(2019)591 - National and European Medicines Agency experience regarding the list of medicines for human use subject to additional ... |
|---|---|
| document | COM(2019)591  |
| date | November 15, 2019 |
4.2Reporting of side effects (ADRs) for medicines under additional monitoring
The primary aim of additional monitoring is to enhance side effects (ADR) reporting. EMA investigated whether ADR reports to the EudraVigilance database (EV) changed after inclusion of the medicine in the additional monitoring list.
EMA used the December 2015 additional monitoring list to identify medicines for analysis as this allowed at least 12 months follow-up for ADR reporting whilst under additional monitoring. The final analysis was restricted to medicines for which at least 10 ADR reports from within the EEA had been received per month. EMA analysed the ADR reporting for 11 medicines for 12 months prior to and 12 months after their inclusion in the additional monitoring list.
EMA reported that the ways in which ADR reporting changed after addition to the list were heterogeneous. Of the five medicines containing a NAS, two demonstrated a statistically significant increase in the slope of ADR reporting after inclusion in the list, the others did not show significant changes. Among the six products included due to a PASS, no changes in reporting were identified for three products, whilst three products showed a significant decrease in the slope of ADR reporting.
EMA noted that the study had several limitations, for example due to the limited data set (11 medicines), the length of the observation period (up to 24 months). Time-dependent confounders could not be accounted for in the analysis and the assumptions for the calculations could affect the results. The power to detect a difference in reporting was restricted.
In summary, EMA indicated that there was some evidence that reporting may be increased for some medicines containing a NAS. There was no evidence that additional monitoring increases reporting of ADRs for products subject to a PASS. EMA noted that the analysis was restricted to a small subset of products and was possibly underpowered, so the results need to be interpreted with caution. In addition, EMA noted that ADR reporting may also have increased due to factors other than inclusion in the additional monitoring list.
The EMA/HMA report concludes ‘If the analyses had shown marked and consistent increases in ADR reporting then it would be reasonable to conclude that AM [additional monitoring] was increasing the reporting for these products. However, the inconsistent and marginal results, combined with the known, disparate external influences on ADR reporting, suggest that even with a larger sample size and longer follow up the potential to definitively demonstrate a causal link between AM and increased reporting, is unlikely.’
4.3Impact of additional monitoring status on safety signals for medicines
A safety signal is information on a new or known adverse event that may be caused by a medicine and requires further investigation 25 . EMA looked at whether inclusion of a medicine in the additional monitoring list affected the detection and management of safety signals related to it. Between April 2013 and December 2016, 269 signals were assessed by PRAC, of which 58 concerned only active substances in medicines subject to additional monitoring while 26 signals involved several medicines some of which were on additional monitoring list.
Of the 58 signals (21%) which concerned active substances only in medicines subject to additional monitoring, 78% related to medicines with a NAS, 19% had an imposed PASS and 3% had marketing authorisation granted under exceptional circumstances or CMA.
A safety review (referral) 26 was initiated in four cases (7%) of signals concerning medicines on the additional monitoring list compared to 2 cases (1%) of those not on the list. Circulation of a direct healthcare professional communication (DHPC) was recommended in 7% of assessed signals related to medicines on the additional monitoring list, compared to 5% for medicines not on the list. However, EMA noted that any differences must be evaluated with caution. With an update of the product information the outcome for 38% of the assessments for medicines on the list compared to 49% of those not on the list. It was concluded by EMA that signal outcomes were similar for the products subject to additional monitoring or not and that it could not be concluded that the additional monitoring status has an impact on signal outcomes.
5. National experience with additional monitoring
5.1Experience of Member States
The SCOPE Joint Action investigated the Member States’ experience of ADR collection, including additional monitoring 27 . It reports that 60% of the Member States do not specifically identify ADR reports for medicines subject to additional monitoring.
In a separate survey in 2017, EMA asked Member States about their experience with additional monitoring. Twenty-six NCAs responded to the survey and all had undertaken at least one activity to promote the additional monitoring concept. Twenty five NCAs had such initiatives in 2013, around the time that the black triangle and accompanying statement was included in the product information. Between 2014-2017, on average eight NCAs per year reported doing new communication activities.
Twenty NCAs reported that there had been an increase in the workload associated with the introduction of the additional monitoring symbol. Where estimates of the additional time were given, the estimated range was from around 0.02 to 1 full-time equivalent 28 , although no information was available on the initial baseline of resources. The main reasons mentioned for the increase in workload were administrative and regulatory tasks such as: signal detection activities; ADR management; increase in ADR reporting; website updates; dealing with queries; other regulatory tasks (e.g. variations of the marketing authorisation, review of educational materials).
In the survey additional comments were made by three NCAs. One noted that there were indications that some patients may refrain from using products subject to additional monitoring. One reported that they had noted awareness among HCPs about the black symbol and that the HCPs specifically report ADRs for the medicines subject to additional monitoring. Two NCAs expressed reservations about the usefulness of the scheme, especially for products with an imposed PASS.
5.2Views of the Pharmacovigilance Risk Assessment Committee
PRAC was consulted on the draft EMA/HMA report on the experience of additional monitoring. During this consultation some members raised concerns regarding an imposed PASS being a mandatory trigger for inclusion of a medicine in the list. The committee noted that additional pharmacovigilance activities, such as a PASS, would be imposed if routine activities, such as spontaneous reporting, do not sufficiently address the safety issue. PRAC also noted that there could be cases where a PASS might be imposed for one product whilst other similar products do not have a PASS imposed. In such cases, only the medicine with a PASS would be included in the additional monitoring list. It was mentioned that some NCAs have experienced that patients may question the lack of consistency, such that among the same-substance medicines some are perceived as ‘safer’ because they do not have the black triangle. PRAC considered that such inconsistency can undermine confidence in the pharmacovigilance system in general and in additional monitoring specifically.
PRAC suggested that additional monitoring status imposed at an active substance level, rather than individual medicinal product level, would prevent situations where several products containing the same active substance have different additional monitoring status. They also indicated that if substance level additional monitoring were considered to lead to other challenges, then many of the difficulties could be resolved by removing the additional monitoring status of products with an imposed study.
5.3Overall conclusions presented in the HMA/EMA report
The overall conclusions presented in the HMA/EMA report of the experience of additional monitoring were that, the results suggest:
·Both more time and more communication are needed to raise the awareness of AM [additional monitoring], as well as the need for ADR reporting in general. The EMA survey results suggest that knowledge of AM is higher in some groups than others and that these data could be used to target the messaging and intensity of communications;
·The EudraVigilance analysis investigating the effect of additional monitoring status on reporting of ADRs was not conclusive and the known disparate influences on ADR reporting raise doubts as to whether a longer period and larger product sample would enable the detection of an impact of AM on ADR reporting and signal detection, if such an effects exists;
·The inclusion of imposed PASS as a mandatory trigger for additional monitoring leads to large numbers of established products being included in the list and is of limited value.
·Additional monitoring status being at product level combined with the inclusion of imposed PASS as a mandatory trigger for additional monitoring were highlighted as major issues with the additional monitoring concept. This is because of the resulting misunderstanding among patients and HCPs, due to situations when several products containing the same active substance have different AM status. Most examples of this inconsistency could be resolved by removing imposed PASS as a mandatory trigger of additional monitoring status;
·PRAC would support reconsideration of the scope of additional monitoring, particularly the mandatory inclusion of products subject to imposed PASS.
6. Conclusions and recommendations
The report presented by the HMA/EMA on the experience of the Member States and EMA on additional monitoring gives an overview of the experience in the three years after the introduction of the black triangle in 2013.
At the time of inclusion of the black triangle in the information about the concerned medicines there were activities organised by the national competent authorities to promote the concept of additional monitoring and the importance of reporting ADRs in general.
Regarding the awareness about additional monitoring, the reported experience of additional monitoring indicates that the groups surveyed, including patients and healthcare professional, had knowledge of the concept of additional monitoring, although the level of understanding varied. The survey of patient and healthcare professionals indicated that there is a misunderstanding about the reasons for a medicine being subject to additional monitoring. It is suggested in the HMA/EMA report that more time and more communication activities are needed to raise awareness of the additional monitoring and the reasons for inclusion of a medicine in the list.
The Commission supported the activities of the SCOPE Joint Action. Through this project various materials have been developed that can support raising awareness of how to report adverse events associated with use of medicines 29 .
Recommendation 1 – Member States and EMA are encouraged to continue promoting ADR reporting and sharing their experience to further develop best practices.
Regarding the impact of the inclusion of a medicine on the additional monitoring list, the EV analysis investigating the effect of inclusion in the additional monitoring list on reporting of ADRs was not conclusive. It was also not possible to conclude on whether additional monitoring status has an impact on the number of signals validated and assessed by the PRAC or on signal outcome.
For the HMA/EMA report a survey of Member States was completed in which it was mentioned by some respondents that the inclusion of medicines with an imposed PASS in the additional monitoring list leads to a large number of medicines which have been on the market for many years being subject to additional monitoring. Some Member States questioned the added value in these cases and the possibility for misunderstanding the reason for inclusion of the black triangle in the product information. It was also mentioned that confusion can be created when products with the same active substance are not always subject to additional monitoring. The issue of whether there is any confusion regarding products with the same active substance was not part of the surveys mentioned in the report.
Recommendation 2 – the evidence does not allow a conclusion on the impact of additional monitoring on the reporting or detection of adverse events. It is recommended to continue to monitor the impact to strengthen the evidence base for future review of the scheme.
Regarding the scope of the additional monitoring list, PRAC indicated its support for the reconsideration of the scope of the additional monitoring obligations, in particular the mandatory inclusion of products subject to imposed PASS.
The Commission notes that there have been observations and concerns from some Member States about the reasons for inclusion in the additional monitoring list, in particular those that have an imposed PASS, and that PRAC supports reconsideration of the mandatory scope for additional monitoring.
The Commission does not consider that these concerns require an immediate review of the legislation but evidence on the implementation and impact of additional monitoring can be considered as appropriate in any future review of the legislation.
Recommendation 3 – competent authorities are invited to continue to collect data regarding the implementation of additional monitoring to allow at a later stage further assessment of the understanding of additional monitoring and its impact with respect to medicines with the same active substance, as well as experience concerning medicines with an imposed PASS.
(1)
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1).
(2)
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67).
(3) Regulation (EU) No 1235/2010 (OJ L 348, 31.12.2010. p 1), Directive 2010/84/EU (OJ L 348, 31.12.2010. p 74).
(4) Regulation (EU) No 1027/2012 (OJ L 316, 14.11.2012. p 38), Directive 2012/26/EU (OJ L 299, 27.10.2012. p 1).
(5) The concept and scope of additional monitoring was introduced in Article 23 of Regulation (EC) No 726/2004 through Regulation (EU) No 1235/2010 and amended by Regulation (EU) No 1027/2012.
(6) Article 1(11) of Regulation (EU) No 1235/2010 amendment of Article 23 of Regulation (EC) No 726/2004.
(7) The ‘black symbol’ is defined by Article 23 of Regulation (EC) No 726/2004 and Article 11 of Directive 2001/83/EC. It was designated as a black inverted triangle through Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional monitoring (OJ L 65, 8.3.2013, p. 17).
(8) Article 1(4) of Regulation (EU) No 1027/2012 amendment of Article 23 of Regulation (EC) No 726/2004.
(9) Article 23(4a) of Regulation (EC) No 726/2004.
(10) European Medicines Agency and Member States joint report to the European Commission on the experience with the list of products subject to additional monitoring, EMA/153015/2018, 8 March 2018.
(11) Data from EudraVigilance is published in the European database of suspected adverse drug reaction reports http://www.adrreports.eu/ .
(12) Leaflet on the black triangle https://ec.europa.eu/health/sites/health/files/files/pharmacovigilance/2013-10_blacksymbol/bs2013_10_en.pdf .
(13) https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medicines-under-additional-monitoring/list-medicines-under-additional-monitoring
(14) http://www.scopejointaction.eu/
(15)
Radecka A. Loughlin, L., Foy, M. et al., Enhancing Pharmacovigilance Capabilities in the EU Regulatory Network: The SCOPE Joint Action, Drug Safety, (2018) 41: 1285. https://doi.org/10.1007/s40264-018-0708-5
(16) https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-x-additional-monitoring_en.pdf
(17) Article 23(1a) of Regulation (EC) No 726/2004.
(18) The cut-off date for the reporting of the EMA experience.
(19) The survey was available to the general public on the EUSurvey platform for 5 weeks between September and October 2017. Information about the survey was disseminated by EMA, NCAs, HCPs and patient organisations.
(20) The remaining replies were assessed as insufficient information, no understanding or not responded.
(21) Presentation by François Houÿez “What does the new PhV [pharmacovigilance] system mean for patients in real life?” Available at: https://www.eurordis.org/sites/default/files/Eurordis_patients_and_pharmacovigilance.pdf .
(22) The research was supported by the Health Products Regulatory Authority, Regulatory Science Ireland and University College Cork.
(23) J. O’Callaghan et al, BioDrugs (2018) 32:267-280.
(24) The figures where NAS is the reason for inclusion in the additional monitoring list include all products which contained a new active substance.
(25) ‘Signal’ is defined in Article 19 of Commission Implementing Regulation (EU) No 520/2012.
(26) Referral procedures are used to address concerns over the safety or benefit-risk balance of a medicine. Safety reviews of signals are on the basis of Articles 31 or 107i of Directive 2001/83/EC and Article 20 of Regulation 726/2004.
(27) Work package 4 - Identification, management and raising awareness of ADR reports for drugs subject to additional monitoring - http://www.scopejointaction.eu/_assets/files/WP4-DEL3-Additional-Monitoring.pdf .
(28) Three NCAs mentioned a low additional workload, whilst four NCAs mentioned 0.5 day per month, 1 full time equivalent (FTE), 0.1 FTE, and 150 hours per year respectively.
(29) SCOPE ADR Awareness toolkit - http://www.scopejointaction.eu/outputsandresults/adr-collection/awareness-levels/ .