REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL on the national and European Medicines Agency experience regarding the list of medicines for human use subject to additional monitoring
Date: 2019-11-15
Institutions: Directorate-General for Health and Food Safety, European Commission
Subjects: EU Member State, European Medicines Agency, consumer protection, drug surveillance, market approval, marketing standard, medicinal product, public health, single market

EN 

  EN 

   EUROPEAN COMMISSION  Brussels, 15.11.2019  COM(2019) 591 final  REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL on the national and European Medicines Agency experience regarding the list of medicines for human use subject to additional monitoring  
 
 
1. 

INTRODUCTION 

In  the  EU  medicinal  products  for  human  use  are  subject  to  strict  testing  and  assessment  of 
their quality, efficacy and safety before being authorised either at national or EU level. Once 
placed on the market the safety of medicines continues to be monitored through a system of 
pharmacovigilance. This means that  anything that  affects  a medicine’s safety  profile can be 
swiftly detected, assessed, and understood. Appropriate measures can be taken to manage the 
issue and assure public and patients’ health. 

Regulation  (EC)  No 726/20041  and  Directive  2001/83/EC2  provide  the  EU  legal  framework 
for  pharmacovigilance  for  medicinal  products  for  human  use.  The  provisions  on 
pharmacovigilance were amended in 20103 and 20124. As a result of the changes the tasks and 
responsibilities  for  all  parties  were  outlined  within  a  proactive  and  proportionate  risk 
management system. The link between safety assessments and regulatory action, along with 
transparency,  communication  and  patient  involvement  were  strengthened.  This  report 
concerns  the  experience  gained  regarding  ʻadditional  monitoringʼ,  a  specific  aspect  of 
pharmacovigilance activities which was introduced through the revision of the legislation5.  

For some medicines there are limitations in the clinical trials, for example because the number 
of patients are restricted and the available evidence has limitations. The experience of use in 
the  real  life  setting  can  complement  the  evidence  form  the  clinical  trials.  Additional 
monitoring aims to enhance adverse drug reaction (ADR) reporting for medicines for which 
the clinical evidence base is less well developed. The main goals are to collect information as 
early  as  possible  to  further  inform  the  safe  and  effective  use  of  these  medicines  and  their 
benefit-risk profile when used in everyday medical practice. 

The 2010 revision6  introduced additional monitoring for certain  medicines and a mandatory 
scope of new biological medicines or those containing a new active substance. The medicines 
which are subject to additional monitoring are identified by the inclusion of a ‘black symbol’7 
(a black inverted triangle) in the product information.  

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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). 
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). 
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). 
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). 
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. 
Article  1(11)  of  Regulation  (EU)  No  1235/2010  amendment  of  Article  23  of  Regulation  (EC)  No 
726/2004. 
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). 

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In  20128  the  mandatory  scope  was  extended  to  include  medicines  with  certain  post 
authorisation obligations. At the time, some Member States expressed reservations about the 
extension  of  the  mandatory  scope.  Therefore,  the  Commission  was  asked  to  report  to  the 
European Parliament and the Council on the use of the additional monitoring list9. 

The Member States and the European Medicines Agency (EMA) collected information on the 
experience of the implementation of the additional monitoring of medicines through: 

a.  A survey to estimate patient and healthcare professional (HCP) awareness of the black 

symbol and the additional monitoring concept.  

b.  EMA’s  experience  with  the  use  of  the  additional  monitoring  list  and  a  study  on 
whether the inclusion of products on the list had an effect on reporting of their ADRs. 

c.  A survey to understand Member States’ experience with additional monitoring. 

A  joint  report  of  the  Heads  of  Medicines  Agencies  (HMA)  and  EMA  based  on  the  above 
surveys and analysis forms the main basis of this report10. 

2. 

BACKGROUND 

The  safety  of  medicines  is  monitored  throughout  their  lifecycle,  including  the  collection  of 
information  on  suspected  ADRs  (side  effects).  EMA  is  responsible  for  developing  and 
maintaining  EudraVigilance,  an  IT  system  for  managing  and  analysing  information  on 
suspected ADRs to medicines authorised in the European Economic Area (EEA)11. 

As  part  of  the  implementation  of  the  new  pharmacovigilance  provisions  the  new  system  to 
label medicines that are being monitored particularly closely, generally because there is less 
information  available  about  them  was  applied  in  2013.  These  medicines  are  described  as 
being under ‘additional monitoringʼ.  

Medicines subject to additional monitoring include an inverted black triangle (referred to as 
the black symbol in the legislation) and an explanatory statement in the product information12. 
For example, the following is included in the package leaflet: 

 This medicinal product is subject to additional monitoring. This will allow quick 

identification of new safety information. You can help by reporting any side effects you may 
get. See the end of section 4 for how to report side effects.  

A list of medicines under additional monitoring is published by EMA and updated monthly to 
add new medicines and any changes in monitoring status of those medicines on the list13.  

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Article  1(4)  of  Regulation  (EU)  No  1027/2012  amendment  of  Article  23  of  Regulation  (EC)  No 
726/2004. 
Article 23(4a) of Regulation (EC) No 726/2004. 
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. 
Data  from  EudraVigilance  is  published  in  the  European  database  of  suspected  adverse  drug  reaction 
reports http://www.adrreports.eu/. 
Leaflet on the black triangle  https://ec.europa.eu/health/sites/health/files/files/pharmacovigilance/2013-
10_blacksymbol/bs2013_10_en.pdf. 

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To support the Member States implementation of the new pharmacovigilance provisions the 
Commission  funded  a  Joint  Action  on  Strengthening  Collaboration  for  Operating 
Pharmacovigilance in Europe (SCOPE)14. SCOPE gathered information and expertise on how 
regulators  in  Member  States  run  their  national  pharmacovigilance  systems  and  developed  a 
variety of tools to support best practice15.  

The  Guideline  on  good  pharmacovigilance  practices  (GVP):  Module  X  –  Additional 
monitoring  drafted  by  EMA  explains  the  general  principles  for  assigning  additional 
monitoring  status  to  medicines,  the  communication  and  transparency  aspects,  and  a 
description  of  the  operation  of  the  EU  network  regarding  the  supervision  of  additional 
monitoring16.  

2.1 

Which medicines are subject to additional monitoring? 

The mandatory scope of additional monitoring obligation included in the 2010 revision of the 
legislation was the names and active substances of: 

  medicinal products authorised in the Union that contain a new active substance which, 
on  1  January  2011,  was  not  contained  in  any  medicinal  product  authorised  in  the 
Union;  

  any biological medicinal product that was authorised after 1 January 2011. 

During the 2012 revision of the legislation, the mandatory scope of the additional monitoring 
list was extended to certain medicines with specific post-authorisation obligations, namely:  

  products for which a post authorisation safety study (PASS) was requested at the time 

of marketing authorisation or following the granting of an authorisation; 
  products which were granted a conditional marketing authorisation (CMA); 
  products authorised under exceptional circumstances; 
  products  authorised  with  obligations  for  stricter  recording/monitoring  of  suspected 

ADRs. 

The legislation also provides the possibility to include medicines subject to other conditions 
falling under the so-called ‘optional scope’ of additional monitoring17. This can be done at the 
request  of  the  Commission  or  a  national  competent  authority  (NCA)  following  consultation 
with the Pharmacovigilance Risk Assessment Committee (PRAC). This option had not been 
used during the period of the reported experience.  

In principle, the additional monitoring status is time limited. This is 5 years for those included 
solely on the basis of being a new biological medicine or containing a new active substance. 

13  

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17  

https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medicines-
under-additional-monitoring/list-medicines-under-additional-monitoring 
http://www.scopejointaction.eu/  
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  
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-
practices-module-x-additional-monitoring_en.pdf  
Article 23(1a) of Regulation (EC) No 726/2004. 

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In other  cases  it is  after  all the conditions  for the inclusion in  the additional  monitoring list 
have been fulfilled. When medicines are no longer subject to additional monitoring the black 
symbol is removed from the product information. 

Only those medicines specifically named in the list are subject to additional monitoring. This 
means that medicines not specifically named are not subject to additional monitoring, even if 
they have the same active substance and indication as medicines in the list.  

The  first  version  of  the  list  was  published  in  April 2013  and  included  105  medicines.  In 
December 201618 the list included in total 2099 medicines (see section 4.1 for details). 

3. 

PUBLIC AWARENESS OF THE CONCEPT OF ADDITIONAL MONITORING 

In 2017 EMA conducted a public survey to understand awareness of reporting adverse drug 
reactions, including for medicines under additional monitoring19. 

In total 2862 responses were received from EEA countries and 56 responses from non-EEA 
countries  (2918  in  total).  Healthcare  professionals  were  53%  of  the  respondents  and  47% 
were non-HCP (i.e. patients or members of the public).  

Within  the HCP group 85% had observed at  least  one ADR, of whom 76% had reported  at 
least one ADR. In the non-HCP group, 67% had experienced at least one ADR, of whom 73% 
had reported at least one ADR.  

Overall, 88% of the respondents indicated they would definitely or probably report an ADR 
for a medicine identified with black triangle (i.e. subject to additional monitoring). From the 
reported experience of ADR reporting, of the 227 responders who had reported an ADR for a 
product  identified  with  a  black  triangle  37%  indicated  that  the  black  triangle  was  an 
influencing factor. Reasons given for not reporting an ADR were: it was already listed (28%); 
it  was  not  serious  (15%);  unsure 
the  medicine  (13%); 
practical/technical/other reasons (18%). 

if  ADR  was  related 

to 

Of all the respondents, 51% indicated that they had seen the black triangle and accompanying 
statement. The highest awareness was among pharmacists (83%), with the lowest awareness 
among patients (30%). The majority (83%) indicated that they understood the meaning of the 
black  triangle/accompanying  statement.  Although  in  response  to  a  question  exploring  what 
the black triangle  and the accompanying statement  meant,  it was judged  by EMA that 53% 
had  acceptable  understanding  and  17%  had  misunderstood  the  concept20.  Among  the 
responses  assessed  as  ‘misunderstanding’,  the  most  frequently  mentioned  themes  for  the 
inclusion of the black triangle were safety concerns or lack of safety data. 

Among all respondents to the survey, 36% showed an acceptable understanding. The level of 
understanding  was  different  among  various  groups  of  responders.  The  best  was  among 

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20  

The cut-off date for the reporting of the EMA experience. 
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. 
The remaining replies were assessed as insufficient information, no understanding or not responded. 

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pharmacists (45%) and lowest among nurses (23%). Nearly half of responders (48%) who had 
previously seen the black triangle had ‘acceptable’ understanding, compared to 24% of those 
who had not seen it before. 

The  HMA/EMA  report  mentioned  a  2016  survey  conducted  by  European  Organisation  for 
Rare  Diseases  (EURORDIS)  on  the  meaning  of  the  new  pharmacovigilance  system  to 
patients21.  According  to  the  EURORDIS  survey,  61%  of  patients  experienced  an  ADR,  of 
whom 84% reported the ADR. Within the survey 20% of the patients reported that they had 
seen a black triangle. 

A survey22 of the awareness of HCP of pharmacovigilance for biological medicines took place 
in  Ireland  23.  The  majority  of  HCP  surveyed  were  aware  of  the  concept  of  additional 
monitoring  (82%).  Among  pharmacists  94%  were  aware  compared  to  73%  of  doctors  and 
nurses. Among those who were aware of the concept of additional monitoring, the awareness 
of the black triangle was 88% of pharmacists and 30% of doctors and nurses. 

4. 

4.1 

IMPACT ON MONITORING OF SIDE EFFECTS 

The additional monitoring list 

Based  on  experience  between  April 2013  to  December 2016,  EMA  analysed  whether  the 
inclusion  of  a  medicine  in  the  additional  monitoring  list  had  an  effect  on  the  reporting  of 
ADRs. 

The first  version of the additional monitoring list  was published in  April 2013 and included 
105 medicines (101 centrally authorised medicines (CAPs) and 4 non-CAPs). The reasons for 
inclusion in the list were: new active substance (NAS)24 70%; new biological medicine 2%; 
an  imposed  PASS  8%;  marketing  authorisation  granted  under  exceptional  circumstances  or 
CMA 21%. 

In  December 2016,  the  list  included  a  total  of  2099  medicines  (273  CAPs  and  1826  non-
CAPs) separated into a main list of 301 medicines and 13 annexes with 1798 medicines. Each 
annex  included  medicines  with  the  same  active  substance  for  which  a  PASS  had  been 
imposed as an outcome of an EU review of the safety of the active substances concerned. The 
reasons  for  inclusion  in  the  list  were:  NAS  9%;  new  biological  medicine  2%;  imposed 
PASS 88%;  marketing  authorisation  granted  under  exceptional  circumstances  or  CMA  1%. 
However, if each of the annexes is considered as one entry in the main list (making a total of 
314 products) the reasons for inclusion would be: NAS 63%; new biological medicine 15%; 
imposed  PASS  18%;  marketing  authorisation  granted  under  exceptional  circumstances  or 

21  

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24  

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. 
The research was supported by the Health Products Regulatory Authority, Regulatory Science Ireland 
and University College Cork. 
J. O’Callaghan et al, BioDrugs (2018) 32:267-280. 
The figures where NAS is the reason for inclusion in the additional monitoring list include all products 
which contained a new active substance. 

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CMA 5%. The majority (87%) of the products in the December 2016 list were non-CAPs due 
to the high number of nationally authorised products subject to an imposed PASS. 

4.2 

Reporting 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.’ 

4.3 

Impact 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 investigation25. EMA looked at whether inclusion of a medicine 

25  

‘Signal’ is defined in Article 19 of Commission Implementing Regulation (EU) No 520/2012. 

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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. 

5.1 

NATIONAL EXPERIENCE WITH ADDITIONAL MONITORING  

Experience of Member States 

The  SCOPE  Joint  Action  investigated  the  Member  States’  experience  of  ADR  collection, 
including  additional  monitoring27.  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  equivalent28,  although  no 
information was available on the initial baseline of resources. The main reasons mentioned for 

26  

27  

28  

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. 
Work package 4 - Identification, management and raising awareness of ADR reports for drugs subject 
to 
-  http://www.scopejointaction.eu/_assets/files/WP4-DEL3-Additional-
Monitoring.pdf.  
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. 

additional  monitoring 

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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. 

5.2 

Views 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. 

5.3 

Overall 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 

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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 medicines29. 

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 

29  

SCOPE  ADR  Awareness 
collection/awareness-levels/.  

toolkit 

- 

http://www.scopejointaction.eu/outputsandresults/adr-

9 

 
 
                                                           
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. 

10