Overview comments received non-spontaneous AE · Overview of comments received on 'Reflection paper on ... In addition, MAHs frequently have staff in many different ... made to the

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11 May 2016 EMA/CVMP/PhVWP/615063/2016 Committee for Medicinal Products for Veterinary Use

Overview of comments received on 'Reflection paper on non-spontaneous adverse event reports' (EMA/CVMP/PhVWP/357539/2015)

Interested parties (organisations or individuals) that commented on the draft document as released for consultation.

Stakeholder no. Name of organisation or individual

1 AVC – Association of Veterinary Consultants 2 EGGVP – European Group for Generic Veterinary Products 3 Elsevier BV – Life Science Solutions 4 FVE – Federation of Veterinarians of Europe 5 IFAH-Europe – International Federation for Animal Health Europe

Overview of comments received on 'Reflection paper on non-spontaneous adverse event reports' (EMA/CVMP/PhVWP/357539/2015) EMA/CVMP/PhVWP/615063/2016 Page 2/32

1. General comments – overview

Stakeholder no.

(See cover page)

General comment (if any) Outcome (if applicable)

1 Administrative burden for small and medium sized enterprises and the benefit / cost ratio should be taken into consideration. For the MAH the data privacy may be a hurdle to receive all necessary information from fora and / or social media users to evaluate and assess the published information.

2 EGGVP welcomes the unification of variable national requirements on literature search in a common reflection paper and the opportunity to comment on this draft. Peer-reviewed published literature Identification and collection of information on Adverse Events (AEs) is of high importance ensuring the safety and communication of benefit: risk of veterinary medicinal products. Literature search is a high administrative burden in pharmacovigilance work because of the ever expanding literature. The MAHs are using well-known national literature databases, which often cover multiple publication platforms. Often all publication platforms list the same article, so a lot of time is spent to exclude duplicates. To keep the variability of information in the EU, it should not be prescribed to use specific literature databases, as uniformity of information will cause a loss of information. Literature search gives rarely information about adverse events not mentioned in the product information. Furthermore articles are published about a year later based in the necessary revision of the


Stakeholder no.

(See cover page)


texts. There is rarely a chance to get further details from the author due to the time passed. It is therefore adequate to give information on literature search in the PSUR rather than to do reporting according to a spontaneous AE. Volume 9B does not give obligation for a yearly literature research. This literature research is voluntary and should therefore be on the MA decision how it is performed. Volume 9B requests to perform a product specific search, so most of the MAHs will do a research for their products at regular intervals and a research on the active substance only at the time of PSUR covering the time since the last PSUR. Resistance to antimicrobials and antiparasitics Assessment of clinical efficacy and resistance development are separate expert reports and it is not affordable to be assessed in the PSUR as well. In the PSUR only information on spontaneous reports should be included. Social media EGGVP has major concerns about sourcing information from social media as it is a tremendous administrative burden and no reliable source or information can be identified. When the MAH holds his own website and social media accounts, he can observe and follow-up the activity on his website. There is no obligation and no sense to monitor movements in social media of breeder groups, interest groups and what so ever. These groups grow like mushrooms and cannot be monitored at all. Furthermore participants use abbreviations, nick names or pseudonyms and share second-hand information or even spread


Stakeholder no.

(See cover page)


rumours. This cannot be recognized as reliable source or accurate information.

4 FVE welcomes the Reflection paper on non-spontaneous adverse event. FVE welcomes trying to complement spontaneous reporting by non-spontaneous reporting. What we miss in the paper is an approach that where MAH just regularly survey veterinary surgeons on adverse events seen with their products and the efficacy of their veterinary medicinal products. Most MAH have very good collaboration with their customers, so short and easy questions for feedback should be easy to build into the system and can provide a wealth of information. This is especially important for new veterinary medicinal products or products they have suspicion of giving adverse events or a lack of expected efficacy. Also we think the conclusions could be a bit clearer and strong, now it seems all quite vague and optional. A standard approach to systematic review must be included in this reflection paper.

5 IFAH-Europe welcomes the opportunity to comment on this draft Reflection paper. Although it is recognised that identifying and collating information on Adverse Events (AEs) has a very important role to play in monitoring and ensuring the safety and communication of benefit: risk to veterinarians, IFAH-Europe has major concerns about sourcing information from social media as these are not considered to be reliable. The proposed changes in detection of non-spontaneous AEs in literature by active ingredient or searching of safety information in


Stakeholder no.

(See cover page)


internet and social media would be a high administrative burden for all stakeholders and is not in line with Vol 9B. The four minimum information for adverse event reports including identifiable source and concerned VMPs (name and marketing authorisation number) have to be fulfilled. Furthermore there is no indication and there are no examples available that the tremendous efforts to detect non-spontaneous reports via literature, social media or internet really improve the safety of products. Please find more specific comments below: Literature Searching: Clarification on what constitutes/should be considered peer-reviewed literature would have been helpful, since there has been discussions with national competent authorities on this. The scientific literature is an ever expanding resource; however that also means that it is ever more resource intensive to conduct comprehensive searches of the nature requested. There should be an assessment of return on investment undertaken for additional literature searching rather than a pursuit of literature searching perfection: is there any evidence that the literature search that is currently conducted by MA is missing important safety signals which are not otherwise identified? Literature searching has been performed by MAHs for years and we know by experience that it has produced very limited results. Very rarely non-spontaneous reports are detected. Furthermore, AEs that were detected by literature search appeared to have been reported already to the MAH or NCA, often months or years before the literature was published. The reported signs were known already and sufficiently addressed in the product literature. In addition, MAHs frequently have staff in many different


Stakeholder no.

(See cover page)


countries and experience shows that where there has been an important safety concern raised, this has been identified by MA staff independent to formal Pharmacovigilance driven literature searching. The fact that all but the most important safety signals should not be reported outside a PSUR means that literature searching should also be conducted on the same frequency to ensure the completeness of the PSUR. The use of multiple databases for literature searching has the disadvantage that duplicate literature references cannot be excluded so that a single reference will inevitably have to be reviewed many times in duplicate without any identified additional value. IFAH Europe is not aware of any way to aggregate multiple differently structured sources to remove duplicates. IFAH Europe is of the opinion that literature search in general does not provide added value, the search in multiple databases should not be requested. The literature search in at least one renowned database should thus be sufficient. Added value of search in different databases should be demonstrated by authorities prior to this request and enforcement. In the peer reviewed published literature, frequently reference is made to the manufacturer and brand in the materials and methods. For this reason, MAs should be expected to only search for their own products. Furthermore the search for an active substance even in combination with other key words such as Adverse Events or toxicity would produce a very high number of false positive “hits” especially for old products or active ingredients which will be used in e.g. Human Medicine or agriculture as well. In our opinion it has to be concluded that literature search, based on active ingredient, does not contribute to improvement of the benefit/risk evaluation. Therefore, additional requirements to the current Volume 9B are neither


Stakeholder no.

(See cover page)


contributing nor acceptable. 5 Antibiotic resistance:

While the scope of veterinary pharmacovigilance includes lack of efficacy (the observed failure of a desired effect in a treated animal), the microbiological measurement of antibiotic resistance is currently neither in scope, nor is it consistently applied (e.g. clinical breakpoints are lacking for certain drug-bug-indication-species combinations or are not necessarily related to clinical outcomes i.e. lack of efficacy). Lack of efficacy to an antibiotic can be caused by a range of different host, pathogen and treatment timing factors other than antibiotic resistance and conversely successful treatment outcomes can occur even in the presence of apparently resistant organisms. With the exception of the surveys conducted by CEESA, there is currently very little well controlled (i.e. standardised and harmonised) data on antibiotic resistance in target pathogens. Some specific comments are provided on the ‘databases’ recommended. The majority of the databases listed do not, in fact, have useful information about antibiotic resistance in relation to veterinary antibiotic indications. For example DANMAP does not survey veterinary pathogens but veterinary commensals and indicator bacteria (including Salmonella) – but these are not taken from diseased veterinary patients (which would be relevant for antibiotic resistance), rather from healthy animals at slaughter and includes samples taken from imported meat. In addition the DANMAP assessment is against the ECOFF (to identify % non-wildtype) rather % above clinical breakpoint (although the results are still being reported as ‘% resistance’). No MIC distributions are provided. For these reasons, there is no relevant information in this survey for


Stakeholder no.

(See cover page)


veterinary target pathogens. To a similar or lesser extent the same or similar criticisms can be made of the other database sources quoted. It is clear that, other than the work conducted by CEESA, there is no data which is directly comparable across Europe as a whole and most countries are not generating epidemiologically structured data from untreated animals which is relevant to antibiotic resistance (based on clinical breakpoints) in target pathogens. Notwithstanding the above, IFAH-Europe questions whether there is a current legal basis for including antibiotic resistance surveillance within the scope of Pharmacovigilance. What is clearly within the scope of pharmacovigilance is the investigation of antibiotic lack of efficacy cases – including where possible or appropriate an assessment of pathogen resistance and the reporting of this information as part of the case and reviewing such cases as part of a PSUR (including other clinically relevant information – if available).

5 Anthelmintic or other parasite Resistance: Much of the published literature on anthelmintic or other parasite resistance is either in essence, individual case reports of lack of efficacy to an individual active or comparisons between different actives. This lack of efficacy cases should be identified during literature searching. In comparison to the situation with antibiotic resistance, much of the in vitro work is class rather than molecule or product specific and this makes its interpretation for an individual product challenging to interpret. What is clearly within the scope of pharmacovigilance is the investigation of anthelmintic lack of efficacy cases – including where possible or appropriate an assessment of parasite resistance and the


Stakeholder no.

(See cover page)


reporting of this information as part of the case and reviewing such cases as part of a PSUR (including other clinically relevant information – if available).

5 Anecdotal Internet Reports: This document does not provide any guidance on what is considered an “identifiable reporter” with respect to the internet (e.g. reporter in interest groups in fora often use invented names). Clarification on what is considered an “identifiable” reporter is needed. Only those reports on the internet or social media which come to an MAHs attention (e.g. through the MAHs own sites or where an employee of the MAH becomes otherwise aware of a forum) and which fulfil the basic criteria for an adverse event: identifiable (/ contactable) reporter, a patient, a company veterinary medicine, and an adverse event should be considered reportable. The other ‘chatter’ such as anecdotes, hearsay or speculation on rumour e.g. “I’ve heard of a breeder who had 4 dogs die…” should not be considered reportable unless the origin of the alleged event becomes clearly identifiable or contacts the company directly or indirectly through a veterinarian.

5 Global Dimension: It is necessary to consider the global dimension when making recommendations on the approach to be taken, as particularly for the internet and social media, the normal country/region boundaries do not exist. Early alignment of the EMA with the relevant Authorities in USA and Japan could form the basis for a more harmonised approach from the outset. Otherwise the risk is each country/region will require its own approach, with for example multiple different searching techniques having to be used despite the objective being the same.


2. Specific comments on text

Line no. Stakeholder no.

Comment and rationale; proposed changes Outcome

24 4 Proposed change: …peer-reviewed published worldwide literature…

Not accepted. Modified to “worldwide literature” as also lay press or other sources can be a source of information.

30-31 5 Comment: The sentence indicates there is a wealth of structured and non-structured information, but it does not take into account if this is valuable and useful information. Proposed change: Please modify this sentence to read: “On the contrary there is a wealth of structured and non-structured information in: to “Safety related information might also be found in:”

Partly accepted. As also information on efficacy should be considered, the sentence is modified to: “Pharmacovigilance related information might also be found in..”

32 4 Proposed change: …the scientific peer-reviewed open literature…

Not accepted. “Scientific literature” is used as a general quotation in this part.

33-34 4 Proposed change : …breeders associations and veterinary associations among others. etc…

Partly accepted. Text to be amended to: “breeders associations, veterinary associations or other relevant groups” in order not to be limited.

35 4 Comment: Please clarify ‘etc.’

Partly accepted. The list is not exhaustive as also other media can be a source of pharmacovigilance information.

43-70 4 Comment: Section 2.1 A standard approach to systematic review must be

Not accepted. The paper gives already a description on what would be expected from a literature search. This is a broad enough




included in this reflection paper. A comprehensive literature search using CAB Abstracts, Medline, PubMed, web of Science and Google Scholar should be described. Some MAH ask the NCA for a list of relevant national literature for searching adverse events. It should be optimal if all MAHs would ask and receive such list. Other than peer-reviewed published literature, since MRL violation is part of pharmacovigilance, NCAs could use their national databases regarding program for monitoring of residues for positive findings.

initial search, preferably with the use a variety of databases and/or searches engines and a justification of the choices.

44 4 Proposed change (if any): …perform a peer-reviewed literature…

Partly accepted. The sentence has been deleted. Section 2.1 on a whole concerns peer-reviewed published worldwide literature.

44-49 5 Comment: This paragraph is not clear: Shall all literature cases be reported in PSURs (as current) or only serious cases? Yearly literature searches in addition to PSURs? It is not clearly defined what would be required for issues requiring urgent attention (e.g. reporting cases as spontaneous report in an expedited manner?). It is unclear what is considered “serious problem” in this context. For ease of the reporting process, following detection the literature cases should be handled in the same way as the spontaneous adverse event reports (i.e. only serious animal AEs and any human AE to be reported expedited). Proposed change:

Partly accepted. Considering Volume 9B, the section is to be modified to: “It is recommended that MAHs search the literature regularly as part of their ongoing surveillance/signal detection procedures and at least yearly for products on a three-yearly PSUR reporting cycle. The MAH should report published adverse events associated with the use of its VMPs in accordance with the requirements for adverse event reporting and in PSURs in accordance with Volume 9B”.




Please amend this paragraph to read: “It is presently a requirement that MAHs should regularly perform a literature search as part of the periodic safety update report (PSUR). However, It is recommended that MAHs search the literature regularly as part of their ongoing surveillance/signal detection procedures and at least yearly for products on a three-yearly PSUR reporting cycle. For ease of the reporting process, following detection the literature cases should be handled in the same way as the spontaneous adverse event reports (i.e. only serious animal AEs and any human AE to be reported expedited). The adverse events identified in literature should also be reported in the next PSUR in a format comparable to spontaneous cases... There is no need for additional literature searches at the time of PSUR creation”. Please also clarify what has to be defined as “serious problems that require urgent attention”.

44-49 3 Comment: Section 4.7 of the Vol. 9B of the Rules Governing Medicinal Products in European Union (EU) mentions: ‘The MAH should report published adverse events associated with the use of its VMPs in accordance with the requirements for adverse event reporting and in PSURs’. The bold text refers to not only literature searching for PSUR-purposes but also to searching literature for

Partly accepted. Modified in line with Volume 9B (see also above, lines 44-49).




identifying single adverse drug reactions that qualify for reporting to the Competent authorities. Proposed change: Line 44-49 ‘The MAH should report published adverse events associated with the use of its VMPs in accordance with the requirements for individual adverse event reporting and in PSURs’.

47 4 Proposed change: …are serious adverse problems…

Partly accepted. The text has been revised (see above, lines 44-49).

50 4 Proposed change: …publish peer-reviewed literature…

Not accepted. Whole section 2.1 concerns peer-reviewed published worldwide literature.

55 4 Proposed change: …on the pharmacologically active substance name (ICD, international common denomination) or synonyms which should then…

Not accepted. The proposals do not provide additional value.

56-57 5 Comment: Flexibility is needed on search terms. Therefore, the word “should” is not appropriate. Proposed change: Please amend the sentence to read: “Similarly the search terms for ‘adverse events’ should not be too restrictive and other terms should may be used e.g. adverse reaction, side effect, toxicity”.

Partly accepted. Flexibility is needed. This sentence has been modified: “Similarly the search terms for ‘adverse events’ should not be too restrictive and other terms should be considered e.g. adverse reaction, side effect, toxicity, idiosyncratic effect”.

57 4 Proposed change : …e.g. adverse reaction, side effect, toxicity, idiosincraTic effect. The MAH…

Accepted.




57-60 5 Comment: Reporting of issues for active substance or if the specific product cannot be identified will lead to creation of duplicates, which will bias the database with negative consequences for trending and signalling and PSUR preparation. Reporting should be restricted to company products only. However, if the exact product is not mentioned in the article, then the company should make reasonable attempts to obtain this information from the author of the article (e.g. follow-up once). Proposed change: Amend the sentence to read: “The MAH is expected to consider reports from their own products only. However, if the reaction of interest is related to the active substance and/or if the specific product is not identified, the MAH should make reasonable attempts to obtain this information from the author of the article. If the information cannot be obtained, the case should not be reported as a valid PhV case”.

Partly accepted. It is expected that the MAH takes these references into account during the literature search and only addresses these in the part on non- spontaneous reporting of the PSUR where it would be relevant for the safety or efficacy of their product. The MAH should report published adverse events associated with the use of its VMPs in accordance with the requirements for adverse event reporting according to Volume 9B. If the product cannot be clearly identified, it would not be expected to fall into this scope and hence would not cause bias. To clarify this, the sentence will be modified to: “The MAH is expected to consider reports from other products than their own if the reaction of interest is related to the active substance and/or if the specific product cannot be identified and where appropriate, discuss the relevance and impact on their product in the part of non-spontaneous reporting of the PSUR only”.

58-59 5 Comment: Often difficult to decide whether an AE is active or formulation related. Furthermore, concentrating on reports based on active ingredients wouldn't be reflecting field situations, as it's not taking into account the possible role of excipients in Adverse Events. Reports based on active ingredient may often not be comparable to the actual product as the

Partly accepted. See comment above, line 57-60.




formulation, strength, target species, route of application and posology may be different. Should remain product based information.

58-59 5 Comment: ‘The MAH is expected to consider reports from other products than their own if the reaction of interest is related to the active substance and/or if the specific product cannot be identified. Taking reports from other products into consideration (excluding the reports that clearly relate to competitor products) could cause bias in writing PSURs, Safety Expert Opinions or interpretation of any other safety information. This all plays a significant role for the relevance of the possible reports. Thus only reports should be considered where MAH product involvement is specified. This action is not taken with any other type of PhV case and should therefore not be included. This is also adding a requirement and not just a clarification of an existing guidance, and is therefore beyond the scope of this document. Proposed change: Delete this sentence.

Not accepted. See above, line 57-60.

60 5 Comment: Contradiction to the sentence at lines 58-59. Should remain product based information.

Accepted. See above.

61-66 2 Comment: To keep the variability of information in the EU, it

Accepted. The sentence “The choice of the databases and/or search engines used remains to the discretion of the MAH.”




should not be prescribed to use specific literature databases, as uniformity of search engines used by all MAHs will cause a loss of information.

“was added.

61-66 4 Comment: A standard approach to systematic review must be included in this reflection paper. A comprehensive literature search using CAB Abstracts, Medline, PubMed, web of Science and Google Scholar should be described.

Partly accepted. Further clarification has been added (see above, lines 61-66).

62-66 1 Comment: The choice of databases should also be discussed. It is preferable to ensure that a variety of databases and / or search engines are searched…” – This should be better defined. For example “Embase” and “Medline” are the common databases for scientific literature; a third database capturing also national literature will extend the information from the published literature. Regular searching in three databases should be enough. The MAH should have the choice to use those search engine(s) which it is familiar with it. Queries in search engines are very complex to receive high quality of right answers. This needs trained staff.

Partly accepted. Further clarification has been added (see above, lines 61-66).

63 5 Comment: It is unclear what is meant by “all national veterinary journals”? Is this suggesting all journals from all EU countries should be included? And is that for all products, regardless if these are only authorised in one country? If so, that would suggest the literature

Not accepted. The sentence “For example databases such as Medline may not necessarily capture all national veterinary journals.” only wants to highlight the possible limitations of using only one database.




search should be done in all languages, which is not feasible. This would require substantial additional resources, where the experience to date has not shown that literature searches has significantly contributed to the safety profile of products. National literature search should only be requested for those EU countries where the product is authorised.

64-67 5 Comment: IFAH Europe is of the opinion that literature search in general does not provide added value, the search in multiple databases should not be requested. The literature search in at least one renowned database should thus be sufficient. There are a lot of proposed different databases which could be used for search activities but the quality of the database used is probably of more importance. Only established ones with a high approved quality (e.g. controlled/maintained by academic institutions or non-profit scientific organizations) should be considered. What can be expected from “Google Scholar” in terms of independency and scientific quality behind the search engine logarithm? Scopus for instance contains articles also available in PubMed. What is the additional value to search both; PubMed and Scopus? Therefore the use of ‘Scopus’ or ‘Ovid’ as a search engine on several databases for peer reviewed literature or 1 or 2 scientific databases for the literature should be sufficient.

Not accepted. The paper indicates that the choice of the databases should be discussed. If needed, the MAH can justify the choice of the databases used.




Proposed change: Please modify the sentence: “It is preferable to ensure that a variety of databases and/or search engines are searched including CAB Abstracts, Google Scholar, Medline, PubMed, Scopus and Web of Knowledge, for example. Should a search engine already include more than one database it may be sufficient to only use this search engine. Examples for possible databases and/or search engines are CAB Abstracts, Medline, PubMed, Scopus, Ovid and Web of Knowledge”.

66 3 Comment: Embase has a broad biomedical scope, with in-depth coverage of pharmacology, pharmaceutical science, clinical research, veterinary science and extensive allied health topics are also included. Currently Embase indexes 156 veterinary and zoology journals, and this number is planned to be increased with another 100 journals by the end of 2016. Embase also includes all of the Medline and index additional 2800 journals that are not in Medline, from which 41 are dedicated to veterinary science. We propose adding Embase as one of the preferred reference databases to screen for adverse events in scientific and veterinary literature, for the following reasons: Literature screening for Veterinary

Accepted.




Pharmacovigilance includes screening of both scientific and veterinary literature for adverse reactions in both animals and humans. We recommend aligning with Section VI.B.1.1.2. ‘Literature reports’ of the Guideline on Good Pharmacovigilance Practice (GVP) Module VI ‘Managing and reporting of Adverse reactions to medicinal products (Rev.1) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172402.pdf; o In this section Embase is mentioned as one of

the reference databases: ‘Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week’;

o In this section it is mentioned that screening of literature should include screening of published conference abstracts and draft manuscripts. Embase includes conference abstracts and in-progress articles and therefore meets the requirements in the sentence: ‘Reports of suspected adverse reactions from the scientific and medical literature, including relevant published




abstracts from meetings and draft manuscripts, should be reviewed and assessed by marketing authorisation holders to identify and record ICSRs originating from spontaneous reports or non-interventional post-authorisation studies’.

Embase is used as database source by the EMA for

its Medical Literature Monitoring Service for over 300 chemical active substances and 100 herbal substances http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/08/WC500191377.pdf;

Embase is mentioned as reference database for

performing systematic reviews in the Cochrane Handbook for Systematic Review of Interventions http://handbook.cochrane.org/;

Embase is mentioned as a core reference database

for developing clinical guideline in the NICE (National Institute for Health and Care Excellence) guidelines manual https://www.nice.org.uk/process/pmg6/chapter/identifying-the-evidence-literature-searching-and-evidence-submission.

Proposed change: Line 66 ’It is preferable to ensure a variety of




databases and/or search engines are searched including CAB abstracts, Google Scholar, Medline, Embase, PubMed, Scopus, and Web or Knowledge, for example’.

67-68 4 Proposed change: …peer reviewed published literature should be searched, where possible, for reports indicative of resistance to antimicrobials or antiparasitics, specifically anthelmitics, e.g. national databases…

Partly accepted. See below, line 67-70.

67-70 2 Comment: Assessment of clinical efficacy and resistance development are separate expert reports and it is not affordable to be assessed in the PSUR as well. According to volume 9B, antimicrobial resistance is not scope of pharmacovigilance duties.

Partly accepted. Resistance indicating an impact on efficacy of the product would be expected to be addressed in the PSUR. The text is proposed to be modified to: “Data on resistance (from the literature and/or other sources) would be expected to be addressed in the PSUR, in case an efficacy concern due to resistance has been identified”.

67-70 5 Comment: This will lead to duplication of work and will not add any value. The cited databases often only include some active substances as representatives of the corresponding class of products. Furthermore one need to consider other important aspects to make any conclusion on “resistance” (e.g. bacteria-species and applicable break-points). There are groups overseeing the resistance situation. It may be appropriate to stimulate the exchange of information between relevant parties at authority level and company level, but searching other relevant sources than peer reviewed literature seems disproportionate and

Partly accepted. See above, lines 67-70.




duplicate work. Delete reference to databases which contain little or no relevant information. Furthermore this is not part of PhV and has already been excluded some years ago. Proposed change: Please delete the sentence: “Relevant sources other than peer reviewed literature should be searched, where possible, for reports indicative of resistance to antimicrobials or antiparasitics e.g. national databases on minimum inhibitory concentration (MIC) values. Such databases are publically available in e.g. Denmark (Danmap), Norway (NORM-VET), Finland (FINRES), the Netherlands (MARAN) and Sweden (SVARM)”.

68 5 Comment: “indicative of resistance to antimicrobials”: Volume 9B, antimicrobial resistance not in scope of PhV. Proposed change: Please delete the sentence 67-70 (also refer to next comment).

Partly accepted. See above, line 67-70.

71-77 1 Comment: In Volume 9B (page 43) it is mentioned the MAH should review adverse events reports submitted through their website; however this paragraph seems to expand the MAH’s responsibilities to the whole internet. Proposed change:

Accepted.




In case this paragraph should be read as an introduction for the different online sources the numbering should be changed: 2.2 Reports derived from the internet 2.2.1 MAH hosted websites and social media accounts 2.2.2 Groups of animal owners on the internet 2.3 Potential for making more use of social media and internet.

71-77 4 Comment: Section 2.2 Other than forums, websites and social media, newspapers (hard copy or online) are also possible source for information of adverse events.

Accepted. Added a section concerning reports form others sources.

83-84 5 Comment: “Similarly MAHs should be encouraged to ... to report adverse events” This active solicitation of adverse events will give very skewed results as will only affect those brands which have active social media (i.e. those in legal categories and/or countries where promotion to pet owners is allowed). It will exclude products in POM-V category as we are not allowed to promote those to the public. This is not a requirement currently, so this is not clarification and therefore is not needed. Contact info to MAH should be sufficient. Proposed change: Please delete this sentence.

Not accepted. This section refers to websites and social media hosted by the MAH and of which it is expected that MAHs are aware. Encouraging facilitating or clarifying adverse event reporting channels to product users is in line with the requirements of Volume 9B. The text is proposed to be modified to: “MAHs maintaining a presence on social media and/or internet are encouraged to make use of these media to inform product users how to report adverse events, by providing relevant contact information and/or facilitating adverse event reporting by providing electronic reporting forms and minimum information required to report an AE.”

83–86 1 Comment: It should be taken into consideration that not every

Partly accepted. See comment above: proposed re-wording.




MAH host a social media account. To host those social media accounts should not be mandatory for the MAH. The administrative burden for small and medium sized enterprises would increase extremely with this request. Proposed change: MAH’s using already social media accounts should inform product users how and when to report adverse events, in addition to the information on their own hosted websites.

83-86 5 Comment: For the purposes of Pharmacovigilance reputable sources with an appropriate quality standard should be used. Every VMP contains standardized product information, in which the topic Pharmacovigilance is addressed. There are diverse possibilities available for users and animal owners to report adverse events. The effort of tracking vague information in chats, which are not addressed to the MAH, bears no reasonable relationship to the expected benefit for Pharmacovigilance. The use of non-MAH proprietary social media platforms should only be considered for matters of Pharmacovigilance when the MAH becomes aware of the information and only when adequate information content is included (i.e. no anecdotal chats)

Accepted.

88 – 91 and 105 - 110

1 Comment: Social network accounts and “fora” of animal owner

Partly accepted. The proposal to modify “every report” to “reasonable effort” is




and breed organisations are various in the internet. It should be taken into consideration that ‘alias’ of users are common in those social networks. Therefore the follow up on possible adverse events to make the decision if this is an adverse event or not may be difficult for the MAH. And the data privacy rules of these social networks should also be taken into consideration, because the MAH will not be able to receive all necessary information for evaluation and assessment of the published data about the VMP. A clear advice how to proceed with such situations would be useful. Proposed change: ‘every effort’ should be replaced by ‘reasonable efforts’, to be aligned with the efforts MAHs undertake in order to receive the minimum criteria for valid cases. (in practice this could be 2 attempts, however, an exact figure should not be mentioned here). This should only apply for MAH hosting own websites and / or active in social media network.

accepted. For further clarification, following change is made “aware of potential adverse events during active searches set up by the MAH, reasonable effort…”

90 5 Comment: Social media are out of any control with regards to authenticity of the report and identity of the chatter. In some chats neither information nor tone is reasonable. Anonymity does allow accusations and cheap propaganda.

Accepted.

92 4 Proposed change: …organisations or associations of individuals and

Accepted.




interest groups… 106 5 Comment:

“every effort” is all encompassing and impossible to quantify Proposed change: Please replace by “reasonable efforts (depending on the circumstances e.g. seriousness of the alleged event, quality of the information provided etc.…)”.

Partly accepted. See comment above: proposed re-wording, lines 88-91 and 105-110.

109-110 5 Comment: ”In cases where the minimum criteria for a valid adverse event report have not been met after efforts to investigate the potential event, it is recommended that MAHs keep a record of these data.” Currently no comparable recommendation for “data records” for spontaneous reports available if four minimum criteria are not met, why needed for internet reports. We can’t see the benefit in this action which in addition would be very time consuming. Proposed change: Please delete this sentence.

Partly accepted. It is put as a recommendation. Keeping such records could be considered part of the quality system and be looked at during inspections. The text is proposed to be modified to: “In cases where the minimum criteria for a valid adverse event report have not been met after efforts to investigate the potential event, it is recommended that the MAHs keeps a record of these data (e.g. reference to the concerned site or fora) in line with the quality systems of the MAH”.

111 5 Comment: As seen here, social media such as chatrooms and the amount of data on the internet are constantly increasing, so it not possible to review all these sources satisfactorily. Even owners of public platforms on the internet are not able sufficiently to monitor the content on their own sites. The observation of selected

Partly accepted. The comment is noted. Moreover, the document is a reflection paper and several difficulties of the data from the internet have been highlighted. See comment above: proposed re-wording, lines 109-110.




forums for Pharmacovigilance issues does not make sense because it does not lead to an objective picture. It seems rather unlikely that the “Potential for making more use of social media and internet” for capturing product or substance related information is able to improve the safety of products! Big human companies (e.g. J&J) started different projects in this area and came to the conclusion that in only few/exceptional cases real useful safety info is provided in social media. To review information from social media will create huge workload in the Companies especially PhV departments with poor results. Therefore the search for potential adverse event reports should further be limited to the websites or social media sites sponsored by the MAH, as it is already the case now.

111-123 2 Comment: Regarding the potential for making more use of social media and internet, it should be considered that using social media has the risk of loss of privacy hence most of the people networking on these sites don’t want to reveal their true self, otherwise there is still a need to increase reporting, improve data quality and ensure consistency and standardisation in the information and reports produced. Sharing of information on adverse events should be strongly encouraged through the EU central database. Due to the fact that some VMP are commonly given in combination with other medicines, it is difficult to discern between adverse events linked

Partly accepted. See comment above (lines 109-110): proposed re-wording.




specifically to one of them. 111-123 4 Comment:

Section 2.5 Potential for making more use of social media and internet It should be mentioned that information on Internet and social media almost always contain veterinary medicinal product name, therefore allowing MAH to relatively easy detect adverse event information. Also often veterinary association or groups of veterinarians (e.g. small animal vets from Belgium) have dedicated social media groups. This will be the first place where they will discuss problems with a veterinary medicinal product. It would be good to monitor these groups.

Partly accepted. Part 2.2.2. describes various organisations or associations as well as interest groups on the internet.

112-119 5 Comment: The current text clearly indicates that these monitoring activities are optional. Proposed change: Nevertheless, please further clarify the text to avoid any misinterpretation of the wording that could imply that companies are expected to actively monitor non-company internet sites.

Accepted. The text is proposed to be modified to: "For media sites which are hosted by the MAH or for active searches set up by the MAH, it is expected that MAHs review information from social media when made aware of a discussion of a potential safety problem and to decide whether the information requires further action”.

112-123 1 Comment: Agreed that MAHs cannot be expected to trawl the internet on the hunt for ADRs. In this context, the wording is not appropriate here: when you are ‘made aware’ of a potential ADR this would either fall under spontaneous reporting, which is not in scope here.

Accepted. See comment above (lines 112-119): proposed re-wording.




IF the MAH comes across a potential ADR during the conduct of an active search the MAH should indeed keep track of the searches (and outcomes), however, this is only the case for: MAH hosted sites/media Selective searches which are carried out

voluntarily by the MAH. Therefore, this paragraph should be rewritten to reflect this. The approach is broad and should be limited because most of the information will already be captured by the established ways of adverse event searching and reporting. The administrative burden for the MAH will increase extremely and in most of the cases the MAH will not receive more information as on the established reporting lines. It should be taken into consideration that the quality of the information may too poor for further evaluation and assessment. The benefit of this will not outweigh the costs of the administrative burden and for the information about the VMP. Proposed change: For media sites which are hosted by the MAH, or for active searches set up by the MAH, it is expected that the MAH review the information from social media and decide whether the information needs further attention.

113-114 4 Proposed change: Partly accepted.




…capturing veterinary medicinal product and pharmacologically active substance specific information…

The text is proposed to be modified to: “…capturing product and active substance specific information…”.

120-123 5 Comment: This is a quite broad and unspecific statement. There might frequently be discussions of potential (!) safety problems somewhere and then the MAH is expected to review all “social media”? The burden should not be on MAH to investigate discussions of potential safety problems on the internet given the unreliability of such reports and the time taken to try and obtain additional information from anonymous users with no way to verify the information

Partly accepted. See comment above (lines 113-114): proposed re-wording.

121 4 Proposed change : …potential safety or toxicity problem…

Not accepted. Toxicity would be considered part of a potential safety problem.

125 4 Proposed change: …MAHs follow the veterinary medicinal products they are responsible for on peer-reviewed published literature….

Accepted.

126-128 1 Comment: It should be kept in mind that there is a high possibility of misinformation in the social media world. Proposed change: Line 127: Please rephrase line 127 (i.e. add in the beginning of) the last sentence like this: “For media sites which are hosted by the MAH, or for active searches set up by the MAH, it is then expected.”

Partly accepted. The conclusions have been modified.




126-128 5 Comment: The conclusion of the document is disproportionate and contradictory with what has been discussed in 2.2, 2.4 ("MAHs would not be expected to trawl the internet to search for potential adverse event reports." - line 105) and 2.5 where it was clear that the intent was that MAHs should pay attention to potential adverse events which come to their attention – why has this now changed to “ensure a general awareness… proactive approach is taken to ensure potential adverse events are identified…”? Proposed change: Please modify the sentence to: “…and ensure a general awareness of follow up pharmacovigilance information which they become aware of from informal sources including social media. It is expected that this follow-up is regular timely and that a proactive approach is taken to ensure potential adverse events are investigated identified and evaluated”.

Partly accepted. The section has been reworded. See also above (lines 126-128).

127-128 5 Comment: Again, for the purposes of Pharmacovigilance reputable sources with an appropriate quality standard should be used. Small companies in particular are not able to monitor the internet constantly and extensively and to investigate all anecdotal information. It is unclear what the expectation around “follow up” is, as this can be a very time consuming requirement with

Accepted.




little value added from social media reports. Proposed change: Please clarify what the expectations for “follow up” are.

Documents

Overview comments received non-spontaneous AE · Overview of comments received on 'Reflection paper on ... In addition, MAHs frequently have staff in many different ... made to the