Guidance

Guideline III Adverse event reporting

Updated 16 December 2024

Applies to England, Scotland and Wales

1. Introduction

The obligations of the Marketing Authorisation Holder (MAH) for recording and reporting adverse events associated with their veterinary medicinal products (VMPs) for which Marketing Authorisations (MAs) are held are defined in the VMR 2013 (as amended) Schedule 1 Part 8 paragraph 57-59.

The term adverse event used in this guidance is as defined in VICH GL24, “adverse event” means any observation in animals that occurs after any use of a VMP, whether or not considered to be product-related, that is unfavourable and unintended.

The VMR 2013 (as amended) includes this definition and defines human adverse event, adverse environmental event, and lack of efficacy which are referred to in this guidance. These definitions can also be found in the Glossary. For authorised VMPs, independent of the authorisation procedure, adverse event reports received from any source should be reported, regardless of whether or not the product was used in accordance with the authorised Summary of Product Characteristics (SPC) and/or any other conditions laid down for marketing of the product in accordance with applicable legal requirements.

The MAH is expected to validate all adverse events reported by all sources to ensure, prior to reporting to the VMD, that the minimum information required is included in the report, minimum information is covered in section 3.1 of this guidance. Reports should be followed-up to obtain additional information relevant to the case as necessary, and relevant follow-up information should be reported to the VMD. All available information relevant to the evaluation of the adverse event should be provided in the adverse event report.

2. Requirements for expedited reporting

The MAH should report all adverse events occurring worldwide for their VMPs which are authorised in the UK, or the equivalent products authorised elsewhere, to the VMD within 30 calendar days of being made aware of them.

The date the MAH becomes aware of a report which fulfils the minimum information should be considered day 0.

The clock for expedited reporting starts, day 0, as soon as the minimum information has been brought to the attention of any personnel of the MAH or an organisation having a contractual arrangement with the MAH concerning conduct of pharmacovigilance.

The expedited reporting of adverse events should occur regardless of whether the adverse event is categorised as serious or non-serious.

If a seriousness category is required for an adverse event report then this should be based on the definition of a serious adverse event as per VICH GL24: “any adverse event which results in death, is life-threatening, results in persistent or significant disability/incapacity, or a congenital anomaly or birth defect. For animals managed as a group only an increased incidence of serious adverse events as defined above exceeding the rates normally expected in that particular group is considered a serious adverse event.”

Electronic reporting of adverse events is mandatory for MAHs, save in exceptional circumstances with prior or simultaneous notice. The VMD should be informed of these circumstances as soon as possible by e-mailing adverse.events@vmd.gov.uk. For pharmacovigilance requirements for other products including submission routes see Guideline VI Pharmacovigilance for other products. This includes Animal Test Certificate holders, medicines for small animals exempt from authorisation, Autogenous Vaccine Authorisation holders, and extemporaneous preparation manufacturers.

Requirements for electronic reporting are covered in section 3.2 of this guidance.

MAHs should submit one adverse event case per XML file submitted. Batch XML files containing multiple cases should not be submitted.

All pertinent information regarding the case should be captured within the case narrative or appropriate data field. The submission of additional documents (for example TXT or PDF documents) alongside the case is acceptable, but it must be ensured that any information within these documents is included within the case narrative or appropriate data field.

MAHs who do not submit adverse event cases using the VMD Gateway should use VMDS AER (VMD Adverse Event Reporting system) where possible to submit cases. MAHs will not be able to upload .xml files with the VICH HL7 format through VMDS AER, but can submit these via VMDS secure messaging. This includes EVVet .xml files. AER cannot accommodate human cases so these should also be submitted by VMDS secure messaging.

Where there are no appropriate fields in which to record specific details, the information should be provided in the case narrative as appropriate.

MAHs should not report adverse events that are likely to have already been reported by other MAHs, for example a report from another MAH found in the database of a different regulatory authority.

2.1 Reporting of adverse events in respect to animals

All reports of animal adverse events should be recorded by the person responsible for pharmacovigilance and reported to the VMD within 30 days. This includes adverse events occurring in animals exposed to the treated animal or in offspring of a treated animal (see sections 4.5 and 4.6).

2.2 Reporting of human adverse events

A human adverse event is defined as a reaction that is noxious and unintended and that occurs in a human being following exposure to a VMP, either directly or by contact with a treated animal or by any other means. All reports of human adverse events should be recorded by the person responsible for pharmacovigilance and reported to the VMD within 30 days.

2.3 Reporting of lack of efficacy

Lack of efficacy is defined as the apparent inability of an authorised VMP to have the expected efficacy in an animal, whether or not the product was used in accordance with the Summary of Product Characteristics (SPC).

All reports of lack of efficacy should be recorded by the person responsible for pharmacovigilance and reported to the VMD within 30 days.

It is important for MAHs to identify if the report involves a possible batch quality problem. If an adverse event involves a batch quality problem, or any other product defect related issue, then it must be reported via pharmacovigilance reporting pathways and should also be reported to the VMD via the product defect report form. Batch quality problems or other product defect related issues that did not result in an adverse event do not need to be reported via pharmacovigilance reporting pathways, but should be reported via the product defect report form.

2.4 Reporting of adverse events following off-label use

Off-label use relates to situations where the VMP is used outside the terms of the MA.

The MAH should collect any available information on adverse events following off-label use related to their VMPs and report this to the VMD within 30 days in the same way as for other adverse event reports.

Examples of off-label use include using the VMP in a non-authorised species, or for a sub-category of animal within that species that the product is not authorised for, for an unauthorised indication, or at a dose that is different to the doses specified in the product literature.

Adverse events may be reported subsequent to off-label use of VMPs following prescribing under the provisions of the cascade.

Reports of off-label use without an adverse event occurring reported to the MAH should be recorded but do not need to be reported to the VMD. Robust internal processes are expected to be in place to ensure that if an MAH becomes aware of a report of off-label use with a valid event through any means of communication, the report is recorded and reported to the VMD.

2.5 Reporting of adverse events following medication errors or accidental exposure

Reports containing adverse events following medication and product use errors should be reported to the VMD within 30 days in the same way as for other adverse event reports.

Those reports without an adverse event occurring do not need to be reported to the VMD. Robust internal processes are expected to be in place to ensure that if an MAH becomes aware of a report of off-label use with a valid event through any means of communication, the report is recorded and reported to the VMD.

2.6 Reporting on investigation of the validity of the withdrawal period

Reports of such cases may arise from different sources including:

• farmers or veterinarians detecting residues of veterinary medicinal products when testing bulk milk for antibiotics

• analytical laboratories or food producers who routinely monitor foodstuffs for residues, for example in slaughterhouses or dairies

• state or regional authorities conducting residue surveillance on food from food producing animals

Where levels of VMP residues in tissues or food products of treated food producing animals are above the established maximum residue levels while the recommended withdrawal period of the given medicine has been respected, this information may cast doubt on the validity of the withdrawal period and consequently should be investigated and reported to the VMD. If the case meets the minimum information required for adverse event reports, then it should be recorded and reported within 30 days even if the information about whether the recommended withdrawal period has been respected is unknown or the report involves a withdrawal period that has not been respected.

For products that have been used off-label in any other way, see section 2.4 of this Guideline.

2.7 Reporting on adverse environmental events

An adverse environmental event means an event where a non-target organism, population or ecosystem is adversely affected as a result of exposure to a VMP, its active substances or its metabolites present in soil, water or animal remains.

Any suspected adverse environmental event related to VMP exposure should be recorded by the MAH as soon as it comes to their attention.

Reports of potential adverse environmental events arising from the use of a VMP should be submitted to the VMD within 30 days of receipt.

2.8 Reports published in peer-reviewed worldwide literature

Adverse event reports from worldwide literature are considered to be reports the MAH can reasonably be expected to be aware of. The MAH is therefore expected to monitor the scientific literature regularly to identify adverse events concerning their products that qualify for reporting.

The MAH should report to VMD published adverse events associated with the use of its veterinary medicinal products in accordance with the requirements for adverse event reporting described above.

Contractual arrangements may be made with a person or organisation to perform literature searches and/or report relevant individual adverse event reports to the VMD. If another person or organisation is performing these tasks, explicit procedures and detailed agreements should exist between the MAH and this person or organisation to ensure that the MAH is promptly made aware of any adverse events described in the worldwide scientific literature to ensure that the MAH can comply with their reporting obligations.

It is recommended that MAHs search the scientific literature regularly as part of their ongoing signal detection procedures, this should be at least once a year. A risk-based approach is advised covering active substance, type of product, the stability in number and incidence of adverse event reports, and stability of the pharmacovigilance profile. Rather than performing a product specific search, it is recommended to begin literature searches based on the active substance which should then be narrowed down to the individual product, however the most appropriate approach will depend on the individual product. Search terms for ‘adverse events’ should not be too restrictive and other terms should be considered, for example adverse reaction, side effect, toxicity, and idiosyncratic effect.

The MAH is expected to consider reports from products not explicitly stated as their own if the event of interest is related to the active substance and/or if the specific product cannot be identified.  For example, an MAH’s product is the sole authorised product containing that active substance, and it is unlikely that any available human equivalent product has been administered, the MAH should consider reporting under their product.

The choice of databases and search criteria will be reviewed during pharmacovigilance inspections. It is preferable to ensure that a variety of databases and search engines are searched, including, for example CAB Abstracts, Google Scholar, Medline, PubMed, and Scopus; the choice remains at the discretion of the MAH.

Data on resistance to a VMP from a literature search and/or other sources would be expected to be considered in the ongoing signal management and benefit-risk assessment of a product.

2.9 Reporting on adverse events from clinical studies including Post-Marketing Surveillance Studies

Any adverse event following administration of an authorised VMP should be submitted to the VMD within 30 days of the point at which there is first awareness of events meeting the minimum criteria for reporting. The 30 days would therefore begin at the time the product can be identified as being the responsibility of the MAH.

See Guideline V Post-marketing surveillance studies for further guidance on post-marketing surveillance studies.

2.10 Reporting on adverse events from the Internet

MAHs should review any reports submitted through their websites and determine whether they should be reported within 30 days.

MAHs should consider utilising their websites to facilitate adverse event report collection, for example by providing adverse event forms for reporting or by providing appropriate contact details for direct communication.

Non-spontaneous adverse event reports and pharmacovigilance information may originate from an ever-increasing number of online resources. The main sources of such information that VMD is currently aware of are discussed below.

2.10.1 MAH hosted websites and social media accounts

Most MAHs have an active presence on the internet in the form of websites and social media accounts, and many MAH hosted websites have ‘contact us’ forms. These may be used by reporters to notify MAHs of adverse events. All adverse events identified via company websites or social media accounts should be followed-up by the MAH and reported to the VMD within 30 days if the information fulfils the criteria for a valid adverse event report.

MAHs maintaining a presence on social media and/or the internet are strongly 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 forms and details on the minimum information required to report an adverse event.

2.10.2 Groups of animal owners on the internet

Various breed organisations or associations of individuals and interest groups have their own websites or social media groups on the internet, these often include the capacity to communicate with each other through discussion boards, threads, and chat rooms. Often these discussions may include information from owners regarding adverse events.

As there are many websites and social media groups, and some of these are not public access i.e. private or closed, MAHs would not be expected to have awareness of these adverse events. However, if the MAH becomes aware of potential adverse events during active searches set up by the MAH, reasonable effort should be made to follow up on the reports to obtain at least the minimum reporting criteria so that the events can be submitted as per reporting requirements and further actions undertaken if required, such as additional review.

In cases where the minimum criteria for a valid adverse event report have not been met despite efforts to investigate the potential event it is recommended that the MAH keeps a record of this data, for example a reference to the concerned site, in line with the Quality Management Systems of the MAH.

2.11 Reports from other sources

If an MAH becomes aware of an adverse event report from sources other than those mentioned above, for example the lay press or other media, reasonable attempts should be made to obtain the minimum information that constitutes an individual adverse event and to follow-up the report. The approach taken by the MAH for reports from other sources would be expected to be like the approach for reports identified on websites and in social media.

3. Required information for adverse event reports

3.1 Minimum information for adverse event reports

An adverse event report must contain the minimum information below to be considered valid:

• an identifiable source or primary reporter

• animal or patient details: as a minimum species should be known (animal species or human)

• VMP concerned

• adverse event details

For the VMP concerned the MAH must use up to date MA numbers, and this must match the UK country of occurrence. For example, a case occurring in GB must be submitted with a veterinary medicinal product MA number for GB. If this does not match, for example with an imported product, then this needs to be clearly indicated in the narrative.

If a single MA number is split into two separate MA numbers at any time, MA numbers submitted in adverse event reports must be aligned with these updates at the earliest opportunity.

For adverse event reports occurring outside of the UK, the MA number should map to the equivalent VMP available in the UK. All up to date local country MA numbers for EEA countries will also be requested as part of the annual benefit-risk report (BRR) process (as part of Product Group Codes) and should be provided where they are available.

Details of known products to which the animal(s)/human(s)/environment were exposed prior to the occurrence of adverse events, should be reported.  

The brand name and current MA number of products for which the MAH is responsible should always be provided, and where possible these details are requested to be provided for products where the product is not the responsibility of the MAH (non-company products). If these details are not added, at minimum a clear brand name should be provided. If details including the brand name of the product administered are unknown, a non-specific product name or active substance name should be provided. If only the type of product is known, such as ‘antibiotic’, details should be added to the narrative only.

The original words and/or phrases used by the reporter should be provided in the adverse event report even if they are also coded using the Veterinary Dictionary for Drug Regulatory Activities (VeDDRA) List of Clinical Terms for reporting adverse events in animals and humans.

The use of internationally agreed standard terminology lists is crucial in harmonising the exchange of pharmacovigilance information. An MAH should use VeDDRA terminology to code clinical signs in adverse event reports, and wherever possible the latest version should be used in line with specified implementation dates. The VeDDRA lists are revised regularly and are available on the EMA website.

Reporter details such as initials and geographic location are important to avoid duplication of reports. All reporter details obtained should be recorded by the MAH, however MAHs need to comply with the relevant data protection laws, for example the General data Protection Regulation (GDPR) and privacy legislation, whenever this information is transmitted. An MAH should not transmit any identifiable confidential information from the reporter when submitting an adverse event report to the VMD. Usually only the initials (last name initial +/- first name initial if known) and the first two letters of the postcode should be included in any adverse event report submitted.

In addition to this the narrative of adverse event should not contain identifiable confidential information, such as specific animal names (for example pedigree or racehorse names identifiable to one individual), veterinarian details, veterinary referral centre details, or diagnostic laboratory details.

3.2 Minimum information for electronic adverse event reports

MAHs must report all adverse events occurring in the UK electronically, unless in exceptional circumstances with prior or simultaneous notice to the VMD.

Electronic reporting must be made using the VICH Extensible Markup Language (XML) format as per VICH guidelines 35 and 42, using terms from the controlled list of terms and vocabulary list as per VICH guideline 30.

As well as the minimum information for reporting as per section 3.1, electronic adverse event reports have additional mandatory data fields that must be completed. As per section 3.1, in addition to the minimum information for electronic reporting, all information relevant for the evaluation of the report should be requested and reported.

All mandatory VICH XML fields for electronic transmission as per VICH guideline 42:

• Regulatory authority name, Street address, City, State/county, Post code, Country (using appropriate ISO-Country code as per tab A.36 ISO-Country of the VICH GL30 Vocabulary Lists)

• Mandatory only for MAH submitting the adverse event report: Business name, Street address, City, State/county, Post code, Country (using appropriate ISO-Country code as per tab A.36 ISO-Country of the VICH GL30 Vocabulary Lists)

• Primary Reporter: last name and country code are mandatory, if last name not provided then WITHHELD can be entered in the last name field (and should be transmitted as WITHHELD rather than ‘W’)

• Primary Reporter Category +/- Other Reporter Category if applicable (controlled list)

• Unique Adverse Event Report Identification Number (using controlled list of Regulatory Authority identifier codes if applicable)

• Original Receive Date (VICH GL35 data type description - “YYYYMMDD”)

• Date of Current Submission (VICH GL35 data type description - “YYYYMMDD”)

• Type of Submission (controlled list)

• Reason for Nullification Report (if applicable)

• Number of Animals Affected

• Species (controlled list, select human for human adverse events)

• Measured, Estimated, Unknown Weights (mandatory if minimum or maximum weight specified, unknown if not available from reporter, controlled list precision categories)

• Measured, Estimated, Unknown Age (mandatory if minimum or maximum age specified, unknown if not available from reporter, controlled list precision categories) and applicable Age Units

• Registered or Brand Name (mandatory for MAH’s products)

• Registration Identifier (for MAH’s products, unless cannot be determined due to insufficient information from the reporter, then “Cannot be Determined” is entered)

• Anatomical Therapeutic Chemical Classification for VMPs (ATCvet) code (for MAH’s products, from WHO list)

• Units for Value for the Interval of Administration (if interval of administration specified)

• Active Ingredient(s) (for MAH’s products, unless cannot be determined due to insufficient information from the reporter, then “Cannot be Determined” is entered)

• Units for Strength Numerator and Denominator (if strength is specified)

• Narrative of AE (adverse event narrative)

• Adverse Clinical Manifestation (from the controlled list of VeDDRA terms available on the EMA website)

• Date of Onset of AE (VICH GL35 data type description - “YYYYMMDD”)

• Duration Time Unit (if duration is specified)

• Serious AE (completed by MAH, Yes or No)

The Unique Adverse Event Report Identification Number (sometimes known as AERID or the worldwide case number) is electronically assigned by the first organisation to send an adverse event report.

This number consists of:

• country of occurrence code (3 characters using appropriate ISO-Country code as per tab A.36 ISO-Country of the VICH GL30 Vocabulary Lists)

• the MAH’s organisational ID (MAHORGID, 8 characters)

• remaining free text (up to 47 characters, which can include a routing ID)

This number must not be changed for any future transmissions. This avoids the creation of duplicate reports.

The original receive date is the first communication of an adverse event from the primary reporter to the MAH or regulatory authority. This applies to date of receipt by any personnel of the MAH or an organisation having a contractual arrangement with the MAH. This date is fixed and cannot be changed in future.

If an MAH does not have a MAHORGID, or suspects a duplicate report, a change to AERID, or original receive date has occurred, then they should contact the VMD via e-mail adverse.events@vmd.gov.uk.

3.3 Additional information for adverse event reports

As well as collecting the minimum information for a valid report, MAHs are also expected to record all information relevant for the evaluation of the report, provided by the sender or obtained during the processing of the case, and include this in the adverse event report.

Reasonable effort should be made to fill out all relevant data fields, and any additional information that does not fit in a data field of the chosen submission method should instead be included in the narrative of the adverse event. Further guidance on data elements of VICH XML data is available in VICH guideline 42.

Where possible, animal age, weight, sex and breed should be included.

The adverse event narrative should serve as a complete and comprehensive summary, presented in a logical time sequence in chronological order. It should contain all known relevant clinical information, including any information that supports or negates an association between a product and an adverse event. The opinion of the primary reporter and attending veterinarian (if not the primary reporter) regarding causality should be recorded. The use of abbreviations and acronyms should be avoided.

Submissions involving linked cases, should mention the worldwide case number of the linked case(s) in the narrative.

4. Guidance on particular types of reports

All electronic adverse event reports should be completed using the guidance from VICH guidelines 35 and 42, using terms from the controlled list of terms and vocabulary list as per VICH guideline 30. All reports should have appropriate VeDDRA terms added from the Combined VeDDRA list of clinical terms which can be found on the EMA website.

Guidance on certain types of adverse event reports has also been included in the following sections.

4.1 Follow-up adverse event reports

The MAH is expected to follow-up adverse event reports with reasonable effort to obtain further pertinent information. Follow-up reports to incomplete adverse event reports should be submitted by the MAH to the VMD, particularly in cases where only the minimum information was submitted initially or when the investigation of the adverse event is completed.

Initial adverse event reports must be submitted within 30 days, there is no specific deadline for follow-up reports and therefore they should be submitted within reasonable time frames. If further information is expected then it may be appropriate to delay submission of a follow-up until that information is obtained, rather than sending multiple follow-up reports in rapid succession.

Where possible it is requested that follow-up reports containing clinically relevant information are submitted, for example new VeDDRA terms, additional clinical details in the narrative, or post-mortem examination or laboratory results. Follow-up reports should not be submitted, where possible, for non-clinically relevant information such as a change or addition of a causality assessment, and ‘no further information expected’ or ‘case closed’ follow-up reports.

In some instances, an MAH may submit a follow-up to a case where the originator is the VMD or another MAH. The VMD’s version of the adverse event report must always reflect all products present, and therefore MAHs should refrain from sending follow-up reports which have been amended to suit their VMPs only.

In some instances, an MAH may submit a follow-up to a case where the originator is the VMD or another MAH. The VMD’s version of the adverse event report must always reflect all products present, and therefore MAHs should refrain from sending follow-up reports which have been amended to suit their VMPs only.

Follow-up reports to another MAH’s case should not be sent when the only update is to provide a best guess for a VMP in the adverse event report that has been partially added, unless that information has been provided directly by the original reporter (for example in situations where a reporter has contacted multiple MAHs).

Any VMD narratives or NCA comments in the narrative should be retained within the case. If an amendment or further detail is required in response to the comment, then this should be added after the comment rather than editing or replacing the comment.

If an MAH adds a comment to the narrative of an adverse event report involving multiple MAHs, they should specify who is commenting in the comment.

For nullifications, the nullification reason should be entered into the nullification reason field (VICH Reason for Nullification Report field or equivalent).

4.2 Human adverse event reports

Information about any human adverse events to VMPs, whether occurring in conjunction with the treatment of animals, the handling of a VMP or following exposure through the environment, should be reported to the VMD. There should be one report per human involved in the adverse event.

Asymptomatic human events should be recorded but not transmitted to the VMD.

The adverse event narrative is very important and should contain all known relevant information, including how the exposure occurred, for example accidental or routine use, the degree of exposure, the volume injected or splashed, the course of events, medical diagnosis, and any other information that supports or negates an association between a VMP and an adverse event. Where appropriate, details of any Personal Protective Equipment (PPE) used should be described.

Minimum information for a valid report should be obtained (see sections 3.1 and 3.2), in addition reasonable attempts should be made to obtain all relevant information regarding the adverse event. In particular information regarding the following is useful for a full evaluation and should be provided in the relevant data fields and/or adverse event narrative when known:

• patient details including patient identification (as appropriate according to GDPR and privacy legislation, such as the initials of the patient)

• details of medical doctor/physician, or Poison Centre, if consulted (initials and first 2 digits of postcode)

• route of exposure, such as respiratory (inhalation), oral, or cutaneous, and duration of exposure

• reason for exposure: accidental exposure or deliberate misuse (note that only deliberate misuse or accidental exposure if precautions/warnings specified in the product leaflet have not been followed, would be considered off-label use)

4.3 Adverse event reports involving lack of efficacy

If an adverse event report includes lack of efficacy (sometimes referred to as LEE) or partial lack of efficacy, then this should be VeDDRA coded with an appropriate lack of efficacy VeDDRA low level term (LLT), with a relevant death VeDDRA LLT added if required. No other clinical signs relating to the lack of efficacy should be coded using VeDDRA.

In lack of efficacy reports following use of euthanasia products, these events should be coded using only the VeDDRA LLTs ‘Lack of efficacy - NOS’ and ‘Unrelated death’; as the death was unrelated to the lack of efficacy.

Electronic reporting using VICH XML format involves the optional selection of ‘Type of Information in Report’. This has terms for ‘Safety Issue’, ‘Lack of Expected Effectiveness’, ‘Both Safety and Lack of Expected Effectiveness’, and ‘Other’ (see tab d. Type of Information of the VICH GL 30 Vocabulary Lists).  If a case contains a lack of efficacy VeDDRA term then the Type of Information should be selected as ‘Lack of Expected Effectiveness’ or ‘Both Safety and Lack of Expected Effectiveness’ as applicable.

Historical adverse event reports submitted using a different XML format may not have the option of selecting both a safety and a lack of efficacy information type, and therefore they may transmit as just safety. Therefore, it is important that information regarding lack of efficacy is clearly included in the narrative as well as the VeDDRA coding.

If a case contains both lack of efficacy and other adverse events that do not fall within the remit of lack of efficacy, events that are grouped under the appropriate lack of efficacy VeDDRA LLT term should be clearly identified as such within the narrative.

4.4 Adverse event reports involving off-label use

Information should be provided in adverse event reports if the product has not been used according to the product literature i.e. off-label use.

‘Use according to label’ should be selected as ‘No’ even if the product was deliberately prescribed not according to label.

If there were mistakes in prescribing, storing, the preparation, or the administration of a product, the event should be reported as off-label use.

Human cases of accidental exposure are not considered off-label use; only deliberate use of a VMP on a human is off-label use or when specified safety precautions are not followed. Off-label use relates only to treated animals, not to human accidental exposure or contact with a treated animal, unless safety warnings have been ignored.

For electronic reporting the appropriate ‘Explanation for Off-Label Use’ should be selected as per tab bb. XML Locator Codes of the VICH GL 30 Vocabulary Lists (from T95028 to T95037).

The following terms are available: Overdosed, Underdosed, Treatment regimen Off-Label, Indication Off-Label, Storage condition Off-Label, Product expired, and Other off label issue.

As well as filling out the relevant fields, all details regarding off-label use should be added to the case narrative, especially in adverse event reports where more than one type of off-label use has occurred, or more than one product has been added but the off-label use only occurred for one product.

If there is an appropriate VeDDRA LLT from the ‘Medication and product use errors’ system organ class (SOC) available then this should be added to the report. Examples include overdose, underdose and intentional misuse.

The VeDDRA guidance provides details on how the terms within this SOC should be used.

VeDDRA LLT ‘Intentional misuse’ should be added when there is deliberate use of a VMP or a medicinal product for human use in animals for a purpose not consistent with applicable legal or medical guidance. This VeDDRA also applies to intentional use of a VMP in humans, unless permitted by legal provision.

4.5 Adverse event reports involving more than one species

If more than one species is involved in the same adverse event, separate reports should be submitted for each species, although it should be indicated that the reports are linked (see section 4.14 on linked reports). This applies when more than one animal species is involved, or when an animal and a human are involved.

4.6 Adverse event reports involving an untreated animal exposed to a VMP via a treated animal

If an adverse event has occurred in an untreated animal exposed to a treated animal, even if of a different species, a single report should be submitted relating only to the animal which experienced the adverse event, with all information regarding the exposure and the treated animal included in the narrative. The patient details should be for the untreated animal exposed, and the administration route details should reflect the route by which the affected animal was exposed, such as oral route if the contact was by licking or grooming, or cutaneous route if there was dermal contact between the treated and untreated animal.

4.7 Adverse event reports involving offspring exposed through a parent

4.7.1. Abortion

A report should be submitted relating to the parent. The animal details should be those of the parent. The ‘Number of Animals Affected’ recorded should relate to the parent. The number of aborted offspring should only be stated in the case narrative and should not be counted as number of animals died. The VeDDRA LLT ‘Abortion’ should be added, unless the product is indicated for reduction or prevention of abortion (for example by preventing the transmission of a pathogen to an offspring), in which case an appropriate lack of efficacy VeDDRA LLT should be selected.

4.7.2 Stillbirth

A report should be submitted relating to the parent. The animal details should be those of the parent. The number of stillbirth offspring should be counted as the number of animals died. The VeDDRA LLT ‘Abortion’, as well as the relevant parent-offspring VeDDRA LLT, should be added.

4.7.3. Adverse events in offspring only

The ‘Number of Animals Treated’ should be the parent. The ‘Number of Animals Affected’ should be the number of affected offspring.

The animal details should relate to the offspring, and the narrative should include information on the parent treated. The VeDDRA LLT ‘Offspring-only event’ should be added, along with any VeDDRAs relevant to the adverse events noted.

4.7.4. Adverse events in parent and offspring

In reports involving adverse events where an unidentified parent was treated, and it is suspected that the treated parent and offspring are affected by this treatment, a single report should be submitted relating to both the parent and the offspring.  The animal details to be recorded should be those of the parent. The number of parent and offspring affected should be recorded in the ’Number of Animals Affected’ field and any details regarding exposure route should be recorded in the case narrative. The relevant VeDDRA low level term ‘Parent-offspring event’, ‘Father and offspring event’ or ‘Mother and offspring event’ should be added, along with any other VeDDRAs relevant to the adverse events noted. If the parent or offspring died this should be recorded in the number of animals died.

4.8 Adverse event involving validity of the withdrawal period

For these adverse event reports the relevant VeDDRA LLT from the ‘Residue investigations’ high level term (HLT) category should be selected, for example ‘Residues in milk’ or ‘Residues in meat/offal’.

Electronic reporting using VICH XML format involves the optional selection of ‘Type of Information in Report’. For these adverse event reports ‘Other’ can be selected.

The report should contain all mandatory information and all other clinically relevant information obtained, in particular it should contain details about:

• the source of the report

• the withdrawal period applied

• date of first exposure

• dates of sample collection and detection of the residues

• the level of residues detected

• the location of the case

• animal weight

• the analytical method used to determine the residues

• the steps taken by the MAH to investigate the matter

4.9 Adverse event involving adverse environmental events

For these adverse event reports the VeDDRA LLT ‘Environmental incident’ should be selected.

Electronic reporting using VICH XML format involves the optional selection of ‘Type of Information in Report’. For these adverse event reports ‘Other’ can be selected.

The report should contain all mandatory information and all other clinically relevant information obtained, in particular it should contain details about:

• the location

• the ecosystem, animal, or plant involved, as appropriate

• the nature of the suspected adverse environmental event

• the suspected veterinary medicinal product

4.10 Adverse event involving suspected infectious agent transmission or suspected reversal to virulence

4.10.1 Suspected infectious agent transmission

For these adverse event reports the VeDDRA LLT ‘Suspected infectious agent transmission’ should be selected.

4.10.2 Suspected reversal to virulence

For these adverse event reports the VeDDRA LLT ‘Suspected reversal to virulence’ should be selected.

4.11 Adverse event reports involving suspected diagnoses

If an adverse event report involves a list of suspected diagnoses, then these should not be individually VeDDRA coded. However, following appropriate examination by a veterinarian if there is only one suspected diagnosis, especially when relevant investigations have been performed or the diagnosis is a diagnosis of exclusion, then the diagnosis should be VeDDRA coded with an appropriate LLT.

4.12 Adverse event reports published in peer-reviewed worldwide literature

Electronic reporting using VICH XML format involves the optional selection of ‘Type of Information in Report’. For these adverse event reports ‘Other’ can be selected.

Details of the publication such as title and authors should be included in the adverse event narrative.

4.13 Adverse event reports from post-marketing surveillance studies

Electronic reporting using VICH XML format involves the optional selection of ‘Type of Information in Report’. For these adverse event reports ‘Other’ can be selected.

The adverse event report should clearly indicate that this is a report from a post-marketing surveillance study, this can be provided in the adverse event narrative.

4.14 Linked adverse event reports

For electronic reporting, the relevant ‘Explanation for Linkage’ should be selected, as per tab cc. Explanation for Linkage of the VICH GL 30 Vocabulary Lists, bearing in mind the definitions for each term.

The AERID (worldwide case number) of the linked adverse event report should be included in the narrative.

4.15 Adverse event reports involving death

If an adverse event report involves death then an appropriate death VeDDRA LLT should be selected.

If a post-mortem examination has been carried out, then the VeDDRA LLT ‘Necropsy performed’ should be added. Findings from the post-mortem examination should also be individually VeDDRA coded with the relevant LLTs. ‘Necropsy performed’ should not be added for lack of efficacy only adverse event reports as these should only contain lack of efficacy VeDDRAs and a death VeDDRA if relevant.

4.16 Adverse event reports involving product defects or counterfeit products

If an adverse event report involves a product defect, then the VeDDRA LLT ‘Product defect NOS’ should be selected.

If an adverse event report involves a suspect counterfeit product, then the Suspect counterfeit product VeDDRA LLT should be selected and the report sent within 30 days. If confirmation of the product being a counterfeit is subsequently received, a follow-up report with a change of VeDDRA LLT to Confirmed counterfeit product should be sent.

4.17 Adverse event reports involving anaphylaxis

4.17.1 Anaphylaxis

Anaphylactic shock is an acute allergic, potentially life-threatening, Type 1 hypersensitivity reaction resulting from the generalised release of potent vasoactive substances from mast cells and basophils. The clinical signs of anaphylaxis can vary between species. The table in section 4.17.2 summarises the clinical signs that may be seen, however this list is not exhaustive.

An appropriate anaphylaxis LLT should be VeDDRA coded if the adverse event report contains clinical signs from this list. In addition, if the reporter’s own words when reporting include anaphylaxis then this should be VeDDRA coded.

4.17.2 Table of clinical signs of anaphylaxis in different species

Species	Clinical signs
Dog	Excitement, urticaria, pruritus, angioedema, vomiting, defecation, dyspnoea, collapse, convulsions
Cat	Pruritus, angioedema, salivation, vomiting, dyspnoea, incoordination, collapse
Rabbit	Tachypnoea, dyspnoea, pallor, collapse, defecation, urination, loss of consciousness, collapse, convulsions
Horse	Shivering, sweating, incoordination, coughing, dyspnoea, diarrhoea, colic, collapse
Cow and sheep	Urticaria, restlessness, pruritus, angioedema, defecation, urination, coughing, dyspnoea, cyanosis, bloat, collapse
Pig	Dyspnoea, cyanosis, pruritus, collapse, vomiting, diarrhoea

5. Reporting following suspension or withdrawal of the MA

Reporting requirements remain following suspension of the MA of a VMP for pharmacovigilance or commercial reasons: see relevant sections of this guideline and Guideline IV Signal management, including benefit-risk reports.

Where an MA is withdrawn or revoked, the former MAH is encouraged to continue to report in line with guidance to, for example, facilitate review of delayed onset adverse events and retrospectively notified cases. It may be appropriate to continue submission of benefit-risk reports after withdrawal or revocation of the MA. This should be addressed and agreed on a case-by-case basis with the VMD.