Periodic safety update reports – GOV.UK

1. Introduction

A Periodic Safety Update Report (PSUR) is an important document provided by the Marketing Authorisation holder (MAH) to the VMD at defined time points post-authorisation. The document is intended to provide an update of the worldwide safety experience of a product, including a summary of all adverse events received during the period covered by the document and a critical evaluation of the benefit-risk balance of the product. This evaluation should determine whether further investigations need to be carried out and/or whether changes should be made to the product information.

PSURs are required regardless of whether or not a product has been marketed; but an abridged version as detailed below, in the PSUR content section, will be accepted.

Electronic copies of PSURs, including line listings, should be submitted to the VMD using the VMD’s digital services.

The VICH have produced a guideline Topic GL 29 “Pharmacovigilance of Veterinary Medicinal Products – Management of Periodic Summary Update Reports (PSURs) which describes the management of PSURs.

2. Frequency and timings of PSUR submissions

A PSUR should be submitted at least every six months after authorisation until the placing on the market. The PSUR covering this period during which the product is launched is considered the last of the six month PSURs to be submitted before ‘initial placing on the market’. The date of first launching always falls after the European birth date (EBD). Therefore, there are at least five 6-monthly PSURs for new marketing authorisations required.

Following the initial placing on the market, PSURs shall be submitted at the following intervals:

  • 6-monthly for the first 2 years
  • annually for the subsequent 2 years
  • thereafter at three-yearly intervals

PSURs should also be submitted immediately on request by the VMD on an ad hoc basis. The Data Lock Point (DLP) and submission date for these ad hoc requests should be agreed between the MAH and VMD, depending on the urgency of the issue.

A different schedule of submission of PSURs may also be set as a condition of the granting of the MA or required due to safety concerns detected during the marketing of a product.

The PSUR cycle should be based on one of the following:

  • the EU Birth Date (EBD): the date of the first marketing authorisation within the European Union of a veterinary medicine
  • the International Birth Date (IBD): the date of the first marketing authorisation for a same or similar product granted anywhere in the world, including any VICH region
  • the EU Harmonised Birth Date (HBD): for veterinary medicines included in the work sharing initiative on PSUR assessments

Each PSUR should cover the period of time since the last PSUR and should be submitted within 60 days after the DLP. Gaps and overlapping of data is not permitted.

If an MAH is unsure of the next DLP for their product, or in exceptional circumstances wishes to change their data lock point; they should contact the VMD PSUR team for assistance.

3. Content of PSURs

All PSURs should be written in English; and must include details of all adverse events arising in the UK and outside of the UK; regardless of the route of authorisation. Inclusion of reports in PSURs should be based on the date of receipt by the MAH.

It is strongly recommended that, before submitting the PSUR, the MAH should make sure that all reports from the line listings have been submitted electronically where required.

For the presentation of data within the PSUR it is strongly recommended to use the template provided on gov.uk.

3.1 The following information should be included for marketed products

MAH and product details:

  • the name of the MAH
  • the veterinary medicine names
  • the MA numbers
  • procedure number, if applicable
  • EBD / Start date for PSUR-submission cycle
  • the period covered by the PSUR
  • the date of initial placing of the product on the market
  • chronological order of PSUR, for example 1st 6 month PSUR after initial placing on the market

3.2 Update on regulatory or MAH actions taken for safety reasons

An overview of regulatory and MAH actions taken anywhere in the world for safety reasons since the last period covered in the PSUR. Changes in the wording of the SPC for the product in other countries should be explained.

3.3 Summary of Product Characteristics (SPC)

The latest version of the relevant SPC must be included for reference and preferably include a copy of the core safety data sheet.

3.4 Estimations of exposure – Sales volume

Each PSUR should contain the number of doses/amount of product sold within the reporting period in the UK and in other countries, if applicable. The UK sales data should be provided per calendar year. The sales information should be expressed per presentation in an appropriate form.

The following forms are suggested:

  • vaccines to be expressed in numbers of doses
  • liquid to be expressed in litres
  • powder to be expressed in kilograms
  • tablets to be expressed in numbers of tablets
  • sprays to be expressed in litres or kilograms
  • collars to be expressed in numbers of collars
  • paste to be expressed in kilograms
  • pipettes for spot-on solution to be expressed in numbers of pipettes

3.5 Estimations of exposure – Number of animals treated

The number of animals treated should be calculated independently of reported adverse events. When calculating the number of animals treated during a period, the following points should be taken into consideration:

  • for some veterinary medicines, for example anthelmintic boli and flea collars, the number of doses, or individual units, sold is equivalent to the number of animals treated. For veterinary medicines formulated as pastes, aerosols, eye/ear preparations or other formulations where it is likely that each unit of product, for example, syringe, single dose pipettes, will be dispensed for the treatment of an individual animal, the number of individual units sold should be considered equivalent to the number of animals treated
  • for the majority of pharmaceutical veterinary medicines, the number of animals treated will be a function of:

a) authorised treatment regimen; daily dose (mg/kg) x duration of treatment (days) as detailed on the authorised SPC. Where a range for dose or duration of therapy is indicated on the SPC, it is appropriate to calculate incidence based on maximum recommended exposure, that is, use the upper limit of the dose range and/or longest duration of treatment. Following from the calculation of maximum exposure, it is acceptable to propose alternative assessments of incidence based on known conditions of use of the product. Any such alternative calculations should be justified. For veterinary medicines indicated for continuous, life-long treatment, a standard duration of treatment should be established and any interval should be justified by the MAH; usually 6 months

b) amount of veterinary medicine sold

c) average weight of target population in kilograms. The chosen average weight is to be justified. Standard weights are recommended in the table below and use of any other standard weight, including for those species not listed below, should be justified in the PSUR. Exposure in pigeons is recommended to be calculated on the basis of 30 pigeons/litre of drinking water

Species / sub-population Standard weight (Kg)
Horse 550
Dog 20
Cat 5
Cow 550
Beef calf 150
Newborn calf 50
Sow/boar 160
Finishing pig 60
Weaner pig 25
Sheep 60
Lamb 10
Poultry, broiler 1
Poultry, layer hen 2
Poultry, turkey 10
Rabbit 1.5
  • standard weights recommended for cats and dogs are 5 and 20 kg, respectively. However, when there are formulations dedicated for a specific range of animal weights, the number of treated animals should be estimated by using the specific strengths: for example ‘y’ small treated dogs, up to 5 kg, and ‘z’ large treated dogs, greater than 40 kg body weight. Once an approach is established, for one veterinary medicine or a class of medicines, this approach should be kept for all subsequent PSURs

  • it is expected that the values used for estimation of the number of animals treated would be representative of the conditions of use of the product. For veterinary medicines authorised for more than one species it is difficult to calculate individual species’ exposure. However, it is suggested to estimate the number of animals treated for all authorised species individually using the estimated conditions of use of the veterinary medicine: sales/species. Additional information to explain how the distribution of proportional use in different species is estimated should be provided. The MAH should make a justified estimate for the assessor to review. The same criteria for estimation should be used over time to allow for the monitoring of trends

  • should be applied over time for the same product

  • for immunological veterinary medicines, the number of animals treated may be considered equivalent to the total number of doses sold. Any calculations should take into account the recommended treatment regimen: initial course plus booster doses

3.6 Incidence of adverse events

The MAH must present calculations to show the relationship between the sales volume of a veterinary medicine and the numbers of adverse events reported. Incidence calculations should be based on the reports that have been included in the PSUR even if the reaction start date is outside the period covered by the PSUR. The following calculations should be presented:

  • Calculation 1 – Ratio of animals expressing an adverse event

The ratio of the number of animals expressing an adverse event, assigned a causality code of A, B or O, including O1, N, during a period to the amount of veterinary medicine sold during that period should be computed as follows:

Ratio of animals with adverse event = No of animals with adverse event during period / No of doses sold during the period.

The worldwide ratio calculation should be based on the total number of animals, including target and non-target species, affected by an adverse event during the PSUR period, regardless of causality code assigned. This calculation can be used reliably to monitor trends from one PSUR to the next. Any increase in this ratio relative to previous PSURs may signal a problem and the need for more detailed evaluation of the pharmacovigilance data.
For PSURs covering 3 years, sales volume should be broken down by calendar year and the ratio of the number of animals with adverse event to the amount of veterinary medicine sold should be computed for each of the years concerned by the report.

  • Calculation 2 – Incidence

The incidence (%) of adverse reactions should be calculated by dividing the total number of animals reacting during the period by an estimate of the number of animals treated during the period of the report and multiplying by 100. This calculation should include all spontaneous adverse reactions coded A,B,O, and including O1; that occurred after recommended or non-recommended (off-label) use in the target species. For clarity, adverse reactions from post-authorisation safety studies should be excluded.

In addition, an incidence for lack of efficacy in the target species should be calculated.

Percentage Incidence = No of animals reacting during period x 100 / Estimated No of animals treated during the period.

For veterinary medicines authorised in multiple countries, incidence should be calculated individually for each country where sales have occurred.

It is expected that the values used for estimation of the number of animals treated would be representative of the conditions of use of the veterinary medicine. All assumptions used for calculation should explicitly be stated.

3.7 Data review

The report should include a data review based on the MAHs analysis, including causality assessment, of the individual adverse events reported during the period concerned by the PSUR and should focus on new or changing safety data.

The analysis of the adverse events reported should be supported by tables or tabulations summarising the main findings especially for those containing a large volume of data.

Examples of tables have been included in the template provided on gov.uk. You do not have to use the templates, but it is essential that all of the information indicated is included.

The data review should include the following:

  • adverse events in target species, including events of suspected lack of expected efficacy and those events occurring after off-label use in target species
  • adverse events reported in humans
  • adverse events after use in non-target species
  • potential environmental problems arising from the use of the veterinary medicine
  • investigations of the validity of the withdrawal period
  • transmission of any infectious agent via a veterinary medicine
  • information on the individual adverse event reports should be presented as line listings

3.8 Non-spontaneous Reports

A narrative overview of available data from other sources, for example, post-authorisation safety studies, published adverse event reports, user experience studies, should be included in this section. The data should be analysed and discussed as part of the benefit-risk assessment.

Summaries from post-authorisation safety studies should be included once final results become available, and should consider all adverse events reported from the study.

A bibliographic listing of the scientific articles that address adverse events and which are found in a widely accepted search engine published during the PSUR period that pertains to the veterinary medicine should be included as an appendix. Information on databases used should be provided. The literature search should primarily be product-based.

Additionally, a bibliographic line listing of the studies that address adverse events and for which the MAH is the sponsor, should be included as an appendix.

3.9 Other Information

Adverse events arising from prescription errors or medication errors, including those due to invented names of veterinary medicines or similar appearance, for example, a mix-up with another veterinary medicine, should be reported in PSURs. A summary report on medication errors, including those due to name confusion, occurring with the product should be submitted as an annex to the PSUR. Where there is no adverse event associated with medication/prescription errors, it is recommended that the MAH keep a record of such events in their own database but these should not be reported as adverse events in PSURs. However, where potential risks are identified as a result of medication errors without adverse events, for example intercepted errors, the information should be summarised in the PSUR together with recommendations for addressing the issue.

3.10 Overall safety evaluation

Together with concise summary information on all adverse events, the PSUR should include a scientific analysis of the data presented and a critical evaluation of the benefit-risk balance of the product in light of any new or changing pharmacovigilance information, written by a suitably qualified expert for pharmacovigilance. It should clearly be stated, whether further investigations will be necessary and whether the wording of the SPC needs to be changed.

This section should include:

  • information on any previous action taken by either regulatory authorities or the MAH as a result of safety issues
  • any new important information on the following:
    • evidence of previously unidentified toxicity or safety concerns
    • increased frequency of known toxicity or expected undesirable effects
    • drug interactions
    • adverse events in animals associated with off-label use, including overdose and its treatment
    • human adverse reactions related to the use of the product
    • lack of efficacy
  • prescription errors/medication errors, including those associated with invented names or with the presentation of the veterinary medicines, that have safety implications, if available
  • information on investigation regarding the validity of withdrawal periods arising from the use of the veterinary medicine
  • any environmental issues, caused by the veterinary medicine under normal conditions of use
  • any urgent safety issues that occurred during the period covered

Note: A lack of new information should be mentioned for each.

The evaluation should in particular:

  • indicate whether the safety information remain in line with the cumulative experience to date and the SPC or whether changes should be made to the SPC or other product information
  • ascertain whether further investigations need to be carried out
  • specify any action recommended and the reasons why

The overall safety evaluation should primarily be organised by VeDDRA System Organ Class (SOC) terminology rather than by categories like serious/non-serious or known reactions/new reactions.

An increase in the frequency of reports for known adverse events is considered as relevant new information.

3.11 Important information received after Data Lock Point

This section is for reporting any important new information received by the MAH since the dataset was locked for review. It may include significant new cases or follow-up data that affect the interpretation or evaluation of existing reports. The impact of this information on the overall safety evaluation should be discussed.

3.12 PSUR line listings

All individual reports, assigned a causality of A, B, O, O1 or N, should be presented as line listings.

Expedited reports received during the PSUR reporting period from post-authorisation safety studies should be included in the line listing. Asymptomatic reports are outside the scope of pharmacovigilance and should not be included in the line listings, however, the MAH may find it useful to record these events in their own databases.

The line listing should be included as an appendix to the PSUR. You can use the template available online, or any other format, providing all the information indicated in the template is included.

You must also include this information separately in a searchable and sortable format, for example an Excel spread sheet).

In order to relate the data review to the line listings, it is necessary to separate data for example, relating to different formulations; dosage form(s) and strength(s), target species; if the veterinary medicine is authorised for use in more than one species, reaction type; that is, serious, non-serious, human adverse event, and the country where the event occurred.

The standard information required in the line listing of a PSUR for adverse events in animals includes:

  • MAH report reference number: country code of country where occurring – EVVet organisation id – report number
  • NCA report reference number, if relevant
  • date/dates of treatment / date/dates of vaccination
  • was the veterinary medicine used as recommended?
  • date of adverse event
  • number of animals treated
  • species
  • age/ages
  • number of animals reacted; this should by approximated if unknown
  • number of animals dead
  • other products, including authorised medicated premixes, used concurrently: Trade name and active substances
  • presenting signs/diagnosis, including timing and duration
  • VeDDRA terminology: for description of signs/diagnosis
  • MA comments: brief, informative narrative
  • causality assessment: A, B, O, O1, N code

The standard information required in the PSUR for human adverse reactions related to the use of a veterinary medicine includes:

  • MAH report reference number: country code of country where occurring – EVVet organisation id – report number
  • NCA report reference number, if relevant
  • date/dates of exposure
  • date/dates of human reaction
  • name/names and region of address: for cross-reference to avoid duplication
  • occupation
  • nature of accident/exposure
  • nature of human reaction/symptoms
  • outcome of human reaction
  • MAH comments: brief, informative narrative

3.13 The following information should be included for non-marketed products

For authorised veterinary medicines that are not marketed and for which no animal or human adverse events were observed; including those from clinical trial or post-authorisation safety studies; abridged PSURs are considered acceptable. These should contain:

  • trade name of the veterinary medicine
  • marketing authorisation numbers of the veterinary medicine
  • name and address of the MAH
  • date of EBD/IBD
  • chronological order of the PSUR: for example 1st 6 monthly PSUR before initial placing on the market
  • a declaration of the MAH’s QPPV, that as the veterinary medicine was not marketed or distributed anywhere in the world during the reporting period and as no animal or human adverse event was observed in any additional trial; for example clinical trial, post-authorisation safety study, the benefit-risk balance afforded by the veterinary medicine has not changed since the date of the MA
  • estimated date for initially placing the product on the market

4. PSUR requirements for the Renewal of Marketing Authorisations

The requirements for the data submissions for the purpose of the renewal of a marketing authorisation are set out in guidance available on gov.uk.

As part of the renewal application the MAH needs to submit a PSUR Summary Bridging Report which is supported, if needed, either by:

  • a PSUR Addendum Report, or
  • one PSUR in circumstances where the PSUR submission schedule is in synchrony with the renewal submission schedule

5. PSUR Summary Bridging Report

The MAH should submit a PSUR Summary Bridging Report, bridging all previously submitted PSURs. The previously submitted PSURs should not be re-submitted, provided that a list of original submission dates is appended to the Summary Bridging Report.

The PSUR Summary Bridging Report should not contain any new data but should provide a succinct summary, bridging and summarising previously submitted consecutive PSURs.

The format of the PSUR Summary Bridging Report should be identical to that of the usual PSUR, but the content should consist of summary highlights and an overview of data from the referenced PSURs.

A Summary Bridging Report should contain the following for the period covered by all previously submitted PSURs:

  • introduction: a brief description of the purpose of the document specifying the time periods covered and cross-referencing any referenced PSURs
  • worldwide marketing authorisation status: number of countries which have approved the product
  • an overview of regulatory authority or MAH-initiated actions for safety reasons: an integrated summary of actions taken anywhere in the world if appropriate
  • an overview of changes, proposed or completed, to the SPC and package leaflet, or to the Reference Safety Information Document if applicable: see further below. This should be based on pharmacovigilance grounds and include any significant changes over the entire period
  • an overview of exposure data, that is an estimation of the total number of animals exposed in the time period, as well as incidence data and overview of human reactions
  • an overview of individual reports: brief statement outlining the total number of reports presented in the series of PSURs. When there is an important specific safety concern that has not been adequately discussed in one or more PSURs, it may be appropriate to include summary tabulation for the types of reports of concern presenting adverse events, pointing out any differences from prior tabulations. In this case, there should be a clear understanding that the tables should be generated from live databases, which change over time as reports are updated. These tables should then reflect the most up-to-date data available at the time they are generated. It is recognised that the report/event counts in these summary tables may differ somewhat from the contents of the individual tables in the PSURs. A general statement describing the differences should be provided
  • an overview of studies: a brief summary of important targeted post-authorisation safety studies
  • an overview of the reported information related to investigations of insufficient withdrawal period arising from the use of the veterinary medicine, lack of expected efficacy, adverse events related to off label use or any potential environmental problems
  • other information: only highly significant safety information received after the DLP
    • overview of the safety concerns and conclusion: unresolved key issues

In addition, the Summary Bridging Report should also contain information highlighting any significant differences between the approved SPC and the proposed SPC.

Depending on the length of time and amount of safety data between the DLP of the previous PSUR and the renewal application, it may become necessary to provide an Addendum Report to the PSUR Summary Bridging Report.

6. PSUR Addendum Report for renewals

A PSUR Addendum Report is an update to the most recently completed PSUR when a safety update is required outside the usual PSUR submission schedule for a renewal application.

Because the renewal is an independent process, a PSUR Addendum Report does not change the submission schedule for PSURs nor has it influence on the DLPs of PSURs, as its content will be part of the following regular PSUR.

The Addendum Report should summarise the safety data received between the DLP of the most recent PSUR and the date 60 days prior to the renewal application submission date.

Depending on the circumstances and the volume of additional data since the last scheduled report, an Addendum Report may follow the PSUR format or a simplified presentation.

The proposed simplified presentation should include the following sections, containing any new information or changes beyond the most recent PSUR to which the Addendum Report refers:

  • introduction: purpose; cross-reference to most recent PSUR
  • changes to the sections of the SPC relevant to pharmacovigilance, including a copy of the most recent document if it differs from the one in the PSUR
  • significant worldwide regulatory authorities’ actions relevant to safety
  • line-listings and/or summary tabulations
  • conclusions: brief overview

7. PSUR assessment

Nationally authorised products are not able to participate in the EU PSUR worksharing scheme and therefore will be assessed on a national basis.

The VMD will carry out an assessment of a PSUR within 60 days of receipt of the PSUR from the MAH. If there are any comments of questions; these should be addressed and response provided to the VMD by the MAH within 60 days. Any changes or variations requested should be submitted within 6 months unless otherwise requested or agreed.

Changes may be requested for any section of the SPC. When addressing requests to make changes to section 4.6 of the SPC, the following points should be considered:

  • the frequency of adverse reactions should be described using the frequency terms described in the guidelines on preparation of summary of product characteristics, which are also included at the end of section 4.6 of the QRD template
  • the most frequently occurring ARs should be listed first. In cases where ARs have not yet been expressed according to this frequency classification, the MAH will be asked to update section 4.6 to include information on frequency
  • the adverse reaction should appear at the start of the sentence in the product information
  • the origin of the information on which the AR frequency is based should be stated, that is whether the ARs have been observed during studies, from spontaneous pharmacovigilance reports or other sources. Note: the source should be specified. The origin of the ARs should be put at the end of the sentence so that it does not detract from their description
  • statements relating to different data sources should be presented in separate sub-sections
  • for ARs that are observed both pre-authorisation; in the context of safety and/or efficacy studies, and post-authorisation; reported through the pharmacovigilance system, the source of the ARs that results in the highest frequency should be retained on the product information. In support of any application to vary the frequency information in section 4.6 of the SPC, it should be made clear within the application on what basis the frequency of ARs has been updated, that is which data source was used
  • the frequency of ARs may be updated in the SPC. However, in general, frequency information originating from controlled studies takes precedence over that originating from spontaneous pharmacovigilance reporting. Therefore, the frequency of ARs observed in controlled safety/efficacy studies should not be replaced by frequency information originating from pharmacovigilance data. However, if post-authorisation experience indicates reporting of an AR at a higher frequency compared with that observed in pre-authorisation safety/efficacy studies, consideration should be given to revising upwards the frequency of that AR in the product information

8. Questions relating to PSUR

If you have any questions these should be submitted to; psur.queries@vmd.gov.uk.

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