Guidance

Periodic safety update reports

Updated 8 June 2022

Applies to England, Scotland and Wales

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

However, for products which are on a 6 monthly submission schedule, the MAHs can submit a request to the VMD to move to annual submissions if they wish to align with their EU signal detection submissions.

Additionally, for those products which are on a 3 yearly submission cycle, VMD can accept annual submissions, again if MAHs wish to align with their EU signal detection submissions.

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 the first marketing authorisation date in the UK, or previous marketing authorisation dates such as EU Birth Date (EBD), International Birth Date (IBD) or EU Harmonised Birth Date (HBD).

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 take into account all adverse events arising in the UK and outside of the UK regardless of the route of authorisation.

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 or the VICH format described in VICH GL29.

The following information should be included for marketed products:

3.1 MAH and product details

• the name of the MAH
• the veterinary medicine names
• the MA numbers
• procedure number, if applicable
• first marketing authorisation date
• the period covered by the PSUR
• the date of initial placing of the product 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 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

3.4 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

3.5 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

Ratio of animals with adverse event = (Number of animals with adverse event during the period)/(Number 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 (%) of adverse reactions

%incidence = (Number of animals reacting during the period)/(Estimated number of animals treated during the period) × 100

This calculation should include all spontaneous adverse reactions 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.

3.6 Data review

The PSUR should be presented with a concise and critical analysis of the benefit/risk balance taking into account all information sources. It should include a summary of the critical evaluation of the regular review of adverse events carried out during the pre-defined time period.

The data review should broadly discuss any new, ongoing, or closed signals; where the evaluation was completed during the reporting interval, as well as ongoing signals that were undergoing evaluation at the end of the reporting interval. Signals may be qualitative (e.g., a pivotal individual case safety report, case series) or quantitative (e.g. a disproportionality score, clinical trial findings, or epidemiological study).

It should be noted that a safety signal is not synonymous of a statistically relevant disproportionate reporting for a specific medicine-event combination, as a validation step is required during the assessment of the signal. Signals may arise in the form of an information request or inquiry on a safety issue from a competent authority (worldwide).

A final benefit/risk statement should be included by the MAH stating whether or not the balance for the product has changed and whether any action is needed.

3.7 PSUR line listings

The standard information required in the line listing of a PSUR is provided in the template for PSURs published in gov.uk.

3.8 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
• 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 assessment

Nationally authorised products 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

5. Questions relating to PSUR

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