Pharmacovigilance, signal detection and surveillance

Veterinary Medicines Info Day 2022

Presented by Jos Olaerts on 13 May 2022

Head of Veterinary Risk and Surveillance Service An agency of the European Union
 - Recalling principles of signal management

- Reassurance/clarification of expectations

- Status update

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• AE collection and recording
• 30 days + non-serious cases
• Yearly sales (+ estimation of exposed Number of target species)

• Continuous AE analysis by MAH (signal management)

• Using EVVET database or own database (+ 1 yearly SD analysis on EVVET)
• Yearly MAH statements + SM outcomes submitted to database

• Regulator oversight through

• PhV Inspections
• Risk based signal surveillance by regulators
• Ad-hoc targeted surveillance

• Pharmacovigilance Master File (+ Quality Management System)

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Regulation 2019/06 – signal management
• MAHs should continuously monitor benefit-risk balance of their products through the
signal management process

• MAHs can use their own database and Union Pharmacovigilance database

• MAHs have to conduct at least one signal detection analysis per year for each of their
active substances or products in Union Pharmacovigilance database

• Signal detection should be done within 2 months before due date

• Aim is to detect new potential signals

• Signals detected and validated should be assessed and submitted in IRIS (VSM module)

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Regulation 2019/06
Submit with 30 day
o Signals where new risk or changes to B/R notification in IRIS

o A signal assessment template has been published and should be used by MAHs when submitting
these signals in IRIS to support the assessment and the proposed actions

Submit any time before

o Signals where no new risk or changes to B/R due date in IRIS

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What is a signal?

A signal is defined as information that arises from one or multiple sources, including
observations and experiments, which suggests a potentially new causal association, or a new
aspect of a known causal association between an intervention and an adverse event or a set of
related adverse events, that is judged likely to justify further investigation of possible causality

• Focus should be on identifying new information

• A signal is an hypothesis; it does not always translate into a potential causal association
• A signal is not defined by a disproportionate ROR in a database. While this helps you
to filter down what to look at, statistical methods should always be complemented by
qualitative analyses

ROR: Reporting Odds Ratio

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What is a signal?

• There is no single approach or method to signal detection

• ROR is a prioritisation tool. A disproportionate ROR does not mean a potential signal
• Medically Important (MI) terms are more important than a disproportionate ROR
• Even in absence of disproportionate ROR, cases concerning MI terms should prompt
further investigation, as they are commonly associated with exposure to drugs
• Other criteria such as the number of cases, seriousness, severity, outcome, etc. are also
useful considerations to have when performing signal detection
• Always consider cumulative cases (i.e. all cases reported in the database) and not just
cases reported in a specific period

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Refuted signals

Signals is refuted

1. When there is not sufficient information (sample size is small) to perform a proper
assessment of a signal, refuting can be proposed with a brief summary of the cases
reviewed (see next slide example)

2. For some signals, a more in-depth assessment might be required (sample size is large),
even when the final conclusion is refuting the signal

 The template for signal assessment can be used and provided as attachment in the signal
submission in support of the assessment

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Refuted signal example
Signals where no new risk or changes to B/R identified
• Total number of cases* + brief summary of cases reviewed + conclusion on the
assessment

Example 1
Signal of diarrhoea and “X product” in dogs:
A total of 6 cases reported. 3 cases with too limited information for assessment. 2 cases
confounded by the concomitant medication known to cause the event (“Y product” has
diarrhoea listed in the product information). 1 case considered related to underlying condition
of the dog (…). Conclusion: Signal refuted.

*Cumulative/Total number of cases reported in the Union Pharmacovigilance database

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 Data Warehouse Output

≠ does not automatically mean that these are all signals!

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Due Dates and Annual Statements

• Due dates are annual dates proposed by regulators to facilitate & coordinate work

• By the due date, MAHs should submit in IRIS:

o Statement confirming the benefit-risk balance of their products Compliance with
Regulation 2019/06
o Statement confirming compliance with published VGVP guidelines

• MAHs do NOT need to submit an “annual statement signal review”, nor a benefit-risk
assessment report, and should not submit signals attached to the annual statements

• Signals detected and assessed should be submitted to IRIS separately at any time before
the due date or with a 30 day notification, as required

• Signal management continues after the due date

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Due Dates and Annual Statements

• By due date, annual statements should have been submitted by MAH

• Some flexibility is allowed, e.g. instead of submitting statements by 15th of month,

submitting by end of previous month

• Even when no signals detected/assessed/submitted during the year, MAHs have to submit
the annual statements (compliance with Regulation 2019/06)

• Signal assessment report template should be used for assessment of individual signals

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Due Dates and Annual Statements

• Due dates for CAPs have been published for 2022

• Due dates for NAPs, DCP/MRPs will follow shortly

• However, signals can be submitted in IRIS already and at any time

• MAHs should not wait for due dates to perform signal detection  continuous process

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Focus on new information

• No obligation to assess historical data

• For first analysis, MAHs can select time period from last DLP of last PSUR and present date
to look for cases reported during this period in context of all cumulative cases

• No need to start looking for potential signals of AEs in database for which no new recent
cases have been reported after last PSUR DLP

• MAHs should not send signals concerning old issues analysed and solved in past PSURs,
unless there is new relevant evidence that justifies new updated analysis

• If new signal is detected, based on new cases, a cumulative review including all cases in
the Union pharmacovigilance database should be performed

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Remember

• Flexibility should be allowed – each signal is different, there is no simple guide on what
to do with each signal, as products are very different, and the cases reported and all
evidence that supports a signal

• Sound clinical judgement should always be applied. Aim is to provide a high quality
assessment of all evidence available and make decisions on a case by case basis, following
the general principles explained in our guidelines and webinars

• Focus on medical important (MI) terms rather than just disproportionality methods

• Knowledge and expertise will grow with practical experience

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P-SMEG (Pilot Signal Management Expert Group)
12 members - 2 years

Aim is to set-up and test new processes through close cooperation

of a group of MS experts with the aim to build an overall sustainable
regulatory operational framework to support provisions of
Regulation (EU) 2019/6 related to SM.

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 Draft process – Signal with a recommendation for amending the product literature

CVMP
Signal assessed with
proposals for action
P-SMEG Rapp / LMS
MAH MAH
expert PhVWP

CMDv

P - SMEG

2-weekly meeting
Art 81 (2)

Variation
VNRA (VRA)
tbc
In case of agreed
amendment to the
product literature

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 # Signals and Annual Statements submitted to IRIS between 28 Jan and 12 May

35

30

25

20 45 Signals
Annual 49
15
statements

10

0
Amendement of the Close monitoring Signal is refuted
product information

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PhV related activities (“Burden”)

PSURS

• Systems
• Processes

2021 2022 2023

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IRIS
(signal/annual statement submission and management tool)

Ongoing “improvements” (+2 months);

- Portal (submission tool – for MAH and regulators)

- CRM (management tool – for regulators)

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n-JIG - Joint Implementation Group
SCOPE and PRINCIPLES
“Sharing technical implementation matters” “open discussions”

• (Pure technical – EVVET, DWH, IRIS) – helpdesk

• Matters of principle/ interpretation/ day to day experiences / specific cases
• AER reporting
• Signal analysis
• Signal and annual statement submissions

When possible please bring forward shared issues (representative issues).

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 Any questions?

Further information
Jos.olaerts@ema.europa.eu

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands

Telephone +31 (0)88 781 6000
Send us a question Go to www.ema.europa.eu/contact

Follow us on @EMA_News

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