Q.01

What is a PSUR?

A PSUR is a Periodic Safety Update Report: a safety summary that a company must prepare at set intervals after a product is on the market. In EU law the term covers two different things. One is the pharmacovigilance report that marketing authorisation holders submit for medicines. The other is the post-market surveillance report that manufacturers prepare for medical devices under the MDR and for in vitro diagnostics under the IVDR.

Medicines (pharmacovigilance)

  • Marketing authorisation holders "doivent soumettre" (must submit) PSURs at fixed intervals. In Belgium they go to the Vigilance division of FAMHP (AFMPS) [1].
  • FAMHP describes PSURs as collective reports from authorisation holders. This sets them apart from reports on single cases, such as spontaneous adverse reaction reports and SUSARs from clinical trials. It also sets them apart from the DSUR, the annual safety report that a trial sponsor prepares while a medicine is still in development [2].
  • Medicines authorised nationally are assessed nationally. Otherwise the assessment is done at EU level by EMA's Pharmacovigilance Risk Assessment Committee (PRAC). The outcome can be a change to the SmPC and package leaflet, a narrower indication or, rarely, suspension or withdrawal of the authorisation [2].
  • EMA's register of PSUR single assessments (PSUSA) records three possible outcomes: Maintenance, Variation or Suspension. Two examples:
    • PSUSA/00002254/202304 ended in a Variation, published 21/12/2023 [3].
    • Hydroxyethyl starch (EMEA/H/N/PSR/J/0031) ended in a Suspension, published 05/12/2023 [4].

Medical devices (MDR, Regulation (EU) 2017/745, Article 86)

  • Manufacturers of class IIa, IIb and III devices "shall prepare" a PSUR for each device, or for each category or group of devices where relevant. It summarises what the post-market surveillance data showed, plus the reasons for and a description of any preventive and corrective actions taken.
  • Throughout the device's lifetime, the PSUR shall set out:
    • the conclusions of the benefit-risk determination;
    • the main findings of post-market clinical follow-up (PMCF);
    • sales volume and an estimate of the size and characteristics of the user population.
  • How often it must be updated:
    • class IIb and III: at least annually;
    • class IIa: when necessary and at least every two years.
  • The PSUR is part of the technical documentation. For custom-made devices it belongs instead in the documentation referred to in Section 2 of Annex XIII.
  • For class III or implantable devices, the manufacturer submits the PSUR through the electronic system referred to in Article 92, and the notified body adds its evaluation there. For other devices, the manufacturer makes the PSUR available to the notified body, and to competent authorities on request [5].

In vitro diagnostics (IVDR, Regulation (EU) 2017/746, Article 81)

  • The same model applies to class C and D devices. The report covers post-market performance follow-up (PMPF) findings in place of PMCF, and must be updated at least annually.
  • Class D PSURs are submitted to the notified body through the electronic system referred to in Article 87. Class C PSURs are made available to the notified body, and to competent authorities on request [6].

Approach: I searched FAMHP's pharmacovigilance guidance, EMA's register of PSUR single assessments, and the consolidated texts of the MDR and IVDR. On medicines, I did not find the article of EU pharmaceutical law that sets the legal content and submission frequency of a PSUR, so the medicines section rests on FAMHP's guidance.

Q.02

When do companies submit PSURs in the EU?

In the EU, a company submits PSURs for a human medicine on the schedule set in its marketing authorisation, counted from the authorisation date. Where EMA's list of Union reference dates (the EURD list) covers the active substance, that list sets the dates and frequency instead. Without either, a default cycle applies: every 6 months at first, then yearly, then every 3 years. Medical devices and IVDs have their own fixed rhythm under the MDR and IVDR. Veterinary medicines no longer use PSURs and instead need an annual benefit-risk record.

Human medicines (Directive 2001/83/EC, Articles 107b-107c; Regulation (EC) No 726/2004, Article 28)

  • Who must submit: Marketing authorisation holders "shall submit" PSURs to EMA, electronically [7].

  • Main rule: The frequency "shall be specified in the marketing authorisation", and the due dates are counted from the date of authorisation [8].

  • Default cycle: This applies to authorisations granted before 21 July 2012 that carry no PSUR condition. It also applies to products authorised in only one Member State that are not covered by a harmonised date. Under it, PSURs are due immediately on request, and otherwise [8]:

    • before the product is placed on the market: at least every 6 months after authorisation, until it is placed on the market;
    • after it is placed on the market: at least every 6 months for the first 2 years, then once a year for the next 2 years, then every 3 years.

  • Centrally authorised products: Article 28(2) applies the same rules to them. Its transitional date for older authorisations reads "before 2 July 2012" [9].

  • Harmonised dates (EURD list):

    • Where several authorisations contain the same active substance or combination, the CHMP or the coordination group can harmonise the frequency and set a Union reference date, after consulting the PRAC. A single assessment is then made of all those PSURs.
    • The Union reference date is the date of the first EU authorisation for that substance. If that date cannot be established, it is the earliest known authorisation date.
    • Marketing authorisation holders then "shall submit" a variation to bring their authorisation in line [8].
    • EMA publishes the list. A change to the dates or frequency in it takes effect 6 months after publication [10].
    • A marketing authorisation holder may ask for a Union reference date to be set, or for the frequency to be changed, on three grounds: public health, avoiding duplicate assessment, or international harmonisation [8].
    • EMA's PSUR page calls the EURD list "a legally binding document". It says the list overrules both the standard cycle and any frequency condition in a marketing authorisation. EMA's news item on the list's publication describes it in the same terms.

  • Generics and similar products: These are products authorised under Articles 10(1) or 10a, and registrations under Articles 14 or 16a (homeopathic and traditional herbal medicines). They need to submit PSURs only in two cases [7]:

    • the marketing authorisation makes it a condition; or
    • a competent authority asks, because of pharmacovigilance concerns or because no PSURs exist for the active substance.

    EMA adds that a requirement can also come through the EURD list.

  • Deadline after the data lock point: EMA's page, citing its good pharmacovigilance practice guidance (GVP Module VII), sets two deadlines:

    • PSURs covering up to 12 months: within 70 calendar days of the data lock point;
    • PSURs covering more than 12 months: within 90 calendar days.

    Since 13 June 2016, all EU PSURs go to the central PSUR repository. This applies to both centrally and nationally authorised medicines (EMA).

  • Assessment timeline:

    • The rapporteur or Member State reports within 60 days of receiving the PSUR.
    • The company and the Member States can comment within 30 days.
    • The report is updated within 15 days, and the PRAC then adopts it at its next meeting [11].

Medical devices and IVDs

  • MDR, Article 86:
    • class IIb and III devices: at least once a year;
    • class IIa: when necessary and at least every two years [5].
  • IVDR, Article 81: class C and D devices: at least once a year [6].

Veterinary medicines (Regulation (EU) 2019/6)

  • I found no PSUR requirement in this Regulation. Under Article 81, marketing authorisation holders must record the results of their signal management "at least annually" in the pharmacovigilance database, including a conclusion on the benefit-risk balance.
  • That article sets one exception. For products under Article 42(2)(c), the recording follows the frequency set in the marketing authorisation.
  • A change to the benefit-risk balance, or a new risk, must be notified "without delay and no later than within 30 days" [12].
  • Implementing Regulation (EU) 2021/1281, Article 19, repeats the annual duty to record the conclusion [13].

Approach: I read the consolidated texts of Directive 2001/83/EC, Regulation (EC) No 726/2004, the MDR and IVDR, and Regulation (EU) 2019/6 with its implementing acts. For the 70/90-day deadlines and the EURD list, I used EMA's own PSUR pages. I did not open the current EURD list, so substance-specific dates are not covered here.

Q.03

How does a PSUR differ from a DSUR?

The main difference is the product's lifecycle stage and who reports. A PSUR covers an authorised medicine. The marketing authorisation holder sends it to EMA on the schedule set in the marketing authorisation or the EURD list. A DSUR covers a product under investigation, whether or not it is marketed. The clinical trial sponsor sends it every year, starting from its first trial authorisation. If development continues after approval, both reports are needed. ICH E2F says each one should be complete and stand alone.

PSURDSUR
Who submitsThe marketing authorisation holder, which "shall submit" PSURs to EMA [7]The trial sponsor, which is responsible for the report's preparation, content and submission. It can hand the drafting to a third party such as a CRO [14]
EU legal basisDirective 2001/83/EC, Articles 107b-107c; Regulation (EC) No 726/2004, Article 28 [9]Regulation (EU) No 536/2014, Article 43: for each investigational medicinal product other than placebo, the sponsor "shall submit annually" a safety report to EMA through the database referred to in Article 40(1) [15]
What it coversPost-marketing safety and benefit-risk of the authorised productMainly data from interventional trials (Phase I-IV), plus expanded-access and compassionate use. It also includes significant findings from observational, non-clinical and literature sources, and from manufacturing changes [16]
ObjectiveBenefit-risk review that can lead to changes to the SmPC or package leaflet, a narrower indication, suspension or withdrawal [2]Four aims: check whether new data fit what was already known; describe new issues that could affect trial subjects' protection; summarise identified and potential risks; update the status of the development programme [17]
Timing anchorThe frequency is set in the marketing authorisation and counted from the authorisation date. Otherwise the default cycle applies (6-monthly, then yearly, then every 3 years), or the harmonised EURD date where one exists [8]Always annual. The year runs from the Development International Birth Date (DIBD), which is the sponsor's first authorisation to run a trial anywhere in the world [18]
Submission deadline70 or 90 days after the data lock point, depending on the period covered (from EMA's PSUR page, as set out in my previous answer)No later than 60 calendar days after the DSUR data lock point [14]
When it endsContinues for the life of the marketing authorisation, on the set cycleStarts with the first trial authorised under the Clinical Trials Regulation. Ends when the sponsor's last trial with the product ends [15]
Reference safety informationThe authorised product information (SmPC)The Investigator's Brochure in effect at the start of the reporting period. If no IB is required, the national label is used (the SmPC in the EU) [19]
Data contentCumulative post-marketing safety dataUnder Article 43(3), "only aggregate and anonymised data" [15]. ICH E2F also asks for line listings of serious adverse reactions and cumulative tables of serious adverse events [20]
ExemptionsGenerics, homeopathic and traditional herbal products submit only if their authorisation requires it or a competent authority asks [7]No exemption based on product type. Placebo is excluded, and one report may cover several IMPs in the same trial if the protocol allows [15]

Where the two meet

  • Overlap is expected. Marketing experience can matter for development, and trial findings on marketed drugs belong in both reports. Both "should be comprehensive and stand alone" because they cover different subjects and have different periodicities and recipients [18].
  • After approval: if clinical development continues once the product is approved anywhere, both a PSUR and a DSUR should be submitted. The sponsor may base the DSUR on the PSUR International Birth Date so the two stay in step. If it does, the next DSUR period must not exceed one year [18].
  • What the DSUR is not: it should not be used for the first notice of significant new safety information, or as the way new issues are detected [16]. In clinical trials that role belongs to expedited single-case SUSAR reports. FAMHP lists those separately from both periodic reports [21].
  • What it replaces: ICH E2F says US and EU regulators consider that the DSUR can take the place of the US IND Annual Report and the EU Annual Safety Report [17].
  • Recipients: the DSUR goes to regulators. Where ethics committees require an annual report, the Executive Summary, with line listings of serious adverse reactions where needed, may be enough [18].

Approach: I read Article 43 of the Clinical Trials Regulation (EU) No 536/2014 and ICH E2F as published in EudraLex Volume 10, and checked them against FAMHP's pharmacovigilance guidance. The PSUR column uses the Directive 2001/83/EC and Regulation (EC) No 726/2004 provisions cited in my previous answer, and my clinical trials sources do not include EMA's GVP Module VII.

Q.04