Pharmacovigilance in the EU – recent and future changes
pharmafile | November 15, 2011 | Feature | Research and Development |
Changes to both post-marketing and clinical trial requirements
The implementation of the European Union (EU) Pharmacovigilance Package (Directive 2010/84/EU amending 2001/83/EC and Regulation EU 2010/1235 amending Regulation 726/2004) in July 2012 is the most significant change in EU pharmaceutical legislation since the introduction of the pan-European regulatory systems, the establishment of the European Medicines Agency (EMA) and the centralised and mutual recognition procedures, in 1995. It will therefore not only have a major impact on marketing authorisation holders’ (MAHs’) pharmacovigilance (PV) activities, but also on a large number of other functions that may not currently be expecting to be impacted by a “pharmacovigilance package”.
Where as the EU PV Package primarily impacts on medicinal products during their approval and post-marketing phases, new requirements for clinical trial drug safety in the EU were introduced in June 2011 by the European Commission’s revision of the “Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’)” contained in EudraLex Volume 10.
Key highlights of the EU pharmacovigilance package
One of the most significant changes in the new legislation is that EU PV requirements will be applied using implementing measures consisting of a mixture of delegated acts and guidelines (see Article 121 of Directive 2010/84/EU). These will replace EudraLex Volume 9A – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. Unlike guidelines, delegated acts are legally enforceable pieces of legislation drawn up and implemented by the European Commission.
Apart from the change in the legal status of the implementing measures other significant changes include:
Individual case safety reports (ICSRs)
- Expedited reporting required for all serious suspected adverse drug reactions (ADRs) from third (non-EU) countries, not just those that are both serious and unexpected.
- Serious suspected ADR reports received from patients, and not just health care professionals (HCPs), require expedited reporting.
- Non-serious suspected ADR reports must be electronically submitted to the EMA’s EudraVigilance database within 90 days.
- All suspected ADR reports from all countries received from patients, HCPs and post-authorisation studies must be recorded by the MAH.
Electronic medicines information
On the 1st July 2011 the EMA published details of the first implementing measure which concerned the new electronic format in which MAHs must submit information on all their medicines that are authorised or registered in the EU, regardless of whether they were authorised centrally via the EMA or by the national Competent Authorities of the individual EU Member States. MAHs are required to submit information in this new format to the EMA by 2nd July 2012.
The new format is known as the EudraVigilance Product Report Message (EVPRM) and replaces the existing EudraVigilance Medicinal Product Dictionary (EVMPD) format. The new format requires significantly more information than the old EVMPD format. Some, but not all, the data items that now must be included are:
- Details of the MAH’s Qualified Person for Pharmacovigilance
- Electronic versions of the SmPC
- The MAH responsible for batch release
- Conditions of marketing
- Description of the packaging
- Pack leaflet
- A significant amount of chemistry manufacturing control (CMC) information concerning not only the product’s active(s), but their excipient(s) and adjuvant(s) as well.
The EVPRM format will not only require MAHs to devote significant resources to its introduction, but the inclusion of so many disparate data items will mean that the maintenance and updating of EVPRM entries will require considerable resources to be committed on ongoing basis.
In addition to MAHs converting their existing EVMPD entries to EVPRM format by 2nd July 2012 they will subsequently have to convert them for a second time into the forthcoming International Standardization Organisation’s (ISO’s) Identification of Medicinal Products (IDMP) format by 31st December 2015.
Medical literature
Although the EMA will take responsibility for screening the medical literature for suspected ADRs for a defined list of active substances from a defined list of publications. MAHs will still be required to monitor these and all other medical literature and report any suspected ADRs from this other literature.
Periodic safety update reports (PSURs)
- PSURs will no longer be routinely required for all well-established, herbal or homeopathic products. In addition the focus of these reports will shift to an evaluation of a product’s benefits as well as risks. Their format will change and they will be submitted electronically.
Product Information
- Non-promotional information on medicines to be provided to the public via web-portals.
- Products requiring additional safety monitoring to be marked with a black symbol.
- Standard text to be included in SmPCs and PILs asking HCPs and patients to report suspected ADRs via their national spontaneous reporting system.
The qualified person for pharmacovigilance (QPPV)
- The MAH’s QPPV must now operate, as well as reside, within the EU/EEA.
- The local PV contact persons at the national level, required by some EU Member States, must have a reporting line to the QPPV.
The pharmacovigilance risk assessment committee (PRAC)
- This new committee will replace the current Pharmacovigilance Working Party and have equal standing to the CHMP. It will be responsible for PV and risk management issues for all medicinal products at the Community level.
Pharmacovigilance system master file (PSMF)
- Replaces the detailed description of the pharmacovigilance system (DDPS) and will be required for all newly authorised products from July 2012 and for existing products from 21st July 2015. Unlike the DDPS it will not be included in marketing authorisation applications (MAAs), only a brief description of PV system and the location of the PSMF will be included in MAAs. Instead it will be a stand-alone living document produced and maintained by MAHs that contains an up-to-date description of their PV system and its supporting quality system. Upon request it must be provided to the EU competent authorities (CAs) within 7 days and be permanently available for inspection at one or more specified sites within the EU/EEA.
- MAHs will be required to perform regular audits of their PV system and prepare and implement appropriate corrective action plans for any deficiencies. Details of these deficiencies must be recorded in the PSMF, but they can be removed once they have been resolved.
Renewals
- Renewal submissions must be made 9 months before a marketing authorisation expires (currently 6 months).
- Evaluation of the safety data from ICSRs and PSURs that have already been submitted will be required, rather than the preparation of a dedicated renewal PSUR as currently required.
- Insufficient patient exposure to the medicinal product will be now grounds for requiring a repeat (2nd) renewal.
Post-authorisation efficacy studies (PAES)
- CAs may impose obligations on MAHs to conduct PAES on existing authorised products if they consider that previous evaluations of their efficacy have become outdated.
- Possible impact on some long established/traditional products that lack a sufficient evidence base to support their efficacy.
Key changes to the ‘CT-3’ guidance on EU clinical trial drug safety
The ‘CT-3’ guideline is part of the detailed guidance for the implementation of EU Clinical Trial Directive (See Article 8 of Directive 2001/20/EC). Some of the changes in the June 2011 version of this guideline are:
- Development Safety Update Reports (DSURs), prepared according to the ICH E2F guideline, should be submitted at least annually to EU CAs and ethics committees. They replace annual safety reports (ASRs) which will no longer be accepted after 1st September 2011.
- DSURs will be required for all clinical trials conducted in the EU regardless of their length. The alternative option for first-in-man and short term metabolism or pharmacokinetic trials of including a safety report in the end of trail notification, included in the April 2006 version of the CT-3 guideline, has been removed.
- Sponsors are now required to submit information on investigational medicinal products (IMPs) to the EudraVigilance Medicinal Product Dictionary (EVMPD) even before submitting a clinical trial application to an EU CA.
- ADRs occurring in a third (non-EU/EEA) country outside a clinical trial in relation to a medicinal product which is marketed in that country, but which is exclusively used as an IMP in the EU/EEA, no longer qualify for expedited reporting as serious unexpected suspected adverse reactions (SUSARs).
By Keith Wibley – director of pharmacovigilance at NDA Regulatory Science Ltd
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