EU Pharmacovigilance Legislation - One Year Later. Sarah Daniels; Senior Partner TranScrip Partners LLP

Transcription

1 EU Pharmacovigilance Legislation - One Year Later Sarah Daniels; Senior Partner TranScrip Partners LLP

2 Since July 2012 we have officially been operating under EU legislation Directive 2010/84/EU amending directive 2001/83/EC for National and Mutual Recognition processes and Regulation (EU) NO 1235/2010 amending regulation (EC) NO 726/2004 for Centralised processes. The legislation was accompanied by the Commission implementing regulation (EU) No 520/2012. In the following paragraphs I will touch on some of the key changes, making no apologies for not covering everything as due to the extensive nature of the new legislation this would be impossible. The objectives of the new legislation in a nutshell are to increase transparency and provide better information on medicines, ensure that the roles and responsibilities of key stakeholders are clearer, rationalise and simplify Adverse Drug Reaction (ADR) and Periodic Safety Update Report (PSUR) reporting and reduce duplication/redundancy, while at the same time engaging both patients and healthcare professionals and promoting and protecting public health. A tall order some might say. Let start with the implementing legislation. This is a new concept. Previously we all worked to the guidelines provided in Volume 9A; though as everyone knows these were only ever guidelines and never had the weight of the law behind them, even though it might have felt like it at times. In this brave new world we are exchanging approximately 150 pages of Volume 9A guidelines for 15 (originally intended to be 16) Good Pharmacovigilance Practices (GVP) modules enshrined in law; the first 7 prioritised modules were released in July last year, and were swiftly followed by 4 more already taking up over 350 pages of text even without annexes. So it seems there will be a GVP module for every eventuality. The remaining modules XI, XII, XIV and XVI on Public participation in pharmacovigilance; Continuous pharmacovigilance, on-going benefit-risk evaluation, regulatory action and planning of public communication; International cooperation and risk minimisation measures: selection of tools and effectiveness indicators, respectively, are currently under development. Modules XI, XII and XIV are scheduled for release for public Page 2 of 6

3 consultation before the end of the year. While the public consultation for Module XVI has completed. Be aware that GVP Module XIII incident management (unlucky for some?) is now to be incorporated into GVP Module XII. The modular format should make it easier to amend the documents on an on-going basis as necessary. Indeed at least 2 modules have already been amended, while revisions to several others are expected. GVP Module I covers quality systems and includes, though is certainly not limited to, the roles and responsibilities of the all-important EU Qualified Person for Pharmacovigilance (QPPV). One thing worthy of note is that he or she must now both live and work in the EU (or Norway, Iceland or Liechtenstein), so working in Switzerland while living in France or Germany is now no longer an option. GVP Module II which has already been revised once, lays out the concept of the Pharmacovigilance Systems Master File (PSMF). This replaces the oft maligned Detailed Description of Pharmacovigilance Systems. Only a summary of the PSMF is required to accompany Marketing Authorisations (MA), though the PSMF must be available to the competent authorities on request. Unlike its predecessor, changes to its content are not automatically notifiable to the competent authorities. Be aware however that the PSMF must be available to the competent authorities on request (the default time period is within 7 days, but immediate access may also be required!), so complacency is not advisable. Indeed in large and/ or complex organisations keeping the PSMF up to date is likely to require an entire team in itself. GVP Modules III and IV (which were part of the second wave of released modules), cover inspections and audits from the EU perspective. For the uninitiated these are useful reference documents, covering pretty much all one needs to know about these somewhat daunting activities. GVP Module V covers Risk Management Planning (RMPs). What s new here? An RMP describing the risk-minimisation strategy has been required for all new MA applications from July However, in certain circumstances some modules may be omitted unless specifically requested by the competent authority. In other words the RMPs should be Page 3 of 6

4 developed in proportion to risk. So while there may be more RMPs they may not all require the same level of detail. A point worth noting is the requirement to ensure the effectiveness of risk minimisation measures, which is re-emphasised in the module although the requirements on exactly HOW to do this are still in development (GVP Module XVI now closed to public consultation). Adverse Drug Reporting (ADR) is defined in GVP Module VI, the most weighty of the GVP modules. In theory this mandates centralised reporting by industry to the Eudravigilance database (currently, reports go via the individual national competent authorities). However this will not actually come into effect until 6 months after Eudravigilance database functionality is updated, audited and approved. This is somewhat of a moving target but is currently thought to be somewhere around 2015; until then transitional measures apply. This means essentially nothing has changed yet in terms of how ADRs are reported. The definition of an ADR has changed subtly though; The text limiting an ADR to one which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function has gone. An ADR is now simply any report where harm has occurred to a patient or any reaction that is noxious and unintended. Effectively this widens the definition and means reports of ADRs that are a result of error, misuse, abuse and off-label use must also be reported. Furthermore reports from patients must now be included as valid, reportable ADRs. Hence in the short term/ transitional period, the ADR reporting burden on MAHs might be expected to increase rather than decrease. GVP Module VII, another large module, covers Periodic Safety Update Reports (PSURs). The PSUR now has an alternative name - the Periodic Benefit-Risk Evaluation Report or PBRER. While it doesn t exactly roll off the tongue, it does give an indication of what is expected from these new look PSURs. There are twice as many sections to the new PSUR, with Page 4 of 6

5 additional sections including efficacy data, signal detection and evaluation, and benefit evaluation. Moreover previously existing sections have been expanded with new sub-sections. The PSUR now requires input from many functions previously blissfully unaware that such a document existed and it is therefore expected to be a much more balanced document allowing for the conduct of a full benefit-risk analysis. This was something of a challenge with the old PSURs as they contained data mainly relevant to risk and not to benefit. The new PSURs therefore require more evaluation and interpretation and are less of a data dump. Unsurprisingly they now require more time to prepare and by way of recognising this, the timelines between data lock point and submission have been increased slightly, though in practice they are still challenging. Identifying and assessing base line efficacy for indications for more mature products can be particularly difficult as much information may no longer be current or even relevant by today s standards, Certainly, from a purely resource perspective, these documents are now more intensive, certainly in the short term. On the plus side, PSURs will not be required for ALL products in the EU as the new legislation waives the obligation to submit PSURs routinely for generic products, well-established use products, homoeopathic products, and traditional herbal products. Also documents including the PSUR, RMP, DSURs etc. are now modular in structure with some modules overlapping one or more documents, allowing for an easier flow of information betwixt and between documents (in theory at least). GVP Module VIII outlines requirements for post-authorisation safety studies (PASS), and the new post-authorisation efficacy studies (PAES). This is another GVP module that has already been revised once with various clarifications and editorial corrections. The new requirements for signal detection are provided in GVP module IX. You may remember there was no definition for a signal in Volume 9A. This omission has now been redressed and detailed requirements around signal detection and management are provided here. The key take home message is that one size is not expected to fit all and document everything. Page 5 of 6

6 GVP Module X additional monitoring is the most recently released (April 2013) module and provides the EU requirements for products requiring additional monitoring. It s not that dissimilar from the MHRA Additional Monitoring Programme. Affected products, identified by an inverted black triangle, will be published on the EMA website on a monthly basis following recommendations by the Pharmacovigilance Risk Assessment Committee (PRAC). Finally, last but by no means least, the final currently available module, GVP Module XV covers all aspects of safety communication, from Dear Healthcare Professional letters to web based communications. In conclusion, the new PV legislation was hailed by the EMA as the biggest change to the regulation of human medicines in the European Union (EU) since 1995 with significant implications for MAHs, and a year later this certainly seems to be the case. However it is probably too soon to judge whether the objectives, in particular to rationalise and simplify ADR and PSUR reporting and reduce duplication/redundancy will be met. The coming months and years will definitely be interesting. Page 6 of 6