What is this about?:
The EMA has released (June 2012) the new “Guideline on Good Pharmacovigilance Practices (GVP) – Module VII – Periodic Safety Update Reports” which covers the new requirements for the submission of post-approval (post-authorization) aggregate reports.
Why do I need to know this?:
If your company, partner, vendor, client etc. handles adverse events and other safety data on a drug marketed in the EU either you or they will most likely have to submit a Periodic Safety Update Report (PSUR). Even if your company is US or Canada based and does not sell directly in the EU but rather licenses the product out for sale there, you will still need to supply cases and other safety data to your EU partners. The new requirements go into effect in January 2013 for all PSURs. Thus the data lockpoint for a January 2013 PSUR is October 2012 – which is just a few weeks away.
In a nutshell:
The new document is 65 pages long and is very detailed. Anyone who writes (or reviews) PSURs must read this document. The “new” PSUR as described here is different in many ways from the “old” PSUR. It is now a risk based document that will evaluate not just the safety aspects of the drug as the old PSUR did but it will now examine the benefits of the drug. The benefits and risks will be weighed in the document and a benefit/risk (BR) evaluation will be made. This is now a risk based document NOT just a safety summary. In fact, it was debated whether to rename the document the “Periodic Benefit Risk Evaluation Report” (PBRER pronounced pee-burr). Instead the EU decided to stick with the old term “PSUR” which is unfortunate as companies will be submitting “new” PSURs in the EU and “old” PSURs elsewhere unless other governments (US, Canada, Australia etc.) accept the new format.
Because the EU now requires that essentially all spontaneous SAEs and non-serious AEs be reported in 15 and 90 calendar respectively (see Module 6 at the URL referenced below), there is no need for long line listings of cases in the new PSUR which is now a summary and analysis document.
The new PSUR is also much more of a cumulative document compared to the old PSUR which was basically an interim look at the drug. It is now required that the cumulative information (clinical trials & post marketing data) be included when doing evaluation of benefit and risk assessments.
Many of the sections of the PSUR are similar to the sections in the older version. These include: global marketing status, actions taken for safety reasons, changes to safety reference documents (SmPC, CCSI etc.), exposure in trials and in the market, data summaries and tabulations, findings from trials, non-interventional studies (epidemiology studies), literature etc.
New sections now include an overview of signals and “safety concerns”, evaluations of risks and “characterization of risks” as well as the effectiveness of any risk minimization efforts (similar to ETASUs in US REMS) already underway.
Then comes the newest and most controversial section: benefit evaluation. Here the EMA is making a distinction between “efficacy” which is what was studied in phase II and III trials versus “effectiveness” which is how the drug works in the real world after marketing. That is, when a larger and more diverse group of patients is treated with the drug after marketing the safety profile will change and evolve. There will be patients who were excluded from clinical trials: geriatric, very young, polypharmacy patients, patients with serious co-morbid conditions etc.
As of yet there is no template or clear idea of what is expected in this section. It is expected that the ICH step four E2C(R2) document as well as a hoped for template from the EMA will clarify this somewhat.
After the safety/signal and benefit sections there is an integrated benefit-risk analysis for each authorized indication as used in real-world clinical practice with conclusions and actions to be taken (if any). There should be a “medical need” summary outlining possible alternative treatments including no treatment at all. Off-label (unapproved) use must also be discussed.
Another big area is the difference and similarities between the PSUR and the Risk Minimization Plan (RMP) as there is much overlap and repetition. The EMA discusses the requirements and differences in detail in the Wave guidelines.
The Timing:
Two issues here: The submission intervals and how long a company has to prepare the actual PSUR from data lockpoint.
Intervals: The submission schedule is now far more flexible. The default is six monthly for two years after authorization, then yearly for 2 years and then every 3 years. However, the EU is publishing a “Union Reference List” giving the dates for some 3100 active substances and whether they will follow the default schedule or a customized schedule for that substance (i.e. more frequent PSURs). Interestingly, many/most generics and older drugs (>10 years) may not need PSURs at all. The Reference List will be revised monthly so Marketing Authorization Holders (MAH) should check it frequently. See: www.ema.europa.eu/docs/en_GB/document_library/Other/2012/04/WC500124998.pdf
Preparation timing: For PSURs covering a period of up to and including 12 months, the MAH has 70 calendar days after data lockpoint to submit the PSUR; for PSURs longer than 12 months, 90 calendar days.
The Health Agencies:
There will be, per the guideline, only one review of each PSUR within the EU/EEA. There is a very complex system within the EU in terms of review at the member state level, at the EMA level (PRAC) and the European Commission depending upon whether the product is centrally approved or not.
PSUR summaries will be posted on the EMA and member states’ web portals. It is not yet clear what will actually be posted.
The Interim Period:
In theory, these requirements went into effect in July 2012 but as many of the EU member states and EMA were not ready (the PRAC had its first meeting in July) an interim arrangement is in place. Thus the first PSURs are due in January 2013. If you have a PSUR due then, you need to use the new format and your data lockpoint is in October, 2012!
Fees:
There is now a fee for PSUR assessment: Up to €80,300 (~$100,000) per PSUR for products authorized more than 2 years ago and up to €40,150 (~$50,000) for newer products! Make sure your budget department is aware of this!
Read the module for yourself:
https://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/06/news_detail_001546.jsp&mid=WC0b01ac058004d5c1# This is the EMA website on the guidelines. You will find each guideline as a pdf link on the right side of the page.
Comment:
This is a brand new concept and document. The PSUR is moving from a somewhat analytical “data dump” to detailed, complex analysis of benefits, signals and risks (both known, possible and unknown). It will clearly be a longer and more thoughtful document than the old PSUR in terms of analysis but without line listings. Companies need to gear up now to do them and they may need to invest more resources than before.
Companies must also decide how to handle PSURs submitted to non-EU countries (US, Canada, Australia etc.) where the health agencies may or may not accept the new PSURs. Remember that there are no line listings in the PSUR anymore and the EMA 15/90 submissions of individual cases are not done outside the EU. So ex-EU countries would never see the non-serious and some serious cases. In addition, the ex-EU agencies will see the benefit and safety reviews too. Companies may need to prepare multiple flavors of PSURS: the EU flavor, the US flavor, the Japanese flavor, the Rest of the World flavor. The concept of always saying the same thing to all agencies at the same time must be balanced with the concept of not volunteering more information than is required.
More information should be forthcoming from the authorities and more experience will be gained though at the expense of the poor folks who have to submit the first ones! Whether this increase in analysis really matters in terms of picking up drug-induced serious medical problems earlier, decreasing hospitalization, morbidity and mortality due to SAEs remains to be seen. Hopefully some folks will do studies at some point to evaluate this.
This has been a very brief overview of the topic. You really need to review the guideline in great detail if you are preparing PSURs.
