Bart’s Corner: EU Regulatory Updates

May 20, 2014
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

EMA Working Programme for 2014

In December 2013, the EMA published its work program for 2014. It covered the many areas that the agency supervises and regulates. Much of the document is devoted to GMP, operational issues and other non-PV areas. But some comments in the PV sections are of interest to us in the PV/DS world.

There are about a dozen PV-related activities planned for 2014. The key ones include:

  • Develop guidance and methodological standards for the design, conduct and analysis of post-authorisation safety and efficacy studies (PASS & PAES respectively), including guidance for joint studies.
  • Develop evidence-based tools for the visualisation of the benefit-risk of medicinal products, to support assessment and transparency of decision-making.
  • Review the risk-management process and update relevant guidance based on experience
  • Review the signal-detection process and guidance based on evidence-based recommendations on the choice and application of methods for signal detection from spontaneous reports (including patient reports) and signal confirmation, including strengthening the threshold of evidence needed for confirming a signal
  • Conduct PV audits
  • Additional work will be done on EudraVigilance
  • Finalise business requirements for a PSUR repository
  • Finalise the guidance on literature monitoring for case reports to be sent to EudraVigilance

They expect to review about 1500 signals (having reviewed 2449 in 2013), act on 55 validated signals (43 were done in 2013), review 490 PSURs (518 were done in 2013 and 535 in 2012). Interesting to see a drop in signals and PSURs reviewed.) They will review 35 PASS/PAES up from only 2 reviewed in 2013.

Eleven PV inspections are planned for 2014 (13 were done in 2013). Keep in mind that many EU inspections are done by the national agencies in the member states also.

The EMA’s budget for 2014 is €297,169,000. It was €251,560,000 in 2013 and this represents an increase of about 18%. Fees and charges (mainly on the industry) total about €236 million and the contribution from the EU is about € 30 million – so the vast majority of the funding for the EMA comes from fees and charges. Spending on PV activities will total about €25,000,000. €1 = about $1.40.

The number of PV inspections is expected to increase at the EU and Member State level (not all member states do inspections though) particularly in light of the new PV requirements put in place over the last 2 years.

In various documents and talks, the EU (and MHRA) have talked about risk based auditing/inspecting and the tie-in between problems in GMP and Quality Systems with other company systems including PV. That is, if a company is found to have problems in the GMP or Quality areas, an inspection of the PV functions may be triggered based on the reasoning that the company is “not in control” of its systems in general. Note also that the EMA and Member States charge the “inspectees” (the companies) up to thousands of euros for each inspection thus bringing in money for the agency.

EudraVigilance Annual Report for 2013

In April, the EMA published its annual report for 2013. This is a very interesting document and worth a look. Here are some highlights:

First, the EMA is working to improve the functionality of EudraVigilance (EV) with the goals of simplifying AE reporting, increasing the quality and integrity of EV data, moving to ISO standards for ICSR reporting, allowing MAH’s to access data, and strengthening signal detection and statistical analysis.

One change that impacted EV was the direct reporting of AEs by patients and consumers in the EU as well as AEs from PASS, medication errors, off-label use and occupational use. In particular, a large impact was felt due to consumer reporting (which has been going on in the US for many years).

EMA is focusing on “quality” by which they mean, for EV, better training, duplicate case detection and merging (EMA estimates that 8% of its reports are duplicates in one way or another), ICSR quality reviews and increased feedback to the companies reporting AEs.

Signal detection is another priority for the EMA, which handles signal detection for centrally authorized products and by Member States which handle non-centrally authorized product signaling. Ninety percent of the signals EMA looked at in 2013 came from EV. The PRAC reviewed 100 signals in 2013 of which 43 were detected and validated by the EMA and resulted in 21 label changes; 57 signals were detected and validated by the member states.

The EMA public website for drug safety, http://www.adrreports.eu/, was launched in 2012 and has over 700 products/active substances. It will be extended to non-centrally approved medications in 2014.

The EMA processes between 80,000 and 100,000 adverse reaction reports per month and over 1.1 million were received in 2013 of which some 370,000 were from the EEA and 750,000 from outside the EEA. Direct patient reports were over 234,000 in 2013 up from 186,000 in 2012 (a 25% increase).

758 MAHs have sent reports to the EV post-authorisation module and 713 sponsors sent reports to the clinical trials module since 2002. Nearly 800,000 ICSRs were sent to the post-marketing module (of which 96% of 15 day reports were on time). Over 75,000 clinical trial ICSRs were sent to the trial module. Note that there are ten times as many post-marketing reports submitted as trial reports.

In addition 31 national “competent authorities” (health agencies) in Europe also send cases to EV and this totaled some 327,000 post-marketing and 20,000 trial cases of which 89% of the 15-day reports were on time.

Note that the health agencies were significantly less compliant with 15-day reporting than the companies (96% vs 89%)!

EV has 459,290 medicinal products in its product database from 3996 MA holders.

In terms of “quality” the EMA provided feedback on data quality to 166 organizations in 2013 and 216 in 2012. Perhaps quality is getting better.

The number of signals the EMA is reviewing and acting upon is rising. This table shows the number of signals reviewed over the last several years. Except for an anomalous 2011, the number is steadily increasing. 91% of the signals originated from EV.

EU Reg Updates_chart 1

The actions taken are noted below in this table. Interestingly, the vast majority of the signals were reviewed and closed. Of the 2400 signals only 43 went to the PRAC.

EU Reg Updates_chart 2

A summary table of the validated signals for specific drugs is included in the report. All represent very severe medical conditions (e.g. blindness, dermatomyositis, convulsions, analphylaxis, capillary leak syndrome, SIADH etc.). Have a look at the document for full detail.

The report briefly discusses internal EMA/MS processes for signal detection and the changes planned.

A review of the requests for information from EV/EMA is included in this report. Such requests come from the internal EU regulatory network, the public, journalists, academia, the industry other EU agencies, consultants and health care professionals.

The source of such requests by country is also most interesting and probably represents, as a surrogate marker, the “interest level” of PV around the world.

EU Reg Updates_chart 3

There is also a large listing of the type of requestors of specific drugs. For example, law firms asked for information on alendronate, flutamide, omeprazole and rimonabant.

Conclusions

EMA is very active and their workload is increasing. They are taking a more active role in safety analysis, signaling, PSUR review and 15-day reports. They are increasing feedback to companies both for content and “quality”. With an increasing workload, it is not clear how these processes will adapt. The EudraVigilance database will change over the next couple of years due to changes in the system itself and the adoption of ISO standards in drug safety and reporting.

So, although we seem to have at first glance two seemingly “dry” governmental reports on drug safety/PV, we actually have a lot of interesting data on what the EMA and the member states are doing in terms of PV and where they want to head. If you want more information, have a look at the reports themselves.

 

Tags: , , , , ,