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Guido Rasi: a day in the life of the European Medicines Agency's executive director

This article was originally published in SRA

Executive Summary

As his first year as executive director of the EMA ends, Guido Rasi tells Neena Brizmohun about his challenges and achievements.

My interview with European Medicines Agency executive director Guido Rasi gets off to an ominous start.

An urgent matter has cropped up and Professor Rasi is now running late after having to deal with a morning of unscheduled meetings.

It is 26 October and France has just announced it is suspending sales of Novartis’s Agrippal flu vaccine as a precautionary measure, after potential quality defects were found in batches of the drug. The EMA is busy preparing a statement on the matter, the agency’s head of communications informs me. I half expect my interview to be cancelled but Prof Rasi manages to squeeze me into his increasingly hectic day.

Prof Rasi took over the helm of the EMA in November 2011. Since then, as well as dealing with the typical responsibilities entailed in running an agency that regulates medicines for over 500 million citizens in the EU, he has been busy with the colossal job of implementing the new pharmacovigilance legislation. The complexity of this legislation, coupled with having to administer it without the additional funding necessary (pharmacovigilance fees payable by industry are not expected to be introduced until 2014), poses a challenge of a magnitude “never experienced” before by the agency, he says.

So far, Prof Rasi has made progress in a number of areas. In other areas, however, things appear to be moving slowly.

Guido Rasi: executive director of the European Medicines Agency

Penalties Regulation and pharmacovigilance

I ask Prof Rasi about the EMA’s recent decision to use the Penalties Regulation as a tool to launch infringement proceedings against Roche for alleged non-compliance with pharmacovigilance obligations. The regulation, which had never been used in such a way before, had been amended only a few months earlier to cover a wider range of pharmacovigilance rules; penalties could be as high as 5% of a company’s annual turnover in the EU.

Should companies be worried that this might be the start of a trend for the agency and when might the EMA use the regulation again? The executive director appears initially to give little away. This is “unforeseeable”, he says, adding that the Roche case was “the first time we have come across this problem”. He then implies, however, that the EMA is prepared to use “all the tools we have” to tackle such problems, whether old, current or new.

Also on the topic of post-market drug surveillance, the new pharmacovigilance legislation brings a whole raft of new safety measures that the EMA must put in place to handle complex information on around half a million drugs. The EMA is of course not the only one struggling; the legislation introduces many new obligations for national competent authorities and industry too.

One requirement that industry expected to struggle over has, as it turns out, run smoothly. The EMA is “very satisfied” with how industry has fulfilled the requirement to submit by 2 July product records for uploading into the EudraVigilance medicinal product dictionary (XEVMPD) and with how the agency’s “unknown” system has responded to this “massive upload”, Prof Rasi reveals. The agency achieved its target of receiving records for 50% of the estimated 500,000 products authorised in the EU.

There are some outliers, however. The EMA does not yet have the full picture on the level of compliance by small and medium-sized enterprises. Prof Rasi urges those companies that are experiencing problems to discuss their concerns with the EMA. “We have a team continuously available” for support that is working on identifying and addressing any problems, he says. “We are learning by experience on both sides.”

The EMA has not yet, however, begun validating the content of the records that industry has gone to a lot of trouble to provide. Companies are concerned that the effort they have put in is being wasted because the data are not being maintained and are not being used. A team is hard at work on a pilot to determine the most effective method for validating the content on a large scale and on a routine basis, Prof Rasi reassures me, adding that the agency wants to develop a methodology that is as close to perfect the first time around.

Handling and processing adverse reports and signals from a range of heterogeneous sources and from 27 EU member states (soon to be 28 with Croatia set to join next year) might be a problem for the EMA, Prof Rasi admits. “We don’t know yet how much duplication we will have and how many false negatives and false positives [will be generated].” The agency has “allocated resources specifically to monitor this potential problem”.

Regarding the Pharmacovigilance Risk Assessment Committee the EMA set up in July, Prof Rasi purports to be pleased with how the committee’s meetings have gone so far. “The competence inside the committee is very high,” he says, with many of the experts having come from the EMA’s now disbanded Pharmacovigilance Working Party. The PRAC’s first EU-wide drug safety review, which is looking to address concerns with codeine-containing medicines used for post-operative pain relief in children, ran “very smoothly”.

As for the list of medicines subject to additional monitoring under the pharmacovigilance legislation that the EMA must draw up and make publicly available, Prof Rasi says it is important to understand that the list should not be a cause for alarm. All products with a new active substance and biological medicines will automatically go on the list. Prof Rasi suggests that a list of the first 100 medicines or so has already been drawn up. [This list does not yet appear to be publicly available. At the time of publication, Scrip Regulatory Affairs was waiting for the agency to confirm its status.] A black inverted triangle that the PRAC wants all new products to display to denote that they are subject to additional monitoring has been presented to the European Commission. The aim is to encourage the reporting of suspected adverse drug reactions with newly launched products, but it could also be used to flag up efficacy issues. Again, Prof Rasi is keen to stress that the symbol does not signal danger; rather it is an indication of the “additional safety that we [are providing] because we are monitoring more closely”.

Transparency and public hearings

Rebuilding the reputation of the agency is another top priority for Prof Rasi. Under his watch, the EMA has managed to convince the European Parliament that it has taken the steps needed to address questions over the transparency and conflicts of interest of its drug evaluators and other staff that have continued to plague the agency over the past few years. As such, parliament recently approved the agency’s 2010 accounts. The EMA has, among other things, announced plans to introduce an ex ante and ex post screening system for experts’ declarations of interest, including random comparisons with CVs and information provided by experts at national level.

Regarding decisions made by the agency’s seven scientific committees, the EMA this year began publishing the agendas and minutes for the PRAC and also for its Committee for Orphan Medicinal Products and Paediatric Committee. It plans to do the same for its remaining four committees, but not until the end of 2013.

Opening up all EMA scientific committees to public hearings might also be on the cards – but clearly not any time soon. Not only is the PRAC currently the only committee authorised to hold public hearings, the definition of a public hearing still has to be finalised, Prof Rasi admits.

Prof Rasi realistically accepts that introducing public hearings in committees other than the PRAC might only happen “in the long term”. First, it is important to see how much value is gained from hearings in the PRAC setting.

Prof Rasi concedes that the EMA still has work to do to make sure its policy on providing access to the documents it holds on medicinal products is used as intended. A report has indicated that most requests for information do not come from scientists motivated by public health needs, but rather from industry with a commercial motivation.

Another problem relating to this policy that Prof Rasi is keen to point out is that the agency is spending a phenomenal amount of effort redacting information (such as personal data) in documents because companies are putting information in the wrong parts of their dossiers. For those companies that might purposely be completing their dossiers incorrectly to slow down the agency’s release of the information, the executive director has a warning: “It’s not going to stop us releasing… so work with us… and whatever is a cost for us is a cost for the [entire pharma] system.” In 2012, the EMA had by 26 October released around 700,000 pages of information in response to requests.

Prof Rasi is now grappling with the task of determining how the agency will begin to proactively publish clinical trial data for drugs – once the marketing authorisation process has ended – and enable access to full data sets. As well as having to figure out how to provide such complex data sets in a manner that is useful, he must deal with an industry that is reluctant to make its clinical study reports freely available. Resolving these issues will take some time. The EMA predicts that it might be ready to start publishing clinical trial data proactively in January 2014.

Better co-ordination and faster approvals

The EMA chief provides a progress report on the much-vaunted scientific co-ordination board he set up in April to boost the agency’s efficiency by improving co-ordination between its various scientific committees. It is no secret that the system of committees was becoming increasingly complex and unfit for purpose. Better co-ordination is expected to help the committees set standards for the development of medicines that are consistent across the whole product life-cycle, thereby increasing robustness and predictability of benefit-risk assessment.

Prof Rasi reveals that the board has now identified a group of experts in one therapeutic area that will sit on the different committees and deliberate on a product throughout its life-cycle. The agency plans to start using this expert group in January. A system of therapeutic expert groups is also expected to help the agency cope with the shortage of available experts it has to choose from as a result of having to compete with industry for the same experts. While one group of experts may on the face of it not appear to be much progress, Prof Rasi is clearly pleased to be the one who is finally tackling this important co-ordination issue.

On the question of how the EU drug licensing procedure might develop, Prof Rasi reveals that the agency is ready to test an adaptive (or staggered) licensing procedure for encouraging the development of products for unmet medical needs.

The adaptive approach, which would be used for drugs for severe diseases “where you can accept more risk”, could enable a product to reach the market as early as before Phase III development; further evidence would be gathered in the post-market phase. “We are at this point waiting for a company to come to us [to test this procedure].”

My interview is interrupted just short of my allotted time as the EMA chief is called on to attend to another important matter.

As for the Agrippal issue, it turns out there was no major cause for alarm. The agency decided not to take a lead in investigations because the vaccine was authorised by national governments; the French ban was later lifted following further tests.

Guido Rasi

Curriculum Vitae

2011-present Executive director of the European Medicines Agency2008-2011 Director general of the Italian Medicines Agency, AIFA1990-2008 Research at the Institute for Experimental Medicine of the National Research Council in Rome, Italy1978-1990 Physician (Professor Rasi holds a degree in medicine and surgery, with specialisation in internal medicine, allergology and clinical immunology)

Neena Brizmohun is the deputy editor of Scrip Regulatory Affairs.

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