The Puzzle Master: EMA's Guido Rasi

Closing in on its second decade as chief arbiter of approvals for the world's largest drugs market, the European Medicines Agency (EMA) is confronting that transitional stage of cranky adolescence, where the gap between expectations and performance is widest. The agency spent its first years treading carefully through the minefields of EU politics, establishing its institutional bona fides by compiling an enviable record of consistency in meeting legislated review deadlines (210 days) for new medicines. That early success produced a torrent of demands to take on new responsibilities, resulting in a mismatch between mandates and resources, followed—almost inevitably—by a perceived leadership vacuum, allegations of improprieties, and more outside scrutiny of how the agency conducts its business. Today, the EMA is scrambling to adapt to a growing tendency to micro-management by the European Parliament, not to mention the EU Commission and 27 EU member governments. Their instruction to the agency is simple but sweeping: talk straight, play for value, and keep it safe.

Dr. Rasi

Matching the jagged pieces of this bureaucratic puzzle requires keen-eyed, adult-level diplomacy and finesse, particularly in navigating a mandate that is unique among regulatory agencies. The EMA enables and coordinates, but does not control. It is—at least officially—politically autonomous, answering to a management board drawn from representatives of local registration authorities and the EU institutions. Day-to-day activities are driven by an extensive—and confusing—cross-subsidization of time, money, and effort among these diverse stakeholders.

The man of the moment for this task is EMA Executive Director Guido Rasi, a physician and microbiologist who assumed the post in October 2011 after three years as head of the Italian drug approval agency, AIFA. One of Rasi's assets was that he was no stranger due to his role in representing Italy on the EMA Management Board. This was important given the surprise disclosures of ethical lapses surrounding the departure in December 2010 of the second EMA Director, Thomas Löngrenn. In addition, Rasi had shown a deft hand in similar circumstances, leveraging family connections to the Berlusconi government to restore public confidence in AIFA after a 2008 scandal involving "pay-to-play" allegations against the previous management.

Rocky start

Criticism over Löngrenn's move as a well-paid consultant for companies with business before the agency delayed the selection process that led to Rasi's appointment. The timing could not have been worse, as the leadership gap occurred in the aftermath of two well-publicized public health emergencies: one involving the failure of French drug-maker Servier to disclose life-threatening heart valve injuries from a diabetes drug it marketed as an appetite suppressant, and the other over the sale of breast implants known to be defective.

Although national authorities bore much of the blame for the toll in deaths and injuries, the two cases exposed serious gaps in the European legal armamentarium to protect the public health, especially once medical products are out on the market. A consensus quickly emerged that a broader regional approach was needed, and in due course the EMA found itself charged with oversight responsibility to coordinate and track the safety of all approved medicines and vaccines, including those secured via the decentralized procedure run by national agencies, through a European-wide strategy and program of pharmacovigilance.

This task alone might rightly be seen as all-consuming, given that the safety net EMA must erect covers a target community of more than 500 million patients. But Rasi confronts a more fundamental short-term challenge, which many observers of the agency now call "the two t's:" transparency and trust. Predictably, both are seen as being in short supply. EMA's paymasters in Brussels are insisting that Rasi put these at the top of his priority list to ensure that confidence in the integrity of the drug supply is maintained. "Credibility is the working currency of regulation, and EMA is no exception," Rasi told a recent Prix Galien Forum panel moderated by Pharm Exec.

More daylight on finances

Advocates for a clean slate at EMA have put their money on the table – literally, by scrutinizing every euro and withholding approval of the agency's €230 million annual budget. Under instruction from the European Parliament, the EU Court of Auditors last year initiated a review of the EMA's accounts for the 2010 financial year, with the aim of assessing the effectiveness of procedures to prevent outside interests from influencing critical decisions on market authorization. The Auditor report, released on October 11, exposed a number of gaps in the system, including the practice of not basing payments for services provided to the EMA by national registration authorities on their real cost, and the allowance for carryovers in spending from year to year, which makes it more difficult to trace where and how resources were actually deployed.

The auditors ended up giving the agency passing marks for a good faith effort. Still, their carefully hedged conclusions failed to impress, particularly when no one at the court could explain why release of the report occurred nearly a year after the investigation was completed. Basically, what the report did was just pitch the issue back to the Parliament. In fact, the Parliament's Budget Committee didn't even wait for the auditor report, voting on October 2 to lift the parliamentary veto on the 2010 accounts after citing changes that Rasi had made shortly after taking office, the most important of which was to make public the declarations of interest of the 4,500 outside experts that the EMA relies on in conducting its evaluation work. In February, the EMA extended this open door policy by publishing declarations of interests provided by agency management and staff. The EMA also committed to periodically screen all declarations to keep compliance up to date; to obtain and cross-check declarations provided by experts working with national regulatory agencies; to conduct retroactive legal reviews of the work of employees who leave the agency for "resolving door" positions; and, perhaps most important, to publish on the EMA website by no later than the end of 2013 detailed minutes of meetings of its seven scientific expert committees (three—on pediatrics, orphan drugs, and pharmacovigilance risk assessment—have complied so far).

While it commended these initiatives, the committee instructed the EMA to do more, including drafting an action plan on additional steps to control and prevent non-compliance with the conflict of interest rules adopted by the management board in 2010; and to introduce a special section in its annual public activity report detailing work in this area. Significantly, the committee endorsed the EMA view that ultimate success in this area was a "two-way street" with the pharmaceutical industry, and that the commission and Parliament should consider legislation on disclosure of company funding of experts and research centers with whom they work.

The full Parliament endorsed the committee report on October 24, formally releasing the EMA from its funding hold. The message to Executive Director Rasi and his team was clear: self-initiate changes to advance trust through transparency, or it will be imposed.

Finding transparency—where it counts

In the drug industry, data is the tangible asset that drives approval and market uptake by clinicians and patients. Precisely because of its value, companies have contested demands for the release of information submitted to the EMA and its scientific committees in pursuit of that all important license to sell. Cracks are appearing in the façade, however, as major companies like GSK move to disclose more such data on their own. Last year, the European Ombudsman ruled that trial data held by drug regulatory agencies could not automatically be determined as commercially confidential. Rasi is now seeking to drop the bar further with a new signature initiative designed to make clinical trial data submitted to the agency more readily available to outside groups. Access to such data will be allowed immediately after a new drug is approved, but the process for obtaining it remains a subject of discussion—and it's not a question of whether to do so, but how.

On November 22, an invitation-only workshop, chaired by Rasi, was held at EMA headquarters in London, to consider ways to channel that access appropriately. It was agreed to fix standards around five key process issues: patient confidentiality; data formatting; rules of engagement with requestors; analytical standards of good practice; and legal jurisdiction. Working groups involving stakeholders will be set up for each of the five; they are due to report in to EMA management with recommendations by April 2013, with the new system of "proactive release" set to start in January 2014. EFPIA Director-General Richard Bergström proclaimed the workshop a success, noting to Pharm Exec that "we have already agreed that almost all clinical data in files should be made public after approval." Trial activists, however, want it all.

Safety savior

The flip side of transparency is risk: and all medicines can be dangerous. The consequences for public health of a product crisis are multiplied when information is inaccessible, hard to interpret, or missing entirely. Politicians and parliamentarians recognized this in approving in December 2010 EU Regulation 1235/2010, which put the EMA in charge of coordinating a new European-wide structure for monitoring the safety of medicines on the market in the 27 EU members and three affiliated EEA states (Iceland, Norway, and Lichtenstein). This has proved to be a huge assignment, extending the agency's purview to ensuring safe use of medicines authorized by some 40 different national authorities through the de-centralized procedure, in addition to drugs approved by the EMA.

At the heart of the program is a new reporting network—EudraVigilance—designed to quickly detect side-effect/adverse reaction problems with marketed medicines, and to coordinate the execution of appropriate control measures to safeguard public health. Responsibility is a shared effort, with national regulatory authorities assigned by the EMA to monitor a list of specific active substances approved in more than one EU member country through the national, decentralized, or mutual recognition procedures. In essence, it means that national authorities will take on a broader leadership role in certifying drug safety for selected medicines outside their own jurisdictions. "Europe is moving toward a genuinely region-wide approach to the key growth area in drug regulation over the next decade—post-marketing surveillance," Ansis Helmanis, principal at the DC-based advisory firm RegLink Associates, told Pharm Exec.

The reporting requirement is being implemented without any significant increase in funding. Much of the burden of compliance is placed on individual companies, who already provide approximately 80 percent of the EMA budget through fees paid to support evaluation of the initial registration dossier. A new data entry tool devised by the agency to facilitate reporting has received mixed reviews from companies.

Looking forward—the adapted license?

The EMA's diffuse mandate gives it more flexibility than its counterparts in considering how it should do business with industry. An interesting example is the proposal in its 2012 work plan to initiate a debate on alternatives to the standard "magic moment," where one decision to authorize lasts for the entire lifecycle of the product. The EMA calls the idea "staggered approval" or "adaptive licensing," in which an approved drug could be reevaluated and its license "adapted"—or perhaps revoked—to conform to new evidence, advances in science, or changes in clinical practice.

In March the management board endorsed testing this approach through a pilot project for completion by year end, pursued in alignment with all stakeholders, including industry. However, no action has been taken to date. Nevertheless, EFPIA Director Bergstrom told Pharm Exec he agrees with this and other efforts to make the regulatory system "more fit for purpose." "The ideas coming from EMA staff on adaptive licensing are very encouraging."

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