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Europe's chief regulator charts a strategy from many moving parts. Dr Guido Rasi talks to Pharm Exec's William Looney.
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.
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.
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.
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.
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.
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.
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."
William Looney is Pharm Exec's Editor-in-Chier. He can be reached at email@example.com.
Pharm Exec's Editor-in-Chief William Looney met with Dr. Guido Rasi on October 16—exactly one year after the 58-year old physician researcher was handed the key to his sun filled Canary Wharf office as the agency's third Executive Director. In the following highlights from that interview, Rasi expounds on his efforts to build an internal culture of trust and transparency, while keeping pace with advances in scientific discovery and information technology as well as industry expectations for a seamless—and timely—approval process.
Pharm Exec: The EMA is in many ways a fragile institution, with a broad remit to advance access to medicines but a high level of dependence on the cooperation of many constituencies. How important is trust to maintaining the external support that is so critical to the successful execution of the EMA's mission? Can recent revelations of conflict-of-interest problems in the agency be remedied by a quick fix of the rules or is a larger, long-term cultural change required?
Rasi: The EMA mandate is by law a decentralized one; we are not a "command and control" enterprise. Given the importance of the EMA's function to approve medicines, our actions are closely monitored. Credibility—the organizational equivalent of trust—is essential to our ability to function. If the medical community and our political institutions do not trust us, then our decisions are not credible and from there it is a slippery slope to losing public confidence in the integrity and safety of the medicines supply.
A strong commitment to transparency and ethical behavior has been the central objective of my first year as Executive Director. Trust in the agency is not completely restored. But the progress we have made in opening up our procedures and raising the bar on conflicts of interest means that trust is no longer an obsession among our colleagues in Brussels. I detect a friendlier atmosphere at the European Parliament, where discussion is moving back toward the technical and scientific issues most appropriate to our role as regulators.
The conflict of interest problems at the agency did not occur because we had no rules. The issue was one of perceptions, interpretation, and enforcement. So what we did was reinforce the rules by improving day-to-day scrutiny on compliance. The rules now cover not only contracted members of our expert committees, but all personnel, including the management board. This sent an important message: that no one is exempt. Everyone now understands that ethical standards of behavior are embedded in the work routine; it is part of the EMA culture.
Pharm Exec: Greater transparency is another way of exposing conflicts of interests before they impair trust in the organization. What measures have you taken here?
Rasi: I have made a commitment to publish the minutes of all seven of our scientific committees by the end of 2013. It will be easier to do this in some committees than others; clearly, the Committee on Human Medicinal Products [CHMP] must be careful that what is disclosed will not confer a competitive advantage to companies active in the therapeutic areas under review. We are also examining procedures to enforce actions against conflicts of interest involving all the scientific experts who advise us on registration decisions. While it is true, as some critics contend, that we in management cannot take preemptive steps by removing an expert who is in breach of the conflict rules, we can prevent that person from participating in decisions, which solves 99 percent of the problem. This happens very rarely; our inability to fire at will actually provides a measure of independence for the committees. It is a problem that is more theoretical than real.
Pharm Exec: Transparency is not simply a legal concept; it is a cultural mindset built on a willingness to communicate around things that are important—especially to others—and to build relationships that stretch beyond the sound bite. How well do you think the EMA is communicating its values and objectives?
Rasi: Communication starts with good institutional ties among our key stakeholders. The agency has built a very important coordination capability through the Heads of Medicines Agencies [HMA] group, which gives us a regular vehicle to promote our alignment goals with 44 national registration and review bodies throughout Europe. Earlier this year, I launched a new Scientific Coordination Board, composed of the seven heads of the committees and leads for a number of working parties, to develop a vision that integrates the expertise of all these groups. The board will not deal with issues of specific medicines but rather on identifying and resolving challenges to the overall drug evaluation process. Improving working contacts with patients is another priority, building on the working party we already have in place that gives patient organizations formal representation on our human medicines scientific committees, including pediatrics. And we are exploring ways to provide more support to help keep the patient groups independent and to allow them to invest in the greater expertise needed to contribute to the complex science our committees must deal with.
I am most excited about the initiative on disclosure of data from clinical trial results. This is where the EMA is playing a global leadership role in making the regulatory process transparent and trustworthy. Our credibility rests on the ability to communicate why we take a decision on a particular medicine, and that depends in turn on displaying in public the data driving that decision. It is also valuable in that disclosure, by encouraging more debate on interpretation of trial evidence, will enhance the rigor, integrity, and ultimately the reliability of our evaluation procedures. This is an important objective, as changes in the way clinical trials are conducted—today, many trials are now global in scope, and beyond the reach of any one regulator—raise many questions about how to keep the current system effective, honest and useful to reviewers seeking the best outcomes for patients.
Pharm Exec: Don't safeguards need to be built into the process for release of data? Will this yield something less than full disclosure?
Rasi: Disclosure is easy in principle, but defining a process can get complicated. We are holding a stakeholder discussion on our initiative on November 22, which will seek to resolve four transactional issues. These are (1) procedures on how to classify and when, or if, to release such data; (2) ensuring that those who receive data have sufficient expertise to analyze and apply it without manipulating or misrepresenting the results; (3) creating specific ground rules to protect patient privacy, including whether to sanction the release of large patient data sets; and (4) commercial confidentiality considerations, including data scrubbing to prevent disclosures that create a competitive advantage or disadvantage. I am confident we can work these issues out, especially as I see many companies moving in this direction, on their own initiative.
Pharm Exec: What is your assessment of the industry position?
Rasi:It is positive and constructive overall. Industry engagement around disclosure makes our efforts easier to execute. Although the industry's stance is not homogenous, I think we all agree that the trend to greater transparency in accessing trial data is irreversible. The challenge lies in making it work at a time when the basic model of the clinical trial is splintering, in the face of advances like biomarkers and other tools of personalized medicine. Regulators have an obligation to clarify standards for trial design and evaluation where there may be two, three, or even more options that companies can follow for a single compound. It simply reflects reality; some tested compounds will benefit from the availability of biomarkers that can serve as surrogate clinical endpoints, while others may not. We must work together with industry to determine how seriously we should invest in validating results based on these new high-tech tools. I would add that predictability from the regulator—on what factors are needed to make a good evaluation—is vital to controlling the soaring cost of these trials.
Pharm Exec: Are you coordinating your approach on trial data disclosure with the US FDA?
Rasi: The FDA is aware and supports our activities. But the US environment is different than here in Europe, where there is strong institutional pressure to take this forward. We will act on this initiative, after November 22. It is my most important priority at the moment.
Pharm Exec: Harmonization of approval standards is an important policy objective for the industry. Can you cite examples of cooperation with the FDA to ease conflicting decisions in the registration process?
Rasi: We are pleased with progress of the Transatlantic Simplification Initiative, which serves as a clearing house for joint rule-making activities with FDA. There are regularly scheduled teleconferences to share insights and move projects forward. We just had a very good outcome from one such project, to harmonize the orphan drug designation process. Continued progress on harmonization is also politically astute. Regulators want to respond appropriately when patients ask awkward questions about why the same medicine is available and benefiting patients in the US, and not here.
Pharm Exec: The flip side of cooperation is duplication of effort. A pressing concern for industry in Europe is the erosion of the traditional "red line" between the basic market authorization decisions you make and access, pricing, and reimbursement activities at the national level. An example of this is overlapping—and often contradictory—information requests from the EMA and local agencies that conduct health technology assessment [HTA] studies on cost effectiveness. How is the EMA aligning its methods with the HTA community to reduce the burden on companies?
Rasi: We offer companies a structured stakeholder consultation called parallel scientific advice. That advice is geared to helping companies identify, at an early stage in the drug development process, what information will facilitate prompt review by us as well as the national HTA authorities. What we offer, quite simply, is a roof under which all questions can be vetted in advance. Some 17 parallel advice sessions have been conducted with companies to date; in addition to the EMA, the participants include some of the key HTA authorities in the region, including NICE in the UK, Germany's IQWiG, HAS in France, AIFA in Italy, the Dutch ZVZ, and the Swedish MPA.
Pharm Exec: Is this "red line" going to disappear entirely at some point in the future?
Rasi: Yes, I think the "red line" will become pink, at least as regards the basic decision on whether to reimburse a drug. We will be more involved in supporting that decision at the national level. Pricing is not as clear; it's another step after reimbursement, and here logic assumes the payer must be in the driver's seat.
Pharm Exec: Last year, the EMA assumed a huge new responsibility, to administer a coordinated region-wide umbrella network of pharmacovigilance on product safety and side effects. How is it working so far?
Rasi: Implementation is going well; so far, we have met all the deadlines set by the 2010 EU Regulation. Our stakeholders are pleased with the way we are interpreting the mandate. The question now is managing a complex signaling and detection system that depends heavily on the performance of high-grade data gathering, integration, and interpretation software we have put in place with the member states. The signals we derive from the system must be definitive and clean to avoid any unwarranted alarms. More than 250,000 coded data points on marketed products have already been loaded into the system, and this is just the beginning. It is also important to note that the responsibility we have assumed is funded by cross-subsidization with the member states. No new money has been allocated. This is a major challenge, as we can rely on the current funding approach to maintain the system only for a limited time.
Pharm Exec: What would you define as the major achievement of your first year?
Rasi: In addition to building trust through increased transparency, I would say it is the launch of our scientific coordination board. Many people thought initially this would just be another layer of bureaucracy, but instead there is a broad recognition that understanding issues around broad therapeutic areas—rather than individual products—delivers real insights on patient welfare and makes for better decision-making overall.
Pharm Exec: Finally, how do you think the role of the regulator will have changed by the end of your mandate in 2016?
Rasi: Progress in science is running ahead of the ability of the regulator to understand it and weigh the implications. Thus, we will see the expertise that we bring to our role expand to encompass other, complementary functions; we can't just be physicians, chemists, and pharmacists. Molecular biologists, ethicists, and technology experts who can aggregate and interpret "big data" are needed. HTA analytics will play a more prominent role too. In addition, to stay relevant, we have to build a much more global orientation and presence. It is where industry is already. This is particularly important in the area of drug inspections—I know the FDA shares our view that this area is vastly under resourced. A worldwide agenda of proactive cooperation is necessary to minimize harm to patients.