The Sum of All His Parts: Career Reflections of Europe's Chief Drug Regulator

The European Medicines Agency (EMA) is a unique institution, pursuing a mandate shared with a complex web of national and regional groups, each able to place a distinctive imprint around the delicate task of certifying the safety and efficacy of new drugs. In return, the EMA has made a virtue of necessity. It filled the regulatory space opened by the relentless progress of science and new information technologies to gradually expand its remit in a way that has maintained consensus among stakeholders. In fact, the EMA has escaped the toxic politics that the US FDA is now mired in by securing a reputation for such predictability that it attracts scant attention from headline-seeking media and the political classes, even as the issues that surround drug approvals become more prominent and controversial.

Photo: Gideon Hart, London; Getty Images/Ian McKinne

Yes, there is bureaucratic merit to being boring, as reflected in the EMA's record of having achieved its prime commitment to meet legislated review deadlines for new drug applications in every one of its 15 years of operation. Much of the credit is attributed to the Agency's outgoing Executive Director, Thomas Lonngren of Sweden, whose five-year term—his second and final, as required by statute—expires on Dec. 31. "Lonngren is not part of a revolving door; his tenure brought stability, and in doing so he has kept the Agency independent," says industry spokesman Brian Ager, who is himself leaving the top job at the European Federation of Pharmaceutical Industries and Associations (EFPIA) after 16 years. Quietly, without much fanfare, Lonngren has made the EMA the "reserve currency" in global drug regulation, pursuing novel approaches to the evaluation of pediatric and orphan drugs; risk management and conditional approvals; expedited pathways for advanced therapies; and partnerships with industry around innovation, culminating in the €2 billion ($2.65 billion) Innovative Medicines Initiative (IMI) to speed development of new standard-of-care therapies. Many companies now see the EMA as a better bet against the FDA "gold standard" in obtaining a fair hearing without the political curveballs thrown by the many interests who see authorization as essentially a lobbying exercise.

An advantage for Lonngren is that unlike the FDA, the Agency is autonomous. It does not report directly to the EU Commission or the European Parliament but to a Management Board composed of a cross-section of institutions ranging from the member states to the EU agencies and even patient representatives. In that regard, the European process remains in many ways an insider game—you know which stakeholders count and how to target them.

However, expectations around the Agency are rising. There is no guarantee Lonngren's successor will be able—or suited—to pursue his low-key Nordic approach, even if the next Executive Director comes from the national agencies (as is likely). Tighter management of risk against the need to jumpstart pipeline innovation is a benchmark issue for Europe, just as it is for regulators in the US. The Agency is inheriting from the member states more oversight on pharmacovigilance, which is certain to attract more scrutiny from the European Parliament. Pressure will increase on the Agency to address the politically charged question of why member countries have different levels of access to medicines, especially now that jurisdiction over the Agency has shifted from the EU Commission's DG-Enterprise to the Public Health directorate, where activists enjoy more clout. Politics also intervened in an unsuccessful effort to downgrade the job level, even as the function itself becomes more vital to the EU's post-Lisbon treaty integration agenda.

With Lonngren now poised to move on—to a post advising governments, professionals, and the industry on the drug regulatory process—Pharm Exec Editor-in-Chief William Looney sat down with him in London last month to review his record, sift through the next wave of regulation, and highlight what's not on the industry's own reform agenda—but should be.

Pharm Exec: Your decade as Executive Director might best be characterized as an era of institution building. I see it as transforming a basic premise—that European integration required a more coordinated approach to certifying drug safety and efficacy—into specific processes, policies, and platforms that today are accepted by key stakeholders. Has the transition you've achieved helped preserve Europe's position as the world's largest market for medicines? What and where is the benefit?

Thomas Lonngren: The Agency is a relative newcomer to medicines regulation, having begun operations only in January 1995—some seven decades after the creation of the US FDA in 1930. So we have had a short learning curve. We are also an institution unique to Europe, with a mandate to coordinate scientific assets from the 27 EU member states and three European Economic Area (EEA) countries for the evaluation, supervision, and pharmacovigilance of medicinal products for human and veterinary use. What this means in practice is that we are an institution built around partnership, with our principal contacts being the national registration authorities with whom we administer a single, centralized EU-wide marketing authorization for new medicines granted through the European Commission. This task is a delicate one, as we must balance the need for process coordination with a complex web of policy interactions. Partnering well requires political wisdom; the metric for success is being accountable to the European institutions and the member states through good science, strong evidence, independent professional judgment, and—most important—a high level of transparency and communication.

The "incentive to consult" avoids the hubris that sometimes accompanies the exercise of power in the public trust. It gives us a rich portfolio of expertise to draw on. We are constantly exposed to different perspectives and are expected to explain and justify our actions to the same competent authorities in each of the member states, which is a guard against complacency and the bureaucratic mindset. This is one of the benefits of our approach, as it fosters a capacity for continuous innovation in the way we regulate. We have to be networked—it's wired into our DNA. The fact that national authorities still have a role in issuing a marketing license makes us nimble and doubly aware of how we impact public health.

Pharm Exec: This was also a period of significant expansion in the "European project," where the Agency was expected—by default—to take on new responsibilities. Which of these were most important in defining what the Agency is today?

TL: When I became Executive Director in January 2001, we had about 150 employees; today we have more than 850. The Agency administers a network of more than 5,400 experts distributed among 44 drug-licensing authorities in 30 countries. We manage six scientific committees responsible for our centralized authorization procedure, which is now mandatory for all new technologies, including biologics, with a seventh committee—on pharmacovigilance—in preparation. On top of that there are 35 expert working parties that supervise the development of clinical guidelines and support the preparation of dossiers.

What happened here was the political leadership in Brussels recognized that completion of the internal market required a stronger European basis for regulating the safety and efficacy of medicines. Directives were introduced in 2001 to clarify and expand our mandate in the human and the veterinary medicines area, with new scientific evaluation committees established in critical areas of unmet health needs, such as orphan drugs. Then in 2004, we had the "big bang"—the entry into our network of 10 new EU member states, followed by two more in 2007. This brought significant challenges in coping with more players at the table while maintaining the commitment to efficient dossier management and timely appraisals. We also saw the introduction of risk and surveillance management planning and the conditional approval track, where companies can gain expedited decisions on products for diseases that are severe and life-threatening and do not have substitutes on the market. Next, we had to respond to pressure to help speed the development of pediatric medicines, resulting in the creation of yet another scientific review committee. Because of the policy sensitivities and the complexity of the science, it was probably the most complicated set of rules anyone has ever had to introduce in Europe.

The Commission Regulation of 2004 also defined a role for the Agency in tracking the pace of scientific discovery to ensure our standards are relevant and supportive to what industry is seeking to deliver for patients. It resulted in legislation to create a Committee on Advanced Therapies to facilitate introduction of novel technologies, such as gene or cell therapies or tissue engineering. This is a real innovation for Europe, as no other national regulatory body has such a group dedicated to fostering timely introductions of the new medicines of the future. One of our key objectives at the Agency—in addition to certifying safety and efficacy—is to stimulate innovation and promote the availability of new medicines. Good regulation can facilitate that; the Advanced Therapy Committee is an example I am quite proud of.

Pharm Exec: What was most critical in helping you cope with this list of expanded responsibilities? What learnings do you draw from a process that demanded doing more without a large offsetting increase in resources?

TL: Focus is important. It was always the priority to maintain the Agency commitment to its stipulated review timelines—a maximum of 210 days from launch of review to a decision, subject to the stop clock proviso where additional data is needed from applicants. That pushes the average timing between the start of the review procedure to adoption of a recommendation to around 310 days. If our record faltered, then we would be vulnerable politically and I knew that would impair our freedom to implement all these new duties in a way that made the most sense. We have kept that commitment for 15 years. It is a significant accomplishment.

There were other factors that helped us. First, we were able to rely on expertise provided through the national authorities. The challenge was handling logistics and minimizing overlap and bureaucracy. The role of the Agency's Management Board in integrating and prioritizing the various interests—and knocking heads where necessary—kept us at pace with expectations in Brussels and the national capitals. Second, the Agency has a stable financial base due to the application fee system, which is largely paid for by industry and accounts for about two thirds of our € 200 million ($262.1 million) annual budget.

The third factor I'd cite is the "road map" process to clarify where I wanted to take the organization and to bring in others for consensus around resources. I knew that relying on the language of the EU statutes to guide us would not serve as a rallying point—the rules told us what to do, but not necessarily how. And I have always been struck by the way the ground moves so quickly beneath us; medicines regulation is a dynamic field. Leadership demands we prepare for the unpredictable—that "shot across the bow" that, if we are not ready for, can imperil the lives of thousands of patients. We've done two such road maps—the latest carries our work forward to 2015—and the process has been invaluable in cementing our value proposition to the outside world. This in turn has had a positive impact on internal morale, especially in helping people cope with change. Some colleagues in Brussels failed to grasp the point of the "road map" exercise, but I'd say now their view has changed.

Pharm Exec: The first "road map" covered the period from 2005 to this year. Now that it's largely complete, where were the successes and the gaps?

TL: We achieved progress in three key areas, each of which was based on a close assessment of the environment for drug approval. One was the review of all our policies to benchmark whether they added to or detracted from the capacity of industry to conduct R&D, so that European patients would gain the clinical benefit from new therapies. The second was to rigorously test our commitment to the highest level of safety, including ways to encourage the rational use of medicines to reduce the incidence of adverse events and to secure better rates of compliance. Third, we re-examined the entire organizational structure to see how to improve the flow of information, to communicate with external constituencies more effectively, and to make transparency the basis for everything we do.

The one area where there is still a gap is transparency. Progress has been made but it is clearly a moving target. Compared to other agencies, we are ahead. But my sense is that here in Europe, our stakeholders are expecting more. For example, a better definition is needed to classify what is commercially sensitive information. The European Ombudsman believes that the Agency should widen access to documents, and in the last few weeks we have moved further in that direction, making a pledge to allow disclosure of all documents—including adverse event reports—within 15 days of a request, subject to the conditions of data protection. Another challenge is making sense of the enormous amount of data we generate on a daily basis. That data has to be transformed into useful information. It's not easy; you cannot just go to the bottom of the pile and say, "This will be public and this will stay confidential." Hence one of our objectives for the 2015 road map is to build the internal capabilities to leverage the volume of information productively.

Pharm Exec: What are the key priorities of the 2015 road map?

TL: Final action on this awaits the decision of the Management Board, which meets this month and is slated to endorse both the road map and an accompanying "Vision to Reality" white paper. I would summarize the priorities to 2015 as follows: 1) maintain our core mission in approving new products through the European Regulatory Network; 2) fill gaps in the development of medicines for urgent health needs, such as antibiotics and the diseases of aging, and work with industry to address high attrition rates for many therapies; 3) adapt regulatory capacity to manage the growth of personalized medicine, through such means as setting standards for the qualification of biomarkers in cancer; 4) improve the scope of legislation covering veterinary medicines and find better ways to create synergies with our work in the human field; and 5) create a stronger preparedness/alert platform to manage public health crises as well as control the distribution of counterfeit drugs. There is a lot of continuation here, which is good, as we are building on success.

Pharm Exec: As we look to the future, what do you think are the most important trends that will influence the actions of regulators like yourself, particularly in the relationship with the R&D industry?

TL: Globalization represents a real game change for the regulator. The perception has been that there is a fixed geographic limit to our mandate. But over the last decade we have discovered that the products we regulate are researched in numerous sites, involving parties with different levels of skill or expertise; are subjected to clinical trials among increasingly diverse patient populations, in dozens of different countries; and are manufactured outside our territory, based on active ingredients formulated increasingly in China and India. The fundamental question is, Can we trust that all this critical work done outside our "span of control" is safe, reliable, and in conformity to our rules?

Pharm Exec: So how are you responding? Are you following the FDA lead and establishing a direct physical presence in markets outside Europe?

TL: No. We are not choosing to do that. Part of our strategy is to focus on executing bilateral agreements, the most important of which is the confidentiality arrangement and implementation plan we now have with the FDA. What is valuable about these agreements is that they facilitate structured contacts and lots of dialogue. For example, I have a representative of the FDA in an office 20 feet away from my own, and just down the hall we have an executive from Japan's PMDA. Our people are located at the FDA as well.

We have also identified the quality and consistency of clinical trials conducted outside Europe as a key area for action. The Agency sponsored a successful conference on this issue in September, a reflection paper is being published, and on this basis we will develop the necessary regulatory framework. The goal is to guarantee that such trials are conducted on patients that are representative of the European population and follow our accepted ethical and quality standards.

A third priority is improving the process of consultation to bring in new countries beyond the triad of the US, Europe, and Japan. The International Conference on Harmonization (ICH) is a good vehicle. The ICH Global Collaboration Group and associated Regulators Forum is the focal point for bringing most of the emerging markets into the fold. That is now taking place. The next step is deciding what we want to do as a larger group. In my view, there are two priorities: 1) sharing information, in the context of confidential agreements between all the regulatory agencies, and 2) promoting the widest possible acceptance of ICH practice agreements—GCP, GMP, and the like. This latter objective is critical for avoiding duplication of effort as more countries seek to regulate in these areas.

I also think it important to consider carefully the right platforms for cooperation. Earlier this autumn, we had a fifth summit of national regulatory chiefs in the UK. It was originally launched on the initiative of former FDA Commissioner Andrew von Eischenbach. Some 22 of us sat around a table and discussed issues, with no publicity or staff support, and a very loose agenda. I think this is a very productive model in sharing how we can cope with the pressures of globalization.

Pharm Exec: Another issue of concern is the relationship between relative assessment of value, reimbursement, and the marketing authorization process. You suggest that the process has been complicated by the growing demands of payers and health technology assessment agencies for the same kind of evidence. This creates more bureaucracy and inhibits your mandate to speed innovation.

TL: Expectations around the R&D industry are very high today. Payers—and patients—want new treatments that represent a therapeutic advance, but they don't wish to go bankrupt in paying for them. Yet the reality is that the industry is suffering from low productivity, and the prices charged for products we do approve are quite high. The reality for us as regulators is that we no longer have discretion in deciding whether patients have access to the medicines we approve. Our external stakeholders are noting this discrepancy. It runs counter to our mandate, which is to promote the supply of safe and effective medicines to all citizens in Europe.

Hence there is potential for confusion, ultimately leading to not one but two drug development programs, which will only increase the cost and probably slow industry productivity even further.

What we are proposing is a twofold approach to limit the possibility that this will become a bureaucratic reality, not just in Europe but elsewhere. First, we want to work together with Health Technology Assessment (HTA) agencies to refine the information we produce and the evidence we require—on efficacy and safety against agreed endpoints—so that it can be extended to help determine relative effectiveness against drugs and other healthcare interventions. One instrument is the European Public Assessment Report (EPAR) we produce as part of the licensing evaluation. The goal is to adapt that document to better suit the information needs of the national reimbursement and HTA agencies. A second instrument here is parallel scientific advice. A pilot project is now under way with a few R&D companies to examine how this might work in practice, with particular emphasis on what kind of data and information our two groups—regulators and HTA bodies—would need for their assessments.

The second plank in our proposal is to cooperate on the execution of post-authorization studies linked to risk management plans. There is room to pool our resources to generate strong observational data and determine how a medicine is actually being used in a patient population. Such evidence is highly relevant to the value determination that reimbursement authorities and HTA bodies wish to make before granting access to patients. I note that under the new EU pharmaceutical legislation, the defining principle of risk management has been widened to incorporate benefit, in addition to risk. This provides a better measure to calculate value, at least from the clinical side.

Finally, the Agency has to take into account the political aspects of the discussion. DG-Sanco is interested in building a common European terminology for HTA. There is now a Commission-financed network of national HTA agencies that some experts believe might lead to a single point of access to establish whether the medicines we approve are actually worth paying for—in all 27 member states. We are not advocating for this. Personally, I see it as taking place many years in the future, if at all.

Pharm Exec: Perhaps the biggest challenge facing regulators is justifying the rigor and integrity of the evidence you compile to grant a license to market a drug. This is a decision of monumental importance; it can save the lives of many thousands of patients—or condemn some to early deaths. It can provide billions in revenues to drug makers—or bankrupt them. And it can either facilitate or constrain interest in new areas of research. Is the criticism and "background noise" around the legitimacy of clinical data politicizing your position as a responsible regulator?

TL: The issue is that the technology that has allowed us to generate increasingly vast amounts of information has not been accompanied by an increase in the ability to interpret it, with perfect judgment as to what it means for providers, patients, and society. Two decades ago we had much less information and were not expected to evaluate risks during the post-authorization phase, when a drug is being used in the community. Today, this is the expectation from the start. In addition, the science has changed; the compounds we review are much more complex. And there is a built-in dilemma in striking a balance between risk and benefit—from a practical standpoint, people prefer to know more about risk because of the implications for health and survival.

I also believe industry marketing practices have skewed perceptions around risk. It frankly makes it harder to fulfill our task in certifying that a product is safe. Consider it this way: In a randomized clinical trial (RCT), the protocols are carefully established with us and the patient profiles are well defined, so you tend to have less "noise" in the assessment of results. Then when the drug is out and being used correctly according to the label, you tend to find more side effects and a higher level of risk. But what really skews the outcome—and creates the conditions for a product withdrawal—is where irrational use and off-label prescribing occurs in clinical reality. Risk exposure soars precisely because the company's product is not being used as was intended by the regulator. A study conducted here in the UK on the GSK drug Avandia included subjects who were known to be at risk for cardiovascular events. They never should have been prescribed the medicine, but the commercial pressure to show a gain in this area was too much of a temptation. What resulted was just more evidence of risk—the negatives were accentuated to the detriment of benefit. Then it is left to us, the regulator, to explain why we approved the product in the first place. Do you see what is lost in the translation?

Pharm Exec: What should the R&D industry do to minimize this prospect?

TL: The best tactic is improving the patient response rate of medicines—to achieve the desired therapeutic effect. Our sense is that at present the response rate for medicines we approve is low. As a patient thinking of whether to take a medicine, I have to ask, "Will I be one of the 20 percent of patients that derive a benefit or one of the 80 percent that don't—and still bear all the risk too?" The goal of industry has to be to clearly identify those who respond, because then you have a very positive risk versus benefit profile that will in turn drive access to the market. The Agency is seeking to encourage this with our new pathway for the approval of biomarkers, which includes a fee reduction for consortia that produce new candidates.

Pharm Exec: There is a downside here, in that a targeted, personalized-medicine approach tends to reduce the potential takeup and size of the market for a new medicine.

TL: True. But I believe this is a better approach for industry because it documents the gains and societal value of innovation. We need better evidence to show that what the industry is producing is actually innovative. I support the notion that innovation can be demonstrated incrementally over time, in products that were initially approved for one indication, but find new life in another. You cannot judge innovation just at the time of approval. This is why we as regulators carry an obligation in the post-authorization phase—in our risk management plans—to assess benefit as well as risk. Often the emphasis is heaviest on the latter.

Pharm Exec: Now that your tenure as Executive Director is ending, do you have any advice for the pharmaceutical industry going forward?

TL: Drug companies need to do a better job at linking their prospects to the treatment and prevention of disease—not just today but especially for the future. Association with the development of advanced therapies like tissue replacement and modification of the immune system through vaccines is vital.

Industry leaders also have to face the question of the limited resources available for health: Are we as a society spending these resources in the right way? This in turn requires the possibility of acknowledging that pharmaceutical interventions are often overvalued. The best tool to solve a health challenge could be something other than a drug. Process innovation is not recognized by the industry as a source of growth. Horizontal prevention strategies, designing devices along with drugs to facilitate improved diagnoses and raise the patient response rate—these are ripe for new approaches. The current business model has to yield to something more holistic.

Pharm Exec: What advice might you have for your successor?

TL: A firm commitment to transparency is critical to success in this position. Transparency is fundamental to trust. Trust is what fosters confidence in our networked authorization system and helps ensure that when there are problems, you have the political leverage to do what is right for public health. This is particularly important given the EMA's expanded remit in supervising the pharmacovigilance process. The next Executive Director will also have to keep pace with progress in science and technology. New areas of regulation are opening up; more needs to be done to clarify standards, as we are doing now for biosimilar antibody drugs, where we are specifying approaches to post-authorization followup studies to better ensure patient safety.

Pharm Exec: What are your plans for the "next life?"

TL: My plan is to remain active as an adviser and supporter of enlightened regulation—it's a force for good in society. How I plan to do this I will announce shortly.