Peter O'Donnell

	There’s just a month to join Europe’s networks of expertise for rare and complex diseases, the European Reference Networks

. Until 30 November, hospital-based specialists can apply to become members of one of the 24 European Reference Networks (ERNs) that the European Union launched in 2017, and that now include 956 healthcare units from 313 hospitals located in 26 countries. They cover a wide range, from bone disorders and pediatric cancers to endocrine conditions, and from epilepsies and congenital malformations to kidney diseases.

	Created under the EU’s 2011 directive on cross-border healthcare, these networks bring together centers of expertise and reference centers of European hospitals to tackle rare or low-prevalence diseases and other complex conditions that require highly specialized healthcare. The aim is to allow specialists in Europe to share their experience with complex patient cases, and to provide advice on diagnosis and treatment. To review individual cases, ERNs convene ‘virtual’ advisory panels of medical specialists across different disciplines, using a dedicated IT platform and telemedicine tools. The underlying principle is that it is the knowledge travels, rather than the patient, with the intention of leading to economies of scale and more efficient use of costly resources.

	The concept emerged from the challenge that knowledge and resources on specific rare conditions are scattered across Europe’s individual countries, none of which, operating alone, has the capacity to treat all rare and complex conditions. The EU’s networks help to connect the dots, maximizing expertise by cooperating and exchanging knowledge at European level, and giving patients across the EU access to the best expertise available.

	It is a peculiarly European response to a peculiarly European problem-a multiplicity of small countries (even Germany, by far the biggest, has only 80 million inhabitants) with distinct healthcare systems and research infrastructures that suffer from a chronic lack of coordination or even communication with one another across the continent’s internal national frontiers. Add to that the specific challenges of tackling rare diseases: as many as 8,000 rare diseases affect the daily lives of around 30 million people in the EU. In oncology alone, there are almost 300 different types of rare cancers and each year more than half a million people in Europe are diagnosed with one of them. But many affected by a rare or complex have no access to diagnosis and high-quality treatment: where patient numbers are low, expertise and specialist knowledge are often scarce.

	The membership application process can look daunting, since a healthcare team has to get endorsement from the head of its hospital and from its national health authority, and candidates are then screened by a board of representatives from the participating health authorities. But the benefits extend beyond the chance for taking part in reviews of complex cases. They include the opportunity to play a role in the development of guidelines and in training, and to join large clinical studies aimed at improving understanding of rare diseases. The patient data gathered also contributes to the development of new drugs and medical devices, and ERNs are influential in the emergence of new care models, and e-health solutions and tools.

	At a time when Europe is facing a string of new tensions-ranging from internal disputes over migration, budgets or carbon-reduction targets (to say nothing of Brexit) to external challenges such as threats to the multilateral trading system, growing disorder in the Middle East, and the shifting power balance between the U.S.A., Russia and China-this local but effective initiative is a welcomed demonstration of how cooperation can function in the common interest.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

		https://ec.europa.eu/health/ern/consultations/2019_call_membership_en 

Articles

With a month left to join one of the 24 ERNs, Peter O'Donnell writes that this initiative is a welcomed demonstration of how cooperation can function in the common interest.

Europe Recruiting Additional Healthcare Teams for Specialized Rare Disease Networks

	Europe's outstanding achievements in basic life sciences research are not getting through to patients as useful treatments and diagnostics-and the urgency of filling those gaps is not getting through to European policy makers, says yet another new coalition jockeying to
	make its voice heard in the crowded space of strategic lobbying in Brussels.
	
	A joint statement from Europe's drug industry and Europe's medical societies calls for a "bold vision" to ensure adequate funding and coordination for translational research. Issued on the eve of the European Union's summit meeting in Brussels on March 21 (where the agenda is dominated yet again by Brexit woes), it makes a plea for recognition from a world where, it says, it is not understood.
	
	Laboriously, it explains the role and importance of translational research, and highlights the challenges it faces. "This type of research is costly and risky involving many steps of collaboration among all stakeholders. Funding activities are scarce," it says. And, it goes on, "instruments aiming to strengthen the various steps in the process of the translational research ecosystem are often fragmented and lack tangible follow through the full medicine’s lifecycle."
	
	In language so convoluted that it risks intensifying rather than clarifying confusion in the outside world it aims to impress, it urges EU policymakers "to work together with the research community, industry, and patient representatives to ensure that these directions are implemented in inter-sector collaborations to progress synergies within and across projects and initiatives."
	
	There's a straightforward action plan-direct and simple. And expressed in just the sort of simple concrete language that politicians love. If that doesn't convince policymakers, then nothing will.
	
	Something better in terms of communication might have been expected from the combined intellects of the drug industry's European Federation of Pharmaceutical Industries and Associations and the 400,000 researchers and health professionals in the BioMed Alliance-the two partners in this coalition. So far, the top item in their plan, as revealed by their statement, consists of "increasing visibility on the role and needs of translational research to better inform policy makers, academia, patients, and the general public." With no irony, BioMed Alliance presents itself in its statement as conveying "the views of its members in a cohesive and comprehensible form to policymakers, professionals and the public at large." Good luck with that.
	
	As it happens, they may be in luck if the summit ever gets beyond the Brexit quagmire, because one of the items on the agenda of EU leaders is developing an “integrated approach” to promote growth in the EU through “an assertive industrial policy allowing the EU to remain an industrial powerhouse.” The leaders are scheduled to request their officials "to present, by March 2020, a long-term vision for the EU’s industrial future, with concrete measures to implement it.”
	
	And in another stroke of potential good luck, a breakthrough on research strategy occurred just days before the summit, when agreement was reached among EU legislators on the outlines of their next long-term research program. This will put more than $100 billion behind European researchers over the next seven years, with a hefty slice of that earmarked for life sciences and health topics. And the entire program is geared to "societal challenges and industrial competitiveness" and "market-creating innovation," with provide a one-stop shop to help bring promising and breakthrough technologies from lab to market application, and assist in scale-up of ideas. Parallel streams are to be set up for early stages research and for development and market deployment.
	
	If the translational research community can't talk their way into benefiting from some of that, they will have no one to blame but themselves.

A statement from Europe's drug industry and medical societies calls for adequate funding for translational research, explaining the importance, and highlighting the challenges it faces.

European Researchers Struggle to Communicate

	"It's obvious, but it's not center-stage," says Ingrid Klingmann, chair of EFGCP. "Clinical trials do not always benefit all the patients participating in the research – despite all the injunctions of the Declaration of Helsinki and GCP." She points to the risks run by participants exposed to non-optimal treatment in a clinical trial, or enrolled in trials that are badly designed, poorly managed, conducted against an unsuitable comparator, or never completed.

	Society has more than 50 years experience of systemized clinical research, and it is time to ask whether it is working well enough for trial participants, she told 

 in an interview in Brussels in mid-January. Trials are of course mandatory for demonstrating the efficacy and efficiency of a treatment, and there is a political obligation to enable faster patient access to more and better treatments, she recognizes. "But are we doing trials in the right way from the point of view of participants? We should never forget that patients entering into the unknown are taking a risk – and there is something heroic about that. We have an ethical obligation to keep these heroes at the center of all these efforts."

	Klingmann reels off a long list of possibilities she sees as just crying out to be exploited across the wide range of clinical research stakeholders – all of them holding out chances of giving trial participants a better deal. One area of promise she identifies is a more adventurous exploration of how to meet regulators' needs for demonstrations of efficacy and safety. Evidence-based decision-making demands data, and clinical trials deliver a lot of data – but is the best use being made of all that data, she muses. Recently increased openness among some regulators to consider conditional authorizations or adaptive pathways is welcome, but clarity is seriously lacking about the wider use and acceptance of new approaches.

	Many of the outstanding questions about the use of real-world evidence, for instance, demand urgent answers to make sure that patient experience – good and bad – is fed into the choice and use of medicines. More determined efforts should be made to leverage patients' often hard-won, real-life exposure into valuable insights, through greater data standardization and interoperability, linking registries, or agreeing guidelines on use of placebo or comparator. And there is a world of virtual possibilities still to be exploited effectively, she says, citing moves to develop a global regulatory acceptability framework and prototypes for simulation and extrapolation through artificial intelligence, as already applied in imaging to improve diagnosis.

	Klingmann sees many instances where industry could also refocus its approach to give greater priority to the interests of trial participants. Over and above its evident moral obligation to reduce harm to patients, industry could do itself a favor by going the extra mile to make a reality out of rhetorical claims to "patient-centered" development – at the same time improving their frequently uneven public image.

	The realms of academia also hold real potential for improvement, she argues. Current academic clinical research projects are not reliably optimal, she considers, citing recent claims that about half the studies initiated are never reported – sometimes because they are not completed, sometimes because sponsors are reluctant to publish, sometimes because journals are unwilling to accept results and sometimes because the studies are so poorly designed that the results are not interpretable. Clinical trial methodology merits development as a medical discipline to ensure that only experts recognized in that discipline are entitled to take responsibility for a clinical trial. "It is unacceptable for participating patients to be sub-optimally protected or involved wastefully," she insists.

	Also high among her priorities are the physicians who are actually treating patients. These represent in her view a massively underused resource. Most practicing physicians are currently unwilling to engage in trials, partly because of limited trust in a collaboration with the pharmaceutical or medical device industries. This is compounded by a politically supported reluctance to expose patients to the risk of treatment options still not evidence-based. In addition, clinical research does not enjoy a favorable reputation among much of the medical community, and the low level of engagement is due in part to a lack of understanding, with clinical research still conspicuously absent from the curricula of medical schools' and post-graduate education.

	Changing that perception could bring benefits to patients as well as to research. At its best, participation in trials is good for patients: if there is no treatment alternative, patients get a chance of access to a first treatment option; and in indications where treatments are available, they get more tests, they are more frequently seen and more closely monitored, and – as increasingly reported in life-threatening disease areas - they enjoy better survival. In addition, widening the net of investigators would ease the chronic challenge of adequate recruitment, and at the same time would widen perspectives by avoiding the current re-use of the same pool of investigators.

	Patients too are themselves an under-exploited resource. There is a patient community that is increasingly informed, and that wishes to contribute expertise in everything from defining research priorities to study design and study conditions, but there is still no adequate infrastructure for their systematic engagement. And it is still the case that very few patients are aware of their options to impact the development of better treatments for their disease. Clinical research remains too susceptible to emotional discussion, and greater objectivity would allow a more mature relationship between public and research.

	"In the public debate on innovation we are also faced with a paradox," says Klingmann. "While there is growing concern that 95% of new medicines come from industry, the funding of clinical research still depends predominantly on the private sector because society has decided not to risk public investment into new treatments." Without a change in funding arrangements, that situation cannot change, she remarks. The limitations of public funding inhibit the engagement of many university-based physicians in clinical research. Meanwhile, the research support efforts made by the EU have so far not been successful in finding ways of efficiently developing new treatments at the same time as making patients safer in clinical trials, she says.

	Klingmann wants to see a change that will put patients' welfare center-stage – and so do many of her colleagues and peers in the different subgroups of the clinical research community in Europe. So the organization she chairs is bringing a 

bunch of them together in Brussels in late February

 in a bid to make change happen. "By getting people in the same room for two days we can hopefully get a clearer view of how to re-center and coordinate the work each of us does with a sharper focus on the patient – so that we better fulfil our ethical and societal obligations to these heroes."

Ingrid Klingmann, chair of EFGCP, speaks to Applied Clinical Trials about the efforts industry can make to change the way all stakeholders can improve clinical research.

Trial Participants: The Unsung Heroes of Clinical Research

	The British government and the country's squabbling parliament are still incapable of deciding when-or even if-the UK should leave the European Union, still less how. But for the European Medicines Agency, the die was cast a long time ago now, by the "leave" result of the UK's 2016 referendum. And now it's happening.

	The EMA will physically relocate to its new home in Amsterdam in early March 2019, as the first stage in its complex move. Complex, because later on it is going to have to move again-from the temporary premises to the new (and supposedly permanent) headquarters still being built for it on the other side of town.

	And EMA can hardly be blamed for the complexity-although it inevitably evokes Lady Bracknell's observation that losing one parent might be considered a misfortune, while losing two looks like carelessness. The immediate fault, if it is a fault, lies with the European Council, which made the decision on the new headquarters (over the head of the European Parliament, which, by the way, is still grumbling about being left out of the discussions-its health committee agreed a resolution this week condemning yet again its exclusion). The European Commission could be blamed too, because it drew up what was in effect an informal ranking among the numerous candidates to host the EMA, which gave the Dutch bid a decent score despite the fact that it couldn't supply an adequate building straight away.

	But of course at bottom the fault lies with the UK, which campaigned vigorously and effectively to host the agency when it was set up in 1995, then 20 years later abruptly turned its back on the EU and everything to do with it, without a moment's thought about the consequences for the EMA or indeed virtually anything else. (The country's current travails as it now struggles to come to terms with the consequences of its own stupidity might seem like some sort of poetic justice-but that is another story.)

	In any case, EMA is now-literally-building its own future. Since early January, EMA’s Executive Director Guido Rasi has been holding the keys in his hand to the temporary new building, known as the Spark, and things are getting underway for the physical move. This is inevitably going to disrupt the agency's operations even more than they have already been disrupted over the last couple of years as preparations have been made.

	Rasi will close the door on the EMA's premises in London on March 1, and for the next week the agency will operate on the basis of extended teleworking, with just a small number of staff present in the new building to cope with any emergencies. During the following week (March 11-15), EMA staff will gradually move into the Spark building, and from March 4, 2019 the official address of EMA will change. But it will not be the Spark building: it will be at the permanent building, in Amsterdam's Zuidas district: European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands.

	Until the newnew building is ready-scheduled for November this year-all EMA meetings and visits will take place from March 15 at the Spark building (which is at Orlyplein 24, 1043 DP Amsterdam). Meetings of the scientific committees will follow the agreed meeting calendar without any changes, and the February meetings of the Committee for Advanced Therapies and the Biologics Working Party will already take place in Amsterdam, which will be the first test of the new premises.

	Throughout all of this, the agency will be trying to ensure continuation of its main activities in line with the business continuity plan it established more than a year ago. The main focus will be on the authorization, maintenance, and supervision of medicines. But at this time of maximum stress, it is going to have to work with minimum staff, because it expects only three-quarters of its current employees to follow it across the Channel.

	Rasi will continue to preside over the agency throughout this turbulence, and on into its new configuration. He said recently that he planned to see out his full contract, which continues until November 2020. By then, hopefully, the whole sorry episode of the move (and the reason for it) will in the past, and the agency can resume its customary role as regulatory leader.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

The British government and the country's squabbling parliament are still incapable of deciding when-or even if-the UK should leave the European Union, still less how.

Brexit or no Brexit, it's an EMA Exit

	Right at the start of the year, the calls for radical change in the way that drug development is organized are emerging thick and fast in Europe. The first week back at work saw a conference in the European Parliament where speaker after speaker denounced the failings of the current model and the rigidity of the authorization and delivery systems in the face of new science and new technology.

	The speakers ranged from the health minister of Belgium to the head of the European Medicines Agency, and from key figures in the European medicines industry to leading academics and experts on health technology assessment. But the central message was the same: opportunities for better care are being missed, and shouldn't be. 

	The flavour of the discussions can be accurately inferred from the contributions of Pier Franco Conte, an oncology professor at the university of Padua, well-known in European academic and medical circles. Moderating one of the debates, he pointed to the challenges facing clinicians and researchers: a proliferation of increasingly sophisticated data and tools, but a persistent incapacity to interpret and use them.

	For Conte, who is at the forefront of the growing understanding of cancer and the potential of targeted therapies,  there is a pressing need to review the way drugs are developed and delivered to patients, because despite all the assets theoretically available, there is a continuing and increased incidence and mortality from the disease.

	He set out a list of changes he believes could improve the situation-and they all tend towards a disestablishment of what has, for decades, been received thinking. He recommends a switch by regulators away from obsessive attachment to statistical significance in clinical trials, and towards the concept of clinical value. It no longer makes sense, he said, to consider positively a randomized trial large enough to demonstrate a p-value difference, while rejecting a single-arm trial showing a clinically worthwhile endpoint in a population selected for prognostic and predictive characteristics. 

	Classic endpoints should be adapted and valued according to the specific setting of the disease and drug under study, he maintains. He offered the example of trials with immune checkpoint inhibitors, where neither response rates nor progression free survival (and not even median overall survival) are good predictors of patient outcomes. In his view, landmark analyses such as the percentage of patients alive at a fixed time point better describe the efficacy of the treatments.

	The risk-benefit ratio also requires some serious nuance as a requirement for approval. A positive ratio based on the primary trial endpoint and the toxicities or quality of life of the patient can be misleading, because it represents the average ratio for the average patient. This can be completely useless in large trials with a sufficient statistical power to demonstrate small differences. In these cases, the number needed to treat and the number needed to harm should be taken into account by regulators.

	Conte is equally harsh on persistent divergences of product evaluation. A significant number of drugs approved by FDA and EMA score very poorly on scales elaborated by scientific societies such as ASCO and ESMO, which take account of parameters related to the setting. "There is no relation between drug prices and these values", he pointed out. "This misalignment between regulators and scientific societies is not justifiable or sustainable, and shared values are now eagerly needed."

	Most tellingly, perhaps, Conte points to "an increasing gap between evidence provided by pivotal trials and real world needs." He attributes this to a range of factors: patient selection ("elderly/comorbidities/co-medications are all underrepresented or not allowed in trials"); or modern technologies are not easily transferable to the real world setting.

	Sometimes the place in therapy is outdated: the new treatment has been tested in a patient population which has not been pre-exposed to state-of-the-art treatments or compared to a suboptimal available comparator, says Conte. "Pivotal trials in most of the cases cannot address some important clinical questions such as sequences of treatments versus best treatments upfront." 

	And safety and efficacy data from trials "are based on limited timeframes", while in the real world setting patients are often treated for much longer. He insists that long-term efficacy and safety data derived from real-world patients are necessary to better understand the risk-benefit ratio of innovative drugs.

	His remarks found an echo among fellow speakers, and one concrete result so far is the creation of a manifesto among many of the contributors 'for a new approach for better medicine in Europe'. The next-and more difficult-step will of course be turning manifesto ambitions into on-the-ground changes in decision, regulation, or practice. That will provide plenty to be watching out for as the year evolves.

Right at the start of the year, the calls for radical change in the way that drug development is organized are emerging thick and fast in Europe.

Another Crack Appears in the Crumbling Clinical Trials Consensus

	The instructions of a legendary 19th recipe for jugged hare began: "First catch your hare". By the same token, the first task of drug developers in this new year should be to make their thoughts known on how to drug development should be assessed-and they have the perfect opportunity to do just that with the construction of a new strategy from one of the world's leading authorities.

	The European Medicines Agency has drafted a plan (

https://www.ema.europa.eu/documents/regulatory-procedural-guideline/ema-regulatory-science-2025-strategic-reflection_en.pdf

) for closer engagement with regulatory science over the next decade, and it is actively seeking comments on its approach. To make it even easier for input, the agency has put a questionnaire on line (

https://ec.europa.eu/eusurvey/runner/EMARS2025PublicConsultation2019

	The proposed ‘Regulatory Science to 2025’ strategy "aims to build a more adaptive regulatory system that will encourage innovation in human and veterinary medicine,” according to Guido Rasi, EMA’s Executive Director. It is an explicit response by European regulators to the challenges that have emerged in recent years from new technologies. Against the background of the long-established classic medicines testing systems dependent on 'gold-standard' randomized clinical trials, it holds out the prospect of a genuine assessment of the benefits and risks of innovative therapies and diagnostics.

	Stakeholders are being asked to give their views on what the priorities should be in this recast. The proposed top themes in the draft strategy range from "catalyzing the integration of science and technology in medicine development" and "driving collaborative evidence generation-improving the scientific quality of evaluations" to "enabling and leveraging research and innovation in regulatory science", with "advancing patient-centred access to medicines" and "addressing emerging health threats" thrown into the mix too.

	Should the clever money go into supporting developments in precision medicine, biomarkers, and ‘omics, or into translating cell, genes, and tissue-based products into patient treatments through the EMA's (so far under-used) advanced therapy medicinal products scheme? Do novel manufacturing technologies get enough attention at present? Should regulators create an integrated evaluation pathway for the assessment of medical devices, in vitro diagnostics and borderline products?

	Should the accent be on leveraging novel non-clinical models and foster innovation in clinical trials, or catering for more digital clinical data generation? What emphasis should be given to initiatives for special populations, to making more use of modelling and simulation? And how far should artificial intelligence play a role in decision-making? 

	The draft ranges across all these questions. But there is also scope for offering additional priorities or approaches too. "Are there any significant elements missing in this strategy. Please elaborate", asks the questionnaire. "We want to hear from our stakeholders whether they consider this strategy is ambitious enough,” confirmed Rasi, launching the consultation at the end of 2018. So, stakeholders, you have until June 30 to influence the future. Over to you.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

The instructions of a legendary 19th recipe for jugged hare began: "First catch your hare".