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

Peter O'Donnell

The European Union needs you—or some of you. It is reaching out for independent experts to help advise on its health development programs, notably in cancer and in needy areas of regulatory science.

Right at the beginning of the year, it has issued a general invitation for input to its Cancer Mission, part of the EU's Horizon Europe research program, which is just getting underway. The mission is targeting improvements to more than three million lives by 2030, through prevention and optimized diagnosis and treatment. The chosen applicants will contribute to recommendations on work programs, project portfolios, communication, policy coordination, and key performance indicators. They will also assist the Commission in preparing related legislative proposals and policy initiatives.

The selection criteria include experience in areas such as innovation procurement or digital services and use of data, and expertise in specific fields such as prevention, screening and early detection, diagnosis and treatment, palliative care, ethics, health financing, or innovative healthcare design. Applicants also need cross-sectoral experience in scientific disciplines at European and international level, demonstrable independence—the requirements on preventing any conflicts of interest are extensive—and good knowledge of English. Ready to pitch in? 

—with all the numerous forms to be filled. And since the deadline for applications is 2 February, right now would be a good time to start. (Don't forget to keep this columnist in the loop if you apply—and still more, if you succeed!)

There's a rather more leisurely timetable for engaging with another opportunity to keep EU thinking moving smartly ahead on needs in drug development, with an invitation from the European Medicines Agency for input into a series of regulatory science topics it has identified as needing further research. They relate broadly to the integration of science and technology in medicines development, collaborative evidence generation to improve the scientific quality of evaluations, patient-centered access to medicines, and emerging health threats and challenges – with an umbrella topic of enabling and leveraging research and innovation in regulatory science. These categories break down into around one hundred specific topics in the regulatory science research needs list that EMA has compiled from stakeholder consultations and interviews with chairs of its scientific committees and working parties.

The agency is aiming to stimulate researchers and funding organizations to consider addressing these topics in their research agendas and share their findings and results with regulators. "By engaging in the Regulatory Science Research Needs initiative, researchers and funders will be able to see their findings translated into regulatory practice, medicines development and public health," it says in an explanatory note. Researchers and funders are invited to get in touch with EMA if they are interested in one of the topics on the list or the initiative in general, and is organizing a webinar to inform patients, research groups and health professionals on January 18, 2022 to 

 and how stakeholders can engage with it.

The year has barely started, and there were already so many things to be done that you had deferred until after the break—and now here's something else inviting your attention…So seasonal best wishes to ACT readers!

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The European Union is reaching out for independent experts to help advise on its health development programs in needy areas of regulatory science.

Helping Hands for Europe and Health?

One of the novelties of the year ahead will be the inception of the European Union's new multi-billion public private partnership for drug research, the Innovative Health Initiative, which is expected to launch its first call for proposals in early 2022.

IHI is the successor to the EU's Innovative Medicines Initiative, which has ploughed billions into nearly 200 projects in early drug research over the last 15 years and acquired in the process a reputation for effective collaboration between commercial pharmaceutical companies and public authorities. The difference between the old IMI and the new IHI is a widened membership, with a deliberately more comprehensive approach to drug development that aims to take account of the changes since the early years of the century, and bringing on board the medical technology, biotechnology, digital health, and vaccine industries.

The concept is a response to science driving new avenues of interdisciplinary research and development within the life-science community, increasing the importance of cross-sectoral discoveries based on medical device / drug combinations, diagnostics deploying artificial intelligence, digital health, big data, and imaging. That is why the initial IMI membership—EFPIA, bringing together the research-based drug industry in Europe, and the European Commission—has been expanded to include four other associations—COCIR, for the medical equipment industry, MedTech for the devices sector, EuropaBio for the biopharma sector, and Vaccines Europe. These partners will cooperate with universities, companies of all sizes, patients, regulators, and other stakeholders, allowing organizations that want to support specific areas of research to become contributing partners.

The IHI vision is to promote Europe at the cutting edge of interdisciplinary, sustainable, patient-centric health research and innovation, and its declared goal is to translate health research and innovation into real benefits for patients and societies. It claims to offer – in addition to access to funding—access to new networks and partnerships, to knowledge and resources at the cutting edge of cross-sector health research and innovation, with early access to project results, and reputation.

A Strategic Research and Innovation Agenda details the areas IHI should work on and helps to guide IHI’s decisions on which ideas should be turned into call topics. A science and innovation advisory body will bring together the scientific community and the wider health sector, such as regulatory bodies, patients, and end users, as well as representatives of the European Commission and the industry partners. It may also invite additional ad-hoc experts to join in discussions of specific subjects. The agenda will have an additional focus on disease prevention and on seeking a better understanding of the determinants of health and priority disease areas. Its $3 billion budget for 2021-2027 is funded jointly by the EU and by industry associations representing Europe’s life science industries, primarily through 'in-kind' contributions. Like IMI, IHI will work by running open, competitive calls for proposals, publishing draft topic texts before the call launch to give applicants time to work on their proposals. And the executive director until September 15, 2022, is Dr Pierre Meulien, who has been head of IMI for the last decade.

The Innovative Health Initiative is expected to launch its first call for proposals early this year.

European Drug Research Takes on A Wider Perspective

Next-generation sequencing has become a key technology in cancer diagnosis, prognosis and prediction, but it is widely acknowledged that wide variations in implementing and using it can lower the quality of patient care. Belgium has developed an NGS playbook to overcome some of these challenges, and the approach was formally announced in mid-December as part of the EU-funded Innovative Partnership for Action Against Cancer, which has just come to an end.

The Belgian approach is comprehensive, with centralized governance, integrated technical and logistic actions with allocated budgets, and standardization across multiple program elements, such as data interpretation, reporting storage, reimbursement, ethics/legal requirements, and societal issues. Partners in the program include the ministry of health, the reimbursement authorities, the professional colleges of oncology and of genetics, government bodies on clinical biology, pathology, the national cancer registry, and the federal agency for medicines and health products.

The approach is possible because reimbursement of NGS tests is covered by the national sickness insurance funds, and Belgium has a health data platform which hosts and links over 50 datasets and registries in the country. In addition, a 2003 law obliges all hospitals and laboratories to send exam results to the cancer registry. But the program did not come into being automatically. A health service evaluation study was conducted in 2015, with the involvement of the national cancer center, Sciensano, and the national health technology assessment agency KCE. Based on the study's recommendations a plan covering 2016-2020 was prepared in concert with the stakeholders, and won approval from the health minister in 2016.

Under this plan the outcomes have included the creation of a national commission for personalized medicine, guidelines on NGS, along with an external quality assessment structure that laboratory are obliged to comply with, and a reimbursement system nomenclature to cover NGS testing. Networks of hospitals and laboratories were authorized to use, analyze and be reimbursed for NGS testing. Centralized data registration was established by 2019, and the link to the national cancer registry opens up the possibility of patient-matching applications to optimize diagnosis or match with clinical trials, for example. And broad consultation was undertaken with patients and citizens on ethical, legal, social implications of the use of genomics information.

The main outcomes to date, according to the launch announcement, have been effective coordination among the many stakeholders, the engagement of relevant experts in sharing experience with NGS, which has resulted in compliance with testing guidelines in routine practice, and consensus on the scope and content of NGS testing, which has increased standardization and made possible common–and cost-effective–purchasing of testing equipment.

In addition, the participatory approach with stakeholders–as diverse as clinicians, pathology, clinical biology, genetics, oncology, bioinformatics and patients/citizen–increases the likelihood of commitment and acceptance of the plan.

The creation of the Belgian approach has, admit its founders, demonstrated that sufficient time needs to be planned for discussion among stakeholders to achieve consensus on practical implementation. It has also shown that centralized data registration requires major information technology investments–and continuous helpdesk support. The standardized technical and clinical approach has proved essential for retrospective evaluation of the effectiveness of the diagnostic testing. And because adaptation of nomenclature for the reimbursement system is a complex and tedious exercise, payers need to be involved from the beginning.

The Belgian example stands in sharp contrast to the wider experience of introducing NGS in Europe. One of the foremost professional bodies in Europe only got round to making some first tentative recommendations during the course of 2021. The European Society for Medical Oncology has recently come out with an explicit recognition that NGS allows sequencing of a high number of nucleotides in a short time frame at an affordable cost, and at the same time acknowledged that although the technology is widely used, there are no recommendations from scientific societies about its use in oncology practice. 2022 may see some more coherent action at EU level–but here is an area where regulation and clinical practice are still far from any significant European consensus.

Object lessons in implementing next-generation sequencing in cancer diagnosis in Europe.

Belgium Develops Approach to Overcome Challenges of Sequencing

The legislation-based boost to the powers of the European Medicines Agency has been well-documented and closely watched. But there are straws in the wind suggesting a further change is creeping over the agency, more a matter of character than of law–and this could spell far-reaching shifts in the role of EU regulators.

First, the formal changes–endorsed in principle by EU legislators at the end of October, and now awaiting full ratification by the European Parliament and the European Council, perhaps as early as December. These changes arise directly from the COVID pandemic, and aim to equip EMA better to manage future health crises, giving it closer control of the management of supplies of medicines and medical devices. The agency will also acquire new authority to release early data of clinical trials conducted in the EU, and fuller data on authorized medicines.

Over recent months, however, EMA has unilaterally adopted an increasingly high profile of its own. Part of this is the result of the inevitable public attention given to its decisions on the assessment of COVID vaccines and treatments, which has elevated not only its operations but also some of its staff to an unprecedented visibility. But part of its new profile is also the consequence of some deliberate seeking of attention, in an equally unprecedented campaign of direct communication to the broadest public. For the best part of a year, the agency has been holding regular briefings about COVID treatments–designed for the media, but also open to the public, and available on YouTube.

As a logical complement to its public briefings, it has become increasingly communicative on other social media. Its interaction with the public has developed from simple reports about the number of COVID vaccines authorized to more timely alerts as to when decisions are scheduled. And as the pace of product development has risen, so too the announcements have become more frequent, with recent days including tweets of the start of its reviews of COVID-related products such as Pfizer's or GSK's sotrovimab.

A further COVID-linked development, inspired by the urgent search for medical responses, is also driving this process: a new degree of regulatory flexibility. Introduced in the wake of the outbreak, this has given rise most obviously to rolling reviews as a way of speeding assessments. But it is accompanied by a new EMA readiness to publicly countenance–if not actually to endorse–member states taking their own decisions on emergency use of innovations that have not yet obtained EU authorization. The announcement of the start of the review of Paxlovid added that the review is "to support EU countries who may decide on its early use for COVID-19 before authorization." Similarly, EMA has tweeted its "advice to support EU countries who may decide on early use of the oral antiviral molnupiravir," outlining that the medicine can be used to treat adults with COVID who don’t require supplemental oxygen and who are at increased risk of severe disease.

The public engagement goes further. Abandoning its traditionally remote and neutral stance as a discreet center of regulatory excellence serving an esoteric scientific purpose, it is moving into overt position-taking and public advocacy. "There are excessive cases of COVID, particularly in unvaccinated people," it tweeted the other day, remarking that "many EU countries have large unvaccinated populations" who "are the most likely to go to hospitals and suffer from severe disease." It went one step further, adding: "We should close the gap between vaccinated and unvaccinated." In similar vein, it is now tweeting recommendations of shifts in personal behavior: "We encourage everybody who is offered a flu vaccine to get the shot and protect themselves and their family, friends, and colleagues." And in connection with the current campaign against antimicrobial resistance, it is itself now campaigning with tweets urging "Let’s educate our children about the risks of antimicrobial resistance and include this topic in family conversations!" and warning that "We cannot get to the point where antibiotics no longer work to treat or prevent infections."

But the latest development crosses a new frontier from the descriptive to the normative. "Pharma companies need to focus more on R&D for innovative medicines against infections," it tweeted in mid-November. "Pharmaceutical companies need to boost research and development." Irrespective of the truth or relevance of this message, the nature of this public communication marks a radically different approach by the agency to the way it presents itself to the world–interventive, persuasive, even combative… and even undaunted in entering into one of the hottest current debates in European medicines policy, about the extent to which the private sector should enjoy autonomy over its operations.

The full implications of this personality mutation have yet to be teased out. But it carries intriguing resonances at a time when the entire EU policy framework for medicines is under review. The amendment to current law governing EMA is just one of a handful of legislative proposals that the European Commission has branded as part of the "European Health Union"–an ambitious but still embryonic concept springing from Commission officials to give the EU more of a say in how member states make their own decisions on medicines.

The EHU brand has yet to achieve enthusiastic endorsement from member states, who are suspicious of a stealthy power grab. But at the same time, member states have not–yet–directly opposed the brand, perhaps sensing that a COVID-weary public might at present be happy to see greater collaboration on health at EU level, and resentful of conspicuous resistance to it from member states. Against this background, EMA's flexing of unsuspected muscles in the public domain takes on another possible interpretation, and raises the inevitable questions as to whether the higher profile is simply the unremarkable consequence of its status at the center of an unprecedented public health emergency, or a conscious bid to boost its own influence over the longer term and on a wider scope.

Increased public engagement leads recent change in EMA profile.

EMA: A Change in Character as Well as Powers?

Everyone, it seems, agrees that health technology assessment in Europe needs improvement. What everyone does not agree on is how that should be done—and the ambiguity has just become more evident.

The European Union has at last agreed on how HTA should be coordinated among Europe's multiple HTA agencies, bringing to an end a three-year process of discussion. The agreement—taking the shape of a formal regulation—was greeted as a triumph by some influential voices.

The EU Council, representing the EU's member states, announced with something approaching euphoria that it had received the green light. A statement claimed that thanks to the new rules, "innovative, safe and effective health technologies will be more quickly available for patients," and "producers of medicines and medical devices will benefit because submission procedures will be simplified."

According to Janez Poklukar, the Slovenian minister for health and currently president of the EU's health ministers, the adoption of this law "is another demonstration of how EU countries, when acting together, can achieve very practical results for their citizens. This new law will benefit patients, producers of health technologies and our health systems."

"Great news: green light on HTA," tweeted Tiemo Wölken, the prominent German socialist MEP who had shepherded the discussions in the European Parliament.

And the news went down well in the powerful European consumers organization, BEUC, too. This agreement "will help improve consumer access to the medicines they need and help cut unnecessary costs in member state health budgets,” said its health spokesperson. “At a time when health ministries face ever trickier decisions about which treatments and medicines to reimburse, this new set of rules should help consumers get the most effective treatments reimbursed by social security systems," she added.

But as this column pointed out back in June, when the EU was in the closing stages of this long negotiation over a text, the new regulation was looking like only a very limited legislative framework. And very limited is what has emerged in the final agreement. It retains a similar shape to the initial 2018 proposal, but it is devoid of most of its substance. Member states will—as was intended—cooperate on joint clinical assessments and joint scientific consultations, and companies will have an opportunity for a single submission that could in principle eliminate the need for multiple local submissions. But—contrary to the plan put forward in 2018 (which enjoyed some support from the research-based industry)—member states will write their own rules for the conduct their assessments and consultations. And even more contentiously, if they reach a joint decision on a product at EU level, they are under no obligation to follow it at national level.

From the outset, key member states were opposed to any EU rule on HTA that would tell them what to do at national level. And in the final text now adopted, the council has given no ground on its flat rejection of what had been proposed as an obligation to apply joint clinical assessment reports in their national HTA procedures. They have instead conceded only that member states will "give due consideration" to them, without impact on their rights to draw their own conclusions.

So even if there has been some support for the agreement among those who do not use HTA—council, parliament and consumers—there has been a conspicuous absence of rejoicing from the constituency which pre-eminently does use HTA: the pharmaceutical industry. Its views on such a compromise were made clear months ago, when its main lobby in Europe, EFPIA, said it "risks introducing an unpredictable system", and called dit a "missed opportunity" that will be felt in "unnecessary administrative and regulatory barriers to patients' access to new medicines introduced in Europe." It had earlier warned that this softly-softly approach to coordination of HTA was "misguided" and could "only lead to an unsatisfactory result." Removal of all obligations on member states to make use of any joint clinical assessments emerging from the system is to deprive it of any value to companies seeking a more efficient system, EFPIA argued. Its silence since the deal was agreed this week is eloquent. It is difficult to resist the conclusion that, as this column suggested, the road to closer collaboration remains full of obstacles, because of persistent national reticences over handing over too much power to the EU. And the losers will be patients just as much as companies.

The European Union has at last agreed on how HTA should be coordinated among Europe's multiple HTA agencies, bringing to an end a three-year process of discussion.

A Breakthrough or A Breakdown for Health Technology Assessment in Europe?

This column reported in August of a push by the current Slovenian presidency of the European Union to drug repurposing—and now, just weeks before the end of its term in the EU's revolving chair, its ambitions have received a concrete endorsement in the shape of the formal launch of an EU pilot program aimed specifically at testing the concept further. Right at the end of October, the European Commission, the European Medicines Agency and the Heads of Medicines Agencies announced "a 

 for a framework to support not-for-profit organizations and academia in repurposing authorized medicines."

Presented as a way of making new treatment options available to patients, the scheme aims at assisting evidence generation on an established medicine in a new indication, with the goal of create a data package robust enough to support a future market authorization application. It will apply to conditions to candidate medicines that are no longer covered by any intellectual property protection, and that could respond to unmet need with significant potential public health benefits. And eligible beneficiaries might be academic units, charities, patient organizations, learned societies, research funders or payers, explains the EU.

Slovenia's principal interest in the concept has been overtly the desire to open an avenue to cheaper medicines. The formal EU approach in this scheme, however, is more nuanced. Ideally, in official EU thinking, it could provide some constructive response to the dilemmas posed by extensive off-label prescribing. "The absence of a bespoke regulatory route for, off-patent, authorized medicines already on the market to be developed for new uses and reach formal regulatory approval sometimes poses problems to physicians, patients and health systems," says the background documentation to the scheme. "Well-established evidence based on off-label use is not converted into on-label use", with possible "negative consequences for patient safety and treatment options." Additionally, "potentially useful new or established non-approved indications will be hampered if the medicine is suddenly withdrawn from the market."

The principal assistance available through the pilot will be in terms of scientific advice. Eligible academic sponsors developing orphan medicines will automatically benefit from a fee waiver. And additional fee waivers will be granted to a subset of selected applications taking into account the extent of the expected public health benefits and the strength of the evidence to substantiate the promise held by the proposal.

As observed in this column in August, there is a long history to this ambition. The concept of support for a repurposing framework features in EMA's Regulatory Science Strategy to 2025 and has been extensively discussed in the European Commission’s expert group on safe and timely access to medicines for patients, STAMP, where representatives of EU member states, EMA and stakeholders from not-for-profit organizations, patients, healthcare professionals, industry, health technology assessment bodies and payers contributed.

But a clearly delineated challenge repeatedly arises whenever attempts are made to turn ambition into reality. As the EU announcement makes clear, any success ultimately depends on the engagement of a pharmaceutical company, and that is far from guaranteed. Non-commercial generation of new evidence "should then be followed by the engagement of the marketing authorization holder/applicant of the concerned medicinal products applying for the new indication through standard regulatory processes." Not "will be followed". Just "should be followed".

The pilot will run until the completion of scientific advice for the selected repurposing candidate projects, says the EU announcement—adding that it will continue "optimally until the filing of an application by a pharmaceutical company for the new indication." It has been immediately and warmly welcomed by non-commercial organizations—notably the Anti-Cancer Fund, a longstanding proponent of repurposing. "We are very glad that EMA and the national medicines agencies are now ready to provide regulatory support, especially scientific advice, to not-for-profit organizations and academia who are willing to investigate existing drugs for new indications," said its managing director, Lydie Meheus. But it has also received a qualified welcome from some industry organizations. The generic industry's Medicines for Europe, which is active in the development of value-added medicines, saw it as "a great first step", but insisted that it "must become a part of a broader sustainable repurposing ecosystem" – by which it means some regulatory simplification, and better pricing and reimbursement policies. 

The pilot may prove that repurposing really can deliver. Or it may indicate the contrary. For European policymakers, the scheme provides a convenient way of deferring any decisions—and maybe making it possible, in the end, to drop the discussion completely, bring to an end what some regard as a futile distraction.

European authorities have announced a proposal for a framework to support not-for-profit organizations and academia in repurposing authorized medicines.