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

Peter O'Donnell, ACT's Brussels Correspondent

The reach of European Union competition law has been graphically demonstrated by its move to protect European cancer diagnosis options by prohibiting a merger between two US companies. In early September, the European Commission's vice president, Margrethe Vestager, issued a decision outlawing the acquisition of GRAIL by Illumina. As the worlds of clinical trials and of diagnosis increasingly overlap in the wake of rapid technology advances, the decision carries implications for health technology developers everywhere.

GRAIL's products, based on next-generation sequencing (NGS) and data science tools, include not only its Galleri test designed to detect around 50 cancers in asymptomatic patients from a blood sample, but also a diagnostic aid to confirm a diagnosis of cancer in symptomatic patients, and a minimal residual disease test to detect potential relapse in patients after cancer treatments. And while it may seem paradoxical that the EU claims the power to intervene in competition cases where none of the parties is based in Europe, in another demonstration of the ever-more interconnected world of innovation, it does, and it can. The governing factor is whether any particular action will have an impact on European patients and businesses.

Vestager, the designated chief for EU competition law, said this merger risks stifling innovation, and reducing choice in the emerging market for blood-based early cancer detection tests—expected to exceed $50 billion per year by 2035. If GRAIL's tests prove successful, they will revolutionize the fight against cancer and save millions of lives—but the Illumina takeover would give it a stranglehold over the market, she claimed. She is planning to go further, even by obliging Illumina—which in 2021 jumped the gun on this merger by going ahead before the EU ruling—to divest the interest it acquired in GRAIL. "GRAIL's independence now needs to be restored," she said in a statement announcing her ruling.

Detection is crucial to the success of Europe's recently adopted “Beating Cancer Plan,” she emphasized, with the "revolutionary" prospect of detecting cancer from DNA of asymptomatic patients using a simple blood draw.

"The more companies engage in a competitive race to develop the most accurate test, the better the chances we have to detect cancer early on, at the lowest possible cost,” said Vestager. “Our decision means that the innovation race between developers of NGS-based cancer detection tests will continue. In the future, Europeans will be able to access this promising technology at competitive prices and have a choice of suppliers."

Illumina has a powerful market position, she acknowledged, because it is the keysupplier of the reliable high-throughput NGS technology essential to run these tests, and all test developers currently depend on its platform. With GRAIL in its pocket, Illumina could cut off direct competitors from access to its technology, in effect putting a halt to rival developers and, Vestager claimed, "lead to less innovation, less choice, and higher prices for European citizens and healthcare systems." GRAIL's rivals may develop new tests, potentially better and cheaper than that of GRAIL, and they deserve protection, she argued.

Proposals that Illumina has made to ease these concerns have been dismissed by Vestager and her officials. The offer of a licence granting access to some of Illumina's NGS patents, for instance, failed to reassure the EU of the early emergence of a credible alternative that rivals to GRAIL could use. Similarly, a commitment to agree a standard contract with GRAIL's rivals still carried the risk that Illumina might choose to degrade technical support for its NGS systems. Vestager is now examining whether to use her powers to dissolve the merger, impose fines, or take other measures.

Articles

Proposed US merger could threaten innovation in cancer diagnosis, Commission officials assert.

Europe Digs in Its Heels Over Cancer Testing Competition

The approach of EU regulators to clinical trials is about to undergo another shift, with the emphasis this time on promoting international trials.

 comment at the end of August from the European Commission's director general for health was one clear indication. Appearing before the European Parliament to defend the Commission's record in tackling COVID-19, Sandra Gallina threw in her view of the future of trials at the end of her remarks. "We need a new approach to clinical trials—more unified," she said. "They are too national or local or guided by fashion." And, she added, "We need more comparative trials."

Her views—expressed, importantly, as the Commission is finalizing its proposal for a review of its pharmaceutical rules—reflect concerns expressed during the pandemic over the proliferation of small trials, and the absence of coordination. The Commission's own "lessons learned" summary in mid-2021 already acknowledged that "A fragmented and divided approach to clinical trials across Europe since the beginning of the pandemic has hampered efforts to track and analyze variants." It went on: "The need for larger and more coordinated clinical trials has become all the more acute in the short to medium term." And looking ahead, it said: "The permanent establishment of a large-scale, flexible, well-resourced platform for multicenter trials would help establish a structured approach to EU clinical trials for future crises."

The EU's recent strengthening of the European Medicines Agency (EMA)—in force since early 2022—explicitly included provision for the agency to take a more active role in overseeing trials—at least in emergency situations such as pandemics. The pandemic "highlighted the need to coordinate assessments and conclusions on multinational clinical trials," says the legislation. It empowers a special taskforce within the agency to provide scientific advice on clinical trials design and product development as well as the rolling review of emerging evidence "to allow a more efficient assessment of medicinal products including vaccines during public health emergencies."

"Experience with clinical trials during the COVID-19 pandemic revealed a tremendous amount of duplication of investigations on the same interventions, a high number of small trials, under-representation of important population subgroups, based on gender, age, ethnicity, or medical comorbidities, and a lack of collaboration, leading to a risk that research will be wasted," says the preamble to the legislation.

The legislation focuses specifically on responding to cross-border health threats, and is designed to provide scientific support "to facilitate clinical trials for medicinal products intended to treat, prevent, or diagnose the disease causing the public health emergency". But the thinking among regulators goes way beyond just tackling emergencies. Even the Commission's 2021 "lessons learnt" summary observed that the strengthened support and simplification of clinical trials it was envisioning could be "an important tool in the fight against cancer or other diseases."

Now, further evidence of European regulators' intentions comes in a workplan they have just published—on the same day that Gallina was addressing the parliament. This sets out the program for the initiative they have jointly created on Accelerating Clinical Trials in the EU, known as ACT EU. Of the dozen "priorities" for 2022-2026, priority No. 2 includes, as a central aspect of the plan, "further development of a scheme to promote larger, multinational trials specifically in the academic setting." Officials speak of "a support process specifically aimed at academic sponsors in order to make the EU a more attractive region to conduct clinical research."

The ACT-EU workplan is no mere think-tank report. The initiative, launched at the start of 2022, fully involves the European Commission, EMA, and the parallel Heads of Medicines Agencies in Europe. Its chosen priorities reflect the recommendations of the European Medicines Regulatory Network strategy to 2025 and the European Commission’s Pharmaceutical Strategy for Europe, and aim "to transform clinical trials in Europe" and "to better integrate clinical research in the European health system." Work on the scheme is scheduled to start at the beginning of 2023, and by 2024 it should see the launch of a "one-stop shop for information on academic support."

Commission pushes for a “more unified” approach to drug development following a period of fragmented coordination during the pandemic. 

European Plans Crystallize for Globalizing Clinical Trials

 who feel perfectly relaxed about the new European clinical trials rules are permitted, without feeling at all smug, are free to ignore this reminder that there are fewer than six months left before the system goes through yet another huge change. As of Jan. 31 2023, no new clinical trial applications in the EU can be submitted via national systems, and all initial applications must go via the Clinical Trials Information System (CTIS). And that’s not all. There are plenty more changes on the way too, including on disclosure of trial information.

The European Medicines Agency (EMA), which is pretty much at the center of the new system, is not confident that everyone knows enough about CTIS or about the new rules in general, and how a lot of other things are going to work from early next year.

In conjunction with national regulators in Europe, it is still working assiduously at the task it faces in encouraging clinical trials stakeholders to fully get to grips with the “inclusive patient-oriented medicines development and delivery” that the new system is intended to bring in.

Driving clinical trial applications through CTIS is meant to lead not only to greater efficiencies, but also to a new degree of transparency. However, how much information is going to made public—and when—on the database at the heart of the new system, or on the associated public website, is still up for grabs. The rules says that the database “shall be publicly accessible” unless “confidentiality is justified” in order to protect personal data, commercially confidential information, or confidential communication between national authorities. But there are nuances, such as where there is “overriding public interest in disclosure.” The fine print of those rules is still under discussion—including on achieving a common understanding of what may or may not be considered commercially confidential.

There’s plenty more novelty on the way, too. What’s in store for complex clinical trials, for instance? Later in 2022, new recommendations will be published—and, simultaneously, a workshop will provide the opportunity to discuss and comment on this new version with a view to keeping it updated. This could be of particular interest to anyone contemplating a platform trial, since the system at present does not provide for them.

What about decentralized clinical trials? Did you know that a recommendation on the use of decentralized elements in clinical trials is also planned for publication before the end of the year? If you didn’t, an EMA workshop on Oct. 4 may be of interest, as regulators, ethicists, and good clinical practice inspectors will be listening to input from sponsors, patients, and investigators prior to the finalization of the recommendation.

And in the background, European regulators are reflecting on how to implement the revised international guideline on good clinical practice, ICH E6 (R3), which describes the responsibilities in relation to monitoring, reporting, and archiving of trials. New guidelines are in the pipeline here, too, and in a bid to ensure they are responsive to current clinical trial practices with all the diversity of trial designs, data sources, and different contexts, yet another workshop will be held later this year prior to the opening of a public consultation on the revised guidance.

Meanwhile, sponsors are increasingly making use of the new system, even while it remains, until next January, optional (applications are still being made at national level under the soon-to-be-superseded—and much maligned—2001 clinical trials directive). The latest official figures, published in late July, show that 195 clinical trial applications were submitted through CTIS during the six months since the launch of the system at the end of January 2022. Most (188) were new applications, four were substantial modifications of existing applications, and three were to add a further member state to a trial. Decisions in total had been issued on 43 applications, split almost evenly between academic and commercial applications, with 10 already in Phase IV, six in Phase III, and 16 in Phase II.

The fastest decision took just five days from submission to decision, but the other 42 received a decision between 16 and 117 days of application. Of these, four trials were classified at the end of July as “ongoing”—which means that they had been authorized in at least one member state and recruitment of patients had started at the clinical investigator sites. For comparison, there had been just 14 applications when this column last visited the question in May.

One of the major benefits of using the new system, according to Inge Christoffer Olsen of Oslo University Hospital, is that its single-entry point of applications for all countries makes it easy to know exactly what has been approved at any point during the process. He is involved in an application for a multi-country adaptive platform trial evaluating treatments in hospitalized patients with COVID-19. He also welcomes what he calls "a tremendous step forward on transparency," which he sees as conducive to "scientific rigor and value of European clinical trials." And he is particularly appreciative of "firm timeframes" in the system, under which tacit approval is granted wherever a member state does not meet decision deadlines.

Still smug? EU regulators certainly hope so. Nothing would please them more than knowing the international clinical trials community is fully up to speed with the new regulation.

https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02014R0536-20220131

https://www.ema.europa.eu/en/events/act-eu-multi-stakeholder-meeting-decentralised-clinical-trials

https://www.appliedclinicaltrialsonline.com/view/dragging-the-clinical-trials-community-into-conformity

Orientation pursuits hit high gear as formal rule compliance inches closer.

Getting Up to Speed on EU’s New Trial Application System 

Given the central importance of data in clinical trials, it may seem perverse to be apologetic for focusing yet again on the subject in this column, but every journalist is naturally and professionally reluctant to test readers’ patience. However, here we go again…another element in Europe’s rapidly developing moves to make sense of new opportunities in drug development, and to bring some order to impending chaos.

A new workplan from Europe’s top drug regulators sets ambitious targets for getting much more out of data analysis over the next three years.

 “Coupled with rapidly developing technology, big data can complement the evidence from clinical trials by filling knowledge gaps on a medicine, and can help to better characterize diseases, treatments, and the performance of medicines in individual healthcare systems,” says the plan.

The plan, designed by the “Big Data Steering Group” set up by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) in Europe, aims at using the evidence generated from big data to benefit public health by speeding drug development and improving treatment outcomes. It takes a decidedly positive view of the potential contribution of big data—in contrast to many more skeptical opinions currently circulating in European regulatory circles. “Knowing when and how to have confidence in novel technologies and the evidence generated from big data will benefit public health by accelerating medicines development,” it states, while laying out explicit deliverables and clear timelines.

The EMA’s flagship DARWIN program—the embryonic Data Analysis and Real-World Interrogation Network that is expected to transform the use of real-world evidence (RWE) when assessing medicines—is scheduled to conduct more than 100 studies per year by 2025. DARWIN will provide results of its analysis of real-world data (RWD) not just to regulators but also to bodies responsible for health technology assessments (HTAs) and payers. Four such studies, involving 10 partners, are to be initiated this year, with 16 studies and 10 additional data partners during 2023, rising to 50 studies by 2024.

To help the EU medicines regulatory network to make an informed decision on the place of raw data in regulatory decision-making, a proof-of-concept pilot will be performed to clarify the benefits and practicalities of access to individual patient data from clinical trials in the scientific assessment of medicines. The plan also envisions installing a data quality framework by the end of 2022 for the use of regulators, after some intensive consultation between now and then with patients, healthcare professionals (HCPs), regulators, the pharmaceutical industry, and academia. Training curricula on biostatistics, pharmacoepidemiology, and data science will be developed as from 2023, and a curriculum on genomics data will be adopted. Some of the modules will be made accessible topatients, healthcare professionals and academics.

A good practice guide on real-world metadata and a public catalogue of European RWD are on the list of deliverables, along with the development of analytics tools and standardized clinical trial protocols. Guidance will be strengthened through expert groups of specialists, initially in artificial intelligence and RWE, and collaboration in analysis of raw data from clinical trials will be promoted through a specifically created “cluster of excellence.” Reports on pilot studies on the use of RWE by EMA scientific committees will be published incrementally and concluded in 2025 with a report on RWE in regulatory decision-making.

There is more to come on data use—and not just on EMA and HMA planning. The legal framework that the EU is proposing for the use of all health data, the European Health Data Space, is now generating significant comment—and some significant pushback from the European health community. And that—I almost regret having to inform you—will have to form the subject of yet another column on data. Enjoy, meanwhile, the summer while it lasts.

https://www.ema.europa.eu/en/documents/work-programme/workplan-2022-2025-hma/ema-joint-big-data-steering-group_en.pdf

Newly unveiled workplan focuses on harnessing the impact of big data on drug development—and ultimately public health.

Europe’s Regulators Plan Real Action on Exploiting Real-World Evidence

It’s been coming for years, but now it’s starting to bite. The medicines development community is struggling to find consensus on how to generate real-world evidence and how to use it, and here in Europe the policy tensions are influencing the scientific exchanges. It’s the latest in a string of hot-button issues, and is keeping the Brussels bubble bubbling, even as those beachside cocktail parties and poolside loungers beckon. Discussions on pediatric medicine incentives, health technology assessment (HTA), or Europe’s beating cancer plan had all been ticked off from the “do before the holidays” list, and safely deferred to the traditional (hard-pressed and overworked US readers may wish to look away now) September return to work in this part of the world.

However, the European Medicines Agency (EMA) and a phalanx of international regulatory colleagues casually tossed a stone into the placid waters of late July with a call for international collaboration to integrate real-world evidence (RWE) into regulatory decision-making. For many researchers, this could be an interesting move. But not for many critics of what they like to depict as a headlong and ill-considered rush into new methods. And those critics include a lot of physicians, HTA agencies, patient groups, and, yes, regulators too. In other words, the stage is set for yet another round of sharp words over the immediate and longer-term future of drug development.

EMA and colleagues in the International Coalition of Medicines Regulatory Authorities (ICMRA) have agreed in a joint statement that notes the rapid increase and evolution in the use of real-world data (RWD) and RWE in developing, authorizing, and monitoring medicines. And right from the start, they address the tough questions. Yes, RWE can help bridge knowledge gaps, they recognize. But “there are still challenges that need to be addressed”—and these include heterogeneous data sources across the globe, different levels of data quality, and the wide range of issues linked to data sharing and access.

The challenges need to be met, these regulators agree, and they now foresee a range of collaborative measures to seek solutions. They plan to start with harmonization of RWD and RWE terminologies, by generating common operational definitions that are clear over their scope and level of granularity—relating to randomized clinical trials and observational studies. Existing international activities touching on RWD at the level of the International Conference on Harmonization can play a role here, too, they suggest. Guidance and best practice need aligning early on, as well, with common principles for RWD quality, metadata to enable characterization and discoverability of RWD; establishing the scenarios where RWE may be suitable in regulatory decision-making; and standardized templates for study protocols and reports that would be accepted in regulators in different parts of the world.

“Readiness”—which has become something of a motto in light of the demonstrated “unreadiness” of the COVID-19 response—also gets top attention from these regulators. They envision strengthening joint work on RWE through specially created expert groups on specific topics, notably including the challenges of “emerging health threats” and how studies based on RWD from different countries could address such public health challenges. They also want to see transparency brought to the entire debate. This means defining common principles and practices for systematically registering prespecified study protocols and study results in publicly available registries—with the additional 

 that they should include details of feasibility assessments. It will also require publication of study results in open-source, peer-reviewed journals, and regulators should exert their influence to promote this, they believe.

None of this is going to be as easy as just making a list of what has to be done. But there is new momentum behind the objective: more than 40 countries, representing medicines regulatory authorities globally, as well as representatives from the World Health Organization have contributed to this initiative, with EMA, FDA, and Health Canada in the lead. And for all the regrets that continue to be expressed about the lack of readiness of health authorities to respond to the COVID pandemic, one evident positive outcome is that international medicines regulators and researchers did learn to work together in new and ultimately productive ways—including in relation to RWE.

As a flavor, however, of the potential conflicts ahead, just take a quick look at some of these recent observations from influential and important organizations that take differing views about the future—drawn from the major EU consultation on its upcoming review of pharmaceutical legislation. For every Takeda urging “greater predictability in terms of the uptake of RWE” or Johnson & Johnson identifying the enabling of optimal RWE use as “a key objective,” there isthe European doctors’ association warning that RWE “should only be considered as complementary to randomized clinical trials and should under no circumstances be promoted as a replacement,” or the influential 

 journal enjoining European and national regulators “not to weaken marketing authorization requirements by shifting the provision of real and strong evidence before authorization to hypothetical and biased real-world data after marketing authorization.” The summer is already unseasonably hot. The arguments this will generate will do nothing to cool it down.

The scope of RWE’s use in developing and approving new medicines is pitting key healthcare stakeholders against each other.

Another Battleground Takes Shape in Europe: Real-World Evidence

Unapologetically, this column returns to the theme of demonstrating drug efficacy, evoked as recently as a month ago in 

“Bringing Evidence Back into Fashion in European Drug Rules”

 after the head of the French government’s health technology assessment (HTA) triggered a discussion of how much evidence was enough evidence—and made clear that at the moment, the evidence is often not enough.

The latest trigger comes from a different quarter—the organizations that pay for medicines in Europe. In Europe’s complex web of healthcare systems, the regulators and their approvals are the initial gatekeepers for medicines, and the HTA bodies are key influences on who will get them, but ultimately the decision in each country depends on whether the payers decide to pay for them. No matter what is coming down the pipeline toward patients and physicians, it is the payers who stand at the end and control the on-off tap. And they are far from happy, to judge from a meeting last week in Brussels.

As the July heat begins to drive away the last officials and diplomats and lobbyists from the airless committee chambers and meeting rooms, some of the tough talk from that meeting continues to echo down the empty corridors.“There is a significant evidence gap,” one prominent figure declared, listing some of what is missing in terms of supporting evidence for new drugs. “There has been an enormous increase in uncertainty,” exclaimed another. “We must explore how to get better supporting studies from companies,” insisted a third. And so it went on, for an hour. And what emerged most clearly was not just dissatisfaction, but a determination that the situation must change.

What raises this event above the normal run of critical exchanges between drug innovators and authorities in Europe was the combined fire-power of this assembly—and the fact that they have decided to go very public with their message. A brief digression will suffice to identify this college of cardinals of drug budgeting (readers wishing chapter and verse can watch the entire discussion on video 

). They come from the Medicine Evaluation Committee (MEDEV), which brings together 22 national authorities for assessment, pricing and reimbursement from 18 EU member states plus Switzerland, and from the European Social Insurance Platform (ESIP), comprising 45 national social security organizations insuring citizens in 17 member states (and Switzerland).

The timing of the meeting is also a factor in its importance. As most ACT readers are well aware, the European Commission is scheduled to propose sweeping revisions of the EU legislation on pharmaceuticals by the end of 2022, intending to address shortcomings in terms of access to and availability of new treatments. MEDEV and ESIP have prepared their own detailed shopping list of the changes they want to see, and their emphasis is on “robust and timely evidence generation.” They are dead against any shifting of the assessment of safety, quality, and efficacy from pre- to post-marketing authorization. They continue to insist that randomized controlled trials “are the gold standard” and they believe that conditional approval pathways should be strictly limited, with tighter requirements for performance of any post-launch studies. The fast-track mechanisms for vaccines introduced as an emergency measure during the COVID-19 pandemic are not a valid model for normal circumstances, they say.

The legislative review is, say the payers, “an unprecedented opportunity to effectively mitigate the negative consequences of the growing weak evidence-high prices conundrum.” They see stronger evidence as the route to an improved world of “informed, timely decisions, better deals, better priority-setting, better chances for the renegotiation of contracts, healthier competition, and better targeted incentives.” They want to see the new pharmaceutical rules give them an earlier—and more influential—voice during the regulatory approval process. And to judge from the tone at their meeting, they are prepared—and preparing—to take their message to the top. Not only are they making their pitch to the European Commission before it makes its proposals, but they are also aiming to recruit the influence of their own national governments to exert pressure. It is clear that evidence is not just coming back into fashion. If payers get their way—and they usually do—it looks like it is here to stay.

Payers join the push for better demonstrations of efficacy of new medicines.