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

There are probably very few readers of this site who are not by now aware that, as from today, arguably the biggest change ever in European rules on clinical trials has come into effect. The EU’s Clinical Trials Regulation (CTR) has been the subject of extensive comment over the last eight years, since the underlying legislation was adopted. Its aim of simplifying and easing clinical trial approvals across Europe is widely seen as valuable, and in official circles is being celebrated today. But it is perhaps worth noting that not everything is going to get easier, and not right away.

For a start, the opportunities for streamlining applications and procedures are accompanied by plenty of new obligations that sponsors must comply with. Many relate to tight and strict deadlines for reporting and for providing the authorities with notifications or replies to questions—and in many cases the penalty for non-compliance is that the application will lapse. The details of all these provisions have been neatly—and more comprehensibly—summarized in a note compiled by the European Commission and published to coincide with this momentous occasion.

The tightness of the deadlines is easily judged: for instance, once a clinical trial approval has been granted and the study has started (defined as the start of recruitment), sponsors have just 15 days to notify this. The same deadline for notification applies to the first visit of the first subject, the end of recruitment, any restart of recruitment, and the end of the trial (defined as the last visit of the last subject in any of the participating member states). Any temporary halt of the trial, its resumption, or its early termination fall under the same obligation. Any breach of the protocol likely to affect safety rights of the subject or the reliability of the data must be reported within seven days, and the seven-day limit also applies to unexpected events—except for serious adverse events, which must be reported within 24 hours

Still more constraining, a new deadline of one year from the end of the trial applies to the filing of a summary of results, accompanied by the novel concept of a laypersons summary. And once a marketing authorization has been granted on the product, a clinical study report must be submitted.

It may be of interest to sponsors beyond Europe that where the provisions of the regulation on good clinical practice differ from those of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, the rules in the EU regulation prevail.

Naturally, there is satisfaction in the emergence at last of a system allowing for a single EU application to be made for a clinical trial that can lead to an approval valid across all the member states. Similarly, many sponsors see as helpful the obligations that are also placed on the authorities. In contrast to the weeks, months, and even years that it has often taken to obtain a decision on an application in just one country, a tacit approval now underlies the system. Broadly speaking, once the EU level procedure has been completed, each member state has to inform the applicant of the result within just five days. Where any of these new deadlines are missed by a member state, the application is deemed to be accepted.

The perennial European Union problem of its very diversity still, of course, tends to dampen hopes for speedy compliance by the authorities. Cristian Busoi, a Romanian physician who heads one of the most influential committees in the European Parliament, today lamented the continuing tendency of different countries to interpret common rules in their own way—which he sees as an obstacle to clear implementation of the CTR. The main drug industry lobby group in Europe, the European Federation of Pharmaceutical Industries and Associations (EFPIA), also greeted the general jubilation with some admonitory comments on “initial problems,” some requiring “extensive work to achieve a resolution.” It urged a focus on “further developing and enhancing the usability and functionality of the system,” which it says “is necessary for the effective conduct of clinical trials and for the EU to remain attractive for clinical research.” In particular it highlighted a lack of alignment of member state requirements, and situations where member states take different approaches to reviewing trials that need to be transitioned to the new system.

https://health.ec.europa.eu/system/files/2023-01/mp_ctr-536-2014_guide_en.pdf#page14

Articles

Formal compliance with EU’s Clinical Trials Regulation takes effect, designed to speed up the application and approval of studies.

Eight Years Later, Europe’s ‘New’ Clinical Trial Rules Finally Come into Force

By now, some of the dust is beginning to settle on the controversial refusal by the European Union to extend its Jan. 31 deadline for compliance with its new Clinical Trials Regulation, and attention among the clinical trials community is gradually turning toward other challenging issues.

But a rankling sense of resentment inevitably remains, both over this specific piece of legislation, and over the broader issues of the quality of the legislative process in the EU. Despite a mid-January admission by the European Medicines Agency (EMA) that some 20% of the arrangements for the operation of this radical shift in clinical trials approval were still not in place, EU officials had insisted that going ahead was, nevertheless justified because of "recent improvements introduced in the system and progress made to prepare for mandatory use."

"More than 80% of the blocking issues and related workarounds have been resolved, with activities remaining on track to deliver a system with no blocking bugs on core functionalities by Jan. 31," said EMA in a Jan. 18 statement. It invoked its "commitment for the system to be functional for Jan. 31, 2023, and in compliance with the relevant Clinicals Trial Regulation provisions from this date." Yet as recently as October, the agency had itself been admitting that the problems presented by the new system were leading to some users needing intensive support. Across Europe, the uptake reported in many countries during 2022 was slow, with repeated indications of serious "teething problems" encountered by sponsors. In November, broad swathes of the German clinical trials community stigmatized the new system as "largely unmanageable for all those involved," and issued a firm call for the deadline to be postponed. Their complaint over the complexity of registering new clinical trials was echoed across Europe.

The sense of exasperation is all the more intense because this was not an unforeseen difficulty, given the well-recognized tendency of new IT systems to over-run on time and budget and to reveal unexpected misfires. The Clinical Trials Regulation was adopted as long ago as 2014—long enough to get everything in place before pressing the "go" button, many critics argue, and strong arguments for deferral if the "go" button is not ready. Salt has been rubbed in the wound by the EU's recent decisions to defer—twice—deadlines for compliance with another major piece of health legislation, covering 

 devices and diagnostics, in response to widespread complaints that neither the sector nor its regulators were ready.

All this is conspiring to reinforce existing concerns that EU legislators are becoming over-optimistic—and even cavalier—in their design and implementation of new rules. The unhappy experience with rules on clinical trials and medical devices is itself disheartening enough (and it is remembered with no satisfaction that the "new" Clinical Trials Regulation emerged only a decade after the EU's first attempt to legislate on clinical trials proved to be so misconceived and full of errors that it had to be replaced). But everyone working in clinical trials in Europe is also well aware that the even more influential 2016 rules that the EU rushed through on data protection were so badly drafted and finalized that the legislation continues to be an obstacle in health research.

The greater concern now is that the wave of new legislation that it is scheduled to hit the EU as from 2023 will turn out badly. And the wave that is gathering is huge. One element is on the table since mid-2022—an ambitious proposal for sharing health data, which is already being criticized for imprecision. But by the spring of this year, the EU is expected to be starting formal debates on updating the principal pillars of EU pharmaceutical law. The proposals, currently scheduled to appear in March, will spell changes to the conditions for applying for and obtaining marketing authorization for medicines, and for incentives for research and development—particularly into rare diseases and paediatric medicines. The preliminary discussions among EU officials as they work toward finalizing their proposals have not been entirely harmonious: an early draft was turned down flat during the summer by one of the legislative watchdogs in the EU hierarchy, and officials were told to do their homework again.

This doesn't mean that the new laws will necessarily lead to catastrophe. As is the case with the clinical trials rules, the legislators' intentions may be constructive. It is obviously important that EU rules are kept up to date with advances in science and technology, and views among officials and across the health sector coincide that there are plenty of areas in need of regulatory improvement. But the risk is that good intentions may not be enough to avert unintended consequences. And recent experience has not inspired confidence. The stakes are high. Getting it right could boost research, development, and patient care in Europe. Getting it wrong could hasten Europe's decline in global health innovation.

The issues engulfing compliance with the Clinical Trials Regulation signal that even the best  intentions with these types of laws may not be enough to avert unintended consequences.

Get it Right Next Time? EU Legislation Under Critical Review

The new year will see the emergence of yet another committee seeking to influence clinical trials. The World Health Organization is in the process of creating the snappily-titled “Technical Advisory Group on Development of Guidance on Best Practices for Clinical Trials,” and is currently sifting through applications for its membership.

This new group will have a very wide brief—in line with WHO’s global reach across 194 member countries and six regions. Top of its list of future duties is to develop guidance to help official implementation of “scientifically and ethically sound” clinical trials at national and regional levels. But the mandate extends further than government bodies. The group will also provide advice for non-state actors—WHO code for stakeholders, ranging from scientists and physicians to the medicines industry and non-profit organizations. This should cover “the design and conduct of clinical trials.”

Beyond those specific elements, the group should also help “strengthen the global clinical trial ecosystem.” What this means, for WHO, is “to meet the needs of major population groups that the intervention is intended to benefit, with a particular focus on under-represented populations”—and this point is further emphasized in the duties. The group should “ensure that the focus on under-represented populations, and that needs-driven research is adequately captured in the guidance developed.” And the group’s views will also be taken into account in WHO plans for strengthening the sustainability of infrastructure for clinical trials.

Part of the job will be assistance in liaising with clinical trials stakeholders worldwide—explicitly, clinical researchers, national regulatory authorities, research ethics committees, patients, and affected communities. A catch-all clause adds the task of assisting WHO “in identifying existing guidance and ongoing initiatives of relevance and ensuring that WHO’s work is complementary to ongoing initiatives.” That should provide some interesting moments in “liaising” with the major clinical trials regulatory activities already well underway in the US, EU, UK, and Japan—to say nothing of China! “The ability to work constructively with people from different cultural backgrounds and orientations” figures as one of the desired qualities of applicants.

There is also a COVID-19-related aspect to the work. The group will not only ensure that guidance adequately captures needs for high-quality trials and strengthening of capacity “in normal times;” it will advise on the development of procedures in place in every member state for rapid implementation of clinical trial protocols in times of health emergencies. Cue further intense liaison moments with other “ongoing initiatives.”

In its current conception, the advisory group is time limited. It will have about a dozen members, and meet virtually “at least three times each year until completion of the guidance.” No one gets paid—except travel expenses. It will be “multidisciplinary,” with members drawn from among scientists, healthcare professionals, healthcare regulators—or from an extensive list of other experts. These areas include clinical trial design, network coordination, infrastructure, and research capacity strengthening,regulatory authority clinical trial approval and product authorization, ethics in research and emergency public health response, patient and community engagement, and “needs of under-represented populations, such as women, particularly pregnant and lactating women, and children.” All members are to serve in their individual expert capacity and not represent any government, commercial entity, or “any other bodies, entities, institutions, or organizations.”

The process springs from a resolution adopted by WHO at its assembly in May 2022—a resolution that spoke of “strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and coordination.” This mandated the WHO secretariat to review existing guidance and develop new guidance on best practices for clinical trials—and was strongly inspired by the preoccupation over recent years with pandemics. Hence, the resolution’s call for infrastructure that can function well “during a public health emergency of international concern.”

If you wanted to apply for the committee, I’m afraid this blog is too late for you. Applications just closed on Jan. 9; the invitation to apply was published only in December, and got lost among other bigger events. If it is any consolation to disappointed would-be candidates, this column will endeavor to provide information on the process and the outcome, so you can then contact the members of the group yourselves when it gets started.

WHO in midst of forming group focused on developing guidance on best practices in clinical trials.

A New Year, a New Clinical Trials Committee—with Global Reach

The first few weeks of 2023 will see a frantic race across Europe to finalize the operational details of the new European clinical trials information system. The looming deadline of Jan. 31 has been common knowledge for years now, but it still implies plenty of adjustments by trial sponsors, national authorities, and the European medicines agency (EMA)—which is responsible for the new system.

The system is, of course, designed ultimately as a simplification of the divergent national rules across Europe, but inevitably the intrinsic complexities of clinical trials and the process of clinical trials authorization affecting dozens of countries mean that the implementation of the new system bristles with its own challenges. Over the last year, since the system was launched on a voluntary basis, EMA has worked with sponsors and EU member states to tackle the technical issues that have come up, in a bid to strengthen the system and its portal ahead of compulsory use.

Some 200 clinical trial applications have been authorized under the new system in the last few months, and another 200 are under evaluation, and this experience has helped to identify some of the areas that need improvement. As EMA has acknowledged more than once over the last few months, some users have had problems with the system, and for months it has been a question of all hands on deck to improve the use of experience for the core processes by the time the use of the system becomes mandatory for all new applications. As an illustration of these complexities, the latest December update from EMA included provisions such as new options for the system to register trial sites not registered in a national business registry, or to allow multiple users to work on the same application, or a facility for clearly restricting publication of certain documents.

Despite all the last-minute efforts, anxieties about the readiness of the system—and of the intended users in the clinical trials community—have been reaching fever pitch in some parts of the EU. A coalition of German researchers, ethics committees, and pharmaceutical industry associations registered their disquiet in a joint statement just before the end of 2022.

“The CTIS portal suffers from serious shortcomings even after 10 months of use, and for all those involved it is largely unmanageable,” they said, claiming that the problems had got worse rather than better. Applications for clinical trials and for processing by ethics committees “are massively impaired and cannot be managed,” they warned. The challenge is even wider, they went on: “If this portal does not function properly, the entire system of the EU regulation is in danger of failing,” which could seriously weaken the competitiveness of Europe as a research location, as well as jeopardizing patients.” The already-worrying drift of drug trials beyond Europe could be massively amplified. What they term “the dysfunctional nature of the portal” is so severe a problem that the deadline should be extended, they argued.

The chances of that happening are low. At the urging of the German coalition, the German delegation at the EU health council in late December formally raised the issue—but the council merely took note of the position. Within weeks, the system, perfect or imperfect, will be in operation and the clinical trial community will just have to adapt to it for the time being.

With compliance deadline at end of month, concerns over readiness remain.

Countdown to Mandatory European Clinical Trials System

The life of regulators is a constant struggle to stay abreast of developments that are always, by definition, ahead of them, and, notionally, a threat to them. As Pierre Joly, the president of the French pharmaceutical industry association SNIP (as it then was), famously remarked as far back as the early 1980s, "If industry was developing a new car it would start by designing the motor, but regulators would start by designing the brakes."

Regulators in Europe have just made a gallant attempt to catch up with something else they haven't designed: decentralized clinical trials. In the final working week of the year (in Europe, anyway—my apologies to those operating under stricter regimes), the European Commission, the Heads of Medicines Agencies and the European Medicines Agency have agreed on recommendations with the dual aim of facilitating the conduct of decentralized clinical trials (DCTs) but at the same time safeguarding both the well-being of participants and robustness and reliability of the data collected.

The move is welcome, because it responds to an evident reality driven largely by shifts in technology. The growing availability of digital tools and telemedicine make possible more mobile and local healthcare. The wider use of home health visits, remote monitoring and diagnostics, direct-to-patient shipment of study drugs and electronic informed consent has eased the introduction of approaches in which patients no longer necessarily have to travel to trial sites to participate in a trial, thus making trials accessible to a wider demographic of participants—and helpfully, reducing the drop-out rates that complicate or even frustrate so many trials.

The paper addresses the roles and responsibilities of the sponsor and investigator, electronic informed consent, the delivery of investigational medicinal products, trial related procedures at home, data management and monitoring in a decentralized clinical trial setting—many of the issues where clarity of procedure would obviously be helpful. But these are sketched out over little more than a dozen pages. The document itself can be seen 

And Europe being Europe (with apologies again to those operating in more harmonized contexts), this is only a collection of recommendations, because even the august institutions that have put them together have no mandate to actually tell the countries of Europe what to do. As it says on the first page, "The views expressed…are not legally binding." They were put together by the European medicines regulatory network with experts from regulatory bodies responsible for the authorization of clinical trials, members of ethic committees, good clinical practice inspectors, methodology experts and representatives of patient organizations, and drafting of the paper was coordinated by the national officials and experts who make up the EU's clinical trials coordination group.

But "it is at the discretion of the member state involved in the assessment of a clinical trial whether the use of certain decentralized elements is acceptable in a specific clinical trial," the guidance makes clear. So although a helpful appendix provides an overview of the current national provisions applicable in each member state, this is explicitly "for guidance purposes only as it is not feasible to give a complete overview of all scenarios for implementing decentralized elements in a clinical trial." The recommendations are—on the admission of the authors—"a first and important step towards clarifying the use of DCTs in the EU." They are—unsurprisingly—expected to evolve as knowledge increases and experience is gained, and the overview of national provisions will be updated on a continuous basis.

So regulators across Europe are still only inching towards a coherent view, each applying its own touches on its own brakes, but with little more than signs saying "caution" at European level. Any definitive "go" or "stop" instructions are still a long way distant, and basically, on DCTs, you're still on your own in Europe.

Despite agreement on recommendations between European regulators, DCT unclarity remains.

Decentralized Guidance Is the Best That Europe Can Do for Decentralized Clinical Trials

As Europe’s healthcare community holds its breath for the European Commission’s wide-ranging proposals on reform of the EU’s pharmaceutical rules, lobbying efforts on all sides are mounting preemptive campaigns on the most controversial issues likely to be covered by the legislation, with incentives for antibiotic research the latest topic in the spotlight.

There is no controversy over the need for urgent action as antimicrobial resistance (AMR) continues to erode the dwindling arsenal of effective therapies for infectious disease, but the emphasis varies on whether to focus on protecting existing antibiotics or whether—and how—to promote the development of new agents.

The debates have been given added urgency by disconcerting reports from European Union institutions on the growing risks of AMR. “We see concerning increases in the number of deaths attributable to infections with antimicrobial-resistant bacteria, especially those that are resistant to last-line antimicrobial treatment,” said Andrea Ammon, director of Europe’s disease control center, ECDC, in November. “Each day, nearly 100 people die from these infections” in the 30 countries covered by her agency’s estimates—“more than 35,000 people each year,” she stressed. The burden on healthcare systems and society has an economic cost, too, with healthcare expenditures and productivity losses totalling nearly $2 billion in the EU.

For ECDC, the focus is on reducing unnecessary antimicrobial use, improving infection prevention and control practices, and ensuring “adequate microbiological capacity at national level.” A decrease of 23% in total antimicrobial consumption in humans over the last 10 years masks a worrying increase in the proportion of broad-spectrum antibiotics used in hospitals.

The World Health Organization identifies AMR as one of the top current global public health threats—it’s up there alongside climate change, air pollution, famine, poverty, and war. European Commission President Ursula von der Leyen listed it as a priority when she took office in 2019, and her health commissioner, Stella Kyriakides, sees the threat as “potentially catastrophic.” The head of the Commission’s AMR unit, Sabine Pelsser, warns that “we must act as one to avert the worse consequences of AMR,” insisting that “no single action will, in isolation, provide an adequate solution.” In light of the experience of COVID-19, her emphasis is on a comprehensive response to help prevent the next health crisis. She foresees progress being made with the upcoming revision of the pharmaceutical legislation, with its dual plan for stimulating development and marketing of new antimicrobials while also addressing appropriate use. She sees “the failure to develop effective new antibiotics” as one of the drivers of the predicament, despite the EU’s injection of close to a billion dollars in antibacterial research and innovation since 2014.

Combatting the threat “is a high priority” too for the European Medicines Agency (EMA), which underlines how the lack of new antibiotics entering the market exacerbates this “global public health problem.” EMA is supporting the development of new medicines and treatment approaches in concert with the Japanese and US regulatory authorities, to provide a single development program that satisfies the requirements of each of the three agencies and to agree on an aligned approach to clinical trial design. There is even a Transatlantic Task Force on Antimicrobial Resistance.

In a Europe where one in two citizens still think that antibiotics are effective against viruses, the European Parliament is helping to spread the message of appropriate use, supporting a campaign under the slogan “Let’s keep antibiotics working.”

But policy statements and slogans are not going to solve the problem, industry executives mutter increasingly loudly in the corridors of the European institutions. “Action is needed to address the market failure for antimicrobials, so as to drive sustained private research and development investments,” says the European Federation of Pharmaceutical Industries and Associations (EFPIA), the main industry body in Europe. And what it wants the EU to introduce in its legislative rewrite is a new incentive in the form of a transferable exclusivity extension (TEE), “to revitalize antimicrobial R&D.”

Skeptical of the ability of current EU schemes to incentivize at the scale required, industry insists that successful innovation depends on reward at a level that is sufficient to attract the investment required, and to take on the substantial risks. In EFPIA’s view, a TEE, entitling a company successfully bringing a priority antimicrobial to the market to a transferable right to extend the exclusivity period of another product, could provide the incentive required.

Debates caught between focusing on existing antibiotics and developing new agents.