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

Peter O'Donnell

Even before COVID stimulated renewed urgency in mechanisms to promote rapid and efficient product development, the drive for innovative–and more complex–clinical trials was already well underway in Europe and beyond. The response to the pandemic has, however, given new momentum to many ongoing reflections on getting a better– and faster–bang from the bucks (or more elegantly, more patient benefit from platform trials) in clinical development.

While the classic RCT may remain the preferred approach for many regulators, there is growing concern over its costs and delays, and a reinforced appetite to overcome the associated challenges in subject recruitment, and in patients finding the right trial for their needs. One of the key tasks of HERA, the European Union's newly-announced strategy for tackling health risks, is to work with the European Medicines Agency "to create a long-term and large-scale EU platform for multi-center clinical trials and corresponding data platforms." This 'European Health Emergency preparedness and Response Authority', unveiled in mid-September, will incentivize "advanced research, innovation and development of relevant technologies and countermeasures–including diagnostics, therapeutics, and vaccines," says the official announcement, and will promote data sharing arrangements that "can lead to breakthrough discoveries and accelerate the development of health solutions." It will, it says, rely heavily on European clinical trial networks and platforms "to accelerate trials and connect all development stakeholders for designing and conducting trials." These platforms should, it adds, be easily adjustable to respond to a broad range of potential threats, and should reduce current lead times.

EU officials acknowledge that the trial landscape in response to the pandemic has been fragmented, with a multitude of small, national trials, struggling to generate robust and actionable clinical data, with great duplication of efforts and direct competition for shared resources and participant populations. Action has already been taken to build a COVID therapeutics network, based on three large-scale multi-center, adaptive platform trials– REMAPCAP, EU-SolidAct and DisCoVeRy. When these are combined, they will encompass around 200 trial sites across half of the EU member states. Another early initiative in this context is VACCELERATE–the first EU-wide network for COVID vaccine trials, which is collaborating with EMA to ensure these trials provide relevant evidence fast for a marketing authorization assessment, and is currently designing three trials that aim to inform future COVID vaccination strategies. HERA envisages that all these networks will be brought together into "a large-scale EU platform for multi-center clinical trials to avoid fragmentation."

But as officials also acknowledge, these trials are demonstrating yet again how hurdles relating to innovative trial designs, long regulatory approval processes and complex site administration lead to delays and underachievement. These must be tackled at European and national level to guarantee the availability of the best clinical management options, they recognize. "Efforts are needed to better address identified barriers and challenges, to ensure the necessary agility and speed of large-scale multi-country trials across the EU," according to an invitation to an official EU meeting planned for October to seek solutions and to build "increased and mutual trust with regard to the implementation of adaptive platform trials."

In parallel to these specifically COVID-related activities, there are plenty of moves within the European clinical trials community to explore and expand understanding of the challenges of matching clinical trials design to the exigencies and opportunities of scientific advances. The European drug industry worked on complex clinical trials in 2020 with researchers in the European Organization for Research into Treatments for Cancer and specialists in the Association of Clinical Research Organizations, as well as with the European Union's Clinical Trial Expert Group, composed of national health ministry officials. This built-in part upon the 2019 recommendation paper on the initiation and conduct of complex clinical trials from the Clinical Trial Facilitation and Coordination Group, a working group of the EU Heads of Medicines Agencies, which covered enrichment designs, adaptive designs, master protocols, and use of historical controls in clinical trials. The EMA Regulatory Science Strategy to 2025 finalized in March 2020 also recognized the need to foster innovation in clinical trials as a priority focus area–a position supported further by Europe's national medicines agencies' network in their strategy to 2025.

Meanwhile, an EU-funded research project with industry input–EU-PEARL–is one of several aiming to make clinical trials more efficient and patient friendly, through adaptive platforms which allow multiple companies to test their candidate drugs simultaneously against a shared placebo group. It is exploring how an adaptive platform trial with a single master protocol can allow new treatment groups to be added at any time, and candidate drugs that prove ineffective to be dropped. Other similarly-funded EU projects include ADAPT SMART, looking at evidence generation throughout the product life cycle and making best use of real world/registry data, GetReal, which is focused on including RWE in drug development using innovative trial designs, and EPAD, which is pioneering a flexible adaptive design for Alzheimer’s disease treatments.

On a broader geographic scale, the US FDA Complex Innovative Trial Design Pilot Program was set up in 2018, and in 2019 FDA released final guidance on Adaptive Designs for Clinical Trials of Drugs and Biologics. The US-based Clinical Trials Transformation Initiative is developing resources that will guide the appropriate use of the master protocols on which complex trials depend. And the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing guidelines on Adaptive Clinical Trials with a timeline of 2023, and on Good Clinical Practice Renovation to address the increasing diversity of clinical trial designs and data sources. And in September the University of Maryland Center of Excellence in Regulatory Science and Innovation organized a workshop on Complex Innovative Trial Design in Advancing the Development of Pediatric Therapeutics to discuss opportunities for leveraging complex and innovative trial designs, and to develop solutions on overcoming challenges, particularly in the use of bridging biomarkers in extrapolation and of Bayesian techniques in pediatric studies.

It is against this background that the European drug industry is sponsoring a multi-stakeholder workshop in October to develop shared solutions for the use of complex clinical trials to optimize drug development in Europe. As the industry grouping EFPIA says, "Complex clinical trials have the potential to accelerate drug development and enable patients to get timely access to transformative therapies." Its workshop is aiming to develop shared solutions in terms of simplified and standardized definitions, and in agreed responses to the challenges faced by regulators, health technology assessment bodies and payers, academia, patients’ organizations and industry. It hopes to define action plans to gain acceptance of complex trials supporting regulatory decision-making. The need may be obvious, but the sempiternal diversity of approaches to health–and particularly to medicines–in Europe may make achieving the objective more elusive than merely agreeing the agenda.

Articles

Pandemic sparks new advancements in clinical trial development.

Europe Seeking Clarity in Complex Clinical Trials

Repurposing of medicines is back on the EU agenda, with the COVID-19 pandemic providing a boost to the long-running arguments for identifying new uses for approved or investigational products outside the scope of their original medical indication. The issue was given new prominence during the summer by Slovenia, the country holding the presidency of the EU health council until the end of 2021. The Slovenian health minister brought together regulators and health officials from across Europe for something of a première in terms of EU discussions on the topic. And it supported the play with a lengthy reflection paper developed in concert with the World Health Organization, ambitiously entitled ‘Repurposing of medicines in oncology–the underrated champion of sustainable innovation.’ The aim was to give sharper focus and new impetus for a more general discussion of repurposing that has been underway among EU health officials for several years now, without reaching any clear conclusions.

The Slovenian starting point is that new technology and new approaches can revolutionize what has been seen traditionally as a predominantly non-commercial and even artisanal approach to drug development. It stresses in its background paper that repurposing previously has moved on from its earlier reliance on an ad hoc discovery process, and can now build on organized, systematic, data-driven approaches to identify suitable candidates, facilitated by the use of big data and artificial intelligence. The focus is on cancer, but the overall argument is that repurposing can deliver innovation in terms of new treatments that resolve unaddressed health needs, and often in shorter timeframes than de novo development.

This chimes conveniently with the EU push during 2021 for repurposing of treatments specifically to counter COVID-19, and also gains strength from the widely-publicized success of the RECOVERY trial in identifying valuable therapeutics for COVID-19 patients–notably dexamethasone. As the paper says, “The lack of effective therapies for the SARS-CoV-2 pathogen highlighted the need to find treatments that can be applied quickly to reduce mortality and morbidity. Repurposing was identified as one main strategy to provide a fast and cost-efficient approach to this purpose.”

But the argument relies too, on more familiar arguments–that repurposing can offer lower costs of development and lower risk of failure–as well as pointing out that many products are already commonly used off-label in cancer treatment, particularly for patients who have no alternative options. “Establishing rigorous scientific evidence and repurposing the vast arsenal of existing approved medicines with established safety profiles may be an attractive strategy to offer more effective treatment options to patients with cancer,” says Slovenia.

The paper also assembles a range of specific points in defense of its thesis, collectively amounting to an appeal for a radical review of the current business and regulatory models of drug development. Most of the arguments are linked to easing conditions for the non-commercial activity that still constitutes much of the repurposing of off-patent medicines, particularly for cancer treatment. Slovenia sees potential for addressing areas that are not attractive for the pharmaceutical industry, such as rare cancers (which it estimates as accounting for a fifth of new cases in Europe). It depicts “traditional models of collecting clinical evidence” as sub-optimal for repurposing, “owing to the high costs involved and the applicability of established pharmaceutical development and testing paradigms,” notably for combination therapies.

The paper perceives particular handicaps in the persistent reliance on the good will of industrial partners. As it observes, only the marketing authorization holder of a given medicine can currently apply for an extension or variation of its marketing authorization. Consequently, even if non-commercial clinical trials confirm the efficacy of a repurposed drug, patient access to these treatments depends on the willingness of a pharmaceutical company to obtain authorization for the new indication and to take responsibility for its risk management–something that experience to date shows has not often been forthcoming. “Returns on investment for repurposed off-patent medicines are expected to be low or nil, and pharmaceutical developers are rarely interested in pursuing repurposing opportunities, even when clinical evidence is made readily available by other stakeholders,” it remarks glumly. In addition, the existing EU legislation that might help in promoting off-patent drug repurposing (such as on data exclusivity or orphan designation) “do not offer the usual level of incentives for the industry compared to alternative investments, and they are underused.”

The paper also reflects a keen awareness of the current debates in the EU–and elsewhere–over the cost of medicines, liberally citing references from official international organizations to the “exorbitant” price of cancer medicines or “market failure” endangering patients’ access through “very high and unsustainable price levels.”

In the best tradition of European problem statements, the Slovenian initiative also contains a range of potential solutions, particularly aimed at assisting non-commercial repurposing. They are rather glibly listed as “reducing the risk of failure by improving the selection of candidates, facilitating generation of clinical evidence, streamlining regulated processes, amending restrictive legislation, improving collaboration and coordination between stakeholders and ensuring adequate funding.” Unexceptionable ambitions–but requiring rather more than enunciation to realize them.

Wide support can be assumed for the proposals for early scientific advice and regulatory assistance throughout the process to ease the generation of evidence, and “exploring the potential for greater reliance on real-world data, data networks, adaptive platform trials and innovative trial designs” finds an echo in much current EU debate. The concept of reducing fees for repurposing of financially unattractive medicines can be seen as consonant with the current approach of easing regulatory barriers for smaller firms or orphan products. But simply citing “artificial intelligence and use of big data” may be considered a little thin as a way of improving selection of candidates. And most strikingly, perhaps, many in industry will bristle at the suggestion of over-riding current rules that permit marketing authorization holders as sole arbiters of applications for authorization of new indications for their products. This proposal is not, many will say, the solution to “removing barriers for non-commercial champions.”

Slovenia brings EU health officials together for increased emphasis on repurposing.

Rhetoric and Realism Colliding on EU Discussions of Drug Repurposing

The UK is aiming to rejig its health technology evaluation processes through NICE, partly as a bid to win business post-Brexit. The wide-ranging changes are open to consultation until October 13, 2021, and can be viewed 

 following a launch couched in terms more inspired by public relations than regulation, replete with "visions" and "deliverables", with "foundation stones" and "pivotal" action, and promises to provide "faster, fairer access to new drugs and devices." It invites ridicule by elevating statements of the obvious to the status of genius insights: "Ensuring rapid access to clinically and cost-effective health technologies is critically important to patients and their families, the NHS and the life sciences industry." And just in case there was any doubt about the heroism of this commitment: "We navigate a complex environment of ensuring the NHS gets the best value out of the products it uses, while at the same time promoting innovation and supporting the life sciences industry in their journey through regulation, health technology evaluation and patient access".

The post-Brexit rhetoric makes an early appearance: "We are shaping a new offer for the life sciences sector in response to leaving the European Union", says NICE. "Being clear how our methods and processes can support early patient access will be even more important, as it encourages companies to launch their products first in the UK market." It will lead to "synergistic collaborations with health system partners across the landscape and countries of the UK."

"Being clear" will result, it emerges, in "a single, modular, guidance development program manual covering four health technology evaluation guidance programs (Diagnostic Assessment, Highly Specialized Technologies, Medical Technologies Evaluation and Technology Appraisal)." This is intended to remove multiple existing individual process and methods guides and reduce unnecessary duplication of content, it admits. The full details appear in the manual, and I leave ACT readers with more specific interests to peruse it at their leisure.

But among the highlights of the promised new approach is "more equitable access for those with severe diseases", which will be affected in part by new weightings for innovation support. This will "put the impact on patient’s lives at the heart of NICE’s work, while creating a more equitable platform."

There will also be "decision-making flexibility where it counts". The proposals are for NICE’s decision-making committees to "use their flexibility when challenged with complex innovative technologies and those for children or rare diseases, to ensure patients benefit from the most cutting-edge therapies sooner, without barrier or delay". The flexibility will however be "clearly defined, transparent and predictable", it adds.

An emphasis is put on "embracing the full evidence base and new data sources", explicitly including real-world evidence. Again, the description is phrased as if from the pen of a communications consultant inebriated with the exuberance of his or her own verbosity: it "will mean industry will have clarity and predictability for their submissions, while ensuring high quality data continues to provide the backbone for robust, rapid decision making from committees", and "allow companies to plan their evidence collection within the trial and data environment in the NHS."

Once the decorative wording has been disregarded and dismissed by those seeking information rather than spin, the responses to the consultation will doubtlessly be at least as interesting as the proposals themselves—and as the autumn advances, this columnist looks forward to hearing more about the review from stakeholders rather than from spin-doctors.

Promises of "more equitable access for those with severe diseases," "decision-making flexibility where it counts," and more in a bid to win post-Brexit business.

NICE Consults On Its New Assessment Scheme Amid A Blizzard Of Spin

The cavalcade of European Union initiatives on health continues unchecked. Early in September, the European Commission’s president, Ursula von der Leyen, is scheduled to propose yet another plan to “get ahead of the curve” in protecting European citizens against infections. The European Health Emergency Preparedness and Response Authority is designed to up the EU’s game in bio-defense preparedness by bringing together science, industry and public authorities in response to major health challenges like COVID-19. This is intended to provide “a permanent structure for risk modeling, global surveillance, technology transfers, manufacturing capacity, supply chain risk mapping, flexible manufacturing capacity and vaccine and medicine research and development,” according to the Commission. And von der Leyen’s project is to be known as HERA–which may amuse lovers of Greek mythology, who will be familiar with the vengeful matriarch of that name.

HERA is one of the remedies that von der Leyen has envisaged for the “structural weaknesses and market failures in our foresight, preparedness and ability to respond coherently, rapidly and appropriately to protect our citizens from health crises.” It will be a dedicated European authority to strengthen the EU’s response capability for new and emerging cross-border threats, portrayed as something of a European counterpart to the US BARDA.

The mission will be to enable the EU and its member states to rapidly deploy the most advanced measures in the event of a health emergency, by covering the whole value chain from conception to distribution and use, engaging both the public and private sectors. At the end likely to be of most interest to readers of ACT, it will “support the development of cross-cutting technologies and solutions sustaining multiple potential future threat responses (e.g. vaccine platform technologies, or the application of digital tools and artificial intelligence) as well as the development of specific countermeasures, including through clinical trials and data infrastructure.”

It will also undertake horizon scanning to anticipate specific threats, identify promising potential countermeasures and relevant underpinning competences. And in practical terms it will monitor and pool production capacity and development facilities, raw material requirements and availability, and ensure that supply chain vulnerabilities are addressed. That will extend to ensuring sufficient production capacity, as well as arrangements for stockpiling and distribution.

Already von der Leyen has used the HERA label to marshal the pharmaceutical industry in Europe into combining its capacities to combat the COVID-19 pandemic. She set up the ‘HERA Incubator’ in February this year “to prevent, mitigate and respond to the impact of the virus and its variants.” She has been personally involved in getting CEOs round the table with her key subordinates in a bid to counter the delays, disruptions and bottlenecks that characterized the early EU responses to the pandemic–and that led to criticism of her management. The incubator has brought together researchers, biotech companies, manufacturers, regulators and public authorities to monitor variants, exchange data and cooperate on adapting vaccines. And it is working towards the ‘EU FAB’ project, a network for single or multi-user, single or multi-technology emergency response production capacity for vaccine and medicine manufacturing at the European level. This will in due course become one of the central assets of HERA.

The activity within the incubator has been focusing on detecting and analyzing new variants of the virus, supporting development of vaccines against resistant new variants, and preparations for producing them at scale and speed. As part of the drive, the Commission is funding new research projects to speed up approval processes and ramp up production. Support for companies working on the adaptation of vaccines or development of new vaccines includes facilitating clinical trials with the launch of an EU-wide network of clinical trials, and backing new technologies to develop adapted or new vaccines. To accelerate approval of adapted vaccines, the incubator is exploring the introduction of emergency authorization of vaccines at EU level, providing guidance on data requirements, and supporting research to include children in clinical trials. And the incubator is helping speed up certification of new or repurposed manufacturing infrastructures. “The pandemic has shown us three things: We have to act early. We have to invest at large scale. We have to partner up”, said von der Leyen, summarizing the core tasks of the HERA incubator.

Just before Europe’s still almost religiously-observed summer break, the first meeting of the HERA incubator’s expert group on COVID variants and treatments held its first discussions. “With our new group of variant experts, we are improving the HERA incubator’s radar screen and warning system,” said von der Leyen’s chief health official, Stella Kyriakides. The group’s contributions “will help us better identify, understand and anticipate variants and will guide us in our work to develop countermeasures,” she said. It will also propose selection criteria for a list of 10 promising treatments for COVID as part of the EU’s therapeutic strategy.

But that summer break for many EU officials–and most of the Brussels bubble–is not being observed by the virus. The World Health Organization and the European Centre for Prevention and Disease Control joined forces as the annual exodus began, to warn that “in much of the European Region efforts must be reinforced to prevent transmission.” The Delta variant “is spreading quickly across Europe and has now become the dominant strain,” it said. WHO’s director general for Europe, Hans Kluge, made clear “we are far from out of the woods in terms of the pandemic ending,” and EDCD director Andrea Ammon insisted on the “need to remain vigilant” to “prevent the spread of disease without having to shut down large parts of society.” Holiday-makers heading for the beaches and mountains were bluntly reminded: “Travel is not risk free.”

If the situation continues to deteriorate and Europe’s plans for preparedness prove insufficient, HERA and the woman who designed it will come in for renewed criticism–and given the duality in von der Leyen’s own normally benignant profile, with its simultaneous capacity for revenge (as AstraZeneca’s boss can testify), any of her subordinates who have failed to deliver will doubtless face torments of their own come the autumn.

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

European Commission proposes new bio-defense preparedness plan.

HERA, A Matriach's Device to Save Europeans from the Next COVID

The official position of the European Medicines Agency and the European Commission is that the clinical trial regulation–that is scheduled finally to come into effect in January 2022–will streamline the entire CT process in Europe. As from then, sponsors will be able to apply for clinical trial authorization in up to 30 European countries with a single application. The predictions may be accurate–but as with any streamlining exercise, there is going to be a quite a bit of preliminary work by all concerned to create an air-smooth body. So forget about the latest spy novel or passionate love story for your beach time reading, and pick up a "sponsors' handbook".

Right at the end of July the final obstacle to the new rules was lifted – with a formal announcement by the EU that the portal and database on which the new regulation relies are now ready to go live, bringing "substantial changes to the authorization and supervision of human research on medicinal products." Between now and the start of the new system, sponsors are going to have to familiarize themselves with the way the new system will operate. Most of the complexities are attached to the clinical trial information system (CTIS), which has proved challenging to build–a task that has accounted for much of the eight-year delay between the legislation's passage and its coming into effect.

No-one is taking this 'streamlining' for granted. EMA has just issued a lengthy sponsor 

 to give advance notice to everyone generating CTs of what they will have to do under the new rules. There is also a training catalogue with "several modules covering the full lifecycle of clinical trial submission, authorization and supervision." Reassuringly, this acknowledges that sponsors "have multiple and complex structures and partnerships for managing clinical trials." But less reassuringly, it then goes on to point out that "there is a need for sponsors to fully understand the CTIS user management functionalities to facilitate completion of processes and organizational designs so that management of user permissions in the CTIS serves the creation, review and submission of CTAs, modifications and notifications through the CTIS. Sponsors also need to understand user/roles so that they can ensure that they have the correct confidentiality agreements in place."

And that's just the start. The 30-page handbook consists largely of references to websites that contain the detail of how those roles will be discharged. CTIS allows sponsors to manage system users and their roles within their organizations, compile clinical trial dossiers including document upload for new and updated trials, cross-refer in the application to other trials, where for example the same product was used, receive alerts and notices for Enhanced Patient Safety Support to Innovation & Research ongoing trials, respond promptly to requests for information, view deadlines, search and access clinical trials and record a summary of clinical study results.

It lists the data fields to be completed and to be uploaded for each form present in the notifications section implemented in the system. They include the start of trial, start of recruitment, end of recruitment, end of trial, global end of trial, temporary halt, restart of trial, restart of recruitment, update anticipated date of summary results, unexpected event, serious breach, urgent safety measure and third-country inspectorate inspection. And in recognition of the scale of the tasks that sponsors will have to take on,

But for all the data that will have to be input by sponsors, "CTIS is, however, not a clinical trial management system." It provides a digital secured archive of documents, decisions and information on a clinical trial, but "it should therefore not be relied upon by sponsors to store information on a clinical trial." Sponsors should ensure they utilize their own information management system to store information needed for compliance purposes, it says.

The regulation, with its nominal aims "to stimulate clinical trials in the EU, to protect trial participants, and to increase transparency of clinical trial information," will be implemented on 31 January 2022–some eight years after it was adopted. Its use will be voluntary for the first year, and mandatory for new clinical trials as from 31 January 2023. And by 31 January 2025 all ongoing trials approved under the current clinical trial directive will need to transition to the new regulation.

Time to start reading–and making notes.

Obligatory Summertime Reading–How to Use the EU's New Clinical Trials Regulation

The message is starting to get through in Europe that high-quality drug development depends on high-technology approaches as well as high-quality science. A specialized European Parliament committee on cancer started work in mid-July on a report that explicitly urges national governments to take molecular genetics seriously. That may seem a bit of a belated call on a matter that should have been taken for granted. But the reality is that the advocates of deploying advanced technology in Europe's healthcare system have long complained—and are still complaining—that official resistance is hampering wide-scale take-up, and consequently depriving European citizens of the benefits that precision medicine that offers.

This is why the draft report from the parliament's cancer committee is noteworthy. It points out that "huge advances in biology have revealed that cancer is an umbrella term for more than 200 diseases, and that precision or personalized medicine can be made available through the drug targeting of various mutations." Pretty obvious to readers of ACT—but not so obvious to the myriad bodies that control Europe's complex mix of national healthcare systems. Not yet necessarily to everyone in the European parliament either. This is only a draft report. It still has to be adopted by the cancer committee, and only then will be submitted—later this year—to the parliament as a whole for full endorsement.

Even if everything goes smoothly, that will only be part of the battle. The parliament has no power to instruct national governments. It can exert pressure on a political, even sometimes on a moral, level. But the best it can hope for is that its message is backed by the European Commission (which can and does propose rules that bind the member states), and ultimately by the Council (which consists of the member states themselves). That is why the text of the draft report, while arguing that "precision or personalized medicine, consisting of a treatment choice based on individual tumor biomarkers, is a promising way to improve cancer treatment," can go no further than to "encourage" member states "to promote the implementation of regional molecular genetics platforms and facilitate equal and rapid access to personalized treatment for patient."

Similarly, the parliament can do no more than call for "the full and rapid application" of the EU's 2014 regulation on clinical trials on medicinal products for human use—and that seven-year delay (and counting) is another measure of the relative impotence of the parliament, as well as of the intrinsic complexity of the regulation itself and the low level of priority attached by member states in implementing it. "The application of the regulation would facilitate the launch of large clinical trials carried out in a harmonized, efficient and coordinated manner at European level in order to facilitate research into cancer drugs and improve cancer patients’ and their families’ quality of life," the parliament's draft report adds, plaintively.

The needs that draft report's author highlights extend beyond molecular genetics and the 'new' CT regulation. Véronique Trillet-Lenoir, a prominent French medical oncologist who won election in 2019 and sits with the liberal Renew group in the parliament, is seeking backing from fellow MEPs on the committee for the development of clinical trials on the use of new cancer drugs in adults and children. And she wants to see "a more sustainable environment for conducting research into the repurposing of medicines for cancer treatment and for the creation of an additional project that uses high-performance computing to rapidly test existing molecules and new drug combinations, starting with treatment for cancers with a poor prognosis and rare cancers."

That's not all. She wants the EU to ensure "rapid, equal and sustainable access to cancer innovations for cancer patients," and for "a large consortium of public authorities, private companies and NGOs, including patient associations, to work together to guarantee the accessibility and affordability of cancer treatment options requiring complex technologies." This, she says, should take advantage of new possibility through cellular therapy and CAR T cells, adoptive immunotherapy through the use of tumor genome extracts and messenger RNA, and nanotechnologies.

The fact that, in the lower reaches of the European political machinery, support is stirring for advanced technology in drug development may provide a crumb of comfort for those working in the field. But it may equally provide a shock of disappointment that well into the third decade of the 21st century, it should even be necessary for such an appeal to be made.

A draft report from parliament's cancer committee highlights the benefits that precision and personalized medicine offer.

Faint Ripples of Support Detected in Europe for High-Tech Drug Development

It isn't just the COVID crisis that is changing the landscape of pharmaceutical policy in Europe—although it’s the COVID-induced changes that are getting most of the headline coverage, in multiple "lessons learned" reviews, and in the continued entrenchment of joint procurement for vaccines, which is giving the EU a new foothold in the hitherto sacred territory of national sovereignty over drug pricing. Not only is the total of vaccines ordered through its advanced purchase agreements now in excess of 4 billion, but its concerted choices of vaccine technology—shifting markedly towards mRNA and other novel approaches—is a striking intervention in previously independent national decisions over acquisitions.

But in what is currently the background of policy, other moves are occurring that will impact on the world of medicines—and particularly the development of innovative medicines, often driven by a broader search by the EU to boost its ability to compete internationally but holding out the prospect of some potentially valuable improvements in the operating context. Early hints emerged at the Global Health Summit (which ACT commented on in May), with its 'Rome Declaration' call for an efficient and effective end-to-end R&D ecosystem to accelerate research.

That call has since been endorsed and amplified by the G20 and then the G7, giving rise to a lengthy G7 communiqué that recommended greater international collaboration and coordination of clinical trials "to facilitate rapid availability of safe, effective and high-quality medical countermeasures while protecting trial participants’ safety and rights and based on good clinical practice." It expressed support for a 'G7 Therapeutics and Vaccines Clinical Trials Charter' of shared principles on accelerating the generation of "robust evidence", and for large-scale international trials to avoid unnecessary duplication and "produce clinical evidence that is generalizable to a larger number of populations and places." Crucially, the G7 also threw its weight behind greater harmonization and standardization in the digital transformation of health, with open health data standards, open-source software tools and related infrastructure to maximize the return on investments in a defined secured framework, such as the promised European Health Data Space, and with the development and international recognition of a framework for the clinical evaluation of artificial intelligence in health.

The EU-U.S. summit in Brussels in mid-June—again ostensibly about post-COVID recovery—offered further encouraging noises about innovation, with a commitment to continue to engage in health research initiatives, "including to develop medical countermeasures in a much shorter period of time." The two sides also intend to explore a new research initiative on biotechnology and genomics with a view to setting common standards. And they backed the drive to digital transformation, and to cooperate on the development and deployment of new technologies.

Just days later, a meeting of Europe's economic and finance ministers added to the pro-innovation music with a statement that pushed back firmly against the selective patent waivers on which the World Trade Organization is now embarking in the context of the pandemic. The ministers' conclusions restated the EU position that intellectual property is a major driver for innovation, competitiveness, economic growth and sustainable development, and a key enabler for knowledge and tech-transfer: "Well-calibrated policies must be put in place for purposes of helping companies to capitalize on their inventions and creations, ensuring that these serve the economy and society as a whole," the ministers insisted.

Progress at last seems to be on track for the introduction of the long-awaited EU regulation on clinical trials, with a satisfactory independent audit of progress in the development of the Clinical Trial Information System that the new system will depend on, operated by the European Medicines Agency. Publication of the final piece of the regulatory framework is now expected at the end of July, which will enable everything to go live on January 31, 2022. The onus is now on stakeholder organizations, clinical trial sponsors and authorities to prepare their staff and processes to work with the new system.

And the EMA itself has just been reinforced (once again with COVID as the impetus) to give permanence to some of the emergency measures introduced over the last eighteen months—including a new scientific task force to swiftly advise clinical trial sponsors on innovative products, and a legal basis to access and analyze real-world healthcare data.

Meanwhile, plans have emerged for a new EU-backed public-private partnership with healthcare industries—the Innovative Health Initiative—which aims to foster a convergence between medical devices, radiological electromedical and IT companies along with biotech, vaccines and pharmaceuticals. With a budget of nearly $3 billion, it will follow on from the long-running Innovative Medicines Initiative with a new strategic research agenda geared to personalized treatments and improved individual health outcomes. This affirms the partners' determination to break down "still existing silos" across discovery science and translational research, as well as between different academic research disciplines and industry sectors. The ambitions relate to the discovery of new molecules, mechanisms of action, processes, technologies, as well as their development and testing, along with methodologies for assessing safety, health outcomes and health-economic evaluation. It has set objectives for 2030 of launching 30 large-scale, cross-sectoral projects focusing on health innovations, with an accent on integrating cost-effective health care products or services with demonstrated suitability for uptake by health care systems.

Almost simultaneously, the EU has started to put into motion its new $100 billion dollar research support program, Horizon Europe, with clear aims that include "generating new knowledge and developing innovative solutions" to prevent, diagnose, monitor, treat and cure diseases. Between now and the end of the decade it will be funding activities as diverse as molecular and neurobiological understanding of mental health and mental illness, understanding the individual host response to viruses, pre-clinical development of the next generation of immunotherapies, biomarkers in treatment optimization, the use of real-world data, patient stratification, smart medical devices, advanced therapies for unmet needs, development of new antimicrobials, and public procurement of innovative solutions. Just as random examples, calls are opening shortly to obtain funding for boosting understanding of the chronic inflammation factors triggering the health-to-disease transition, or development of therapies for rare diseases, or building a European platform for repurposing medicines, or scaling up data anonymization techniques and synthetic data generation or improving the access for clinicians and researchers to electronic health data and metadata.

Big changes are underway to health technology assessment, too. After three years of often vigorous discussion, the EU proposal for closer coordination of national and regional HTA work across Europe finally won acceptance in June. It is a compromise that satisfies both the big countries like France and Germany that didn't want other countries to interfere with their well-established processes, and the many smaller countries that can benefit from shared work. Even the European Commission, which initially wanted a system that eliminated any duplication of HTA work in the EU, has pronounced itself satisfied with the deal. Over the next few years its provisions for joint scientific consultations will provide medicine developers with some greater degree of certainty in planning their evidence development both for marketing authorization and for reimbursement negotiations. The European drug industry wanted something more binding on member states, to require the use of joint assessments, but companies will nevertheless learn to derive the maximum benefit from the less-than-perfect outcome.

Not only is the EU trying to ease the HTA experience. An analogous process is underway in the semi-detached-no longer in the EU, but still an important (if reluctant at senior government levels) part of Europe, where NICE is updating its procedures for the review of commercial and managed access requests. It says it "wishes to ensure that those who are bringing technologies forward for possible use in the National Health Service can make the best plausible case for the use of their product." Initial discussions with NICE will focus on submission of a simple patient access scheme proposal—the default commercial proposal, which NICE says can cover most situations when a company needs to improve the cost effectiveness of a technology. However, if NICE identifies that a technology is not likely to be cost effective with a simple patient access scheme, it will liaise with the company to assess the potential for submitting a managed entry request.

And as it that wasn't enough, the EU's determination to press ahead with the creation of its European Health Union is behind spasmodic progress on a raft of other medicine-related initiatives, from the Beating Cancer Plan to the European Health Data Space, and from the revision of the decades-old pharmaceutical legislation to urgent reviews of the incentives to researchers in the orphan drug and pediatric medicines schemes. As an industry executive closely involved in EU policy on medicines innovation remarked to ACT recently, "There's plenty of change coming that's going to see me through to my pension." And that was a young man speaking.

Not just COVID is changing the landscape of pharmaceutical policy in Europe.

Convergent Drivers of European Medicines Policy

Growing evidence of deficiencies in clinical trial reporting in Europe has impelled the authorities to—somewhat dilatory—action, and discussions on how to improve the situation are now beginning among national regulators, the European Medicines Agency and the European Commission.

The move was prompted by a recent letter from transparency and health campaigners that documented widespread failures by trial sponsors to meet the requirements for reporting results. This alleged that more than 4,000 clinical trials of medicines—nearly a third of all trials undertaken in Europe—are missing results on the European trial registry, in violation of long-standing transparency rules. The University of Amsterdam has run 195 drug trials, but marked only 14 as completed—and posted results for none of them. Germany, France, Italy and Spain also stand accused of regulatory inaction, with data from EMA in late 2019 showing that results were missing for over 500 applications linked to drug trials involving children in those countries.

The letter, to the Heads of Medicines Agencies—the national regulators in the EU, urged the creation of a process to ensure that national competent authorities adopt and implement common minimum standards for promoting sponsors’ compliance with clinical trial results reporting requirements. "Despite significant improvements in sponsor compliance in recent years, thousands of due clinical trials are still missing results," it said. "The persistent failure of many sponsors to meet their obligations indicates that the European medicines regulatory system is currently neither effective nor efficient," it continued. It suggested that even minimal engagement by national authorities could rapidly improve sponsors’ compliance rates.

The Heads of Medicines Agencies have now confirmed that they discussed the letter, and there was wide recognition of "the importance of the sponsors fulfilling their obligation to make trial results public." However, the responsibility under European law lies with each national regulator, and “HMA is not in a position where the organization can impose standards on the national competent authorities.” So, it promised to "reach out to the European Commission and the European Medicines Agency with a view to initiate joint actions to improve clinical trial sponsors’ compliance."

TranspariMED, a civil society organization that has played a leading role in tracking non-reporting, welcomed the HMA engagement, while urging it to immediately provide a forum for national regulators where common standards could be developed for following up on unreported trials. Till Bruckner, founder of TranspariMED, said his organization "hopes that HMA will now actively work towards the creation of a regulatory system that no longer idly stands by when rules are broken, taxpayers’ money is wasted, and patients’ interests sidelined.”

He added that some national medicines regulators are already acting. He cited Denmark and Austria as recent examples where attention has led to significant improvements in trial reporting. But he raised questions over how energetic the authorities were being in Germany, France, Italy, Spain, the Netherlands, Belgium and Ireland. Bruckner says that the failings often result from ignorance among sponsors of the reporting requirements, and that national authorities could achieve some easy improvements simply by issuing alerts: many regulators are not even contacting those that break the rules, let alone enforcing compliance. “Running a single clinical trial can cost millions of Euros, but that money is wasted if the results are never made public. Is it really too much to ask regulators to send out a few hundred reminder letters to prevent valuable medical knowledge from being lost forever?” he asked.

The pressure for change is backed by Cochrane. It's Karla Soares-Weiser pointed out that without access to reliable information from all clinical trials, the evidence base on which to make judgements is incomplete—which "limits the scientific community’s ability to learn from research findings and can lead to patients being harmed.” Bettina Ryll, founder of Melanoma Patient Network Europe, another signatory to the initial letter to HMA, said that protection of future patients is being neglected, and "regulators must stop turning a blind eye."

Allegedly more than 4,000 clinical trials of medicines are missing results on the European trial registry, in violation of transparency rules. 

Putting the Squeeze on Trial Reporting Failings in Europe

The shift towards a more comprehensive and efficient form of European collaboration between regulators, health technology assessment bodies and drug developers is evident in a 

 from the European Medicines Agency and EUnetHTA, the soon-to-be-terminated organization of European health technology assessment bodies. 

The trend is apparent in figures on the use of early scientific advice for drug developers in Europe. There have now been 31 'consolidated parallel consultations' completed under the single process for parallel consultation which was revised to ensure that scientific consultation involves both EMA and HTA bodies. This has gradually replaced the former parallel scientific advice procedure with EMA (known as individual parallel consultations) in which medicine developers had to contact member state HTA bodies individually. In fact, so popular has the new process become that the demand from developers exceeded the capacity by HTA organizations to keep up, demonstrating the need—say EMA and EUnetHTA—for "a sustainable framework with adequate financial resourcing." The same joint approach has served in parallel consultations on registry qualification and on the qualification of a project under the EU's Innovative Medicines Initiative, where HTA bodies were fully engaged alongside EMA.

This parallel consultation platform is also being used now to provide guidance on requirements for post-authorization data generation and data collection plans, including registries. This experience with early discussion of post -launch evidence has so far focused on plans with specific products such as advanced therapies or on specific regulatory processes or tools such as conditional marketing authorization, adaptive pathways, or the priority PRIME scheme. The process is proving its value in improving later decision making, but, says the report, "more proactive proposals from developers for discussion in parallel consultation are needed." Better utilization of patient-reported outcomes is also highlighted as a valuable element in evidence generation plans. "This is an area of great importance for future collaboration in view of the developing methodologies and stronger reliance on such data in the context of decision making," it observes.

The report also records recent joint work on methodologies to identify the treatment eligible population, in which experience has been shared on how regulators define therapeutic indications and the impact of their wordings in HTA boards’ definition of who should qualify for treatment. It has been agreed to continue sharing information on how labelling and European public assessment reports are taken account of in decision making, especially regarding subpopulations where limited data is available. This discussion has been closely linked to a search for mutual understanding of the extrapolation concept, particularly in the pediatric population. The report concludes that while the concept of extrapolation or evidence transfer will be relevant in certain developments, such as those affecting small populations, it will require further joint methodological work, and "It is important to understand each other’s reasoning for accepting extrapolation acknowledging the different remits" of EMA and of HTA boards.

The work has also encompassed improving understanding of the similarities and differences between the concepts of significant benefit and added therapeutic value in the context of orphan drugs. No major differences between significant benefit assessment and relative efficacy assessments have been identified, and the conclusion is that early interactions between stakeholders might further diminish differences in the future. "HTA organizations might benefit from reviewing the orphan maintenance assessment reports, as provided on the EMA website," the report recommends. But on unmet medical need, where work has also been undertaken, the conclusion is that it is necessary "to explore further collaborative work on the concept to inform prioritization by different decision makers."

There is a long list of items requiring further discussion. "Priority topics for the work stream" include increased personalization leading to smaller patient populations, smaller trials, less evidence, and increased need to manage uncertainty. The list also features companion diagnostics and other diagnostics for targeting therapeutics but where not directly related to use of specific therapeutics, such as genetic signatures and next generation sequencing. New treatment paradigms such as highly individualized combinations of immune-oncology products targeted through NGS also feature on the "to do" list, as do operational issues around patient access to companion diagnostic tests.

The clear identification of achievements and of outstanding tasks comes at a crucial moment in the evolution of European cooperation on HTA, with EU member states on the brink of agreeing on only a very limited legislative framework to take forward the work conducted by EUnetHTA over the last fifteen years. Within weeks it is expected to become clear whether the road to closer collaboration remains open, or whether national reticences over handing over too much power to the EU will inhibit progress.

A new report from the EMA and EUnetHTA shows a shift towards a more efficient form of collaboration.

Closer European Collaboration on the Ground on HTA and Marketing Authorization—But Under a Political Cloud

Much has already been written about the impact of the COVID pandemic on thinking about healthcare in general and drug development but the recommendations on clinical trials from an influential scientific panel received strong backing in late May from senior figures in world affairs, giving them a better-than-average chance of leading to some improvements.

The occasion was the—rather grandiosely—titled Global Health Summit that took place in Rome on May 21, organized under the G20 umbrella, and co-hosted by the Italian government and the European Union. This was a response to the pandemic at the level of the economic and finance ministers of the countries that between them represent some three-quarters of the world's economic activity and amounts to a heavyweight intervention from political figures who carry (with no disrespect to health ministers) real responsibility for decision-making.

The conclusions from the meeting, contained in a so-called Rome Declaration adopted at the meeting, provide plenty of support for research, innovation, investment and incentivization (alongside, or course, plenty of commitments to equal access to care and better preparedness against health crises). But of greater interest to readers of ACT may be the background paper for the declaration, which sets out in greater detail some specific measures for raising the game in drug development in general, and clinical trials, in particular.

So, while the scientific panel notes with satisfaction that "research and innovation have been one of the few bright spots" in the COVID response, with "unprecedented advancements in record time," it laments the lack of a global strategy at the outset of the crisis "to optimize and coordinate research and development efforts."

Its central recommendation therefore is to establish an efficient and effective end-to-end R&D ecosystem, to accelerate research—and it has clear ideas on how to do this. They include creating an open-source library of phase II-ready drugs with broad cross-reactivity across major virus groups of pandemic concern, and a pipeline of just-in-case vaccines and monoclonal antibodies that target World Health Organization priority pathogens.

The familiar call for increased investments in basic research is accompanied by more concrete recommendations to deliver products, including digital innovation and infrastructure, data science, artificial intelligence, and modelling and forecasting. The panel calls for the urgent establishment of "large, pragmatic, collaborative clinical trials networks and protocols, globally and regionally, for therapeutics and vaccines." It wants to see early support by regulatory authorities for clinical trials. Other aspirations are for cross-disciplinary research, including risk communication, implementation science for more effective public health measures, as well as social and behavioral research. An end-to-end R&D ecosystem also demands real support for biotechnology entrepreneurship and innovation, it adds.

The international dimension of the recommendations is evident in calls to "genuinely" involve research groups in low- and middle-income countries. The pandemic underlines the urgent need for bringing together researchers and developers from all countries, to benefit from the diverse experience gained in different contexts, to ensure that the scientific outputs are relevant for and accessible in the countries in which they will be implemented, it says. This will also improve the coherence of the research response affecting all countries. "It is crucial to conduct clinical trials of medical products in a diversity of populations where products proven safe and effective will be rolled out," it insists.

This implies a strengthening of collaborative research networks regionally and globally, increased funding for "equitable" research partnerships, and sustainable finance that can "ensure research continuity, particularly in times of crisis." It also means better integrated disease surveillance, data collection, analysis and sharing "at all levels," it underlines. Countries need to have more capacities for data collection and analysis, including through genome sequencing for early detection, pathogen characterization, surveillance of pathogen spread, and assessment of disease dynamics. The corollary is the development of well-funded and coordinated global and regional networks for pathogen surveillance, underpinned by a common set of principles for data sharing. That in turn requires improved standardization and validation of tests and assays, and the comparability, sharing and interoperability of accessible digital data, along with adequate quality assurance. And repositories must be set up that provide for universally accessible sample collection.

The interface between science and policy gets plenty of attention too. With absolutely no hint of a reference to Wuhan, the panel urges action to "promote transparent and rapid sharing of data and information on outbreaks and other health issues." And in a section entitled "strengthen and protect science advice", it recognizes that "scientific advice to policymakers may always be challenging." This may be even more so in pandemic situations when there are major uncertainties, knowledge is fast evolving, risks are large, and evidence is preliminary and limited. "Nevertheless," it goes on, "evidence from science is crucial to help develop sound public health policy and mitigation measures." Measures are therefore needed to "ensure independence of experts and government advisory bodies, and safeguard against the politicization of science." There should be new clarity brought to the boundaries between science, scientific advice, and politics, and this should include "a transparent definition and demarcation of advisory versus decision-making roles." The mechanisms for rapid advice and evidence-informed decision-making in times of crisis should be strengthened to reduce delays between scientific information and decision-making. And an open dialogue is necessary between the public, scientific experts, and authorities about uncertainties and disagreements between decision makers and scientists, as well as among scientists themselves. The simple slogan adopted is to provide clarity about what is known, partially known, unknown, and unknowable.

Over and above their relevance for tackling the pandemic, these recommendations resonate across many of the issues that regularly generate difficulties for drug development everywhere around the world, and across all therapeutic categories or pharmaceutical forms. It is not so much in the originality of the prescriptions—many of which are already well-rehearsed—that the potential significance of this event lies, but in the context in which they are made and endorsed. Now the ideas are formally backed by G20 countries, heads of international and regional organizations, and representatives of global health bodies, after co-hosting by European Commission president Ursula von der Leyen and Italian prime minister Mario Draghi. If nothing happens afterwards, everyone will know who is to blame.