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

At a recent major European meeting on health technology assessment (HTA), the head of the French drug agency HAS said she was very much in favor of comparative evidence in drug evaluation. It was an observation that might have passed unremarked in other circumstances, since it is what would normally be a statement of the obvious from the head of a prestigious body whose work is based on evidence. But it was remarked, and it was remarkable. Because invocations of “evidence” have recently acquired a new resonance in Europe among those who are suspicious of what they see as a headlong rush to shortcuts in drug approvals. And the observation was all the more conspicuous because it came from a distinguished European figure who had just chaired the first meeting of the committee of 27 EU member states who will play a decisive role in the operation of the new European HTA system.

The following day, at a Brussels seminar on treatment optimization, the head of European Social Insurance Platform (ESIP), one of Europe’s biggest health insurance organizations said: “We need strong evidence for informed and timely decisions. It is important to strengthen cooperation on data requirements among decision-makers.” That remark came on the heels of ESIP’s publication of its proposals for the upcoming review of European drug rules, which emphasized the healthcare payer’s interest in ensuring “robust and timely evidence-generation” enshrined in the new legislation. ESIP considers “the gold standard” to be randomized controlled trials with an active comparator using clinically meaningful endpoints, and warns against the trend to shifting the assessment of safety, quality, and efficacy from pre- to post-marketing authorization. Conditional approval pathways should be limited, it says, and standards of quality and study design enforced, with increased transparency over their methodology.

The background to that seminar, according to AIM, another major grouping of healthcare payers, and one of the meeting’s co-organizers, is that “many therapies enter the market without sufficient evidence on their clinical benefit for patients,” creating “a challenge of ensuring sustainable access to efficient therapies.”

Such comments highlight a shift in attitude to innovation among many key healthcare constituencies in Europe. The heady days of a decade ago, when the likes of Hans-Georg Eichler—then the senior medic at the European Medicines Agency (EMA)—were advocating exploration of adaptive approvals, have given way to a more cautious approach. Many national health authorities in Europe harbor concerns that faster approvals on limited data are more of an industry-promoted Trojan horse for cutting corners on the way to the marketplace, rather than a rational method of exploiting new science and new data. The dilemma sits at the heart of the EU’s own thinking on how to update its pharmaceutical legislation. “The main source of evidence for the authorization of innovative medicines should remain robust clinical trials with suitable comparators reflecting the standard of care in the EU,” said the European Commission in its 2020 “pharmaceutical strategy” that launched the legislative process—despite its avowed aim “to revise the pharmaceutical legislation to adapt to cutting-edge products, scientific developments (e.g., genomics or personalized medicine) and technological transformation (e.g., data analytics and digital tools) and provide tailored incentives for innovation.”

Europe still has plenty of vigorous advocates of innovative approaches. The main drug industry lobby in Europe, The European Federation of Pharmaceutical Industries and Associations (EFPIA), told the EU in the latest consultation on the plans for legislation that it “must put in place a framework to accommodate tomorrow’s innovation, with the regulatory flexibility to adapt as and when the technology does.” The European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), a European grouping of drug firms with a heavy involvement in advanced therapy products, says adequate policy focus on drug development “has so far been prevented by unfavorable regulatory conditions.” And addressing specifically the prospects for the new EU HTA system, it says that “evidence generated outside of the strict randomized controlled trial design must be accepted such as real-world evidence (RWE), while post-launch evidence-generation should be routinely implemented.”

EUCOPE points out that orphan drugs and advanced therapies in particular, due to their smaller patient populations, rely on less conventional methodological approaches. The HTA discussions chaired by Dominique Le Guludec, the French official quoted above as a champion of comparative trials, provoked an instant response from supporters of a more liberal approach to evidence-generation. RWE4Decisions, a consortium of organizations with an interest in exploring the potential of RWE more extensively, publicly queried what guidance will emerge for the use of RWE in the upcoming joint HTA system in Europe, “since oncology and advanced therapies are priority areas, and often come with little evidence insofar as randomized controlled trials are not always possible.”

Over the next three years, as the EU puts its HTA system fully into place, and revises its pharmaceutical legislation, some of the current battle lines over acceptable or obligatory evidence may be softened by clearer definitions. But, at the same time, the discussion will become more confused because of the growing overlaps and distinctions between evidence for EU marketing authorizations and evidence for national decisions on pricing and reimbursement—a subject which deserves a separate article.

Articles

Battle lines being drawn among key healthcare constituencies, as discussions around new approaches to drug evaluation and decision-making heat up.

Bringing Evidence Back into Fashion in European Drug Rules

A new and highly effective form of reporting pressure has been brought to bear on clinical trial sponsors in Europe over the last five years—much of it attributable to just one man: Till Bruckner, the founder of TranspariMED. Almost single-handedly, Bruckner, a self-confessed “transparency and accountability nerd,” has campaigned to tighten up compliance with trial reporting requirements by drug firms and research institutions.

Laxity and non-compliance in this area has been an issue for years in Europe, resulting in 2019 in a European Medicines Agency reminder to all sponsors of their obligations to report on all trials, and more recently in the stringent rules on reporting introduced by the new EU clinical trial regulation that came finally into effect in January. Bruckner, based in Bristol, UK, says his motivation springs from his conviction that the “ongoing public health crisis” of failure to register and fully report clinical trials results in harm to patients, waste of taxpayers' money, and unjustified obstacles to the development of new treatments, vaccines and cures.

In a crowded international field of healthcare campaigning, the demonstrable impact of his own engagement has been largely due to his innovative use of social media, publicly and very visibly naming and shaming failings by individual sponsors, commercial and non-commercial, and by the national authorities responsible for enforcement. Successive studies—often in cooperation with larger and more established organizations he has induced to add their weight—have provided the evidence for Bruckner’s exposés: Transparency International, major consumer defense bodies and health-related civil society bodies like Cochrane, Health Action International and Universities Allied for Essential Medicines are among the allies he has recruited.

He also pays tribute to the EU Trials Tracker and the FDAA Trials Tracker—two online tools kept updated by Nicholas DeVito at Oxford University that he says make possible TranspariMED’s ratings of academic institutions in Europe and the United States. Without these trackers, he says, it would be impossibly time-consuming for a small campaign to compile ratings manually, or to compare national regulators' performance across Europe.

His work has, he says, convinced 23 of the 26 top medical research institutions in Europe to make trial results public. And most major non-commercial sponsors in Europe and the United States have become aware of their legal obligation to report their trial results, with some choosing to “get ahead of the curve and routinely report the results of all their clinical trials on registries. ”He is pleased to see the tighter reporting rules that the clinical trials regulation will impose on sponsors in Europe, claiming some small part in the lobbying that contributed to this outcome. His inquiries into national regulators’ performance in enforcing compliance are also starting to generate some valuable responses, he says. His work has also highlighted the risks of fragmented research efforts, and he is gratified to see the UK now asking research funders and sponsors to wind down clinical trials that have little chance of being completed, so as to free up resources for more promising research projects.

Bruckner explains his involvement in clinical trial reporting—an unusual focus for a PhD in politics and international relations with a professional background as an aid worker in Afghanistan and the Caucasus—as the consequence of an opportunity to pursue research in something of a neglected field. A chance engagement with AllTrials as a researcher on clinical trial transparency sparked his interest, and he set up TranspariMED in 2017 to fill what he saw as a gap in studies in the sector. He suggests that his rather different background has led him to employ unconventional approaches both to prosecuting his work and to drawing attention to the results.

One of his most recent tweets announced, “Great news from the last 

 update on clinical trial reporting in the US: Nearly all top pharma companies and universities now have a reporting rate of >90%.” He adds: “Sad exceptions,” naming four institutions: MGH Medicine, Icahn Mount Sinai, Brigham Womens, and the University of Virginia. In another recent tweet—one of his favored communication techniques for its efficiency and access—he congratulates Charite Berlin, Germany's largest medical university, because it has “hit a clinical trial reporting rate of 92%.” Equally impressive, he notes, are the Medical University of Vienna and KU Leuven, and he highlights others who are “now catching up.” But his interventions have also repeatedly excoriated backsliders and urged them by name to improve their performance.

Bruckner’s identified ‘”targets” are policy makers, regulators, research funders and research institutions, using his chosen tools of reports, blogs, submissions of evidence, FOI requests, media coverage, and direct lobbying. And he has won a profile both within the clinical research community and across European media.

But he remains modest, both about his resources and his current ambitions. His output is produced without external funding, and he receives only a monthly partnership stipend from a UK-based nonprofit, augmented by his own consultancy earnings (“no pharma or medical device clients”), he insists.

For the present, he still sees plenty to do in his chosen field and admits to no wider intentions in relation to broader health-campaigning agendas such as the issues around the actual conduct of trials, or questions over medicine pricing. Declining to offer any broader views on EU or US health policy, he says, with the characteristic restraint of a researcher, “I like to go in deep rather than spread myself thinly.”

The reporting of one man in Europe is changing accountability with compliance.

Naming and Shaming is Driving Improvements in Reporting of Clinical Trial Results

The coming into force of the EU’s Clinical Trials Regulation (CTR) early this year “represents a major milestone for clinical research in the EU,” according to the just-published annual report for 2021 of the European Medicines Agency (EMA).

 And it should work well for everyone, the agency implies, suggesting that the engagement of national authorities and trial sponsors throughout the development of the legislation will ensure that the new system of harmonization of assessment and supervision processes for trials is in line with user needs. It is backed up by new monitoring and coordination tools for a companion regulation on clinical trial safety that came into effect on the same date, stipulating how member state authorities should cooperate on safety assessment on the basis of the clinical trials regulation.

Clinical trials are also highlighted in the report in relation to the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in late 2021 with the aim to “transform how clinical trials are initiated, designed and run,” building on “the momentum of the CTR to further promote the development of high quality, safe, and effective medicines.” It is designed, says EMA, to reinforce the European environment for clinical trials while at the same time keeping protection high for trial participants and ensuring data robustness and transparency. What is also clear, although less explicit, is that ACT EU is an attempt to win back studies that are increasingly shifting abroad—or, as EMA more obliquely puts it, “to further develop the EU as a focal point for clinical research and to better integrate clinical research in the European health system.” Ten priority actions identified for 2022/2023 include enabling innovative trial methods, modernizing oversight and supporting the modernization of good clinical practice. Another priority actions will be to establish a multi-stakeholder platform “where all voices, including those of patients, can contribute to enabling better clinical research.”

Elsewhere in the annual report (alongside extensive coverage of EMA’s involvement in tackling COVID-19), a section provides an update on EMA plans to build up European regulatory capability and capacity “to deliver robust evidence for benefit-risk decision-making.” Progress during 2021 included projects to strengthen scientific advice on products under development, support to marketing authorization assessments, and delivery of expert methods advice and data analysis for medicines already on the market. DARWIN EU, the EU’s nascent Data Analysis and Real-World Interrogation Network now being developed to provide real-world evidence from across Europe on diseases, populations, and the uses and performance of medicines, is intended to provide European regulators with data applicable for decision-making throughout the life of a medicine. EMA will request studies to support itsscientific evaluations and regulatory decision-making, providing a crucial link between real-world data studies and benefit-risk decisions. An advisory board is already functioning composed of regulators, patients and healthcare professionals, and payer and health technology assessment organizations.

The “Big Data Steering Group,” set up by EMA and national authorities, is also acting on the agenda it set itself with its work plan through to 2023, including increasing the utility of big data in regulationby boosting data quality and study methods. Its eleven priorities relate in particular to data standardization, artificialintelligence, and real-world meta-data.

The report, with its stilted formal language obligatory in set-piece publications of this nature, provides some signposts to EMA priorities, but fails to convey the vigorous sense of ambition and even excitement that many of its officials display in person in discussing the agency’s future. Nor of course does it dwell on the acute difficulties that the organization and its staff have faced during the twin challenges of COVID and the forced removal from London, or on the real funding challenges it now faces as additional responsibilities are heaped on it by the EU (and more recently by a demanding public). The consequences of all of that unspoken ambition—and exasperation—will be more clearly revealed in what happens in the coming years rather than in a formal report on what happened last year.

https://www.ema.europa.eu/en/documents/annual-report/2021-annual-report-european-medicines-agency_en.pdf

But despite showing a tightening of focus on clinical trials and evidence, the annual report doesn’t paint the full picture.

New EMA Report Highlights Milestones and Momentum

As concerns over the risks of future international health crises begin to replace the crisis-mode responses to the COVID-19 pandemic, the European Medicines Agency (EMA) has published an update of its 10-year-old guideline on development of antimicrobials.

 reflects scientific advice that has emerged over the last decade, including modified recommendations for primary endpoints, primary analysis populations, and non-inferiority margins in trials.

As EMA says in its consciously moderate language—a sober contrast to some of the more attention-grabbing statements that have attempted over recent years to trigger concern over anti-microbial resistance—“in the face of increasing problems posed by bacterial resistance, there is a pressing need for new antibacterial agents suitable for treating infections in patients with few remaining therapeutic options.”

The document also clarifies recommended clinical programs for antibacterial agents expected to address an unmet need and for combinations of beta-lactam agents with beta-lactamase inhibitors. Guidance has also been added on clinical trials to support treatment of uncomplicated urinary tract infections and uncomplicated gonorrhoea. The document offers descriptions, too, of situations in which single pivotal trials may be accepted to support infection-site-specific indications.

EMA emphasises the international validity of the document, which takes account of “discussions between regulators in the EU, United States, and Japan. There is a need to ensure that each clinical trial conducted can be designed to meet the requirements of multiple regulatory agencies, it points out, in order to facilitate clinical development programs for new antibacterial agents and to support modifications to the uses or regimens for licensed agents.

According to the new guidance, a non-inferiority trial design is acceptable when there is a licensed treatment for the infection under study for which the magnitude of the treatment effect over placebo is known or can be estimated from existing data. The choice of active comparative regimen “is critical to the overall validity of non-inferiority trials”, and the regimen selected should be considered one of the best available treatments based on clinical trials, medical opinion, infection type-specific treatment guidelines, and the anticipated prevalence of resistance to the comparative agent at the trial sites.

The selection of the non-inferiority margin should consider the need to indirectly demonstrate superiority of the test agent over no antibacterial therapy for the infection under study and how large a difference between the test and reference treatments could be considered clinically important, EMA advises. And it offers a warning over the use of historical data, which “may be used to estimate the no-treatment effect,” but where “the relevance of these data to a prospective randomized trial design reflecting contemporary medical practice may be questionable.” It offers the example of general patient management changes “to such an extent since the historical data were obtained that constancy cannot be assumed.”

A non-inferiority margin of -10% is recommended for primary analysis in trials of treatments for acute bacterial skin and skin structure infections, community-acquired pneumonia, and complicated intra-abdominal infection, but 12.5% in the case of hospital-acquired pneumonia and ventilator-associated pneumonia.

https://www.ema.europa.eu/documents/scientific-guideline/guideline-evaluation-medicinal-products-indicated-treatment-bacterial-infections-revision-3_en.pdf

EMA’s new release factors in scientific advances, clarity on trial designs.

Updated Guidance on Clinical Trials for Antimicrobials

The protection of patients is being undermined by the European Medicines Agency’s (EMA) renewed reticence about releasing clinical data for independent review, according to an influential non-profit drug monitoring organization, which sees recent shifts to a more liberal approach falling victim to drug industry pressure.

Since it was set up in 1995, the EMA had come under attack from health campaigners, academics, and some prominent politicians over what they described as its excessive secrecy with the clinical trial data underlying the decisions the agency takes on drug approvals. A decade ago, when Guido Rasi took over as EMA director, significant relaxations and wider access were hailed as real progress, even by the—highly critical—EU Ombudsman. But the improvements are now being rowed back, says 

, the Paris-based publisher of independent drug reviews.

EMA’s transparency policy is “marred by too many failings,” it says in a lengthy analysis it published in May.

 It says secrecy has persisted and even become more pronounced in some areas, with new processes increasing response times with a queuing system, provision of documents staggered over months, and a delay to allow drug companies to institute legal proceedings when they disagree with the disclosure of their documents. Under the new processes, the identity of applicants for release of data can also now be disclosed to the pharmaceutical company that produced the document requested, 

 adds, suggesting that this risks undue pressure on its operations.

, when pharmaceutical companies have brought cases before the European courts to prevent EMA from releasing documents relating to marketing authorizations, EMA has refused to provide documents requested by 

, citing the existence of these legal proceedings as grounds for its refusal, “even when our requests were unrelated to the case.” The EMA’s intention in refusing to disclose these reports was to protect the commercial interests of the pharmaceutical companies that produced them, and to prevent the theoretical risk that a competitor could use the data as a basis for developing a similar drug. But the EU Ombudsman found the argument that disclosure of these clinical study reports could undermine the companies’ commercial interests to be unfounded, argues 

. The Ombudsman’s opinion led EMA to reform its transparency policy from 2011.

But EMA “struggled to meet its obligations on transparency,” and now the implementation of its policy of proactive disclosure appears to have stalled, too. The “major advance” achieved when EMA began spontaneously publishing large quantities of clinical data from marketing authorization applications in 2016 has been blunted by the opportunity given to companies to black out portions of these documents before their publication, including data from clinical study reports. On occasions, as much as 90% of the document has been so redacted. EMA has been particularly secretive toward 

, it alleges, systematically refusing to disclose major documents containing clinical data produced by pharma companies, as well major documents on adverse effects such as vital data in periodic safety update reports.

Hopes that EMA’s new transparency policy would provide wide access to clinical data from marketing authorizations proved over-optimistic, as disagreements between the agency and pharma companies over some or all of the reports disclosed have ended up before the European courts, and the disputes “have made EMA less transparent, at least in its dealings with 

’s case is built upon what it calls the right of European citizens to access clinical data related to marketing authorization applications. “This is a right that helps better protect patients,” it argues. The right of access to documents held by European institutions is a general principle in European Union law, it says. “Transparency is supposed to be the default position for European institutions, and non-disclosure of data the exception.” EMA is required to apply these principles, it insists.

The failings are of a scale that should justify an official inquiry to analyze the causes, according to 

, which expresses the hope that an inquiry would trigger renewed attention from the European Parliament and lead to appropriate remedies. What Prescrire wants to see is additional resources for EMA so it has no excuse for delays in meeting its transparency obligations. It also wants “strict oversight and close monitoring” of any redactions made to released documents. And it wants “fair consideration of applicants with no ties to industry, such as 

It blames the pervasive trend among drug regulatory agencies to withhold information on “a weak culture of transparency” and “fear of legal challenges by pharmaceutical companies.” The 2014 Clinical Trials Regulation, in force since the beginning of this year, included a number of advances in transparency, requiring EMA to publish clinical study reports once marketing authorization has been granted, via a publicly accessible database maintained and controlled by the agency. This went live in late January, “but we fear that the transparency requirements set out in this regulation will be undermined,” admits 

. The rules still allow pharma organizations to redact any data they consider commercially sensitive. “EMA must show that its policy is in line with the need to keep patients safe, rather than pretending to be transparent while allowing pharmaceutical companies to hide clinical data,” concludes 

https://english.prescrire.org/en/26A06BA9AEE5C0FDC137141EB68F92D2/Download.aspx

Just-released analysis by Prescrire contends that the agency “is backtracking on commitments to clinical data transparency.”

Report Admonishes EMA Efforts to Reform Trial Transparency 

It's three months since the European Union's clinical trials regulation came fully into force (and eight years since the legislation was adopted), but knowledge and understanding of the new rules is still—to say the least—patchy, and compliance, consequently, far from guaranteed. The European authorities are, however, taking a softly-softly approach to getting the clinical trials community up to speed, and since January the European Medicines Agency (EMA) has been providing weekly titbits of information and advice about the regulation, in order to woo trial sponsors into learning to live with it. The metrics of this service provide an interesting surrogate endpoint for measuring engagement of those who need to know.

The so-called Clinical Trials Information System (CTIS) was launched on Jan. 31, when the legislation entered into force. Sponsors could, from that date, log in to use CTIS to draft and submit new clinical trial applications, and could also transfer into CTIS trials that were initiated under the now superseded Clinical Trials Directive. It had a slow start. Over the first week, the number of logins to CTIS was just 1,260 a day, and just 53 draft applications were made, with just one actual application submitted—small beer in a region where some 4,000 clinical trials a year are conducted, according to the EU.

However, by the following week, logins were running at 2,000 a day, 87 applications were in draft form, and there were three submitted applications—one of which was the first multinational clinical trial in the system, and also the first trial to use CTIS to transition from the regime of the old directive to the new regulation. By late February, there were 4,000 logins a day, 185 draft applications, and seven applications submitted—including the first by a large pharmaceutical company. In addition, three of the applications passed validation by the regulatory authorities—the first step in the clinical trial application evaluation process in CTIS, when a check is made that the application dossier documentation is complete. The trend continued: as of mid-March, over 6,000 logins to CTIS had been recorded, more than 220 applications were in draft,and14 clinical trial applications for assessment by the regulatory authorities had been submitted—most of them from academic sponsors.

By early April, with numbers still rising steadily, the first clinical trial was authorized through the new system. This trial had been ongoing under the clinical trials directive and was transferred to the regime of the clinical trials regulation. And in line with the provisions of the CTIS, details were publicized indicating that it was a randomized Phase III trial in Sweden of vasopressin and steroids in addition to adrenaline in cardiac arrest. The sponsor was Tiohundra AB, a Swedish healthcare company listed as "non-commercial." CTIS also provided details on the inclusion and exclusion criteria for recruitment, primary endpoints, the full trial protocol, the planned number of subjects, the trial sites, the informed consent form, and the CV of the investigator. The information is open and accessible to all—patients, healthcare professionals (HCPs) and clinical researchers—and equally to the general public.

One of the key elements of CTIS is the additional transparency it brings to trials. Part of CTIS is a searchable database (euclinicaltrials.eu) that is open to patients, HCPs, and the general public. Patients can find clinical trials that are recruiting participants within their country and therapeutic area of interest and can obtain sponsor contact information to request more information about joining specific trials. And when trials have ended, the sponsor must upload a summary of the results of the trial in lay language, making clinical trial results easily understandable to the public.

Late April saw a continuing rise in engagement, with 13,000 logins a day, 366 draft applications, 31 submitted applications, and one more authorized application—this time for a completely new trial rather than a transition from the previous regime. And, again, details were listed on the public section of the CTIS website.

This time the trial is a prospective Phase II study of calcium electroporation in combination with irreversible electroporation and immunotherapy in patients with pMMR metastatic colorectal cancer, conducted by Zealand University Hospital in Denmark. It is described as an investigator-initiated study involving CE approved devices and an EMA approved drug, to determine the efficacy and safety of Ca-EP performed concurrently with IRE followed by a PD-1 inhibitor (pembrolizumab). CTIS also lists eight secondary endpoints, and recruitment is due to start in June.

The CTIS listing provides for similarly public information (as it becomes available) on unexpected events and urgent safety measures, as well as summary results, a lay person’s summary, and clinical study reports. Reports on any corrective measures and the results of inspections are also provided for.

As from May, monthly reports will replace the weekly bulletins that EMA has been publishing in order to familiarize the clinical trials community with the new system, to offer alerts to obligations and rights, and to track the evolution of take-up. But EMA will continue to provide the range of advisory services that have been set up to ease the implementation of the new system.

And for anyone apprehensive about the extent of information being divulged to the public, some reassurance—or at least clarity—may be found in provisions that allow sponsors to upload “for-publication” and “not-for-publication” versions of certain documents, including the protocol and the investigator brochures so as to protect personal data and commercially confidential information.EMA is currently preparing guidance on this protection in CTIS, and has published a draft 

 for open consultation, with a deadline of Sept. 8 for comment.

EMA continues to familiarize industry with new clinical trial legislation.