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A Staff Working Document on EMA’s fees published by the EU Commission

Giuliana Miglierini
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A Staff Working Document on EMA’s fees published by the EU Commission

The consultation launched by the European Commission on the Inception impact assessment on the evaluation of the fee system of the European Medicines Agency (EMA) closed on 16 October. The Impact assessment is part of the Staff Working Document released by the Commission on its site. EMA’s fee system has been generally considered efficient and effective, but there are opportunities to make it more flexible and sustainable in order to adapt to future regulatory developments, says the Commission.

Open issues call for a review of fees

The entry into force of regulation EU 2019/5 on the financing system used by EMA and of regulation EU 2019/6 on veterinary medicines are the two main causes that pushed the Commission to re-evaluate the current framework for regulatory fees. 

The veterinary sector, in particular, needs urgent intervention in view of the entry into force – in January 2022 – of the new EU 2019/6 regulation, which include activities currently not covered by EMA’s fees. Possible fluctuations of the financial incomes of the European Medicines Agency and the complexity of the current remuneration system are among other reasons to review it. According to the report published by the Commission, many fees might be not aligned with real costs, both in excess (i.e. for variations) and in defect (i.e. for the initial submission of the request of a new marketing authorisation). Fees specific to some kind of activities are also lacking, for example in relation to paediatric investigation plans or orphan designations. The same applies also to activities run at the national level by local competent authorities. 

According to the Commission, a more coherent approach would thus be needed at the level of the two regulations governing fees and pharmacovigilance fees, both at a central and national level. Many are the possible options envisaged in the Staff Working Document to reach a better financial sustainability for EMA’s and local regulatory activities, paying also attention to the provision of services of different complexity or to particular categories of products, markets or applicants which may be subjects to special fees (i.e. SMEs or veterinary medicines). 

The options on the table

The Inception Impact Assessment presents three different levels of options to simplify and better align EMA’s fees system, each of one characterised by many secondary alternatives. 

The easier choice would simply actualise costs and re-align fees requirements to the two above mentioned regulations. Under this entry, fees for the renewal of the authorisation of veterinary medicines would be due just in some specific cases, as the authorisation itself will assume undefined duration. The same kind of fees as today will apply, with a very limited revision just in some specific cases. 

New fees or charges in the veterinary field should also include costs for the reporting of adverse effects and for the process of signal management, as well as costs to maintain authorisations, for pharmacovigilance, to manage the European databases for products, pharmacovigilance and production, import and distribution. Under this option, fees and charges should also reflect costs to collect data on content of antimicrobials.

National competent authorities (NCAs) remuneration would remain the same as today (full fees), without any modification for human medicines. This choice assumes that veterinary fees calculated on costs are lower than those for human products. The Commission also proposed different options for the possible modification of reductions and incentives. 

The other options impact also on human medicines

The second option would act on both human and veterinary medicines, without changes of the general framework. Each single fee would be recalculated based on a weighted media taking into account the actualisation of both costs and time. NCAs remuneration would also be recalculated on the basis of the different procedures and costs. The same as above would apply to the veterinary sector. 

A new structure for fees and charges would be created to include specific items related to EMA’s committees for orphan and paediatric medicines. Incentives would be linked to the specific legislation that applies to each case, while financing would result from a redistribution of costs on other sources of economic return for EMA. This would also include redefining the distribution of incentives between the central European Agency and national competent authorities. The document details several possible alternatives to reach this goal. 

Under the third option – again relative to both human and veterinary medicines – an overall simplification and a better efficiency of the fees system is foreseen. Many are the Commission’s proposals, for example fees specific for not-pharmacovigilance procedures of centrally authorised medicines (CAPs) might be included within a single annual fee due for each CAP. Complex procedures (i.e. line extensions) would be excluded from this possibility. Pre-authorisation and inspection fees may also be simplified, and a flat fee may be created to include the great part of activities in the field of pharmacovigilance, both at a central and national level. A full recalculation for veterinary fees and NCAs remuneration would be also run.

The possible impact

According to the Commission, no macro-economic impacts are expected from the review of the fees system, but some effects on regulatory costs to be afforded by the pharmaceutical industry may be possible. EMA and NCAs may benefit from a more fair fees framework and a more predictable financial impact, leading to lower fluctuations of EMA’s budget and a lower administrative burden. The higher remuneration of NCAs may also result in the possibility for national authorities to better support companies, thanks to a better efficiency of regulatory activities at the European level. The Commission also expects an indirect social impact, due to the faster access of patients to new treatments consequent to the increased regulatory efficiency. 

Science Europe’s report on interdisciplinarity of research

Giuliana Miglierini
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Science Europe’s report on interdisciplinarity of research

Complex questions are at the core of next generation scientific discoveries and innovations: a true challenge for researchers, that requires an interdisciplinary approach to find creative and disruptive solutions. Interdisciplinary research integrates many different skills within the single research team – from medicine to informatics and engineering, for example; but it may sometimes result quite difficult to merge the different points of view. This difficulty also exists for the evaluation of the interdisciplinary scientific project, both following the application for a new call and afterwards, the outcomes of the funded activities. 

Interdisciplinarity of research has been at the centre of the third Symposium organised by Science Europe, the association representing the main European funding institutions (find here the final report). “Interdisciplinarity is the norm: disciplines have to argue why they exist”, said Marc Leman, member of Science Europe’s Scientific Advisory Committee, closing the Symposium.

Many open issues waiting for solutions

The lack of experts with sufficient expertise to peer review interdisciplinary research projects has been identified during the debate as one of the major issues waiting for sustainable solutions. Other priorities to be addressed include the lack of common standards and criteria for this evaluation, and the possible negative impact that may result on the progress of the academic career of interdisciplinary researchers. 

“Interdisciplinarity is not new, but it has gained increasing traction in the context of the global transformation of societies, the Sustainable Development Goals, and the ‘Mission-oriented research’ concept of the European Commission”, said Science Europe’s Head of Research Affairs, Bonnie Wolff-Boenisch. According to her presentation, there would still exist some confusion about how to effectively collaborate and evaluate projects. Interdisciplinarity itself would be a good subject for research, as it is characterised by a quite elusive nature. “To properly organise and fund interdisciplinary research, there need to be more tangible elements than principles and unexpected results”, added Søren Harnow Klausen, member of the Scientific Advisory Committee of the association. 

A recognition of the different levels and types of multidisciplinary research may represent a first step towards the optimisation of its impact. Four elements have to be considered fundamental to reach this goal, according to Gabriele Bammer, professor at the Australian National University, starting from how the new interdisciplinary knowledge is created from what is already know at the level of the single disciplines. A lack of familiarity with best practices and critical issues typical of each discipline, the dimensions of the integration compared to the number and complexity of each scientific field involved in the project and the need the implementation of the research outcomes should be integral to research itself, with definition of the final targets (governments, industry or society), are other factors impacting on the current potential of interdisciplinarity. 

“Funding Agencies have a leadership role in making interdisciplinarity a reality”, said Bammer. The creation of high level organisations – as peers’ colleges, professional associations, etc. – responsible to reach a common consensus on shared frameworks and coordination models has been suggested as a possible way to overcome the current fragmentation of interdisciplinary research. 

The role of funding institutions

A list of nine non-exhaustive measures that may be exerted by funding institutions in order to increase the impact of interdisciplinarity in research has been discussed during the Symposium. These include long-period investments and vision, the creation of a strong leadership able to recognise experience at the level of project evaluation, and attention to the quality of the methods used to be paid by peer-reviewers. This last action should also involve the use of more uniform criteria for the preparation of the section relative to interdisciplinary methods during the drafting of projects or scientific papers. 

The education of multidisciplinary young scientists and their career are other key points that should be considered to better sustain the diffusion of interdisciplinary research, says the report. “Interdisciplinarity as it exists can be accommodated by research funders using existing mechanisms, but for truly interdisciplinary sciences to flourish, it would need more fundamental and structural changes in the research and education systems”, said Benjamin Turner, representing the European Research Council.

The examples already available

Many are the examples already activated in different European countries to improve the efficiency of interdisciplinary research that have been discussed during Science Europe’s Symposium. According to Uwe von Ahsen, Head of Department Strategy & Development National Programmes of the Austrian Science Fund (FWF), the last few years saw an increasing trend towards team-oriented research and increasing interdisciplinarity (15%) according to discipline classification, even if the approval rate of interdisciplinary project applications is slightly lower with respect to other programmes. “Pilots for interdisciplinary research provide learning for all stakeholders involved regarding definitions and scopes of interdisciplinarity”, said von Ahsen.

The ERC’s Synergy Grants, for example, are funding teams of two-four Principal Investigators interested in working together to tackle ambitious research problems. Evaluation of the proposals is made by the ERC on the sole criterion of scientific excellence, and taking in consideration also the additional meaning of outstanding intrinsic synergetic effect.

The Academy of Finland (AKA) is using algorithm-based analysis to evaluate multidisciplinarity in proposals. Examples of application of this new method include both funding of long-term programme-based research where top-down multidisciplinarity is required and support to academy programmes and projects aimed to improve the impact of Finnish science and bottom-up research. 

In Austria, the FWF’s Young Independent Research Groups (YIRG) is a postdoc programme specifically targeted to the creation of innovative, interdisciplinary teams, where early-career postdocs are given a medium-term opportunity (4 years) to run interdisciplinary research collaboration on a complex, innovative topic with a mixed team of three-to-five researchers.

Good communication is important

Communication skills are not a secondary point to be addressed while planning interdisciplinary projects, according to Science Europe. “It is important to openly communicate indirect commitments that matter to project decision-making in interdisciplinary research projects”, said Michael O’Rourke from Michigan State University. 

Communication includes relational aspects at the basis of the sharing of information and interpersonal exchanges, that can be affected by cultural, value and language bias across the different disciplines. A robust eco-system for inputs from the single disciplines would thus be needed, according to O’Rourke, to make available coherent answers to the interdisciplinary team on how to conduct research and to better define expectations. 

The new, interdisciplinary knowledge should be stored overcoming the silos fragmentation typical of many scientific areas. Education is also very important, and it should include competences on new digital and artificial intelligence technologies. Deep learning algorithms are expected to play an increasing role within interdisciplinary research to find solutions for complex real-world problems. The Chair of Science Europe’s Scientific Advisory Committee, Ola Erstad, made the example of Finland and Norway, where an holistic approach based on deep learning is gaining an increasing role within school curricula. 

Verification, review, and check: approximation and implementation in terms of data integrity

Giuliana Miglierini
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Verification, review, and check: approximation and implementation in terms of data integrity

Data integrity is a central requirement to validate the production of pharmaceutical products according to the good manufacturing practices (GMPs). According to the World Health Organization’s Guidance on Good Data and Record Management Practices, “data integrity is the degree to which data are complete, consistent, accurate, trustworthy and reliable and that these characteristics of the data are maintained throughout the data life cycle”.

Data integrity was first introduced into regulatory requirements in 1971: the UK’s “Orange Guide” asked that copies from master records should avoid transcription errors and were carrying initials of people who performed each activity. A record of the history of each batch had also been provided. The concept entered European GMPs in 1989, establishing that each alteration or correction of data had to be signed, with specification of the reason and allowing reading of the original data. EU GMPs also defined that records must be completed at the time the action is taken, detailing also the name of the person in charge of performing and checking the action. According to the expert of pharmaceutical development Gilberto Dalmaso, almost 500 warning letters have been issued by the FDA in the last few years reflecting deficiencies in data integrity; many letters released by the UK authority MHRA in 2015 also involved data integrity lapses.

An article published in the American Pharmaceutical Review shows that the number of warning letters which include data integrity issues greatly increased in the period 2014-2018, from 18 to 69 respectively, while far less pronounced was the increasing in the number of letters without data integrity (5 in 2014 vs 22 in 2018).

What is data integrity

GMPs do not define exactly common terms – such as verify, review and check – that are typical of data integrity controls. The issue has been addressed in an article by James Vesper published on Pharmaceutical Online.

Another article signed by Chris Brook on Digital Guardian discusses the distinctions between considering data integrity as a state or a dynamic process. When data integrity is considered a state, explains Brook, the data set has to be valid and accurate; measures and other information are used to demonstrate this validity and accuracy when data integrity is considered as a process, and they have to be stored in a database. The article defines many possible sources for rejecting data, such as human or transfer errors, informatics viruses or malware and hacking activities, hardware problems or physical compromise to devices. Verification and checking of data integrity allow to exclude all these possible threads, thus confirming that the acquisition and transfer of data occurred correctly; data can thus be considered reliable and trustworthy. 

The lack of clear definitions

James Vesper discussed the lack of a unique definition for the above mentioned terms governing data integrity. The GMPs released by the authorities of different geographical areas (US, EU, Canada, UK or PIC/S) just ask for a confirmation that these activities were run correctly during pharmaceutical manufacturing. Industry is completely free to decide how to apply these concepts, and data integrity is then subject to the inspection activities carried out by regulators. 

According to the classification proposed by Vesper on the basis of the most common industrial best practices, the “verification” step corresponds to the presence of a witness monitoring in real time through direct observation that all critical manufacturing activities are performed correctly. This “4 eyes” observation can be also referred to the CFR requirement that all manually recorded information needs to be verified by a second signatory.

The “review” step usually refers to controls run by a second person on documents and technical procedures in order to verify they reflect all needed requirements. These are better evaluated during the “check” step, when the specific activity is posed under strict scrutiny to confirm it complies all regulatory requirements. Both the checking and reviewing are not necessarily real-time processes, and can involve repetition of certain activities by a second person in order to confirm they have been run correctly (“double check”). 

QRM to guide data integrity activities

Quality risk management (QRM) has become the new standard for pharmaceutical quality; the principles identified in the ICH Q9 guideline can be used to guide all activities related to risk assessment and management also in the field of data integrity. 

As reported by the Vesper’s article, another useful reference to plan the verification and review process is represented by the guideline published by the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The document highlights the critical records that should be considered during the exercise, i.e. those documenting critical steps within batch records, batch production records of non-critical process steps or laboratory records for testing steps. Each of these records requires a specific approach to verification, review and checking, which should be described by local standard operating procedures (SOPs).

On this basis, James Vesper suggests a possible approach to confirmation of data integrity that can be flexible in terms of the rigor applied to the exercise and to the relative criticality of each action, event or data considered. Under this hypothesis, the review step should be carried out “after-the-fact” by a second person in charge to examine data and evidence to confirm everything has been done correctly. The checking should involve the direct observation of the “result” of a certain action or event, while the verification should be run through the real-time direct observation of events or by a second, independent performance of the task. And because many tasks are now automated, humans should also perform a review of machine-generated records/data and qualify all equipment and devices used in manufacturing operations in order to control the correct actions were incorporated within their functions. 

MedTech Europe asks a better devices’ interoperability to pursue digital health

Giuliana Miglierini
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MedTech Europe asks a better devices’ interoperability to pursue digital health

Lack of interoperability is one of the main barriers to be overcome in order to achieve full implementation of digital health technologies and services, says MedTech Europe. The association representing the industry of medical devices has published a call to action position paper to improve interoperability, on the basis of four different targets: the development of a clear leadership and guidance by governments and healthcare authorities, the option of common standards and mandate adherence to them in all procurement activity run by payers and providers, investments from the EU Commission and member States to continue building digital health infrastructures and solutions, and convergence on interoperable data systems also from other types of industries, i.e. consumer devices and IT companies. “Patients will benefit from better interoperability of medical technologies through better quality of care and improved outcomes”, said Serge Bernasconi, CEO of MedTech Europe.

An ecosystem to inform and empower citizens, healthcare professionals and providers

The data ecosystem proposed by MedTech Europe should be fully compliant to applicable privacy and data protection principles and allow for the free and secure movement and sharing of health data across borders and vendors. The ultimate goal is to better inform patients, citizens, healthcare professional and providers, payers and authorities and to provide safer and more integrated services.
The initiative embraces the widely diffused patient-centric vision, and is expected to improve remote monitoring and self-management of chronic conditions, thus reducing the need to visit medical centres while increasing the availability of real world data to be analysed using the new tools made available by artificial intelligence.

Advanced connected devices and in vitro diagnostics are critical to achieve a better sustainability of healthcare, but their full implementation would require an improvement in interoperability, says MedTech Europe in its position paper. Interoperable devices and software are able to exchange information and use it for the correct execution of a specified function without changing the content of the data. They can also communicate with each other, and work together as intended, according to the definition given by the Medical Devices Regulation.

Overcome the current fragmentation of data

Data silos are still a strong reality in many cases, reducing the ability to share healthcare data between different stakeholders within the digital ecosystem. A situation resulting from market fragmentation, according to the “Blueprint – Digital Transformation of Health and Care for the Ageing Society in 2016” published by the European Innovation Partnership for Active and Healthy Ageing (EIP AHA).
MedTech Europe’s suggestion to overcome these barriers is to invest in the creation of open platforms and international widely adopted standards to develop digital health applications and devices, on the example of the harmonised principles of individual control over personal data and the importance of patient consent introduced with the adoption of the EU’s General Data Protection Regulation in May 2016. The industrial association endorses the adoption of the Electronic Health Record Exchange Format released by the EU Commission on 6 February 2019, and the specifications and profiles released by DICOM (Digital Imaging and Communications in Medicine), HL7 (Health Level 7), and IHE (Integrating the Healthcare Enterprise) initiatives.
Other proposed actions to overcome fragmentation include a better access of patients to their healthcare data – with the possibility to opt for their sharing with healthcare professionals -, the building of electronic health record (EHR) systems and other infrastructures for their management and conservation, and the facilitation of cross-border exchange of health data based on open, international standards. According to MedTech Europe, this effort should also support investments in digital health infrastructures, an essential feature of the value-based healthcare models. Small and medium size companies may also benefit from a wider adoption of interoperable systems, as they are often first line players in the development of new healthcare technologies, services and applications.

Latest advancements in the EU-US Mutual Recognition Agreement for Pharmaceuticals

Giuliana Miglierini
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Latest advancements in the EU-US Mutual Recognition Agreement for Pharmaceuticals

The recognition of Slovakia by the FDA as the last European country needing to be approved within the US-EU Mutual Recognition Agreement (MRA) came on 11 July 2019; the agreement was signed just a year before, in July 2018, by US’s president Trump and Jean-Claude Juncker representing the EU Commission.
MRA applies by now just to human medicines, but the authorities of the two continents will continue to work to expand it also to veterinary medicines, human vaccines and plasma derived medicinal products. “The MRA means that, on both sides of the Atlantic, the authorities in charge of medicines can now rely on inspections results to replace their own inspections. Today, the US Food and Drug Administration has completed the capability assessments of the 28 EU competent authorities, the result of five years of close transatlantic cooperation” said Vytenis Andriukaitis, leaving EU commissioner for Health and Food Safety.

Comparable procedures to run GMP inspections

The range and relevance of the MRA can be easily understood while considering that 80% of medicinal products marketed world-wide are produced either in the EU or US, on the basis of the adoption by pharma companies of strict good manufacturing practices (GMPs) governing all the steps of the productive processes. The implementation of the agreement to share GMP inspection results is based on the assumption that the procedures used by regulatory authorities (centrally or at the national level) are also comparable. The terms of the MRA asked the FDA to run a formal assessment of the procedures used by each European national competent authority, an exercise now come to an end with Slovakia.

The avoidance of duplicate actions in the inspection of a specific pharmaceutical manufacturing site will make possible to reinvest the financial resources to expand the number of the inspected sites in other large producing countries. In the first phase of implementation, the agreement applies only to inspections conducted in the respective territories, and not in extra-EU or extra-US countries (even if this possibility is contemplated by Article 3.1 of the GMP Sectoral Annex to the MRA). But this provision, warns EMA in a just published Q&A document, is not yet active and further guidance will be released in future to guide this sort of activities. Starting from 1 November 2017, European NCAs are not duplicating inspections already run by the FDA, and the US agency is expected not duplicate inspections run by a recognised EU authority. The MRA exceptionally reserves both the EU agencies and FDA the right to inspect in each other’s territory at any time.

Human medicines included in the MRA are comprehensive of medical gases, herbal products, homeopathics, biological medicines, allergens, pharmaceutical intermediates, active ingredients and bulk drug substances. Veterinary medicinal products are expected to be included in the MRA by no later than 15 December 2019, while the inclusion of human vaccines and plasma-derived products will be considered just after 15 July 2022.

The batch testing waiver

Another fundamental outcome of the MRA to become fully active after the final approval of all EU competent authorities is the batch testing waiver (Article 9 of the GMP Sectoral Annex): for a US manufactured medicinal product imported in the EU, Qualified Persons (QPs) from the European importing companies will no more need to repeat quality controls already performed in the United States. QPs still have to verify that the product was manufactured and the controls have been carried out in the US. Furthermore, according to the MRA, each batch should be accompanied by a batch certificate issued by the manufacturer and attesting the compliance with requirements of the marketing authorisation, and signed by the person responsible for batch release.

A long way to increase collaboration

The initial working to prepare content of the MRA was started in 2014, when teams from the EU Commission and EU national competent authorities, EMA and the FDA started auditing and assessing the respective supervisory systems. On June 2017 the EU Commission was the first to recognise FDA’s capacity and procedures to carry out GMP inspections at a level equivalent to that of the European Union. This was followed on November 2017 by the initial recognition by the FDA of the capability of a first set of eight European countries (Austria, Croatia, France, Italy, Malta, Spain, Sweden and United Kingdom).
Another mutual recognition agreement was signed between the EU and US in 1996, which included a Pharmaceutical Annex, but it was never fully implemented. This Annex formed the basis of the 2017 new agreement, together with results of several pilot initiatives on GMP inspections.

Regulatory decisions from EMA and FDA are well aligned

EMA and the FDA are aligned in more than 90% of marketing authorisation decisions for new medicines, says a joint study recently published in Clinical Pharmacology & Therapeutics. The analysis – the first of its kind – compared decisions on 107 new medicine applications received by the two agencies between 2014 and 2016.

Different opinions on the efficacy of the proposed new treatments has been the main cause for divergence in the final approval decisions reached on the two sides of the Atlantic. Some differences were also observed in the assessment of clinical data, often due to the different timing of their submissions: in general, applications to the FDA were submitted at a first instance, and the subsequent application to EMA may include data coming from additional clinical trials or, particularly for oncology medicines, more mature data from the same clinical trial. As a result, EMA was found more likely to grant standard approval, a broader indication, or use of a medicine as first-line therapy.
“The high rate of convergence in the authorisation of new medicines at EMA and the FDA is the result of expanded investment in dialogue and cooperation since 2003 and has fostered alignment between the EU and the US with respect to decisions on marketing authorisations, while both agencies evaluate applications independently of each other,” said Zaide Frias, head of EMA’s human medicines evaluation division. ”Our cooperation clearly supports both agencies in achieving a common goal of maximising patient access to safe, effective and high quality medicines in both regions,” she added.

PwC’s CEO survey 2019

Giuliana Miglierini
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PwC’s CEO survey 2019

With the advent on new and emerging technologies – both in the pharmaceutical, health and digital fields – companies are called to make an effort to update their business models to include latest advancements while keeping under control the very high costs of pharmaceutical development (especially for innovative medicines). The sentiment of the top managers of the health sector has been captured by the PwC’s 22nd Annual Global CEO Survey, showing in 2019 a marked decrease in the confidence the global economy would be able to resume a positive economic growth (down to 38% from the 67% of the previous year).

A negative outlook has been foreseen by 21% of the CEOs participating to the survey, vs 5% in 2018; worsening of the future economic scenarios is expected by 31% of top managers operating in the pharmaceutical sector, vs 7% just a year before. The 2019 PwC’s CEO Survey has taken into consideration the input from around 1,400 business managers coming from 83 different countries.

The possible dangers for the economic growth

The globe is suffering a period of high political uncertainty which together with an over-regulation of the health sector, would be the main drivers for the negative economic period, according to the survey. The new EU Commission is going to entry into force on 1st November and US president Trump is entering an electoral year that will end in November 2020 with critical elections to determine the renewal of his mandate. Only 55% of the interviewed CEOs said their company may increase the number of their workers (63% the previous year), while a 15% decrease of the workforce in 2019 is expected at the global level (8% in 2018). On this basis, PwC expects over 12,9 million health professionals will be globally missing by 2025.
Increasing health costs are the main reason of concern (81%) while constraints in resources (82%) and the need to pay attention to social determinants potentially impacting on health management (42%) are other causes of worry for CEOs in the pharmaceutical sector.
Business decisions are mainly targeted to safeguard the brand value, the company’s reputation and its financial potential (94%). Not an easy exercise in the first case, as data on which these decisions are based can be considered adequate just in 28% of cases, while this percentage increases to 45% for decisions based on financial data, said the CEOs. Patients’ needs are another important driver (93%) for companies operating in the health sector, even if data are considered adequate in just 17% of cases, followed by the possible risks that might affect the business (91%, with 22% data adequacy). The low perceived quality for the data used for decisions may be explained with the many silos still present, the low propensity towards their sharing, and the lack of analytical capacities suited to manage the very large amount of data available.

The importance to implement AI

Artificial intelligence is expected to exert significant changes on business models by 81% of the CEOs participating to the survey (75% in the pharmaceutical sector), but its full implementation is still far to become a reality. None of the participating pharma companies’ CEOs said to have already implemented AI on the large scale (4% in the overall health sector), and 34% said not to have plans to do it in future (31% on the total). According to PwC, an extensive use of artificial intelligence might contribute $15,7 trillion to the global GDP by 2030, but there is still need to overcome a trust issue affecting this sort of technology. An issue that touches also CEOs, says the survey report, and that requires to clearly explain the true AI potential value to all citizens.

Malta: Implementation of the Delegated Regulation on Safety Features

Giuliana Miglierini
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Malta: Implementation of the Delegated Regulation on Safety Features

Malta terminates stabilisation period at wholesale dealer level but extends it at pharmacy level

The six months stabilisation period established by the Malta Medicines Verification Organisation (MaMVO) in February 2019 to monitor the implementation of the Delegated Regulation on Safety Features ended on the 8th August 2019. During this first stabilisation period, Maltese pharmacies continued to dispense medicines according to normal procedures. Thus, even if an alert had been triggered, the medicine was dispensed provided there was no evidence of falsification and it was purchased through the legal supply chain. Similarly, wholesale dealers continued to release incoming products into the saleable stock unless there were concerns of possible falsified medicines to be involved. During this period MaMVO monitored the rate of use of the system by end users, as well as the generation and management of alerts.

Following this first stabilisation period, the outcomes achieved have led MaMVO to issue a first note advising of the ending of the stabilisation period with respect to wholesale dealers, followed by a second note extending the stabilisation period for a further six months with respect to pharmacies, in order to improve the systematic use of the system, with the final goal to diminish the number of “false alerts”.

MaMVO’s choices have been motivated by the opinion of the European Medicines Verification Organisation (EMVO) that the objectives of the system can only be achieved by gradual elimination of the release of false positive alert-generating medicinal products into the pharmaceutical supply chain, and hence a need to significantly reduce the multifactorial generation of such “false alerts”. In a recent note taking stock of the situation across Europe after five months from the entry into force of the Delegated Regulation, EMVO noted that around 40% of manufacturers and 25% of other supply chain actors (pharmacies, hospitals, wholesalers, dispensing doctors) have still not yet connected to the various medicines verification system(s).

EMVO reported the rate of “false alerts” is around 3%; with possible reasons including missing data upload into the European Hub, incorrect data upload, incorrect scanner configuration of end-users, pharmacy/hospital software systems not being updated, procedural reasons, and inappropriate use of the system. EMVO’s suggestion is thus to allow end-users to dispense products which trigger “false alerts” until the overall alert level has stabilised below 0,05%, since the current rate of ‘false alerts’ could lead to up to 2,000 products being in short supply. EMVO warned against the risk of dispensing serialised packs to patients without verification/decommissioning, as criminals could make use of discarded packaging to re-introduce falsified medicines into the supply chain, and suggested that current critical points may be overcome, if national competent authorities (NCAs) were to start enforcing the primary requirements of the Falsified Medicines Directive and Delegate Regulation, including inspections of all supply chain actors.

Commenting recently on the impact of Brexit on the supply of medicines to Malta, the Chairman of the Malta Medicines Authority, Prof. Anthony Serracino Inglott, also highlighted the challenges of concurrently implementing the Delegated Regulation, whilst seeking to mitigate the effects of Brexit. In particular, Prof Serracino Inglott described how the six-year derogation period granted to Italy and Greece creates further difficulties since medicines cannot be imported from these markets unless they are first rendered compliant with the provisions of the Delegated Regulation. The difficulties in maintaining a supply of medicines from the United Kingdom post-Brexit are further complicated since, in the event of a no-deal Brexit, Statutory Instruments (SI) The Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 ensures that there will be no obligations on the UK supply chain to affix the safety features.

Malta Minister of Health, members of Valletta Declaration, call for more transparency on medicines prices

The ten countries which in 2017 give rise to the Valletta Declaration (Malta, Cyprus, Greece, Ireland, Italy, Romania, Portugal, Spain, Slovenia and Croatia) met again last July in Valletta to discuss the current situation of their lobbying activities to reach better deals with pharmaceutical companies on prices of medicinal products.

Addressing a press conference after the event, Malta’s Health Minister, the Hon. Christopher Fearne, pointed out that a technical report submitted during the meeting had found that the prices of medicines could vary up to seven times across different countries, with non-disclosure agreements signed by governments during price negotiations representing one of the main barriers to achieve better transparency. The Hon. Fearne suggested that one solution could see Member States signing information-sharing confidentiality agreements.
The Times of Malta reported the European Federation of Pharmaceutical Industries and Associations (EFPIA) as opposing the price-sharing proposal, arguing that it could reduce access to medicines, and rebates on prices that are currently negotiated under strict confidentiality. A spokesperson for the Ministry of Health commented that “Malta believes that transparency of prices between the countries, who are ready to participate in the sharing of prices between themselves, would increase the negotiating power of the countries concerned when they are negotiating prices of individual products with the industry on a national level.”

The Hon. Fearne subsequently elaborated on the topic in an opinion piece published in The Times a few days after the meeting. “The operative word here is that for the market to deliver a win-win result it has to be ‘free’. […] Unless prices are publicly known to all prospective buyers, they cannot compare and make a rational choice.”, going on to add that “[…] this is not a free market. It is not transparent, grossly distorted and certainly not of benefit to the impacted 160 million European citizens”. The Minister called for governments to “sit to the negotiating table with pharmaceutical companies knowing there will be equality of arms”.

The next Valletta Declaration meeting was scheduled to take place in Rome in September, with the objective of taking the matter before the EU Health Ministers Council.

Spain: LIF-neutralizing antibodies coupled to immunotherapy to promote tumor regression

Giuliana Miglierini
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Spain: LIF-neutralizing antibodies coupled to immunotherapy to promote tumor regression

The Leukaemia Inhibitory Factor (LIF) interleukin 6 family cytokine is a pleiotropic cytokine involved in several different differentiation processes, among which the induction of hematopoietic differentiation in normal and myeloid leukemia cells and neuronal cell differentiation. It can act as an oncogenic factor, and it also promotes the regulation of cancer associated fibroblasts, radioresistance and chemoresistance. Patients expressing high LIF levels are often experiencing shorter survival (find more here).
It also plays a fundamental role since the very early stages of embryo development, as it generates a local immunosuppressive microenvironment in order to protect the embryo from the mother’s immune system. Its action is needed to afford blastocyst implantation in the uterus.
The role of LIF cytokine in inflammation has been addressed since the early 2000’s, when it was suggested that LIF may act as a mediator of bi-directional cross-talk between neural tissue and the immune system (see here more on Pulmon. Pharmacol. & Ther.)

A new candidate therapy, MSC-1, has now been developed at the Vall d´Hebron Institute of Oncology (VHIO), Barcelona, combining LIF-neutralising antibodies with immunotherapy to promote tumor regression and trigger immune memory. Initial results have been recently published in Nature Communications.

VHIO’s gene Expression & Cancer group directed by Joan Seoane (credit: Katherin Wermke)

According to the study, the new approach may open the way to the identification of new targets for cancer treatment, and MSC-1 represents a possible new first-in-class therapy. “The blockade of LIF in tumors expressing high levels of LIF promotes effector T cell tumor infiltration transforming a T cell excluded tumor into an inflamed tumor”, write the authors, who thinks therapies against LIF may be prove useful for broad applications in cancer treatment. Results indicates that the synergy created with checkpoint inhibitors may be able to induce tumor regression also in very aggressive tumors such as glioblastomas.

A dual mechanism of action to fight cancer

The approach developed by researchers led by Joan Seoane, co-program director of Preclinical and Translational Research at VHIO, and ICREA research professor, is currently undergoing a Phase I clinical trial for safety and efficacy at the Vall d’Hebron University Hospital (HUVH), Memorial Sloan Kettering Cancer Center (New York, USA), and the Princess Margaret Cancer Center (Toronto, Canada).
MSC-1 – a LIF neutralising antibody – acts as a LIF inhibitor able to exert a double mechanism of action. Spanish researchers showed that LIF plays a critical role in the regulation of CD8+ T cell tumor infiltration, and it promotes the presence of protumoral tumor-associated macrophages. Multi-functional cytokine LIF is often highly expressed in tumor cells, where it promotes the proliferation of cancer stem cells. MSC-1 blocks LIF, thus resulting also in a blockade of the tumor-initiating stem cells. More particularly, the pharmacological action causes a decrease of CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages.
The study also showed that combining LIF inhibition with anti-PD1 therapy finally results in the possibility to stop the spreading of metastatic cells and cancer recurrence. “Once the T cells infiltrate the tumors, they are activated by anti-PD1 immunotherapy. In animal models the pairing of both agents not only halted tumor growth but also, in some cases, made tumors disappear. In these cases, the immune memory is activated and the system ‘remembers’ the tumor and that particular does not reappear even when more tumor cells emerge” observed Monica Pascual-García and Ester Bonfill, co-first authors and post-doctoral fellows of VHIO’s Gene Expression and Cancer Group.

Reactivation of the natural immune response

LIF is an important factor in establishing a crosstalk between the innate and the adaptive immune response: one of the features characteristic of an high LIF expression in tumoral cells is that it causes the block of the natural anti-tumor alarm system and the consequent activation of the immune response. Reactivation of natural immunity may be achieved by LIF inhibition, have now demonstrated researchers. “We have discovered that LIF silences this alarm which enables cancer to dodge the immune system’s innate response. It´s just like a bank robber deactivating an alarm to escape detection by the police” explained Joan Seoane.

Novel agent reactivates an immune call by LIF blockade (credit: Joan Seoane/VHIO)

According to the study, LIF inhibits the CXCL9 gene acting as a signal to immune system T cells. “We have observed that LIF inhibition in tumors expressing high levels of this protein reactivates the signal to T cells to target and destroy cancer“, said Joan Seoane.
The further development of MSC-1 is managed by Mosaic Biomedicals, a VHIO-born spin-off founded by Seoane.

Authorities ask to publish results of clinical studies and the latest news on open publishing

Giuliana Miglierini
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Authorities ask to publish results of clinical studies and the latest news on open publishing

European institutions jointly published a letter to remind all stakeholder their obligation to make publicly available in the EU Clinical Trials Database the summaries of results of concluded trials.
In the meantime, cOAlition S released a revised guidance on Plan S implementation, which has been postponed one year and will now take effect from 1 January 2021. The debate on models for open access (OA) is continuing: the example of the Swiss Medical Weekly has been addressed in a paper recently published on Nature.

Sponsors called to publish clinical results

Transparency in the development of new medicinal products should represent a major goal for the pharmaceutical industry, as it allows the general public and health professionals to be better informed about new treatments. Transparency is also an important feature to widen access to cures, but still many sponsors do not comply with the request to publish the summary results of clinical trials in the centralised EudraCT database. The issue has been addressed by a joint letter signed by the EU Commission, the European Medicines Agency and the Heads Medicines Agencies (HMA) and aimed to solicitate sponsors to respect the one-year deadline from the completion of the studies for publishing results. This time decrease to only six months in the case of paediatric studies.

The problem mainly refers to academic sponsors, as they proved far less efficient (23,6%) than industrial sponsors (77,2%) in complying with the publication of data in EudraCT. According to the three European authorities that signed the letter, it should be considered the importance of transparency for patients that took part to the studies: a punctual publication of results represents an acknowledgement of the importance of their decision for the benefit of the entire community of patients suffering for the same disease.
The letter is not the only initiative undertaken at the European level to facilitate adhesion of sponsors to the request to make available trials’ final results. A monitoring initiative was launched in September 2018 to monthly check studies still missing results; reminders are then forwarded to not compliant sponsors to sensitise them to the transparency obligations they should respect.
In April 2019 the EudraCT database contained data for more than 57 thousand clinical studies, 27% of those (27,000) were completed. Just 68,2% of sponsors for completed studies resulted in compliance with the publication of results; data were still missing for the remaining 31,8% (5,855 studies).
All information inserted by sponsors in the EudraCT database is then make public through the European register of clinical trials (EUCTR); it is also shared at the international level on the ICTRP platform managed by the World Health Organisation.

Plan S shifts to January 2021

The timetable for the implementation of the Plan S for open access to scholarly publications (see the March 2019 newsletter) has been postponed at the end of May, and it is now expected to take effect from 1 January 2021. This means that starting from January 2021 all publications resulting from research funded by cOAlition S members grants must be published in OA journals and platforms or made available in an OA repository. The three years transition period will conclude with a formal review process on the implementation of Plan S to be run by cOAlition S.

A new version of the guidance on the implementation of the plan has been also released on the basis of the feedback (more than 600 inputs from 40 countries) received during the consultation phase. The principles of Plan S are now more committed to revise methods of research assessment according to the San Francisco Declaration on Research Assessment (DORA), reflecting the line of action indicated by the funders. “We are committed to implement what is one of the most significant and ambitious changes to the research system and with the final plan now in place we look forward to more funders, from across the world, supporting the transition to full and immediate open access by joining and aligning with cOAlition S”, said Marc Schiltz, president of Science Europe and co-initiator of Plan S.
A full explanation of the rational to the guidance is provided on the initiative’s website. Fundamental principles have been confirmed: no paywalls for scholarly publications, immediate open access without embargo, Creative Commons Attribution CC BY licences, commitment of funders to support open access publication fees at a reasonable level, no support to publication in hybrid (or mirror/sister) journals unless they are part of a transformative arrangement with a clearly defined endpoint. The final target of open access may be pursued by making papers freely available at the point of publication either in the form of the Author-Accepted Manuscript (AAM) or Version of Record (VoR), a modality already practiced by some publishers.

These transformative agreements should facilitate the moving away from existing subscription agreements and they will be supported until 2024. More options for transitional arrangements have also been considered, including transformative agreements, transformative model agreements, and ‘transformative journals’. Read-and-publish or publish-and-read agreements with publishers are possible examples. There is no a predefined route to achieve compliance, says cOAlition S, the initiative remains open to support different and sustainable solutions and models in order to answer the specific needs of the different scientific disciplines. Transparency in open access publication fees is also a goal, aimed to reach funders’ potential standardisation and capping of payments. The technical requirements for OA repositories have been also revised, as well as the criteria for research reward and the incentive system in order to adapt them to value researchers and scholarly output.
cOAlition S has announced the intention to further collaborate with many of the European and international associations involved in the theme of OA publishing to further improve the implementation road to Play S. Many new funders joined the coalition in just few months after the initial publication of the plan, which has now become a global initiative. In May 2019, for example, cOAlition S launched the ‘São Paulo Statement on Open Access’ with the African Open Science Platform, AmeliCA, OA2020, and SciELO.

The possible model of the Swiss Medical Weekly

Not all voices agree with the cOAlition S roadmap, or at least with part of it. In a recent commentary published in Nature, Adriano Aguzzi discusses the possible problems arising from the author-pays model, as it may lead journals to increase the number of accepted papers in order to increase their profits. At the expense of the overall quality of contents. Aguzzi, the director of the Institute of Neuropathology at the University of Zurich (CH), says about Plan S that “I am concerned the implementation of this honourable goal could cause long-term damage to the integrity of the scientific record”.

The proposed solution – called by its author ‘Public Service Open Access‘ (PSOA) – would see journals competing each other to attract grants from public-research agencies instead of charging authors for publishing, in a process very similar to the calls for application typical of research grants. Applications should be reviewed by a panel of experts in scientific publishing based on quality criteria, turnaround times, searchable database, etc.
The PSOA model has been elaborated on the example of the Swiss Medical Weekly, the journal Adriano Aguzzi was the director of for four years. All costs to be afforded to publish papers (estimated in 1,900 CHF each) are covered by a consortium of Swiss university and cantonal hospitals, the Swiss Medical Association, the Swiss Academy of Medical Sciences and charities. Reviewers obtain 50 CHF for each report, the access for readers and authors is completely free of charge. Articles are published under the CC BY-NC-ND licence, more restrictive than the one proposed by Plan S, but for Aguzzi more useful to maintain the integrity of the published records. The Swiss expert also thinks the proposed ‘read-and-publish’ transformative deals, were libraries are to pay for a subscription, to be non-transparent and favourable to monopolistic publishing.
Other possible impacts on desynchronization and file corruption might arise, according to Aguzzi, from the many platforms providing open access to preprints or accepted manuscripts. A strict a clear guidance should be also provided to avoid conflicts of interests in both publishers and funders, these last one being possible tempted to preferentially support the publication of the research they funded.

Comments from stakeholders to EMA’s Regulatory Science Strategy 2025

Giuliana Miglierini
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Comments from stakeholders to EMA’s Regulatory Science Strategy 2025

After the closure of the public consultation period, several stakeholders involved in the pharmaceutical life cycle released their comments to the proposed EMA’s Regulatory Science Strategy 2025.
“It’s the first time that the EMA has actually invested in pulling together a reflection on this very broad topic. Knowing that these strategic decisions would have a very long-term impact with even a 5 to 10 year perspective, it is good to hear the real voice of the stakeholder groups because they are very diverse”, said in an interview the Agency’s Head of Scientific Committees Regulatory Science Strategy, Tony Humphreys. EMA’s representative also announced the probable organisation of workshops in Amsterdam in Q4 2019 to discuss results from the analysis of the comments received.

Among the entities that forwarded their comments is EFPIA, the European Federation of the Pharmaceutical industry representing 40 research-intensive biopharmaceutical companies and 36 national associations, that has highlighted three top priorities from the industrial perspective: innovation in clinical trials, provision of regulatory advice along the development continuum and use of high-quality real-world data (RWD) in decision making. A main target for EMA should be balancing “the requirements to deliver near-term process improvements with long-term strategic direction for delivering meaningful change”, says EFPIA’s note.

A key enabler to boost innovation

According to the Federation, the implementation of the new Regulatory Strategy – which comes in a complex period for the European Union, facing the entry into force of the new Commission and the expected closure of the Brexit – would represent a key enabler to sustain further development of innovation in medicine. Regulatory authorities should focus on make available a true, competitive system at the global level, so to improve the convergence of activities within different geographical areas. Many of the priorities identified in EMA’s Strategy are interconnected each other, thus according to EFPIA an action on one of them may result in progress also in other fields. Particularly important would be the ability of the new strategy to accommodate the peculiar characteristics of many emerging technologies in the biomedical sector, i.e. advanced therapies (ATMPs), digital therapeutics, artificial Intelligence, advanced analytics, and in silico studies.
EMA’s proposal to sustain the development of personalised medicine, health and treatments has been also welcomed by the industrial representative, as well as the goal to facilitate the implementation of new manufacturing technologies and the optimisation of the modelling, simulation and extrapolation capacity.
EFPIA asks a better coordination of the advice services to the industry provided both by the regulatory and the Health technology assessment perspectives. The Federation final objective would be a formal recognition that processes and decisions at the regulatory, HTA and pricing/reimbursement level are distinct from one another and occur at different phases along the development of a new medicinal product.

Three actions to sustain the pharmaceutical industry

Priorities set forth by EFPIA include the advancement of novel clinical trial concepts (e.g., umbrella, basket, master protocol trials, trials in small populations) and quantitative approaches (e.g. Model Informed Drug Discovery and Development – MID3). Not less important are new sources of clinical evidence – such as registries, real-world data, big data, and historical controls measures (e.g., endpoints, biomarkers, wearable digital devices), and methodologies (e.g., MID3).
In the field of scientific advice, the process should be more dynamic to easily accommodate specialised input for specific types of products (e.g. paediatrics, drug-device combination products). EFPIA also suggests this sort of activities to wider extend in order to better bridge the advice and decision-making gaps across the EU regulatory system and, for example, the US FDA one.
Real world data may prove truly useful only if access to data sources is made available to the industry, also through the implementation of global standards and alignment of requirements. Acceptability remains a key issue to be solved, and it should be pursued in the basis of the experience gained in the course of multi-stakeholder collaborations and demonstration projects.

The opinion of vaccines’ producers

The voice of the innovative research-based vaccine companies and SMEs has been reported by Vaccines Europe, which has recalled in its note the still unmet medical needs that might be addresses through vaccination, such as infectious diseases for which safe and effective vaccines remain elusive (e.g. cytomegalovirus, Chlamydia trachomatis, Clostridium difficile, Staphylococcus aureus), or those efficacy should be further improved (e.g. seasonal influenza, tuberculosis, herpes zoster).

Attention should be paid also to specific populations that could be better protected (e.g. elderly, immunocompromised patients, travelers). The availability of new vaccines may also prove useful to prevent the expansion of antimicrobial resistance or to boost the immune system in older people.
According to Vaccines Europe, the complexity of the next generation of vaccines and of their targets will make their development much more complicated and costly. EMA should thus work with stakeholders to facilitate the development of and access to innovative vaccines, paying attention also to the need to harmonise approaches with other regulatory authorities at the global level.

The organisations of healthcare professionals

EMA’s Regulatory Science Strategy 2025 has been addressed also from the perspectives of other types of stakeholders of the product life cycle, among which medical doctors. The Standing Committee of European Doctors (CPME) indicates the need to critically reflect on how to integrate the new technological advances in existing regulatory frameworks, while simultaneously maintaining the highest standards of quality, efficacy and safety of new drugs. A goal that may be achieved by reinforcing the pre-submission activities, in order to generate appropriate evidence. “The challenge is about completing the scientific evidence collected through clinical trials rather by collecting additional data rather than replacing clinical trial data”, writes CPME. Post-market authorisation studies would be thus relevant to reduce the uncertainty about the efficacy and safety of new drugs.

The European Forum of Primary Care (EFPC) has welcomed EMA’s “highly ambitious agenda” and its wider scope in addressing problems with access and availability of drugs. “We know it is difficult for political reasons to address the consequences of strategies of countries/pharmaceutical companies. Yet, it is an obligation to the EU-citizen to make absolute clear where the patient interest is not served by protective or marketing mechanisms. We miss that attention a little”, writes EFPC from its website. The request for EMA is to better focus areas of research currently out of the industrial innovation processes due to protective or self-interest strategies of countries and/or pharmaceutical companies.

EPHA’s point of view

The European Public Health Alliance (EPHA) filed its comments to the RSS 2025 on behalf of not-for-profit organisations active in public health, patient groups, health professionals, and disease groups. A modernisation of the overall regulatory process should be a priority to be pursued by raising the bar for approvals of new medicines, innovating processes and prioritising public health needs, says the document.

A better transparency of the system and impact assessments of accelerated approval schemes such as PRIME or conditional marketing authorisation (CMA) is suggested, as “they need to remain the exception as they increase uncertainty and put patient safety at risk”.
A Strategy and Planning team, including external, non-industry experts, should supervise in a public and transparent manner EMA’s organisation and procedural decisions, schemes and regulatory pathways. Data from clinical trials should be freely available to the scientific community for re-analysis and further drug development. Comparative and superiority studies on cohort’s representative of the final intended population of patients should be run whenever possible, and one of the two (compulsory) studies to obtain approval should be run by an independent party. Confirmatory studies may also prove useful to confirm patient relevant outcomes. The duration of the treatment should be also assessed. Another suggestion is for EMA to independently run in-house statistical analysis on raw data.
Stricter criteria are also envisaged for the post-marketing phase, both for surveillance and confirmation studies, with a particular attention to monitor toxicity and effective outcomes on the base of real-world data, and on the reporting of adverse effects. EMA should also pay great attention while defining the scope and questions supporting the collection of RWD, and should include pragmatic trials as in “close to everyday practice”.
Finally, but not less important, EPHA wishes that EMA may in future years be more open to constructive criticism and foster a dialogue with critical voices. “It needs to proactively dispel any mistrust caused by the links with the pharmaceutical industry”, writes the association, for example by timely punishing companies that do not publish data of clinical trials.

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