Giuliana Miglierini
Post-Brexit era
The Free Trade Agreement governing the new relationship between the European Union and the United Kingdom was eventually signed on Christmas Eve, followed by the new status of third country for Great Britain starting from 1st January 2021. The beginning of the post-Brexit era is marked by many actions to complete the new regulatory framework on both sides of the Channel in order to guarantee the proper functioning of trades across the new borders.
The main point of the Free Trade Agreement
The new economic and social relationships, a partnership for citizens’ security and a horizontal agreement on governance are the three pillars of the Free Trade Agreement, which covers all areas of possible collaboration and interaction between the EU and the UK. Limiting our attention to sectors of possible interest for the pharmaceutical industry, no tariffs neither quotas will be applied on trades of all goods that comply with the appropriate rules of origin. Transports will benefit of a continued connectivity, and competition in this area will be based on a level playing field. A new model for trading and interconnectivity will be put in place in the energy sector, and social rights will be preserved for both EU and UK citizens, including people working in the UK/EU or traveling after 1st January 2021. UK’s researchers will continue to participate to Horizon Europe and other flagship European research programmes for the period 2021-2027, provided the payment of a financial contribution by the UK government to the EU budget.
A strong cooperation for law enforcement and judicial cooperation is foreseen in order to fight and prosecute cross-border crime and terrorism. The UK is called to ensure adherence to the European Convention of Human Rights and its domestic enforcement in order to avoid the risk of suspension of security cooperation. A newly formed Joint Partnership Council will be responsible for the correct implementation of the Agreement, and for the discussion and settlement of any issue that may arise. The Protocol on Ireland and Northern Ireland (NI) is being implemented starting 1 January 2021, at the end of the transition period.
EMA’s advice on how to apply the Protocol on Ireland and Norther Ireland
The European Medicines Agency (EMA) has published a Q&As document to discuss the main points pharmaceutical companies should take in mind while implementing the new Protocol on Ireland and Northern Ireland. According to the Commission’s decision C(2020) 7126 final, starting from 1st January 2021 the UK regulatory authorities can no longer fully access the Article 57 database containing information on medicinal products authorised in Northern Ireland. The UK has become a non-EU/EEA country, thus the submission and maintenance of records for authorised medicinal products (AMP) authorised outside the EEA in the Art. 57 database is now a voluntary procedure. For products listed in the database under the code ‘United Kingdom (GB)’, marketing authorisation holders (MAHs) were called to complete by 31 January 2021 the review of existing data, and change the country of authorisation to ‘United Kingdom (Northern Ireland)’ (country code ‘XI’) for products that will continue to be authorised by UK’s authorities with respect to Northern Ireland after 31 December 2020. An eXtended EudraVigilance Medicinal Product Report Message (XEVPRM) was then to be submitted to communicate the updating of the record.
A similar modification of the country indication is also needed to update the address information in Art. 57 database for MAHs, registration holders, qualified persons for pharmacovigilance (QPPVs) and pharmacovigilance system master files (PSMFs) located in Northern Ireland; all these functions must be established in the EU/EEA for medicinal products authorised or registered in the EU/EEA. All details can be modified through the EMA Management Account portal, and changes have to be notified within 30 calendar days.
EMA also provides indications on how to calculate the fees for nationally authorised products in EMA Pharmacovigilance procedures. Access for UK authorities to EudraVigilance database is now granted just on a write basis via Gateway submissions in relation to individual case safety reports (ICSRs) from the Northern Ireland territory. EMA provides details on how to report safety post-authorisation issues originating in NI, while third countries rules apply to cases originating in the rest of Great Britain (“GB” code). The same also apply to the communication of all clinical trial SUSAR cases, irrespective they are occurring in the UK or Northern Ireland.
From 1 January 2021 MAHs can access ICSRs in EudraVigilance just for their products authorised in the EU or carrying the Authorisation country ‘United Kingdom (Northern Ireland)’. Sponsors of clinical trials cannot be based in NI, and have to nominate a legal representative in the EU/ EEA should this be the case, while it is possible the Qualified Person of the trial is based in NI. All data can be updated using the EudraCT application. Electronic application forms (eAF) will also see the move of the ‘United Kingdom’ country code to the third countries section; the term ‘United Kingdom (Northern Ireland)’ is available to be used when appropriate with reference to EU/EEA, depending on the type of regulatory procedure used.
The PSUR repository will continue to be fully accessible to UK authorities, but products are available for selection only if the corresponding information in Article 57 database has been correctly updated as discussed above. EMA also provides information on how to submit new PSURs for products authorised in the United Kingdom with respect to Great Britain (which will not be part of EU single assessment procedures). The local representative for NI has to substitute the UK’ one on Product Information of centrally authorised medicinal products. All information needs to be updated by no later than 31 December 2021. Different deadlines are in place to update the marketing status of products, according to the actual area of their commercialisation.
Batch release procedures and controls performed by QPs located in Northern Ireland are automatically recognised for import of medicinal products in the EU/EEA, without need to run duplication of the analysis. This is not true for medicines manufactured in Great Britain and imported in NI starting 1 January 2021, which are then subject to reassessment. GMP and MIA certificates released by UK authorities in relation to facilities located in Northern Ireland will continue to be recognised in the EU and to be available in the EudraGMP database. The same does not apply to certificates released after the end of the transition period and relative to manufactures located in the Great Britain, as this is now considered a third country. Despite this, the risk based approach agreed by EMA’s GMDP Working Group still allows to use certificates issued by UK authorities and pertaining UK or third countries manufacturers to demonstrate GMP compliance. The written confirmation of GMP compliance issued by UK’s third country regulatory authorities is not needed for active pharmaceutical ingredients manufactured in Northern Ireland and imported in the EU, while it is a compulsory requirement for imports from the rest of the UK.
MHRA updated its guidances and launched the ILAP programme
The UK’s regulatory authority MHRA has also made a big effort to update all the relevant legislation and guidance for the pharmaceutical industry to reflect the new post-Brexit status of the country. A dedicated webpage is available on MHRA’s website, listing the new documents to be followed by companies wishing to run their business in Great Britain in the field of clinical development, medical devices, and import and export of pharmaceuticals.
The new Innovative Licensing and Access Pathway (ILAP) has been launched on 1 January 2021, a programme aimed to favour rapid approval of innovative medicines developed in the UK. The new integrated platform sees the collaboration of the different stakeholders, including the National Institute for Health and Care Excellence (NICE), the Scottish Medicines Consortium (SMC), NHS England and NHS Improvement (NHSE&I). Products accessing this regulatory pathway will receive an “Innovation Passport” designation, which will correspond to a “Target Development Profile” (TDP) document, aimed to dynamically describe the roadmap to reach patient access in the UK. Patients themselves will be active part of the entire process, and a toolkit will be available to optimise the development programme.
“Now we have left the EU, we have the freedom to innovate and cut red tape to speed up the approval process for new treatments and ensure patient safety is at the heart of everything we do. The new pathway represents a totally new way of thinking and is a truly collaborative approach between the healthcare system, the pharmaceutical industry and patients with the common goal of getting the best products to the people who need them as safely and quickly as possible”, said UK’s Minister for Innovation, Lord Bethell.
ABPI’s Chief Executive Richard Torbett also commented the new initiative, “which will help our companies get new treatments to patients faster by offering them a similar rolling review as was done with the Pfizer/BioNTech vaccine and concurrent review by all parts of the health system. This is something we’ve been calling for as the MHRA prepares for Brexit”.
Comments from the industry on the Free Trade Agreement
A joint statement has been released by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Association of the British Pharmaceutical Industry (ABPI) upon the announcement of the signature of the final Free Trade Agreement. “We have always said that a deal is in the best interest of patients in the UK and the EU. This means ongoing collaboration in key areas including scientific research and cooperation in areas like medicines safety. We will now take the time to look at the detail to understand what it means for our members and the future of the pharmaceutical industry” said Richard Torbett on behalf of ABPI and Nathalie Moll for EFPIA, while reassuring industry will continue to ensure efforts to mitigate any disruption in the flow of medicinal products across the Channel.
The Chief Executive of the UK’s BioIndustry Association (BIA), Steve Bates, highlighted the importance of some early details of the Agreement, such as the possibility to self-certify the origin of goods sold and the that to enjoy ‘full cumulation’, making it easier to comply with requirements and obtain zero-tariff access. Specific measures for pharmaceuticals and chemicals, the possibility to still access the Horizon Europe programme and the absence of equivalence of conformity assessment are other positive points, according to BIA. “In his first remarks on the deal the Prime Minister mentioned positively the concept of ‘mutual recognition’ and stressed his desire for the UK to be a ‘collaborative science superpower’, ‘able to set our own standards, innovate in the way we want, and to originate new frameworks for sectors like bioscience’”, Steve Bates added.
The Royal Pharmaceutical Society (RPS) also highlighted its priority areas of action (inclusive of protecting patient care, supporting the pharmacy workforce, and ensuring the continuity of medicines supply, see here), asking for a rapid action of the UK government. The Society focus for 2021 will include the support to change the legislation in order for community pharmacists to make minor changes to prescriptions to enable the safe and effective supply of medicines to patients where there are routine medicines shortages. Counterfeiting of medicinal product will continue to represent an hot issue, paralleled by patient safety and minimisation of price hikes.
EMA and HMA’s new joint regulatory strategy
Six priority areas will characterise the work of the network of European medicines agencies (EMRN) for the next five years. The goals have been established by the new joint regulatory strategy to 2025 published in December 2020 by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA).
Areas of activity will include the availability and accessibility of medicines; data analytics, digital tools and digital transformation; innovation; antimicrobial resistance and other emerging health threats; supply chain challenges; and the sustainability of the network and operational excellence. The strategic objectives, which also underwent a phase of public consultation from July to September 2020, will be transformed into concrete actions by EMA and the network of European national competent authorities.
“The Covid-19 pandemic has highlighted the pivotal role of medicine regulation for the protection of public health,” said Emer Cooke, EMA’s Executive Director. “Lack of availability of medicines, either because they are not marketed or due to supply disruptions, has shown to pose serious threats to patient and animal health, animal disease control programs and sustainable livestock production. This strategy ensures that we join forces across the EU to effect tangible improvements for citizens.”
The EMRN network is expected to grow further in the next five years in order to achieve an improved sustainability and operational excellence. The actions planned in this direction are part of the sixth priority discussed in the joint strategy, and will be based on the availability of adequate resources (financial, expertise, competence, and skills), business processes, IT capabilities, as well as of an efficient governance structure.
The new EU’s pharmaceutical legislation is growing
EMA-HMA’s joint strategy aims to provide a medium-to-long term reference framework to coordinate all actions of the complex network of stakeholders working at the development, approval and commercialisation of pharmaceuticals. The 27 national competent authorities (plus those of Iceland, Liechtenstein and Norway), the EMA and HMA are represented by the European medicines regulatory network (EMRN); other stakeholders include among others the associations representing the pharmaceutical industry, patients, payer and health technology assessment (HTA) bodies.
The challenge is double: on one hand, the need to ensure a steady supply of already available medicines, on the other one, the opportunity to exploit new technologies in the medical, biomolecular and informatics fields to develop new approaches to treat unmet medical needs. The Pharma 4.0 paradigm is becoming the new normal under the manufacturing perspective, and it has to cope with new European and global policies addressing sustainability, climate change and green economy.
The Covid-19 pandemic has highlighted the need to ensure a better governance of the global supply chains providing the European pharma industry with APIs and excipients. These issues have been also addressed by the new Pharmaceutical Strategy for Europe (see the article in the December newsletter), and are now complemented by the more operative goals set by the EMA-HMA joint strategy.
Availability and accessibility of medicines
Access to medicines is the first priority to ensure patients can always find in the market the medicines they need. The strategy plans to run a deep analysis to better identify the multifactorial root causes of unavailability of patented and off-patent products, for example with reference to authorised but not marketed products, or low volume paediatric medicines. “It is important to differentiate shortages caused by safety, efficacy or quality/supply chain issues from availability issues for commercial reasons, where political engagement may be necessary”, states the joint strategy.
Shortages shall be addressed by the improved sharing of data and the inclusion of marketing status data in the SPOR programme; it needs a coordinated action across different countries to find sustainable solutions and avoid unilateral actions which may further exacerbate the problem. A better understanding of the different roles played by the various stakeholders along the supply chain is also foreseen in order to improve transparency of the overall process and favour the better monitoring by regulatory authorities. The removal of national barriers still limiting the free flow of medicinal products in the EU market is another area of attention, which might include the implementation of the electronic Product Information (ePI), the sharing of best practices and increased coordination of the EMRN. The final adoption of the new Veterinary Medicines Regulation is also expected to resolve many availability issues in the field of medicines for animal health.
Processes leading to regulatory approval shall be improved to ensure a better collaboration between medicines regulators and other decision makers along the entire pathway (including political actors and international organisations), from evidence planning, to reviewing of evidence and methodologies. Participation to horizon scanning activities, also at the international level, and an improved collaboration with HTA bodies on scientific advice procedures (including pre-planning and generation of post-licensing evidence) represent useful tools to favour a rapid access of patients to innovation. It is also important to ensure transparency in the communication of scientific evidence and regulatory assessment of new products, as emerged during Covid-19 vaccines and treatments development.
Support to the digital transformation
The digital transformation represents a cross-sectorial area planned for the actions of the von der Leyen Commission for next years, to be supported also through the creation of the new European Health Data Space. The EMA-HMA joint strategy aims to enable access and analysis of the great amount of routine healthcare data available both at the point of care (e.g. electronic health records, eHR) and by use of smart devices, including the analysis of individual patient data from clinical trials. Artificial intelligence and machine learning will represent fundamental tools to achieve this goal, and will contribute to generate evidence from real world data to be used for regulatory and decision-making purposes, particularly with reference to post-approval clinical studies.
A goal that requires a better standardisation of targeted data (as reflected in the EC’s policy on Open Data and the Public Sector Information Directive); modernisation of regulators’ internal processes and the creation of a suitable infrastructure within the Network to deal with statistics, epidemiology, real world data and advanced analytics are other planned actions. The wide integration of medicines and medical devices calls for a collaborative effort with HTA bodies to jointly map the current status of the digital regulatory infrastructure and plan its upgrading. The analysis of real world data will also represent the basis for the creation and implementation of dynamic regulation and policy learning policies within the current regulatory framework, taking into consideration also aspects referred to data security and ethical considerations.
Europe as a leading hub for innovation
The regulatory science developed by European agencies historically represents a leading reference at the international level. Four new goals have been identified to improve the action of the EMRN network in order to support innovation in the pharmaceutical field, starting from the integration of science and technology in medicines development. This requires the Network to develop suitable competences to support innovators during medicines development. Research and innovation is also expected to play an enabling role in regulatory science. Advanced Therapy Medicinal Products (ATMPs) coupled with new biomarkers are supporting the rapid expansion of personalised medicine. This also correspond to the development of new formulation strategies (including the use of nanoparticles) and of small batches manufacturing techniques (e.g. 3D printing).
Collaborative evidence generation should represent the final target, and should see the cooperation of all stakeholders along the lifecycle, including HTAs, and pricing and reimbursement authorities. Large, multicentre and multinational clinical trials with a shared protocol and standard are foreseen by the strategy in order to produce robust evidence in support to decision makers.
Antimicrobial resistance and other health threats
Antimicrobial resistance (AMR) continues to represent the first priority of action to prevent possible risks for the public health. High quality information on antimicrobial consumption and surveillance data on AMR in animals and humans is needed, according to the strategy, to better support policy development and proper implementation of Regulation (EU) 2019/6 on veterinary medicinal products.
Multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are the main two areas to be addressed as for AMR, using a One Health approach. Emerging health threats will also require great attention in order to prevent the occurrence of new possible epidemics.
EMA and HMA have planned to continue the actions supporting the responsible use of antimicrobial agents both in the human and veterinary sectors. Reduction of antimicrobial use and misuse is considered critical to decrease the burden of AMR. This should be paralleled by development of new antimicrobials or other therapeutic options and the maintenance of a sufficient production of older products to cover the EU’s market needs.
Ensure the sustainability of the supply chains
An enhanced traceability along the global, highly complex supply chain of human and veterinary medicines, from manufacturing of APIs and excipients in third countries to their importation and final use, is the main target set forth by EMA and HMA. It will require to improve inspector capacity building and extensive cooperation at the international level, particularly with reference to APIs production in extra-EU countries (e.g China and India). “For example, the network should make optimum use of mutual recognition agreements (MRAs) through expansion of scope to include more product categories where appropriate or recognition of inspections by MRA partners in third countries where GMP certificates are available from those partners”, states the document. Pre-approval inspections of APIs facilities may be also addressed, leading to routine assessor-inspector joint inspections.
Dependency on a limited number of manufacturers and sites is a critical issue to be solved to ensure continuity of supply and availability of medicinal products in the European market. A risk-assessment evaluation detailing the supply capacity and measures for mitigation of any potential disruption may be required to manufacturers of the API and finished product for inclusion in the application for a marketing authorisation. Measures to favour manufacturing in the EU are also possible.
A more coherent approach by regulators and industries to the standards for medicinal products for human and veterinary use is indicated by EMA and HMA in order to reinforce the responsibility for product quality. Good distribution practices (GDP) and guidances may be revised to support a better standardisation among member states and to promote synergies among GDP actors.
The regulatory framework is also expected to evolve to accommodate new manufacturing technologies based on artificial intelligence and the Internet of Things (IoT), as well as innovation in manufacturing and distribution of medicinal products. An example made by EMA and HMA is that of tabletop-sized machine with integrated production and purification, that might turn useful to run decentralised manufacturing in a hospital pharmacy or operating theatre, or in mobile clinics to provide personalised medicines for the individual patients.
Trends in APIs development for 2021
The second millennium has seen the surge of new approaches to drug development. The wide and cheap availability of gene editing techniques has favoured the increasing role of Advanced Therapy Medicinal Products (ATMPs, including gene and cellular therapies) over traditional medicines based on small, chemical molecules. Biotechnological last generation products are no more just limited to CAR-T therapies, as acknowledged by the new family of mRNA vaccines developed against the SARS-CoV-2 virus. Many opportunities are also present in the development of highly potent active pharmaceutical ingredients (HPAPIs) and in the use of fermentation as a source of new drug substances. We summarise here some of the most recent trends in APIs development.
Many opportunities for biotechnology products
CAR-T are one of the newest classes of therapeutics, characterised by a still limited range of indications. Bi- and tri-specific antibodies able to recognise different cancer epitopes can also represent very interesting products within development pipelines, according to an interview to Inthera Biosciences CEO’s, Martin Bonde, published in Labiotech.eu.
Personalisation of treatments is also expected to grow, thanks to the progress in human genomics and the availability of specific biomarkers useful to better stratify patients that may respond to a certain treatment. According to the article, the third decade might see the first gene therapies based on CRISP-Cas9 and other gene editing techniques reaching the market, even if some technical issues are still to be solved. Single-cell technologies able to target specific cell types/organs based on receptor expression may also gain increased importance, said Alexandra Bause (Apollo Health Ventures).
The market for highly potent APis
Antibody-drug conjugates (ADC) are a class of highly potent APIs those manufacturing poses many challenges from the point of view of the management of the complex supply chain of the different starting materials and intermediates needed to obtain the conjugate. As discussed in an article by Brian Clark published in Pharmaceutical Online, this may include different manufacturing sites for the antibody, the small cytotoxic molecule and the conjugate, as well as a dedicated filling facility for the drug product, a maybe also a labeler/packager, and a logistics company for distribution. Current trends for the ADC sector indicates the preference for highly specialised and integrated CDMO contractors, able to run at a single manufacturing site all these different phases up to the finished product.
This market sector continues to offer many opportunities, explained three executives from Lonza in an interview published on Outsourcing-Pharma.com. Highly potent APIs pose challenges also from the formulation point of view, due to the need to obtain uniform dispersions of the active ingredient, and require the complete containment of the plants to protect operators from the possible health hazards. According to an article by Cynthia A. Challener published in Pharmaceutical Technology, the increasing molecular complexity of HPAPIs represents a further issue that adds to the ones previously mentioned. This complexity is reflected by the great fragility of many molecules, thus requiring formulation as liquid dosage forms for parenteral or i.v. administration instead as the more traditional oral dosage forms. Another possible conflict arises from the need to offer patients HPAPIs’ oral dosage forms for chronic or frequent administration, in indications different than oncology. Microdosing, liquid-filling of capsules, and wet granulation are examples of the possible solutions, according to Challener’s article. Many of these techniques can also be used for the preparation of low-dosage formulations of HPAPIs, while microdosing may prove useful to formulate poorly bioavailable highly potent ingredients.
The potential of artificial intelligence
Artificial intelligence (AI) is playing an increasing role in drug discovery and development. Many tasks typical of the discovery lab can now be completely automated, as well as the collection and analysis of the resulting data using machine learning algorithms. The first drug candidate completely developed by the AI to reach the clinical phase for the treatment of obsessive-compulsive disorder (OCD) has been developed by the British firm Exscientia, and it is now under a phase I experimentation run by Japanese Sumitomo Dainippon Pharma, after a development process that took just one year instead of the usual five.
Exscientia is also leading the small molecule drug design activities in the CARE consortium (Corona Accelerated R&D in Europe), an initiative funded under the IMI public-private partnership framework to speed up the development of treatments against the SARS-CoV-2 virus.
Screening of large libraries of molecules and rational-based drug design are just two of the main application of AI and big data analysis in drug development. A big multinational company such as Merck, for example, has already developed some 300 AI predictive models for compound properties, in order to reduce both time and costs of development.
A new life for fermentation-based processes
Fermentation has a long history in the manufacturing of pharmaceutical active ingredients, both small molecules and biotechnology products, thanks to the simple reaction conditions and the use of cheap starting materials. Many new, engineered micro-organisms are today available thanks to the advancements in molecular and synthetic biology, adding to the more traditional ones used to run fermentative processes. The current situation of fermentation for the production of APIs has been examined by Cynthia A. Challener from the pages of Pharmaceutical Technology.
E. coli and P. pastoris (Komagataella phaffii) are the micro-organisms more frequently used in the pharmaceutical industry, according to the paper. Engineered strains, for example at the level of the biosynthetic pathways, benefit of a higher stability and a more predictable profile supporting the easier development of the fermentation process and leading for example to overproduction of the desired API and reduction of the related impurities.
Artificial intelligence is increasingly used in this case too to design and optimise the characteristics of the bacterial strain in order to produce a specific target molecule. Automation is growing also in this field, and many steps are now run automatically upon checking of the right conditions by mean of in-process controls and reals-time sensors able to keep monitored all process conditions.
Time for change: The digital transformation of the Pharmaceutical Industry
The digital transformation is not a new topic for the pharmaceutical industry, as the increasing role of data and insights and their usefulness to improve customer experience is being discussed since the last decade. The Covid-19 pandemic and the consequent lockdowns have favoured the transition of many activities from the physical office to remote working, affecting all the different functions of a typical pharma company.
This is especially true for digital marketing, that switched to remote interactions between doctors and reps since the very beginning of the pandemic. According to an article by Richard Staines published in Pharmaphorum, the pharmaceutical industry is now running to fill its historical gap in digitalisation, being this the last industrial sector to move towards the new business model.
The growing of digital marketing
Pharmaceuticals’ digital advertising is growing very rapidly, with estimates to reach $9.53 billion in 2020 (14.2% vs 2019) and $11.25 billion in 2021 (+18%, data eMarketer). Launches of new medicines are now mostly managed online, with companies able to provide also through this new channel highly accurate and robust scientific information to doctors, and in full compliance with all regulatory requirements. The interactions occurring on the digital platforms, explains Staines, may contribute to improve the efficiency of the relationships between reps and healthcare professionals (HCPs), thanks to the possibility to personalise the digital channels for the preferred interaction. Sharing of the marketing documentation, after its preventive and uniform approval across all the different geographic areas of operation of the company, becomes also easier, as well as the tracking of the reps-HCPs interactions needed to provide feedbacks to the top management.
A report by Ethoseo identifies five trends for digital marketing in 2021, starting from the increasing role played by artificial intelligence (AI) and automation. The use of progressive sequences of questions in automated chat conversations may help in better identifying visitors’ needs and to provide automated and selected feedback under a personal custom workflow, so to achieve an higher degree of personalisation of the customer’s journey.
Apps or websites developed by healthcare providers are increasingly becoming a reference point to find structured information for patients searching online. Telemedicine and remote care are also gaining increasing importance, as they allow to optimise the interaction with patients while keeping costs under control. According to Ethoseo, “non-intrusive methods that can educate patients about conditions and treatment options” represent an interesting opportunity for pharma companies to cooperate in order to overcome the big about of misinformation about health and medicine on the web. New strategies are also needed to win the “race” to appear within the first positions of a Google search, as the algorithms are favouring snippets containing key terms. Digital videos are expected to become an increasingly important tool to engage patients to pro-actively take care of their health conditions.
A survey on the transition to the digital model
A survey run in April 2020 by Reuters and Omnipresence on 1,365 senior professionals mostly working in pharma (82.8%) in the EMEA region (73%) and biotech, medtech/device or consumer health companies took a picture of how companies were adapting to the new digital mode of working and interactions. Investments in infrastructures are key enablers for the creation of unified platforms to be used to manage data from multiple digital channels in order to provide a true omnichannel customer experience, explained the CEO of Omnipresence, Sanjay Virmani, in an inteview published in Pharmaphorum. “If different departments are not coordinated, how can the customer get all the information they need with the proper context? And if the company does not provide that seamless experience, the customer has to glue it together themself or not get it”, he said.
According to the survey, half (50%) of the respondents expected new investments for technologies and software to occur in their company in order to improve customer interactions, while just a quarter (25%) said investments would have been directed to improve internal processes. This despite 84% said remote working will permanently increase. A decrease in budgets for medicinal conferences were also foreseen in April 2020 (75%), paralleled by growing difficulties to access face-to-face interactions (74%), the need of strong investments in customer experience (80%), and a negative expected impact on the numbers of salesforces (49,5%). Webinars and webcasts have been the mostly used channels of interactions during the Covid-19 (86,6%), followed by live remote or phone detailing (85,4%) and emails (76,6%). The great majority of respondents (78.8%) said the company performed a repurposing of marketing contents for fully support virtual engagements and have activated specific e-training sessions for salesforce (65.3%). More than half (59,4%) of participants to the survey said also HCPs who historically preferred face-to-face interactions are transitioning smoothly to remote engagement efforts.
Platforms still need improvements
The survey also presents data on the more widely diffused technologies and solutions in the pharmaceutical sector. Veeva maintains a leading position in the CRM segment (51%, vs 26% for Salesforce), while more uniform is the situation as for remote collaboration software (32% Microsoft Teams, 28% Veeva Engage, 20% Zoom). In the salesforce automation software segment, a significant 20% of respondents said the process is handled by and agency (vs using 27% Salesforce Marketing Automation,10% Adobe).
In the CRM area, 70% of the interviewed managers said CRM software still need to better convert the insights obtained from different channels into digital workflows/CRM. Another critical point identified by the survey is the need for a more agile method to insert and consolidate insights across channels (75%), and for improved method and quality for the collected data (65%). Still around one third of the respondents (29%) did not dispose of the right platform capabilities in order to achieve the complete digitalisation of sales and marketing; significantly, 47% of the sample would not support a complete virtual engagement journey of healthcare professionals, but a third (29%) said changes to CRM was under consideration.
Digitalisation in Medical Affairs and clinical trials
The Medical Affairs function is gaining a strategic importance within pharmaceutical companies, due to the role played to ensure robust development and scientific communication frameworks for the products. According to the Omnipresence’s survey, 88% of respondents said the need for medical affairs leadership in the company has never been greater than during the Covid-19. The pandemic caused many people working in commercial departments to show a more open attitude towards collaboration with medical affairs (73%); the improved perceived value of this internal function is expected in most cases (69%) to represent a permanent change within the company.
The digitalisation impressed by the health emergency had also a great impact on the modalities to perform clinical trials, as the lockdowns pushed clinical research associates (CRAs) to run remote monitoring instead of visiting the clinical centres involved in experimentation. According to the Omnipresence survey, just 44% of the respondents said the rapid implementation of digital processes allowed the company to save the majority of its trial. Half of the sample (50%) was not confident about the ability of CROs to run a fast transition on the short-term; the confidence is much greater (92%) on the long-term, with reference to the opportunities offered by digital technologies to contribute to the optimisation of the cost-effectiveness of clinical studies. This transformation will require pharmaceutical companies to run systems for the acquisition of remote consent, perform remote randomisation and remote data capture. This last action may also benefit from the wider diffusion of wearables and other devices able to collect data from remote and to generate clinical real-world evidence (RWE) to be used for regulatory purposes.
Trust in the potential of RWE is increasing both internally to pharmaceutical companies (69%) and between patients (76%),even if according to the survey specific expertise in RWE is still needed (70%). The Covid-19 experience also showed the importance of the customer response as the main source to inform the decision-making processes, together with the direct contribution of patients.
Changes in market access
According to Omnipresence, around half of respondents (47%) said Covid-19 also caused the acceleration towards the development of more innovative payment models; payers and other market access stakeholders have also become more open to innovative ways to provide scientific and clinical evidence (54,2%).
The market access experience turned to be a need also for other internal functions during the pandemic, according to 65.3% of respondents. The increasing adoption by payers of performance-based schemes and data capabilities is expected was a main outcome in the post-pandemic, with new models able to create better health outcomes for the patients (78,9%), or a permanent change of operating models expected by an half of the sample (55%).
Real-time control of the access to cleanrooms
The new industrial paradigm of digital integration is yet well established in the pharmaceutical sector, where the Industry 4.0 approach takes on the more specific declination of Pharma 4.0. «With this term, we mean the development of a holistic, systemic control strategy to manage the entire life cycle of a medicinal product, and all the factors contributing to the process», explains Dos & Donts’ CEO, Piercarlo Soana.
Processes compliant to the new Annex 1
The integrated approach is also key to the new Annex 1 to GMPs, those final version is expected to be published shortly. «Quality in a pharmaceutical process must be based on Quality Risk Management (QRM), leading to the adoption of a Contamination Control Strategy (CCS). It involves the definition of the critical elements, to then prove the effectiveness of the controls and monitor the adopted measures. This dynamic process recalls the principles of Galileo’s scientific method, and the Deming cycle (Plan-Do-Check-Act) linked to the Japanese-style “lean production” known as Kaizen», adds Piercarlo Soana. The presence of operators in sterile areas is a critical element to be considered, as it represents the main risk factor for contamination. «The number of people working in sterile rooms must be minimised, on the basis of a specific risk assessment», underlines Dos & Donts’ CEO. The design of the facilities and equipment, the utilities, the environmental monitoring and the preventive maintenance should also be considered.
A qualified staff is important
Personnel must be properly trained and qualified before receiving authorisation to enter cleanrooms. «Training must also extend to the staff responsible for cleaning and maintenance. It has to be repeated at least once a year, for example with regard to the correct dressing methods or the simulation of the aseptic process (media-fill), which represent critical elements subject to periodic evaluation», explains Piercarlo Soana. Furthermore, an additional “aseptic process qualification” is required to access grade A and B areas. Should a risk of cross-contamination be identified, Annex 1 establishes that for a certain period of time the personnel who worked in one production department cannot access a different department. «A qualified operator can become “dis-qualified” for a certain time», underlines Soana.
The importance of access control
Control of accesses to sterile areas can be achieved by use of automatic electronic systems in order to authorise a certain operation only if the operator holds a valid credential. The system tracks the code associated with each person, which also contains all information about his/her qualifications and daily actions performed within the plant. «A control system for access to cleanrooms cannot be compared to the ones used to manage payrolls. Even if the technologies are similar, their purposes are completely different, as well as the equipment used, and the functions and characteristics of the software», underlines Piercarlo Soana. «Dos & Donts access control system has been internally designed and built by our engineers; it is calibrated to reflect the needs typical of areas subject to control of contamination. Its implementation strictly follows the evolution of the legislation». The most adequate technology to track accesses to cleanrooms – also under a usability perspective – is represented by RFID (Radio Frequency IDentification). It consists of a transponder chip (tag) containing the identification code, an antenna governed by the controller and a reading unit used to read the information, that can write the tag’s memory and transmit the data to the central PC control unit.
A case-study on the implementation of access control
«Implementing an access control system is more complex than a simple supply. Teamwork involving both the user and the supplier is needed from the very early steps. Clarity on roles and objectives is a critical factor of success; it is desirable both teams are coordinated by a project leader able to monitor all phases, and to act as the collector point of information within its group», explains Piercarlo Soana. Dos & Donts has collaborated with Liosintex, an Italian company part of the Recipharm Group, to implement a new access control system specifically dedicated to two departments manufacturing, respectively, penicillins and cephalosporins antibiotics. «The need to overcome the use of paper logbooks to record entries/exits from the production departments (including a daily check at the end of each working day) emerged as the result of a inspection run by the Italian regulatory agency AIFA. The agency considered these methods not enough suited to guarantee a preventive block of access for people who had previously operated in one of the two antibiotics’ departments. We run a small manufacturing site, thus we cannot make use of dedicated staff to operate in the different areas. Therefore, our strategy aimed to implement a strong control system. With this respect, we have found a competent and reliable partner in Dos & Donts», explains Federico Barberis Negra, Plant manager and QP at Liosintex.
Planning the monitoring of entrance/exit gates
The first step in the project saw the definition of the entrance/exit gates of the two antibiotics’ departments needing for the activation of “anti-pass-through laws”. This is particularly true for the gates giving access to areas where the pharmaceutical product is exposed. «A critical issue, for example, was represented by the bulk, lyophilized powders of beta-lactam antibiotics. We had also to take into consideration the structural and dimensional constraints of the facility», explains Federico Barberis Negra. Access to the aseptic areas has been regulated by mean of a Personal Identification Number (PIN) additional to the badge, so to overcome the problem operators cannot bring any object with them in certain sterile areas. «The reading unit checks the operator did not enter another production department in the previous 11 hours. In the case of an absolute need to access, we have requested the intervention of the QA manager in order to remove the block. This approach allowed us to solve the non-compliance received from AIFA. Access control is important also from the point of view of aseptic manufacturing, as it enables the monitoring of the flows of people entering and exiting the different areas, as well as residence times. These data are then verified vs the maximum number established for each area and manufacturing step, as challenged during the process simulation». For Federico Barberis Negra, the adoption of this access control system has proved essential in order to comply with the requests of the regulatory body, avoiding divergences that could potentially cause the issuance of a non-compliance. Furthermore, the availability of a computerised register of accesses has allowed Liosintex to completely eliminate paper documentation, and to better support the editing and revision of the production documents.
About Dos & Donts
Dos&Donts is operating in the Pharma sector since the beginning of the ’90, when it specialised in the development and production of access control and automation systems dedicated to cleanrooms. Its solutions have been implemented in many pharmaceutical facilities world-wide. Following the adoption of the Industry 4.0 paradigm, since 2015 Dos & Donts is being developing a modular and scalable platform to implement integrated solutions in various fields needing for the control and security of manufacturing facilities.
About Liosintex
Liositex’s manufacturing site is located in Lainate, close to Milan (Italy); it is the Recipharm Group’s sterile facility for the lyophilisation of beta-lactam antibiotics. The manufacturing plant has been inspected and approved by the Italian Regulatory Agency AIFA (EU-GMP) and the Japanese Ministry of Health, Labour and Welfare (MHLW); it exports its productions in many international markets, including Japan.
Hungary: Logistic challenges in the pharma industry due to Covid-19
The Hungarian pharma industry is an important regional logistics hub serving mostly Eastern European countries. The sector directly employs more than 14,000 people and indirectly provides support for 34,000 families (see here more); it is represented by the MAGYOSZ association on behalf of local manufacturers, and the Association of Innovative Pharmaceutical Manufacturers (AIPM) representing 26 R&D oriented pharma companies.
The Hungarian pharmaceutical sector has been greatly impacted by the Covid-19; a new challenge has emerged on how to ensure continuous product supply through closed borders, with a shortage of workforce and prolonged lead-times for customs and border control. An issue that impacted on all European and global supply chains, and which has been analysed in many articles and studies (see for example the analysis on the food supply chain published on the Int. J. Production Res. )
The impact of Covid-19 on logistics
Covid-19 is having a dramatic effect of the health of many economies, especially in Europe, further exacerbating the recession dynamics already present before the pandemic. The global economy is expected to contract 3% in 2020, according to the IMF, thus a second wave could be expected in the incoming months as for demand.
“Today’s global value chains require greater resilience and efficiencies in the flow of goods between and within countries”, writes the International Finance Corporation (IFC), part of the World Bank Group, in its analysis on the impact of the pandemic on logistics. Big logistics players are less affected than the smaller ones, also thanks to the strong increase in services linked to the e-commerce explosion, even if players such as DHL or Ceva Logistics in April 2020 declared Force Majeure and closed contracts due to the unexpected circumstances.
According to an article by E. Mazareanu published in Statista, the gross value added by the logistics industry may fall 6.1% in 2020 due to the Covid-19 pandemic. Italy is expected to suffer the stronger impact (-18.1%), while China (-0,9%) appears to have almost completely recovered from the spring values; North American sea and air freight forwarding market is expected to contract by 12.1% and 9.5% respectively compared with 2019.
Interconnected global supply chains forms a complex network often difficult to be fully acknowledged even by central institutions (see the article on the EU Pharmaceutical Strategy in this newsletter). According to IFC, logistics costs may reach 25% of GDP in some developing economies, compared to 6–8% in OECD countries.
China is the main supplier of active, ingredients, excipients and raw materials for the pharmaceutical industry, as well as of many components used in manufacturing plants. The first wave of the pandemic, in Chinese Wuhan city, almost completely blocked exports from the country towards Europe and other global destinations. The closure of borders between EU countries characterised the second wave of Covid-19, greatly limiting the movement of goods in the Single European Market. Green lines have been established by the EU Commission to ensure delivery of essential goods, among which are pharmaceuticals and medical devices.
Ocean, land and air transportation
Ocean, land, and air are the three key global transportation segments. The first one saw in the first months of 2020 a drop of 10.1% for total container volumes handled at Chinese ports, says IFC. Other key exporter countries (e.g. Brazil, India, and Mexico) have been similarly impacted, resulting in many blank sailing (cancellation of the call of a vessel at a certain port or certain region, or the entire leg) due to the weak demand towards Europe and the US.
Even if land transports continued operations during the hot spring months, extremely long queues formed at closed borders in the EU; lockdowns and the viral infection itself and related restrictions also impacted on the number of truck drivers available for service. Food and pharma/medtech supply chains belong to the essential flow of goods preserved even during the emergency, but the impact on the components needed for manufacturing, for example, might in many instances proved to be a critical issue for many companies. Rail transport increased in correspondence to the difficulties experience by road services, mentions the IFC report.
In the US, “hot spot” areas highly impacted by the virus saw the complete disruption of local supply chains, resulting in transport of good from distribution centres located far away and in the subsequent creation of a supply/demand imbalance for trucking companies, tells KPMG’s expert Yatish Desai.
Air freight transportation was also affected by the first phase of pandemic in China (-19% in March 2020), to then recover both in capacity and volumes in the following months. According to E. Mazareanu, the weekly number of international scheduled flights declined by roughly 46.4% during the week of March 23, 2020, and of 69.9% in the week starting May 4, 2020 compared to the corresponding weeks of 2019.
The opportunity to implement new models
Cargo shipments are in many cases the only still open activities in many ports and airports worldwide, that are experiencing the almost complete reduction of passenger’s transportation. The IFC report identifies the need for a closer collaboration between governments and third-party logistics companies to solve the remaining bottlenecks and facilitate clearances. The long-term costs of transportation may increase, say the authors of the report, due to the tighter cross-border processes and controls.
New safety protocols and social distancing in warehouses have been put in place to safeguard the health of workers, but this type of intervention is considered by IFC not enough to guarantee protection against outbreaks in these confined spaces. The crisis of passenger’s flight induced many airlines to convert their aircraft for cargo in order to reduce losses, and the same might occur for many warehouses and groceries switching their focus towards more essential products.
No-contact delivery options (e.g. including robots) are also under experimentation, and investments in information technologies would be required for logistics companies to maintain their competitive position. According to KPMG, in future new operating models (e.g. 4PL and 5PL) based on the collaborative portfolio mindset may substitute the more classical insource vs. outsource provider models and benefit from the potential of AI, cognitive/ML, blockchain, drones, cloud solutions, warehouse management systems, etc.
Disruption of critical supply chains, as the pharmaceutical one, may be prevented by nearshoring (diversification through alternative partners) or reshoring (bringing home of strategic value chains), says IFC. Both these alternatives will bring to shorter supply chains, leading to countries having good manufacturing capacity (e.g. Mexico, India and Colombia) to become valuable alternatives to China.
KPMG suggests the steps to keep in mind to face logistics emergencies, both on the short and medium/long-term perspective. The availability and activation of contingency plans and an improved communication with carriers supports the prompt management of emerging issues. Key and alternative suppliers in primary and secondary locations should be also identified, as well as key transport lanes, distances, and lead times. An analysis of carrier capacity and service is useful to prevent shortfalls and constraints, and to determine mitigation strategies. New short-term contracts with third parties may help to provide additional capacity when needed. A recovery assessment of the transportation network and operations may be helpful to prepare to mid- and long-term scenarios, suggests Yatish Desai. Micro Supply Chains of strategic suppliers should be the final outcome of this exercise, which may also benefit of a modelling software analysis to better identify cost and service impacts.
The new European Education Area
The last quarter of 2020 saw the issuing of many new policies by the European Commission, among which is also the Communication on achieving the new European Education Area (EEA) by 2025. The initiative complements with the Next Generation EU and the long-term budget of the European Union for 2021-2027. The new policy will be part of the European Pillar of Social Rights, being the right to quality and inclusive education, training and lifelong learning its first principle.
According to the Communication, 100 million Europeans had to face during 2020 completely new modalities for teaching and learning. The Covid-19 pandemic had a strong impact on education in all European countries, with children, teenagers and students that in many instances had to remain home and follow online courses provided by schools and universities. Workers were also impacted, as professional training had to be postponed, run online or even cancelled. A challenge that might turn into a structural barrier making more difficult to access employment opportunities, both for young and experienced people, if not properly addressed and supported by the European legislator.
The creation of the EEA is in line with contents of the New Strategic Agenda for the EU 2019 – 2024 adopted by the European Council on 20 June 2019, and it will be coordinated with the European Skills Agenda, the renewed vocational education and training (VET) policy and the European Research Area.
The EEA will be built upon the results of the Education Training 2020, a first step initiative aimed to set common EU targets and provide a broad range of mutual learning and policy support tools.
“Education is essential to the vitality of European society and economy. The European Education Area aims to bring to the education and training communities the support they need to fulfil their fundamental mission, in challenging and exciting times”, wrote President Ursula von der Leyen in the preamble of the communication.
Six directions to redesign education and training
Quality, equality in terms of inclusion and gender, green and digital transitions, attention to teachers and trainers, higher education and the geopolitical dimension are the six domains around which the new European Education Area will be built. All of them are analysed in the Communication, starting from the need of proficiency in basic skills, including the digital ones. The importance to achieve this quality target is easily understandable if considering that in 2018 the proportion of European pupils who fail to complete basic competencies stood at 22.5% in reading, 22.9% in mathematics and 22.3% in science (data OECD-PISA). Basic skills should be also complemented with transversal skills such as critical thinking, entrepreneurship, creativity and civic engagement, a target that according to the Commission may be pursued through trans-disciplinary, learner-centred and challenge-based approaches.
In the digital era, even education will be increasingly delocalised and shared; from this point of view, the EEA shall promote the freedom for learners and teachers to be mobile and for institutions to freely associate with one another. Difficulties with transnational mobility are still experienced in many cases, as well as lack of full recognition of learning outcomes and qualifications. And no matter to say, from the language learning perspective a multilateral Europe is envisaged as a condition to improve mobility and discover cultural diversity.
National structural reforms of education systems will be supported by the EU Commission, especially in the field of curriculum and assessment; this action will also include the cooperation between stakeholders to develop policy recommendations on innovative and multi-disciplinary teaching and learning approaches for basic skills. An update of the learning mobility framework both for students and teachers and a wider implementation of the 2019 Council Recommendation on a comprehensive approach to the teaching and learning of languages are also planned, as well as the development of a European perspective in education.
The critical role of a better inclusion
A better inclusion, independent from the social, economic and cultural status, should represent be the key factor to improve educational success. From this point of view, education systems should comply with the UN Convention on the Rights of Persons with Disabilities; vocational education and training (in line with the Commission proposal for a Council Recommendation on VET) should be used to facilitate continuous education.
An improved gender sensitivity is also envisaged to support better opportunities for women, which according to the Communication are still under-represented as students in the technical fields (26% in engineering, manufacturing and construction, 18% in ICT).
Dedicated platforms for mutual learning and cooperation are the chosen tools to support sex disaggregated data collection and innovation for inclusive and gender equal education. Inclusion, equality and diversity should also play a major role within the Erasmus and European Solidarity Corps Programmes. Several actions are planned to support these goals, e.g. the Pathway to School Success to support proficiency in basic skills, and a policy guidance on reducing low-achievement and increasing secondary education attainment. An expert group will work on new strategies to develop supportive learning environments for groups at risk of underachievement and for supporting well-being at school. The fifty newly created Centres of Vocational Excellence will act as reference points for both initial training of young people and continuing up- and reskilling of adults.
The green and digital European agendas
The green and digital transitions are two main pillars of the von der Leyen Commission, also playing a social impact on how the post-Covid recovery shall be developed and implemented. It may turn very difficult in future to find a new job without at least some basic digital skills, warns the Commission: “Practically all further learning and jobs in all sectors will require some form of digital skills, yet on average two in five Europeans aged 16-74 are lacking these skills”. Furthermore, a deep change in behaviours is only possible starting from education, and it should proceed in the direction of the skills needed for the green economy. Entrepreneurship and learning to learn competences may also prove important to successfully navigate the completely new labour market.
The end of 2020 should see the launch of the Education for Climate Coalition, that will act in synergy with the European Climate Pact to provide networking opportunities and resources for teachers and students. Next year shall see the issuing of a Council Recommendation on education for environmental sustainability and the proposal of a European Competence Framework to support new skills and attitudes on climate change and sustainable development. The education infrastructures need a profound restructuring to be able to accommodate the new competencies and pedagogies, a target that may be pursued in collaboration with the European Investment Bank. The new Digital Education Action Plan shall support the expansion of lifelong learning in the field of digital technologies, while the Digital Europe Programme shall provide funding to developed advanced digital skills in key areas.
The evolution of teaching
Online teaching technologies will also acquire increasing importance, as acknowledged during the closure of schools and universities. This shift toward digital modalities to provide education should correspond to the renewal of competencies for professionals working in education. Shortages of teachers characterise many European countries, one of the main challenges to be overcome in order to achieve the EEA. A better social and financial recognition would also be needed to ameliorate the value of teachers perceived by the society, together with more opportunities of training on new skills.
Actions to support competence development and career paths shall include the launch of the Erasmus Teacher Academies in 2021 and a European guidance for the development of national career frameworks in 2021-2022. The establishment of a European Innovative Teaching Award will also help to recognise highly valuable teachers.
Mobility is an added value for higher education
Study-abroad experiences, such as the Erasmus+ programme, have proven fundamental to improve the chances to rapidly find employment opportunity just few months after graduation. The number of students that can access this kind of international mobility offer is still very low (< 5%) and new models of cooperation between institutions across the EU are under experimentation (with involvement of 41 universities pilots and 280 institutions).
Joint curriculum development and common courses are among the targets of the EEA in this area, together with the development of a pan-European talent pool. A dedicate policy framework should facilitate transnational cooperation between universities, which are also expected to evolve to become “knowledge squares” and key actors in the educational play field. With this respect, an automatic recognition of qualifications and study periods abroad should also be pursued, as well as the recognition and portability of short courses leading to micro-credentials. Advanced courses in the key area of artificial intelligence, cybersecurity and high-performance computing are also needed to make available highly skilled experts for the digital transition.
An online public consultation is planned to start the process that should lead to a transformation agenda for higher education by the end of 2021. New higher education curricula for engineering and ICT based on the STEAM49 approach shall also be developed, as well as a European Degree that could support the improved implementation of educational services provided by transnational Universities alliances. The Commission will explore the necessity and feasibility of a legal statute for such alliances, e.g the European Universities.
Mobility of students shall be supported by the availability of the Erasmus+ Mobile App, a digital tool that is expected to represent a one-stop-shop for students and a great form of simplification for universities, to be implemented within the European Student Card initiative. The automatic recognition of a qualification awarded in one-member state in any other member state for the purpose of accessing further learning activities should become possible by 2025. The European graduate tracking initiative is expected to record the employment history evolution of 80% of graduates by 2024.
Soft power to implement the geopolitical agenda
Educating young people on the key principles of the new vision of the European Union and cooperation in education among member states are key tools to smoothly implement the new EU external policies. Improved connectivity among people shall inspire the spreading of the European fundamental values world-wide, thus contributing to shape the relationships with extra-EU countries. “In the international dimension of the European Education Area, reciprocity, level playing field, as well as ethical and integrity standards will be a central part of the roll-out of ambitious partnerships with partner countries across the globe”, writes the Commission.
VET, the sector of youth and tertiary education of people from third countries coming to the EU to complete their studies are identified among the first priorities. The ability to attract the best international talents and to promote peer learning and joint international research and innovation projects are also foreseen. The availability of a new Team Europe approach should support greater cooperation with member states on EU’s external activities of education and training institutions, strengthening its positioning as a partner at global level. An Erasmus Mundus Joint Master’s Degrees is expected to boost EU’s attractiveness and international partnerships.
Comments from the stakeholders
Positive remarks on the Commission’s EEA vision have been published by Cesaer, the association representative of European universities. The document also suggests three other lines of intervention in order to further deploy the full potential of the EEA initiative.
Advance research-based education and training and scientific and technological excellence should inspire the selection and funding of projects under the Erasmus programme and the funding of European University alliances. Universities should also play a stronger role in lifelong learning, for example in the form of validation of non-formal and informal learning, flexible learning pathways and micro-credentials, and support the reinforcement of Mathematics, Informatics, Natural Science and Technology (MINT), and Science, Technology, Engineering and Mathematics (STEM) skills of students and teachers of the secondary education level.
The knowledge society may benefit of an improved leadership for universities, which may also turn useful in supporting the transition towards the digital and green agendas. On a broader perspective, the international potential of the EEA should include all the signatory countries of the European Cultural Convention and allow for partnerships with neighbouring countries, is the suggestion of Cesaer. Universities alliances should not represent the only possible form of collaboration, and networking should include also extra-EU counties such as Israel, Norway, Serbia, Switzerland, Turkey, Russia and the United Kingdom. Funding availability, particularly for the Erasmus programme, remains a critical factor to ensure the proper implementation of the EEA, both at the central, national and regional levels, together with a simple and clear governance structure for the Area.
Regulatory sandboxes to experiment real-world innovation
Real-world experimentation of new pharmaceuticals is gaining increased importance, and it requires the implementation of a new reference framework to better define from the regulatory point of view the structural features to be put in place in order to ensure full compliance of trials. Real-world experimentation is not limited to the pharma sector, as it is becoming a widely diffused approach for the testing of many new technologies, especially in the digital field.
Regulatory sandboxes are the tool envisaged by the European legislator to achieve this objective; they are intended to allow – for a limited time and in a limited part of the area under regulatory supervision – the real-world experimentation of innovative technologies.
The European Council adopted on 16 November 2020 its conclusions on the role regulatory sandboxes and experimentation clauses are expected to play in an innovation-friendly, future-proof, sustainable and resilient EU regulatory framework. The conclusions are part of the Council’s effort to support the availability of transparent, simple and highly efficient regulatory tools as one of the key drivers for Europe’s future growth. The request to the European Commission is to implement a broader use of experimentation clauses on a case-by-case basis during the drafting and reviewing of all new legislation. Results of the ex-post evaluations and fitness checks based on an exchange of information on existing experimentation clauses between member states should be presented in the first half of 2021 under the Portuguese Presidency, suggests the Council, while final results and practical recommendations on the possible future of regulatory sandboxes and experimentation clauses at EU level may be released in the second half of 2021, under the Slovenian Presidency.
The main objectives of the regulatory sandboxes
An agile and evidence-based framework to support the recovery of European businesses in the post-Covid — with a particular attention to small and medium sized enterprises (SMEs) – is identified by the Council as a fundamental instrument needed to achieve a fully functioning EU Single Market, and preserving at the mean time both citizens and businesses.
In the design of regulatory sandboxes, the “Innovation Principle” should pair with the subsidiarity, proportionality and precautionary ones to inform and review European policies in all domains. To this instance, sharing of best practices among member states and the Commission should follow the example put in place in 2017 by the Maltese Presidency of the Council, is the suggestion. The final goal would see the availability of a new, flexible, future-proof regulatory ecosystem able to fully sustain European competitiveness and growth, as well as technological sovereignty and sustainability. This direction of future development was already highlighted by the November 2019 “Study supporting the interim evaluation of the innovation principle” and the Commission’s Science, Research and Innovation Performance Report 2020. Pilots of regulatory sandboxes were also encouraged by the Commission in its Communication on the new SME Strategy.
A new framework to test innovative products and services
Regulatory sandboxes are expected to provide a structured context for the real-world experimentation of innovative technologies and services, especially those related to digitalisation. The new approach should involve just a selected part of the target sector for a limited period of time, in order to guarantee the appropriate safeguards and regulatory supervision.
The legal basis for regulatory sandboxes is represented by experimentation clauses (already used by many member states), to be activated on a case-by-case basis in order for the authorities to guarantee flexibility. This is especially true in the case of emerging and potentially disruptive technologies, where regulatory sandboxes may prove the best tool to test early stage approaches and develop real-world knowledge to be used to draft new policies.
The Council’s communication suggests the use of experimentation clauses and the impact of regulation on innovation to be assessed by the Regulatory Scrutiny Board. An overview of the main existing experimentation clauses already existing in the EU law should be also carried out by the Commission, as a preliminary exercise to identify new possible areas and regulations where to implement this legal instrument. The Fit for Future platform (F4F) or targeted consultations are the tools suggested to involve member states in the development of the new approach.
The central role of digital technologies
Artificial intelligence and blockchain technologies have become the new normal in many different sectors, and their role is gaining increased importance also in healthcare management in order to support the availability of improved services for patients while safeguarding the sustainability for governments and payors.
According to the Council’s document, a first pan-European blockchain regulatory sandbox developed by the EU Commission in collaboration with the European Blockchain Partnership may become operative in 2021/22. Other regulatory sandboxes are also planned to be activated in Greece, Estonia and Poland within the structural reforms managed with the supervision of the DG for Structural Reform Support and the European Bank for Reconstruction and Development.
The EU Commission published the new Pharmaceutical Strategy
The long waited new Pharmaceutical Strategy for Europe was finally published on 25 November 2020 by the EU Commission: a fundamental act that will inspire legislative and non-legislative actions in this key sector for the European economy for coming years. The Strategy builds upon four different pillars, including access to affordable medicines and attention to unmet medical needs, supporting competitiveness, innovation and sustainability of the EU’s pharmaceutical industry, enhancing crisis preparedness and response mechanisms, and promoting a high level of quality, efficacy and safety standards worldwide.
“The coronavirus pandemic has highlighted the vital need to strengthen our health systems. This includes access to safe, effective and high-quality medicines at an affordable price. In the challenging economic and social times the EU is currently facing, the strategy adopted today will ensure that Europe and Europeans will continue to benefit from such medicines. I call on member states and the Parliament to endorse this approach which will be rolled out in the next three years, and beyond”, said President Ursula von der Leyen.
“With our Pharmaceutical Strategy for Europe, we are delivering on our commitment to create a future-proof and patient-centred pharmaceutical environment in which the EU industry can innovate, flourish and continue to be a global leader. It is our long-term vision for open strategic autonomy, and our response to the challenges of today and the vulnerabilities exposed by Covid-19”, added Stella Kyriakides, Commissioner for Health and Food Safety.
Breaking down all barriers
Despite the many advances in pharmacological treatments made in the EU during the past 20 years, still many barriers prevent a sustainable access to medicines. Unavailable or unaffordable products continue to represent an issue for many people, and further vulnerabilities emerged as a consequence of the Covid-19, e.g. data availability, shortages and manufacturing capacities. The pandemic has also represented a sort of testing exercise for improved forms of cooperation among stakeholders, for example in the case of the advance purchase agreements for vaccines signed by the Commission on behalf of member states.
The new Pharmaceutical Strategy aims to overcome these barriers, and to fully enable the additional potential arising from the implementation of the digital technologies to further increase competitiveness. According to the Commission, the European pharmaceutical industry provides 800 thousand direct jobs and a €109.4 billion trade surplus, and saw over €37 billion contribution to research investment in 2019. The starting point for the future evolution of the second pharmaceutical market in the world is represented by the very robust European regulatory framework, which already supports drug development and commercialisation.
The Pharmaceutical Strategy will act in synergy with other pieces of legislation from the von der Leyen Commission, including the Europe’s Beating Cancer Plan, the Zero Pollution ambition part of the European Green Deal, the strategy on Shaping Europe’s digital future, the creation of a European health data space and the European One Health Action Plan.
New approaches for unmet medical needs
The development of new antimicrobial agents is the priority area of unmet medical need addressed by the Pharmaceutical Strategy, together with rare diseases (in the field of neurodegeneration, paediatric and rare cancers) which are often not attractive for the industry to invest on.
The 2021 should see the launch of the first flagship initiative aimed to testing new approaches to provide incentives for the development of novel antimicrobials and new public procurement schemes for this type of medicines. Planned actions include the proposal to revise the paediatric and rare diseases legislations to include tailored incentives. EMA’s PRIME scheme for priority medicines may be included in the regulatory framework in order to expedite the approval of new products in areas of unmet need. Joint meetings with participation of existing committees/networks of regulators, health technology assessment (HTA) bodies and payers should favour a better collaboration between different institutions. In particular, a parallel scientific advice on clinical study design by EMA and HTA bodies may be considered in the context of the new HTA Regulation.
The promotion of investment and the coordination of R&D, manufacturing, deployment and use for novel antibiotics will be managed by the newly established European Health Emergency Response Authority (HERA, see below). The EU’s pharmaceutical legislation may be also reviewed to restrict and optimise the use of antimicrobial medicines. Non-legislative tools that might be used to tackle antimicrobial resistance include harmonisation of product information, draft evidence-based guidance on existing and new diagnostics, promotion of the prudent use of antibiotics and communication to healthcare professionals and patients.
The Commission also supports early collaboration between scientific disciplines on R&D, including regulators, academia, healthcare professionals, patients’ organisations and healthcare providers and payers. This should facilitate the breaking of the still existing silos that slow down the development and approval processes of new medicines. New forms of information sharing, such as horizon scanning, are advised as useful tools to complement cross-country collaborative approaches in public procurement and joint pricing and reimbursement negotiations, while waiting for the adoption of the proposed HTA Regulation.
How to favour access to medicines
The fragmented availability of a certain medicinal product in different EU’s national markets is due to many different factors, from market size to pricing and reimbursement policies, from size of the population to type of healthcare systems. High pricing of innovative medicines is often related to a lack of transparency in R&D costs or return on investment, and it may be tackled by mean of innovative payment approaches, such as risk-sharing arrangements and deferred payment schemes.
The Commission also aims to revise the system of incentives to possibly include greater ‘conditionality’ in relation to intellectual property rights to support broader access for patients and increase competition. Root causes of deferred market launches will be investigated in a pilot project; attention will also be paid to favour greater generic and biosimilar competition through interchangeability and clarification of the ‘Bolar’ provision to conduct pre-approval clinical studies on patented products.
Review and enforcement of EU competition rules and innovative procurement procedures seeing a closer cooperation of buyers (as already done in the Big Buyers initiative) are other tools announced by the Pharmaceutical Strategy. Competent authorities will also be called to share their best practices on pricing, payment and procurement in order to improve affordability, cost-effectiveness and sustainability of healthcare systems. Guidelines on principles and costing methods for establishing R&D costs may also favour better access for patients.
The support to innovation
The Pharmaceutical Strategy closely complement the Commission’s Intellectual Property (IP) Action Plan with regard to the review and simplification of EU’s pharmaceutical IP system, with a particular attention to supplementary protection certificates (SPCs) which are expected to become more transparent and efficient.
Access to interlinked systems of comparable and interoperable health data will prove key to sustain research and innovation, as well as evidence generation and efficient regulatory processes. The European health data space and its related interoperable data access infrastructure go in this direction to allow secure cross-border analysis of health data while safeguarding individuals’ rights to privacy and data protection.
Specialised skills are needed to advance towards these goals, and they will benefit of the initiatives planned under the new European Education Area (see the dedicated article in this newsletter). Funding will be provided through different sources, including the EU4Health programme, Horizon Europe, Cohesion Policy, the European Defence Fund, and public-private and public-public investment partnerships. Special initiatives to support small and medium sized companies are included in the SME strategy for a sustainable and digital Europe and Startup Europe.
New tools for innovative therapies
Gene and cellular therapies and vaccines will continue to represent key factors of innovation in the pharmaceutical pipelines. New business models may be required to accommodate the increasing trend of more personalised, one-time treatments of patients under a “bedside” manufacturing of individualised medicines perspective. Platforms based on data sharing agreements shall support the identification of new therapeutic approaches and data analysis, also assisted by artificial intelligence (AI). Access to genetic data is planned in order to develop new prevention strategies; the secure federated access to 10 million genomes across EU’s borders should become possible by 2025 in order to use them for R&D, clinical application and personalised medicine.
Artificial intelligence may also support the identification of new drug substances and the repurposing of the already existing ones, thus reducing the risk of failure for the pharma industry. Digital therapeutics and app-based platforms may be especially useful to treat chronic diseases from remote; the combination of medicines and medical devices is another rapidly expanding area needing a better tuning of the relevant legislation and clarification of roles and responsibilities of the different parties involved in the development and approval processes.
The full implementation of the Clinical Trials Regulation will allow to reach a harmonised, more transparent and coordinated approach to the assessment of clinical data. New study designs will also be explored, including pragmatic trials, where the treatment is prescribed and used as in normal daily practice.
New roles for the regulatory agencies
The role of the robust network formed by the European Medicines Agency and national competent authorities under the Heads of Medicines Agencies may receive a full, formal recognition by the Commission. The reviewing of the regulatory legislation may lead to new approaches to assess scientific evidence supporting applications while reducing approval times. The experience with the rolling reviews for Covid-19 treatments is just a first example, that will be used to further expand the initiatives in this key area.
A study on the authorisation and monitoring of medicines for human use is also planned as a prerequisite for the simplification of procedures (e.g. for variations management) and regulatory costs. EMA fees system should be revised. A critical area in regulatory assessment to be evaluated during the review of the current legislation is represented by the requirements needed to authorise medicines for human use containing or consisting of genetically modified organisms (GMOs).
Other planned actions include the possible introduction of a single active substance master file for substances to be used in different generic medicines, so to run a single assessment process across member states, and the upgrade of the Commission’s Union Register of centrally authorised products to include a statistical dashboard and make data fully available for secondary use. Electronic product information (ePI) should also become the standard for all EU medicines.
Secure supply chain to prevent new crisis
The Covid-19 has highly stressed the resilience of the European pharmaceutical supply chain at a grade the EU Council has recognised that “achieving strategic autonomy while preserving an open economy as a key objective of the Union”.
The Pharmaceutical Strategy third pillar aims to better identify root causes for shortages and dependencies in health. Diversification of manufacturing and supply, and strategic stockpiling are two options available to improve the current situation, to be operated in parallel with the support to new investments in Europe. Reinforcing the obligation for continuous supply is also envisaged, based on a revision of current legislation; earlier notifications, enhanced transparency of stocks, and a stronger coordinating role for EMA in monitoring and managing shortages may represent possible future actions.
Enhanced cooperation between member states, for example for joint procurement for critical medicines, and making available at the EU level tools and instruments on prices and reimbursement to be used by countries are other examples.
The importance of GMPs
A major criticality emerged during the pandemic is represent by the fact many technologies needed to manufacture pharmaceutical active ingredients and intermediates are no longer available in the European Union, thus supplies come from extra-EU countries (e.g. China and India). Lack of access by regulators to complete information about the structure of the manufacturing and supply chains proved to be a critical issue to be solved during the Covid-19 emergency.
A structured dialogue with all stakeholders will initially be pursued by the Commission in order to gain better understanding of the functioning of global supply chains and identify specific causes and drivers of vulnerabilities. Results from this exercise will support the proposals of new measures and policy options useful to secure the supply of critical medicines, active ingredients and raw materials. Dialogue with WTO members will also help to improve the predictability of the trading environment in health products, on the basis of increased cooperation of trade partners to avoid unnecessary disruptions. A better transparency of the supply chain will be encouraged by favouring the voluntary adhesion of its different actors. Funding within the EU4Health programme will support the development of guidelines and the availability of tools to address structural shortages.
HERA will add to EMA and the ECDC
The European Health Union package, the first response of the Commission to increase preparedness and resilience to cross-border health threats, redesigns the landmark of European agencies in the health sector.
EMA will expand its role to act also as central hub for scientific excellence in order to better coordinate all scientific advice and evaluation procedures, and to prevent shortages by mean of an improved assessment and monitoring of the supply capacity.
The European Centre for Disease Prevention and Control (ECDC) will also find a new vocation in providing support for epidemiological surveillance and scientific recommendations for appropriate health measures to be implemented.
The new European Health Emergency Response Authority (HERA) shall be established within the announced Regulation on serious cross-border threats to improve preparedness and response; this agency will act as a coordinator of operations along the entire value chain in case of a new crisis. Horizon scanning and foresight will be its main tools to anticipate new threats and enable new technologies. HERA will also be involved in production capacity monitoring and pooling and in the development of crosscutting technological solutions (e.g. vaccine platform technologies). In order to set up HERA’s activities and organisation, the Commission will run a preparatory action focused on emerging threats to human health, and will launch an impact assessment and consultation on the establishment of an EU authority, with the target to release the mandate proposal in 2021.
An eye to the Commission’s green agenda
Looking at the Commission’s green agenda, the robust implementation of good manufacturing and distribution practices is considered essential to prevent new occurrences similar to the nitrosanime’s one, which led to an extensive risk assessment (and in some case testing) of all medicines present in the European market. Increased capacity for inspection and audit programmes and a better collaboration with international partners is mentioned in the Pharmaceutical Strategy, as well as a feasibility study to improve information in existing databases or linked repositories pertaining the status of production sites.
Decentralised and continuous manufacturing are emerging technologies that will be strictly monitored to better assess their regulatory impact. A stronger Environmental risk assessment may become integral part of the regulatory documentation in support of a marketing authorisation.
Waste management is another priority of action which complements the EU Green Deal zero-pollution target in order to limit emissions or residues of pharmaceuticals in the environment. Separate collection of household hazardous waste, reduction of pack sizes and realignment to real use, and use of safer chemicals as raw materials for production are among the foreseen actions.
Strengthening of EU’s international leadership
The European framework governing pharmaceutical development and commercialisation often represents a leading standard to inspire other countries in setting up and operate their own systems. The leading role played on different levels by the Commission, EMA and national competent authorities will continue in future years, for example to make more attractive the procedure for issuing opinions on medicines intended exclusively for markets outside the EU. and convergence will be pursued through participation to the International Pharmaceutical Regulators Programme (IPRP) and the International Coalition of Medicines Regulatory Authorities (ICMRA). Higher quality levels, efficacy and safety standards should be the common target in order to facilitate global development of pharmaceuticals.
Newsstand
-
NCF International n.2 - 2025
-
NCF International n.1 - 2025
-
NCF International n.3 - 2024