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Giuliana Miglierini

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A new Strategic Agenda for cell-based interceptive medicine

Giuliana Miglierini
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A new Strategic Agenda for cell-based interceptive medicine

It might sound a paradox saying that cells are deeply impacted by diseases. It is not if considering the resolution available up to now to study the mechanisms underlining the development and progression of the pathological condition. A complex network of interconnected biochemical pathways are often involved in the onset of a disease, thus it may result difficult to isolate and target its exact cause with the pharmacological treatment. This difficulty is further exacerbated by the low resolution used to study multifactorial disease mechanisms and the therapeutic effects of the administered drugs, as diagnostic methods usually gives a picture at the level of the impacted organs or tissues. A mean signal is thus obtained, representing an average value measured taking into consideration the total of cells.

The ambitious goal to obtain a high resolution picture of the disease at the single cell level is the main objective of the LifeTime initiative, which has just launched its ten years roadmap research programme aimed to integrate single-cell multi-omics, imaging, AI-based technologies and personalised medicine models (e.g.organoids) to analyse large molecular and clinical datasets in order to identify new molecular mechanisms, predictive models of disease progression and new therapeutical targets.

The LifeTime initiative is one of the six preparatory actions selected in 2018 by the European Commission to address major technological and societal challenges in the areas of ICT (information and communication technology), health and energy. The Commission will also integrate the concepts described in the roadmap to plan contents of the new Horizon Europe research programme. The LifeTime Consortium includes more than hundred members, among which  leading European laboratories, institutions in the field of computational technologies and infrastructure, bioethicists and important clinical scientists, plus 80 private companies, patient organisations and European scientific societies. The network is coordinated by Nikolaus Rajewsky (Max Delbrück Center, Germany) and Geneviève Almouzni (Institut Curie, France).

The new research field of cell-based interceptive medicine

The identification, pharmacological targeting and monitoring of single cells involved in a specific disease may represent a future breakthrough innovation impacting on how new therapeutic options will be developed by the industry and administered to patients. These last shall be approached under an ethical and patient-centered vision requiring the fine-tune coordination of interactions across academia, hospitals, patient-associations, health data management systems and industry. 

The Strategic Agenda of the LifeTime initiative has been presented in a paper published in Nature, available on the initiative’s website. Key areas of research will initially include cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases. The interception of the molecular determinants of the disease at the single cell level is the final goal, giving rise to a completely new branch of medicine known as “cell-based interceptive medicine”.

The new approach is expected to better address the mechanisms responsible, for example, for the low response to certain treatments, or the development of resistance against the drug substance. A better prediction of the cells’ behaviour should favour the development of more effective and less invasive or aggressive treatments, especially for chronic conditions. “Timely detection and successful treatment of disease will depend crucially on our ability to understand and identify when, why, and how cells deviate from their normal trajectory”, write the authors of the Nature paper.

A better knowledge of the disease heterogeneity in tissues is the looking forward that will inspire the research run within the LifeTime initiative. This target has been already vertically addressed under the activities of the Human Cell Atlas Consortium, but it now requires to be further studied under a longitudinal perspective to span the entire life of a patient. The data arising from large cohorts of patients should be then integrated, a very complex challenge considering the extremely high number of different phenotypes possible. 

The main technologies under the lens

Identification of early biomarkers indicative of the possible entrance of cells into a disease trajectory, together with a better understanding of the molecular aetiology of the same disease may support the easier selection of the better treatment available for a certain patient. The identification of new diagnostic and therapeutic molecular targets shall be supported by the extensive use of transcriptomics to create reference atlas of normal and pathological tissues. Data will then be integrated with additional information about chromatin accessibility, DNA methylation, histone modification, 3D structural organisation of the genomic materials and presence of mutations. Information about proteomes, lipidomes and metabolomes shall also contribute to better characterise the profile of the specific patient. Spatial mapping of the different cell types may benefit of advanced imaging techniques, while cell lineage tracing may help the monitoring of the information along time life. 

This heterogeneous pool of data requires the availability of advanced IT infrastructures to be stored, analysed using machine learning and elaborated, while also ensuring the interoperability of different data types (including those contained in electronic clinical records). This challenge will require the LifeTime initiative to collaborate with European and national legislators to include molecular data into the electronic health records, using interoperable standards and formats. “Machine learning and advanced modelling approaches will be used to integrate and analyse the different layers of cellular activity, and can generate multi-scale and potentially even causal models that will allow us to infer regulatory networks and predict present and future disease phenotypes at the cellular level”, states the Nature’s paper.

A Launchpad to identify priorities

The five areas forming the initial set to be addressed by the LifeTime initiative have been selected using the Launchpad tool, a mechanism developed to systemically identify medical challenges which may benefit from the integrated approach of studying the underlying mechanisms of the disease. 

The first ten years targets have been selected by working groups formed by experts in the different therapeutics areas on the basis of established selection criteria. These include the impact on society, evidence for cellular heterogeneity, availability of samples from biobanks, relevant preclinical models, existence of patient cohorts (also enabling longitudinal studies), clinical feasibility and ethical considerations, and alignment with national and EU funding priorities.

In cancer, the project will tackle early metastatic dissemination and therapy resistance, while early events in the onset of the disease will be the main focus in the neurological area. Infection mechanisms and development of the host response will characterise activities in the area of infectious diseases, in order to develop new precision immune-based therapeutics. Understanding the impact of cellular heterogeneity in the development and progression of chronic inflammatory diseases is expected to support a better prediction of the outcomes for available treatments. Understanding of abnormal cardiac cell structures and functions should support early diagnosis and therapy of cardiovascular diseases. 

Three distinct phases will characterise the activities, starting with addressing the identified challenges with the already available technologies and methods. The further development of new technologies will represent the second phase, to finish with their application for the longitudinal analysis of patient samples and the development of patient-derived models combined with machine learning to generate predictive models of the disease.

Patients may in future be stratified on the basis of a risk analysis using specific predictors and biomarkers. The activation of an experimental design working group is also planned in order to guarantee for the availability of systematic procedures to be used in all cases for the acquisition of samples and the definition of  clinical cohorts of patients. 

Thematic clusters to optimise the effort

The complexity of the activities planned in the roadmap will be addressed through the creation of a multidisciplinary network of LifeTime Centres across Europe, each one aggregating complementary thematic clusters and working in close coordination with hospitals. Data collection and usage will benefit of the expansion of the European Open Science Cloud (EOSC) and the EuroHPC providing high-performance computing capacity. The network of the European Life Sciences Research Infrastructures will also be involved, in order to avoid duplication of efforts. A joint Data Coordination Centre will be responsible for the transparent control of the access to data, their compatibility and standardisation. 

The ethical impact of the innovation resulting from the LifeTime initiative shall be assess in real time by mean of a parallel ELSI (ethical, legal and societal issues) programme, with the final goal to improve citizens’ trust. The introduction of the new methods in the clinical practice will also need to train health professionals through an extensive Education and Training Programme, as well as updating the infrastructures. “Bench to bedside and back” will be the paradigm of the new approach to education, with researchers and clinicians to exchange and communicate each other their respective perspectives and needs.

Updates on the activities of the EU’s Pharmaceutical Committee

Giuliana Miglierini
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Updates on the activities of the EU’s Pharmaceutical Committee

The EU Commission’s Pharmaceutical Committee held on 21 October its 90th (virtual) meeting, which saw also the endorsement of the action plan on the vulnerability of the global supply chains. Other points of the agenda included the discussion of the new EU pharmaceutical and vaccine strategies and the action plan of pharmaceuticals in the environment. 

How to improve the European supply chain’s resilience

The critical dependance of the supply of pharmaceutical active ingredients (APIs) and excipients mainly from extra-EU countries has emerged from the Covid-19 spring emergency as one of the most critical key point needing to be addressed by the European Commission by mean of a completely new vision of both fluxes of goods and availability on internal manufacturing capacities to face new potential threats that may hamper the distribution of many critical medicinal products on the internal market (see more here). 

An “Ad-hoc working group on the vulnerabilities, including dependencies, of the global supply chains” for pharmaceutical active ingredients (APIs) was established during the 88th meeting of the Pharmaceutical Committee, in order to assist in the development of new solutions to be included in the incoming Pharmaceutical Strategy. It includes representatives from Germany, Poland, The Netherlands, Czech Republic, Ireland, Malta, Denmark and Spain, and the European Medicines Agency; the first meeting of the group, on 16 September 2020, saw the participation also of many other member states. Other national departments and agencies which may contribute alternative and complementary points of view on the problem of supply chain security – including industrial, research, procurement, trade, and competition – are also entitled to participate to next meetings of the ad-hoc working group. The initiative shall act as the reference point for the exchange of information on identified vulnerabilities between member states, and it shall be responsible for the coordination of all actions at the European level to tackle the insufficient supply of medicinal products destined for the EU.

As discussed during the 88th meeting of the Pharmaceutical Committee, a multidimensional approach to the issue of vulnerabilities and dependencies of supply chains is needed, in particular with reference to the possible impact on the regular supply of essential medicines and on public health. Another moment of discussion on the same issue also occurred during the informal Health Council on 16 July, under the German presidency. 

A better transparency of the EU’s manufacturing capacity and more incentives for supporting it within the already existing funding instruments were the main suggestions coming from member states, as well as more inspection on the suppliers of active ingredients. The report summary of the meeting indicates that self-reliance is not the envisaged outcome and the final goal should be the security, resilience and diversification of the EU supply chains. To this regard, essential medicines (including broad-spectrum antibiotics) should represent a strategic product for the European manufacturing framework. The proposal of a strategic approach to define what to be considered an “essential medicine” and create a list of these products has found the agreement of many member states. 

Pharmaceuticals in the environment

The ad-hoc working group on pharmaceuticals in the environment will operate to provide recommendations for the initial period 2020-2023 (it can be further extended) in the field of human medicines and with respect to the action to reduce the spreading of medicinal products in the environment set forth by the Commission Communication of 11 March 2019 (COM(2019) 128 final) (find more here).

Exchange of best practices and the possible development of guidelines for healthcare professionals to instruct the prudent use of medicinal products is scheduled for years 2020-2022, together with the exploration of the possible inclusion of environmental aspects in medical training and professional development programmes. This line of work will be led by The Netherlands. Members states will be then called (2021-2023) to exchange best practices also on how to include these aspects into the advertising and prescription of medicinal products, and more generally in the choice of the therapy.

Optimisation of package size for medicines is considered fundamental in order to reduce waste, while ensuring the appropriate quantity is dispensed to patients to cover the entire treatment. This action will be led by France, and it will be followed by the consideration of how healthcare professionals can improve the disposal of medicinal and clinical wastes and the collection of pharmaceutical residues. A preliminary activity led by Spain will assess the implementation of current collection schemes for unused medicinal products, and how to increase both public awareness and producers’ responsibility. 

A more uniform approach in the risk assessment on human medicines which fall under the responsibility of member states will be the target of the action led by Germany along the entire period of the action plan. 

Barriers to generic and biosimilar entry on the market

Giuliana Miglierini
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Barriers to generic and biosimilar entry on the market

It’s time to completely redesign the European framework governing the life cycle of medicinal products, from R&D to dispensation. While still waiting for the European Commission to publish its new Pharmaceutical Strategy, the debate is flourishing between stakeholders on how to optimise the new system. 

The announcement of the Pharmaceutical Strategy should also parallel the launch by the EU Commission of the IP Action Plan, within which open issues such as the updating of the regulation on Supplementary Protection Certificates (SPCs) should also be addressed. 

Many barriers are still affecting the timely entry of generic and biosimilar medicines in the market, which have been discussed in a webinar organised by Medicines for Europe that saw the participation of experts also from DG Grow and DG Competition and of the the Polish government.

The association representing the European generic and biosimilar industry has published a white paper to deeply analyse the many factors which may impact the launch of a new off-patent medicine, and conversely the ability of the producing company to compete in the EU market. “This white paper informs stakeholders on IP issues that limit the full potential of the generic and biosimilar medicines sector. The paper provides clear legal alterations and competition law recommendations for policy makers to initiate reforms in the upcoming EU pharmaceutical strategy and Intellectual Property Action Plan”, said Medicines for Europe General Counsel and External Relations director Sergio Napolitano.

Many strategies to delay generic competition

“Evidence suggests that the patent system is being exploited to artificially extend the duration of the monopoly beyond the period for which it was originally designed”, states the white paper. The European Parliament in March 2017 voted a Resolution on EU options for improving access to medicines in which it was deploring the litigation cases aiming to delay generic entry. Two reports examining the problem were then issued in 2018 (see here) and 2019 (here) by the EU Commission.

The white paper, authored by Pinsent Masons and co-sponsored by Medicines for Europe and Accord Healthcare, describes the many different strategies the innovator industry often uses to delay the entry of generic and biosimilar competitors in the market.

Secondary patents, for example, are widely used to create the so-called “evergreening” strategies. Patent thickets (where multiple “follow-on” overlapping patents cover different aspects of the same product and may be filed in multiple jurisdictions) were already mentioned in the 2009 report published by the EU Commission following the Inquiry run in 2008. 

Patent thickets may include protection of polymorph or hydrated forms of the active substance (API), its salts or isomeric forms, a substantially pure form of the API or an impurity formed in the manufacturing process, formulations, different concentrations of dosage forms, the manufacturing and analytical methods, the use in specific patients groups or for diagnosis, or a second medical use. “The practice of creating a ‘thicket’ of patents around devices is particularly problematic in the biosimilar space, where it is difficult for biosimilar companies to switch between devices”, says the white paper.

The proliferation of divisional patents

Divisional patents – deriving from an earlier parent application – are often used to overcome the unity requirement for patentability. Recent examples discussed in the 2019 report on Competition Enforcement in the Pharmaceutical Sector (2009-2017) published by the EU Commission include Pfizer’s glaucoma drug Xalatan and Boehringer Ingelheim’s patents on treatments for chronic obstructive pulmonary disease (COPD). 

Divisional applications have the same date of filing of the parent one and their contents cannot exceed the scope of the earlier application. The association of this practice with patent thickets results in the great increase of the risk of patent infringement, as a foggy network of related application is created. Divisional applications may be filed at any time while the parent application is pending, and they may maintain validity even after expiration of the first patent. This is also true in the case generic and biosimilar companies have already filed the application for marketing authorisation (MA), or have even launched the product, thus creating a great burden of uncertainty. “This can also be seen in patents covering routine clinical studies, adverse effects or dose adjustments that cannot be carved-out from the SmPC. Recently, we have seen an increase in the number of parent patents being abandoned before an adverse decision is made in appeal proceedings, sometimes even at the oral hearing itself, in favour of divisionals that are at early stage of examination or recently granted” is the comment by a member of Medicines for Europe reported in the white paper.

Opposition before the European Patent Office (EPO) or revocation actions at national courts can be filed only upon granting of the innovator’s patent, thus leading to great delays in market access. “A patentee can choose to maintain the legal uncertainty by keeping a series of divisional patent applications pending for an extended period of time. Every time one patent approaches grant, another may be published and thus restarts the lengthy grant process creating an interminable version of legal ‘Whack-A-Mole’ ”, state the white paper.

The document also addresses the process known as “divisional game”, leading to filing of “cascades” of divisional patents and their exploitation before the EPO and national courts. This complexity may be overcome, as proposed by the white paper, through the imposition of specific time limits for the filing of such patents, especially with respect to the third, fourth, fifth etc generation divisional patents. The analysts considers less useful the “Arrow declarations” introduced for example by UK and Dutch’s courts to declare a certain product or process is not new or it’s obvious at a specific point in time. Other countries, i.e. Italy and Germany, have enforced their own vision of “unfair competition” to prevent the illegitimate use of a legitimate right. The availability of increased resources for EPO to reduce the time needed to reach granting of patents is also envisaged. 

Medicines for Europe also suggests the possible revisions of the European Patent Convention, for example in order to decide within a unique opposition or appeal proceeding the validity of an entire family of patents. Appropriate compensation by the patentee in the case no patent infringement had been found would restore the generic company from the negative impact caused by injustice provisional preliminary injunction (including compensation of losses). To achieve this goal, a uniform implementation of article 9 of the IP Enforcement Directive (2004/48/EC) should be reached in all EU’s member states. A similar provision may also apply to national healthcare providers and other payers which had sustained improper costs.

The deterrent action of identified cases of abuse of dominant position and the potential introduction of the Commission Competition Tool are other suggestions made by the report. Sharing of collaborative actions between several generic and biosimilar companies may also help to reduce the high costs for litigations and to address the asymmetry of resources with respect to the defendant originator industry and the impossibility to access its internal strategy documentation. 

SPCs still looking for a solution

New formulations or new indications are often the object of secondary patents, filed after the primary one which protects the drug substance itself. Multiple SPCs granted for the same product are also a frequent burden, even if the Court of Justice of the European Union (CJEU) has judged SPCs may not be granted in the case of a new medical use for an existing product. The opacity of the SPCs’ granting process is contributing to the great uncertainty for companies wishing to invest in the development of a generic or biosimilar medicinal product. Another source of uncertainty is represented by the timeframe during which paediatric studies are run by innovators under a Paediatric Investigation Plan (PIP) filed with EMA; in this case, the final paediatric line extension is reflected by a six months increase of market exclusivity (two years in the case of an orphan medicine). 

The innovator industry has a long track record in requesting the legislators for a strong IP European framework as a tool to support R&D and to remunerate the high costs for research and development ($1,9 billion estimated in 2012) through the 20 years market exclusivity (+5y for SPCs protection). This approach often conflicts with the need to ensure broader access for patients to affordable medicines, resulting from the pressure on pharmaceutical expenditure posed in many countries by the economic crisis. According to the white paper, in 2016 the total EU’s retail expenditure on pharmaceuticals (excluding hospital care) was more than EUR 210 billion, a 5% increase vs 2010. Medicines also represent approx. 20% of total healthcare expenditure (9.6% of EU’s GDP in 2017).

The white paper also recalls the data from the European Patent Office’s 2019 Quality Report showing that just 76.9% of patents granted last year were found to be compliant with legal requirements, compared to 85,4% in 2016. Furthermore, in the case of a litigation the patentees often requests the Court to issue a preliminary injunctive relief (and in some cases also the payment of provisional damages) to prevent the generic product to be commercialised in a certain market. “This is because in some markets there is no obligation to provide a cross-undertaking to compensate the competitor for the time they were wrongly held off the market by the injunction”, explains the white paper. And the economic gain obtained by patentees may well exceed the possible financial burden represented by a possible damages award.

The impact of regulatory barriers

Regulatory barriers, especially at the national level, are also delaying generic competition. The practice known as “patent linkage”, for example, connects the approval of the MA for a generic or biosimilar medicine to the status of a patent (or patent application) of the reference product. Even if prohibited by the European law (Art. 126 of the 2001/83/EC directive), this misbehaviour still represents a problem, as recognised by the 2017 Resolution of the EU Parliament. This impact also on the Bolar exemption, under which generic and biosimilar companies can conduct clinical trials before patent expiration – without the risk of patent infringement – in order to shorten the timeline to reach approval. 

Pricing and reimbursement procedures are highly critical, as the Transparency directive (89/105/EEC) does not contain a similar provision; in 2017 the EU Parliament indicated the need to revise this directive, but the request is still pending. This type of misbehaviour takes different forms in several countries, e.g. Portugal, France, Italy, Poland, Germany; examples are provided in the white paper, also with respect to the similar “procurement linkage” and “prescription listing based linkage”. Medicines for Europe asks for the insertion in the new European Pharmaceutical Strategy of an express prohibition of patent linkage with reference to pricing and reimbursement activities, which should be possible also for generic and biosimilar companies during the market exclusivity period.

This last two practices may result in possible infringements should the generic product enter procurement procedures or be listed in the formulary of prescription medicines. “Put simply, regulatory competent authorities are experts in matters other than patent infringement or validity and may be pushed to make assessments on those questions based upon incomplete information”, states the white paper with reference to the overlapping of competences with national courts.

Improved formulations and dominant market positions

The practice known as “product hopping” sees innovator companies replacing (partially or completely) a product in the market which is going to lose patent protection with a new, improved formulation with an extended market exclusivity. According to Medicines for Europe, this behaviour forces patients to switch to the second generation product, often more expensive than the parent one. Prescribers’ inertia may also contribute to the difficulties encountered by first generation generic competitors to successfully enter the market. The white paper provide extensive examples of the price and hard/soft switching strategies put in place to maintain or conquer patients and prescribers’s trust. A forced switch, for example, is highly probable in the case the first generation product is withdrawn from the market just before the expiration date of its patent. 

Medicines for Europe asks the EU Commission to consider a possible new legislation to contrast product hopping, similar to the one pending since September 2019 at the US House of Representatives. The target of the American proposal is to justify hard or soft switches towards follow-on medicines only in the case the company can demonstrate the same withdrawal actions would have been taken regardless of generic competition. Innovators should also maintain access to first generation products on the market until patent expiry allows for generic and biosimilar entry, to ensure full awareness of the significant cost benefits for patients.

The abuse of dominant position

The excess of dominant position is prohibited by the European and national legislations, but there are many examples of malpractices leading to abuses in this area, such as predatory pricing and anti-competitive rebates, which are common also to industrial sector other than the pharmaceuticals. 

Predatory pricing sees the originator marketing a certain product at loss in order to exclude competitors from the market. Rebates on pricing may result to be anti-competitive whenever the customer would buy more than 80% of its supply needs for a certain product from a single dominant company. Various examples are discussed in the white paper, including the Napp Pharmaceuticals and Remicade cases investigated by the UK Competition and Markets Authority (CMA). 

“In the pharmaceutical market, misleading information may have a particularly detrimental impact, as given the characteristics of the medicinal products market, it is likely that the dissemination of such information will encourage doctors to refrain from prescribing that product, thus resulting in the expected reduction in demand for that type of use”, explains the white paper, with reference to the possible denigration of generic or biosimilar products made by dominant companies. The reference case to this instance is represented by the Avastin-Lucentis disputes ruled by the Italian and French competition authority, where Novartis has been judged responsible for having exaggerated the risks related to the off-label use of the competitor drug Avastin. A fine of €444 million was issued in September 2020 by the French authority on Novartis, Genentech and Roche for abuse of dominant position.

Towards the new EU Pharmaceutical Strategy

Giuliana Miglierini
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Towards the new EU Pharmaceutical Strategy

The consultation by the European Commission on its proposal for the new European Pharmaceutical Strategy – an integral part of the broader EU’s Industrial Strategy – closed on 15 September (242 comments receveid, see here); the final launch is expected by the end of the year. Among the main challenges for  the key pharmaceutical sector are the redefinition of the entire life cycle for medicinal products, the translation of emergent science and technology into practice, the need to invest to develop new antimicrobial agents and how to better prepare to possible new pandemics.

An online workshop organised by DG Santé has took place on 14 and 15 July with a selected group of stakeholders as a discussion moment supporting the ongoing consultation process. Many stakeholders have also released official statements highlighting their priorities to be included in the new strategy.

The proposals from the Dutch Parliament

The Dutch Parliament issued a detailed document on key points to be taken into consideration, starting from an holistic approach to build an all-inclusive, evidence-based pharmaceutical strategy. Sharing of studies’ results with member states is considered an essential element to support transparency and cooperation and  to respond to real needs expressed by the stakeholders.

A jointly-developed working plan on pharmaceutical policy 2020-2025 is suggested as the operative tool to ensure cooperation between the Commission and member states in the definition of goals and short-term activities, in order to achieve clear and transparent governance and procedures. The Dutch representatives asked for coherence across all ongoing and upcoming EU policies. No matter to say, innovation should play a central role in the identification of unmet medical needs; with this regard, the incoming legislation is expected to adapt to the new challenges arising from digital, scientific and technological advances while ensuring regulatory flexibility, harmonisation of procedures and an easier access to the market. Advanced therapy medicinal products (ATMPs) and paediatric medicines are among the priorities identified.

A better characterisation of vulnerabilities along the supply chain and an improved cooperation at the European level should help to face the issue of shortages; multi-language packaging information and e-leaflets may represent additional tools, as well as a better resilience to threats similar to those faced during the Covid-19 pandemic. Preliminary discussion on a possible European list of essential medicines may support initiatives directed to the EU’s active pharmaceutical ingredient industry.

Joint Health Technology Assessments (HTA), says the Dutch Parliament, may represent a form of voluntary collaboration to improve transparency and equal access to medicines across Europe. The debate on R&D costs may impact both shortages and fair access: “As prices escalate, it is legitimate to question the degree of innovation and value offered by certain new, high-cost therapies. The sustained financial performance of pharmaceutical companies further underwrites the assumption that current prices do not accurately reflect the costs of production and research and development. Furthermore, even though public funding often supports the R&D of many new pharmaceutical products, current pricing practices of some companies do not reflect their social responsibility to contribute to the sustainability and affordability of health care.”, wrote the Dutch Parliament. Marketing of a new medicines in all EU countries should be compulsory upon approval through a centralised procedure, is one of the suggestions. The document also discusses how to tackle the environmental impact of pharmaceuticals and the related issue of antimicrobial resistance.

The voice of community pharmacists

The Pharmaceutical Group of the European Union (PGEU) on behalf of community pharmacists also forwarded its comments on the Pharmaceutical strategy. The  Group supports a more European supply chain for the production of APIs, excipients and finished products, particularly those more critical in terms of supply. A fair framework for pharmaceuticals, comprehensive of guarantees for security of supply for patients, is the suggested tool to face this challenge.

A stronger enforcement of the marketing authorisation holder’s (MAH) responsibilities and a closer cooperation between public institutions and national governments are the options considered most effective in enhancing the quality of medicines. The problem of shortages represents a great concern for community pharmacists, which need to invest many time and resources to deal with it. PGEU proposes that the pharmacist would be allowed to substitute the missing product “with the most appropriate alternative as part of a shared decision-making process with prescribers and patients or in accordance with national protocols where appropriate”.

Community pharmacists also commented the practice of market withdrawals for commercial reasons, which mostly affect cheaper and older products. When no or little alternatives are available on the market, the request is to ensure sufficient safeguards to ensure continuity of access, for example through the permission to pharmacists to prepare compounded formulations if possible. 3D printing may also represent a valuable technology to be used within pharmacies, but according to PGEU a tailor-made regulatory framework, as well as  financial investment and reimbursement for this technology would be needed.

Commercialisation of the smallest package relevant for a specific treatment is envisaged to reduce the environmental impact of pharmaceutics. PGEU also suggests an expansion of community pharmacy services, for example for the home delivery of medicines in selected cases, or the safe renewal of repeat prescriptions for chronic medications.

Focus on fighting antimicrobial resistance

The members of the MEP Interest Group on AMR of the European Parliament on October 6th addressed a letter to the EU Commission’s VP for Promoting our European Way of Life, Margaritas Schinas, and Health Commissioner, Stella Kyriakides, to highlight the main issues regarding antimicrobial resistance to be considered the final version of the pharmaceutical strategy. 

The EP suggested to better integrate the development and access to new affordable and quality antimicrobials, with an eye on their environmental sustainability. The key recommendations are in line with the Parliament’s resolution on the EU’s public health strategy post-Covid-19, and include a stronger role of the Union in global discussions about antibiotic shortages and a special attention to the resilience of supply chains to disruptions. 

Another instance to be faced is the impact of market failures in antibiotic R&D; the suggestion by the MEP  Interest Group goes towards the adoption of an end-to-end approach and the development of needs-driven models to fix the antibiotic development pipeline. Prevention represents a valuable tool to reduce dependance on antibiotics and improve research into possible alternatives, such as phage therapy. 

The goal of a better transparency in the pharmaceutical industry should be based, according to the letter, on a strong legislative framework able to take into consideration all aspects, from R&D to authorisation procedures and environmental risks. This last issue should be tackled through more tight manufacturing requirements, i.e. including the development of antimicrobial resistance in the Environmental Risk Assessments. Quality standards and concentration limits in water and soil should also be set.

EIPG’s vision on Annex 1 to GMPs

Giuliana Miglierini
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EIPG’s vision on Annex 1 to GMPs

EIPG is among the sixteen European professional and industrial associations recognised as relevant interested parties by the European Commission in the review process leading to the completely updated version of the Annex 1 to GMPs.

On 28 September dr Francesco Boschi (head of AFI’s Microbiology working group) discussed in a webinar the EIPG vision of the final draft of the new Annex 1, as resulting from comments received by members of the different EIPG’s national associations. The EIPG’s working group led by Dr Boschi collected and examined all the opinions, and elaborated the output documents then shared with the other stakeholders. As a result of this exercise, EIPG has forwarded a formal communication to the EU Commission highlighting the technical comments from the point of view of Industrial Pharmacists. A joint letter has been also signed by all the recognised associations and addressed to the Commission to highlight the need of flexibility in the use of alternative approaches, clarification of few critical points and the request of a better dialogue with regulators. 

The EIPG working group received a fundamental contribution from AFI (the Italian association representing industrial pharmacists, which prepared the first draft circulated to EIPG’s delegates) as well as from Belgian and Spanish experts to prepare the final integrated document submitted to the EU Commission. The Covid-19 emergency posed many challenges to the entire process, which took place entirely through online meetings.

A completely new vision

The new Annex 1 represents a radical revision of the rules governing GMP manufacturing of sterile medicinal products (both terminally sterilised and aseptically filled). The original document was released in 1971 and a first, limited revision occurred in 2008. 

The current draft is the result of a first proposal made by the European institutions in 2017, followed by a consultation phase that led to the collection of more than 6,200 single lines of comments. The second draft elaborated thereof was subject to a limited round of consultation involving just the sixteen recognised associations (including EIPG); a parallel consultation also occurred at the level of WHO and PIC/S in order to maintain the global alignment of standards. AFI contributed to the first round of consultation issuing three general comments and some other 40 on specific points. All comments were submitted to EMA through EIPG, and several of them have been reflected in the second draft.

«The new Annex 1 shall represent one of the most important documents in incoming years, it may also influence GMPs. Many concepts have changed with respect to the 1971 and 2008 versions – explained Francesco Boschi -. Quality risk management (QRM) has now been introduced, as well as new process technologies and sections, leading to a more detailed document and to a more logical flux of information».

The new concept of Contamination Control Strategy (CCS) is the key to fully understand the approach of the new Annex 1: the risk analysis should lead to the definition of all the critical control points, the assessment of the efficacy of planned controls (at the design, procedural, technical and organisational levels) and of the mitigation measures put in place to manage the identified risks. «The CCS is a dynamic document, which should be actively updated in order to drive to continuous improvement of the manufacturing and control methods», said Dr Boschi.

The main points needing attention

The second round of consultation was limited to selected parts of the draft Annex 1 (chapters 4, 6, 7, 8, 9, and 10), even though comments were possible also on other sections. For each of the involved paragraphs, during the webinar dr Boschi explained the suggestions elaborated by the EIPG working group. 

As for Chap. 4 (Premises), a clarification would be needed on how to implement the use of barrier systems, including RABS and isolators aimed to minimise the contamination associated to human intervention. «Many companies have already in place approaches other than RABS in existing facilities, which should be supported in the CCS by a documented Risk Assessment considering both historical data and established controls», explained Francesco Boschi (par. 4.3).

Another critical point (par. 4.23) is represented by the need to sterilise RABS gloves used in Grade A zones. EIPG’s experts suggested they should be sterilised before installation and then sterilised or effectively decontaminated by a validated method prior to each manufacturing campaign. «A 6 log reduction can only be achieved by a process such as VHP, which is not feasible in open RABS – said Dr Boschi -. A validated sanitation ensuring a 3 log reduction of vegetative cells and a 2 log reduction of spores is typically adequate». 

Clarification of the 4.29 paragraph has been also proposed, to avoid any discrepancy in the testing provisions for larger particles. The EIPG working group suggested that for Grade A zone and Grade B at rest, classification should include a minimum measurement of particles ≥ 0,5 µm, making reference to ISO 14644-1 Table 1 for particle size and limits should there be need for assessment of larger particles. «We have also suggested a modification to Note 2, as the correlation with CFU is not always possible nor scientifically supported, asking to scientifically justify the limits applied on the basis of the use of new technologies that present results in a manner different than CFU», said Dr Boschi.

Utilities and personnel

Chapter 6 discussing Utilities (i.e. water, steam, compressed gases) is complete new addition to Annex 1. Among the suggestions made by EIPG, the use of the term “data” with respect to water testing after regeneration or disinfection, in order to include also endotoxins and/or chemical residues (par. 6.12). «Data should be available and evaluated by the QA before the water system is returned to use, and results should be approved before release of impacted batches», said the EIPG expert. 

The access of untrained and unqualified personnel to restricted areas always represents a great source of potential risk, and the second draft of Annex 1 mention it should be never allowed in presence of exposed product or critical components and surfaces (par. 7.6). «We suggested access should never occur in such instances, it should be assessed and recorded according to the Pharmaceutical Quality System. This because the supervision cannot effectively mitigate the risk of contamination spreading by the unqualified individual», added Francesco Boschi.

The reduction of the risk of contamination also refers to the use of sterile face masks and eye coverings to prevent the diffusion of droplets and particulates (par. 7.14i). This may result a critical challenge in the manufacturing of highly potent products, where respiratory protecting mask are used that cannot be sterilised. The suggestion is here too use a validated decontamination process.

Sterile manufacturing  and process monitoring

Chapter 8 represents the core of the new Annex 1, as it focuses the attention on the aseptic production processes and technologies. EIPG’s experts judged ambiguous the wording of par. 8.41, and suggested Biological Indicators (BIs) placed at appropriate locations must be used to validate the sterilisation process. «A validated process should not need to be confirmed by routine use of BIs, unless required for specific processes (i.e. ethylene oxide)», said dr Boschi. 

Pre-use post sterilisation integrity testing (PUPSIT) represents another critical point, as it may represent a real challenge when handling very small volumes of solutions or other process constraints. EIPG suggested to remove the specific example from the wording of par. 8.88 to ensure greater flexibility. 

Another point needing attention is the simulation of media fills, a process which is now named Aseptic Process Simulation (APS). «As for par. 9.47i, we suggested to remove the statement about conditions “similar to those for visual inspection”, and make instead reference to conditions that facilitate the identification of any microbial contamination. Some requirements for products visual inspection are not applicable to inspection of culture media», explained dr Boschi. EIPG also suggested to remove reference to three media fills successfully completed in order to demonstrate the process is under control, as it considered to be excessive in some instances (par. 9.48iii). The decision on the actual number of media fill should be driven by the investigation outcomes. 

Quality controls and other general comments

Chapter 10 deals with Quality Controls, and sterility testing is a main point of attention in this contest. Comments from EIPG suggest to modify par. 10.6i to make reference to testing needed after any “significant” intervention, as determined by the CCS. Samples taken from each lyophilisation load should be also assessed (par. 10.6iii). 

EIPG working group also presented some further comments on parts of the draft Annex 1 different from the ones under specific consultation. Among these, the possibility to use in existing facilities a validated decontamination method as an alternative to sterilisation for indirect contact parts, provided it is supported by a Risk Assessment and by procedures minimising the contamination risk (par. 5.5). «With reference to the Glossary, we have also recommended to replace the term “non-viable particles” with “total particles” in the whole document, as particulate counters measure both types of particles, they cannot distinguish them», said dr Boschi

The EU Parliament approved the report on shortages of medicines

Giuliana Miglierini
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The EU Parliament approved the report on shortages of medicines

The European parliament voted on 17 September the report addressing the root causes of medicines shortages; the need for an increased EU response to tackle this long-lasting problem is the key message, as acknowledged during the Covid-19 health crisis. The report follows the adoption on 13-14 July by the ENVI Committee of its own-initiative report on shortage of medicines.

According to the European Parliament, the number of shortages increased 20-fold between 2000 and 2018, and 12-fold since 2008. Easy to manufacture cheap starting materials and ‘mature’ medicines present the higher risk of shortages. Around half of medicines in short supply falls in the therapeutic areas of chemotherapeutics, products to treat infections (vaccines, but also antibiotics) and nervous system (epilepsy, Parkinson’s disease); other affected areas include anaesthetics and medications for hypertension and heart disease.

Considering the great dependance of pharma imports from third countries, especially China and India, according to the EU Parliament “The European response to the shortage of medicines must be based on three pillars: a return to health sovereignty by securing supplies, stepping up European action to better coordinate and supplement member state health policies, and enhancing cooperation between them”.

The main contents of the report

The approved motion highlights “the geostrategic imperative for the Union to regain its independence” with regard to all aspects of healthcare management, including the prevention of shortages and the fair access to the supply chain. 

A target that according to MEPs would require the establishment of a diversified supply chain for the Union’s pharmaceutical industry, and a medicine shortage risk mitigation plan to cope with vulnerabilities. The report recall the coordination role the EU should play with respect to the different national pharmaceutical and public health policies; a better harmonisation of terms such as ‘shortage’, ‘tension’, ‘supply disruptions’, ‘stock-out’ and ‘overstocking’, for example, would be required. To this instance, a starting point might be represented by the definition of ‘shortage’ proposed by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) joint Task Force in 2019. 

The Parliament also asks the Commission to better distinguish between ‘medicinal products of major therapeutic interest’ (MITMs) and ‘medicinal products of health and strategic importance’ (MISSs), being for these last ones the interruption of treatment a cause of immediate threat to the patient’s life. The report welcomes the call for tender launched by the Commission for a study on the causes of shortages of medicines in the EU, which should be complemented by a second study on the impacts on patient care, treatment and health.

Suggestions for the future

The new European Pharmaceutical Strategy should represent the way to activate actions to address these issues; MEPS also proposed the Commission to incorporate measures for the pharmaceutical sector into the 2021 due diligence law proposal for companies.

From the patients’ perspective, the report underlines how access to medicines may be limited by higher prices of the substitute product proposed, a lower reimbursement rate or complete lack of reimbursement. The EU should become less dependent on third countries as for the supply of APIs and medicines of major therapeutic interest; the request to the Commission is for a map of EU’s production sites in third countries and an evolving map, to be used as a reference, of the existing and potential production sites within the EU. The manufacturing of essential APIs and medicines in Europe should be also encouraged from the regulatory point of view.

Transparency in supply chain management should be pursued through the fight of inadmissible business practices. The return to a more European-based industry should be also supported by financial incentives, protection of Europe’s strong pharmaceutical industrial base and support to relocation of pharmaceutical operations in the EU, for example by rewarding investments in the quality of medicines and in the security of supply. 

Compliance by the industry should be facilitated by the provision that “all public funding must be made conditional on the full transparency and traceability of investments, on supply obligations on the European market”. Obligations for MAHs under Directive 2001/83/EC should also be reinforced, and the Commission should release guidelines for member states on how to best implement the most economically advantageous tender (MEAT) criteria with reference to Directive 2014/24/EU in order to overcome the lowest price approach. Investments in the manufacture of APIs and finished medicinal products are an option, for example, as well as the number and location of manufacturing sites, the reliability of supply, the reinvestment of profits in R&D and the application of social, environmental, ethical and quality standards. Tenders leading to just one successful company, or only one production site of the basic substance, should be avoided as they may exacerbate vulnerabilities of the supply chain. The creation of one or more European non-profit pharmaceutical undertakings to manufacture medicinal products of health and strategic importance is another possibility foreseen by the EU Parliament. 

A better dialogue with all the stakeholders, with an eye on the improvement of the circular economy, is also mentioned with respect to agriculture, horticulture and forestry, in order to favour the production of active ingredients in the EU. A robust European intellectual property framework should be the tool to support the innovator pharmaceutical industry to invest in R&D and manufacturing in Europe; SMEs should be also better included in the pharma supply chain. More funding for medical-oriented R&D activities to be run within the new Horizon Europe is another priority set by the Parliament, while deploring the litigation cases aimed at delaying generic entry and asking the Commission to ensure the respect of the end of the commercial exclusivity period for patented drugs.

The possible role for EMA

EMA should represent the key node of a new European unit for preventing and managing shortages and, in the long term, should deliver marketing authorisations subject to the fulfilment of supply and accessibility requirements. The creation of common stocks and baskets of drugs for the treatment of cancer, infections, rare diseases and other areas particularly affected by shortages are other suggestions contained in the report. The digital transition should represent an opportunity to improve the real-time management of stocks in each member state. 

Mature medicines at risk of exiting the market may benefit of a special statute to support industrial investment in their continuity of supply. A European contingency reserve for medicinal products of health and strategic importance (MISSs) is also proposed by MEPs, which may possibly result in the creation of a European “emergency pharmacy”. Joint procurement at the European level should also be encouraged, especially in the field of rare diseases. The 10-year market exclusivity clause associated to Regulation (EC) 141/2000 on orphan medicines should be revised in order to reverse the burden of proof that the product is not sufficiently profitable to cover R&D costs. The report also discusses how to better face new shortages associated to health emergencies in light of the experience gained during the Covid-19. 

Comments from EIPG

EIPG signed on 6 December 2019 a joint statement on root causes of medicines shortages in collaboration with other stakeholders, including EPFIA, Medicines for Europe AESGP, EAEPC, GIRP and Vaccines Europe. The document represented a starting point for discussions on how to approach the issue, and clearly summarise in a table the main possible root causes from the industrial perspective and under the regulatory, manufacturing and QA, economic and supply chain dimensions. The main bias refers to centrally authorised medicinal products vs the ones authorised at the national level, that impacts on the possibility to market a certain product in the entire European market space and delays the filing and approval of variations.

Pharmaceutical manufacturing requires severe GMP’s standards to be put in place by companies, resulting in the need of high financial investments. Other factors that may play a role are the possible disruptions of production arising from natural disasters, manufacturing lag times linked to the complexity of processes, inaccurate forecasting resulting in surging demand, and quality issues with APIs or excipients. 

Many different actors take part to the pharmaceutical supply chain, each of them exerting a certain influence on the market conditions. The decision made by a company to enter or not a specific market is a typical example, together with the positioning in terms of price and reimbursement. Pricing policies are often intended to contain pharmaceutical expenditure, without consideration of factors that would require price adjustments. Single-winner, price-only tenders further exacerbate price erosion, explains the joint statement, impacting on the number of alternative sources for a certain medicinal product. Other measures often used to contain the expenditure (e.g. payback mechanisms, payment delays, etc.) are not appealing for the industry. All these mechanisms can finally result in the decision to withdraw the marketing authorisation for a product in a certain country; an occurrence that may have a dramatic effect on patients’ access, should it be taken by all the alternative suppliers of the product. 

The complexity of the pharmaceutical supply chain may also result in differences between the volumes released on a given market, the volume of exports and imports and the actual need of the said market. According to the associations, MAHs often apply supply quotas on distributors based on estimates of national patient needs, but this approach may nor reflect the fluctuation of demand. And the product might result available, but cannot be accessed by patients at the point of dispensing, for example if stocks are not positioned at the right location.

The joint paper asked for a harmonised definition of shortage as well as of the ‘risk of shortage’ for essential medicinal products. “High-risk” medicines should be prioritised, suggested the associations, and should be tackled by a more efficient European cooperation providing greater regulatory flexibility, efficiency and incentives. A predictable and sustainable environment for pricing & reimbursement would be needed to support a broader number of alternative suppliers in a certain market, a direction opposite to the short-term cost containment measures often utilised in many countries. 

Comments from the pharma associations

Several associations representing the different interests along the pharmaceutical supply chain commented the ENVI and/or EU Parliament reports on shortages of medicines. 

Medicines for Europe had positive reactions towards the clear recognition of the key role played by off-patent medicines to favour patient access to essential medicines and the indication for targeted guidelines on medicines procurement made by the EU Parliament. A more healthy competition for generic and biosimilar medicines is among the request of the association, which also asks to include the ENVI approach to root causes for shortages in the new pharmaceutical and industrial strategies under development by the EU Commission.

Regulatory flexibility on pack size and the introduction of electronic product information are other important points for Medicines for Europe, together with the amendment of the EU Variations Regulation and the implementation of the telematics reform. “While all companies have well defined supply obligations under existing contracts with established penalties for failure to supply, doubling penalties and fines on companies will discourage them from participating in tenders and will not help solve medicines shortages”, is the comment with respect to a possible punitive approach to procurement.

The European Healthcare Distribution Association (GIRP) welcomed the Parliament’s initiative, recognising the importance of the issue to be addressed by short, medium and long-term measures. “Due to the lack of availability of medicines, full-service healthcare distributors encounter difficulties ensuring the continuous supply of the full range of medicines”, said GIRP president, Bernd Grabner. The assessment of root causes and the call to implement an early warning system to monitor shortages have been particularly welcomed by the representatives of distributors. GIRP also support the use of early notification of potential and confirmed shortages by MAHs to full-service healthcare distributors (in addition to National Competent Authorities) as an essential tool to optimise the allocation of available medicines. As added by Mr Grabner, “Full-service healthcare distributors are perfectly suited to support a European mechanism and to guarantee the timely and continues supply of healthcare products wherever they are needed, even in case of crisis. They are an integral part of the solution.”

The European Public Health Alliance (EPHA) also commented the report voted by the EU Parliament and presented its list of priorities for the next steps to be planned. A European study on the impact of shortages on patient care, treatment and health is considered essential, as well as the clarification of supply and notification obligations for MAHs and wholesalers under Directive 2001/83/EC, and the availability of dissuasive and proportionate sanctions in the event of non-compliance. Diversification of suppliers for APIs, excipients and finished products is considered more important than the simple relocation of production in the EU.

The tool of a centralised digital platform should be used to declare available stocks at the European level and for reporting shortages, including real-time communication to healthcare professionals and patients. A harmonised approach to shortage prevention and management for MITMs is also envisaged, together with procurement tenders leading to multiple winners.

E-leaflets should not completely substitute printed information, which should in any case remain available to patients. A Joint Action funded by the new EU4Health programme to prevent shortages, the exploration of European non-profit undertakings for essential medicines at high risk of shortage and new innovative and coordinated strategies and exchange of good practices in the area of stock management and transparency are other actions supported by the European Public Health Alliance.

How the future of health systems may look like

Giuliana Miglierini
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How the future of health systems may look like

The main features of the future of healthcare in the EU have been addressed by Ursula von der Leyen in her speech on the State of the Union, held on 16 September at the European Parliament. A speech that came just prior the second wave of the Covid-19 pandemic started to regain strength, and during which president von der Leyen expressed how this difficult challenge represented “The moment for Europe to lead the way from this fragility towards a new vitality”.

Towards a stronger European Health Union

The Covid-19 crisis activated many initiatives to improve the coordination of European policies in the health sector. After the release of the new EU4Health programme as the main tool to face challenges posed by the pandemic, Ursula von der Leyen announced in her speech the intention to reinforce and empower both the European Medicines Agency (EMA) and the European Center for Disease Control and Prevention (ECDC) in order to improve crisis preparedness and management of cross-border health threats. The EU Commission also plans to create a new Agency for biomedical advanced research and development, a “European BARDA” to be modelled on the example of the similar agency of the US government. Another important goal impacting on the pharmaceutical sector is the activation of strategic stockpiling to face issues with supply chain dependencies. 

The EU4Health 2021-2027 programme was expected to invest  €9.4 billion to completely redesign the organisation of healthcare systems in the EU; funding should be provided at the countries level under the Recovery Fund, as well as to health organisations and NGOs. The total budget was then reduced to €1,7 billion upon request of the “frugal countries” (Austria, Denmark, Netherlands and Sweden) during the July 2020 EU Summit (read here more on Euractiv). 

The creation of reserves of medical supplies and HC staff and experts to face new cross-border health crisis is the first target of the programme. The digital transformation is a key driver to support many objectives of EU4Health, from improved resilience to epidemics to the support to prevention and health promotion linked to ageing. Improved access for vulnerable groups and affordability of drugs and medicinal devices are other areas of planned intervention. Environmental aspects are also included in the strategy, ranging from a more prudent use of antimicrobials to innovation towards greener manufacturing processes. The fight against cancer and anti-microbial resistance will remain the higher priorities, together with the improvement of vaccination rates. 

Redefining the framework of European agencies 

The proposal of a European BARDA, the true novelty in Ursula von der Leyen’s proposal on health, was anticipated on 1st September by Philippe Aghion and other economists from the columns of VoxEU, a main European economic think tank. The lack of coordination across member states and different funding schemes for R&D in healthcare are indicated by the group as the reason why the EU is behind the US as for incentives for vaccine innovation. “This is problematic because the best way to get one’s economy back on track is to eliminate the virus.”, wrote the experts.

The article compares the numbers put in place on the two sides of the Atlantic to fight the Covid pandemic. In the US, BARDA was able to use $6.5 billion allocation to provide funding to more than 40 companies for research and development of new treatments, vaccines and diagnostics. According to the authors, the approach followed by the EU has been less coherent overall, with splitting of funding along different lines of action. The EU is also highly active in international cooperation efforts (i.e. the Coronavirus Global Response or the Coalition for Epidemic Preparedness Innovations).

The economists suggest the new European BARDA should see the participation of member states on a voluntary basis, with a beneficial impact deriving from the possible adhesion also of Great Britain. To reach the optimal setup of the new agency, the trade-off between scale and adaptiveness/flexibility should be identified, together with a science-based and transparent decision process. “Naturally, ‘pressure’ on pharmaceutical companies to avoid excessive profits, as well as sufficient international (public and private) aid to ensure global access, will be very important”, add the authors.

According to Science Business, the proposal of a European BARDA made by Ursula von der Leyen may represent a response to the CEOs of AstraZeneca, Pascal Soriot, and Sanofi, Paul Hudson, who affirmed a similar agency would be needed in order to negotiate advanced purchase agreements for Covid-19 vaccines in a similar way than in the US. The EU Commission is already acting on behalf of all member states to negotiate contracts for these vaccines, using a €2.3 billion emergency fund for down payments (read here more).

The US’s BARDA was created in 2006 to contribute in setting up responses to possible bioterrorism and pandemic threats, especially in areas less covered by the pharmaceutical industry (i.e. Ebola, Zika, anthrax, and swine flu). The debate is now open on how to better design its European version, and many are the question marks with regard to the possible occurrence of undue political influence, the different type of funding schemes used in the US and the EU and the role played by the pharmaceutical industry, which should include the avoidance of conflicts of interests (read here more).

The WHO Europe’s vision

The transition towards new models of healthcare for European countries is also supported by WHO Europe, the regional representative of the World Health Organisation; its vision for future has been published on The Lancet and it shall align “with the needs and expectations of the governments to which WHO is accountable”. International solidarity and willingness to learn from each other are the inspiring principles highlighted by the Regional Director of the WHO Regional Office, Hans Kluge.

The final goal is a pan-European Culture of Health, “in which health goals guide public and private decision making, and everyone can make healthy choices”. WHO Europe’s strategy is made up of six different lines of action, starting from the support to countries for the identification of emerging health challenges and possible responses. The WHO Health Emergency Programme shall be involved in better prepared European countries to respond to health emergencies and threats, while the WHO pan-European Transformational Leadership Academy shall represent the coordination point to assist the scaling-up of effective and sustainable innovations to transform health systems. The improvement of healthy life styles, scientific literacy and trust in health authorities are other goals of WHO Europe, that will also work to strengthen its strategic partnerships and to ameliorate its own structure and processes. 

The vision of the stakeholders

EFPIA, on behalf of the innovator pharma industry, published a reflection paper to comment criticalities emerged from the Covid-19 emergency and the possible options to improve the current situation. The crisis should represent “an opportunity to implement an ambitious reform agenda for European health systems, including discussing the mandate of the EU in the field of health”, states the document.

The societal and economic value of health has been greatly put under discussion by the recent emergency, according to EFPIA; health expenditure should not be regarded anymore as a cost, but as an investment, thus avoiding new budgets’ cuts. The delivery of healthcare services with regard to personnel constraints and cross-borders activities should be also considered. Solidarity between member states should be improved “to achieve common preparedness as well as equal access to healthcare and comparable outcomes for patients”. Integrated budgets – including both health and social care – should represent the tool to overcome the still existing silos leading to fragmentation of healthcare systems and services. 

E-health and telehealth have been experimented during the Covid-19 and may represent useful options to free hospitals from chronic patients, whose assistance should be reorganised at the territorial level to also include home care delivery. This last approach may represent the new key modality to run clinical research, providing the availability of high-quality, real-time and comparable health data for analysis and decision-making. The fragmentation in the collection and classification of Covid-related mortality data between different countries is for EFPIA a clear example of this need. Interoperable Electronic Health Records (EHR) and the planned European Health Data Space would help to overcome this challenge; they should be complemented by the creation of a European Health Data Institute, as recommended also by the EU Health Coalition. 

According to the Federation of the pharmaceutical industry, the optimisation of the supply chain for essential medicines and medical equipment would benefit by an improved role of the  ECDC or another EU structure in the monitoring and assessment of national and regional healthcare demands and capacities. 

The European Public Health Alliance (EPHA) published its comments to president von der Leyen’s speech on the State of the Union. According to the Association, the key points are to be found in the support Mrs von der Leyen expressed with respect to a stronger “European Health Union” and the possibility to reconsider EU’s health competencies in the context of the Future of Europe conference, to be held during the next G20 in Italy. This last option would request a revision of the European treaties: a not so easy task to be achieved, but which may now be favoured by the increasing cross-border threats posed by the pandemic. According to EPHA, “It will be important for civil society to play an active role in the process to ensure that whatever comes of the proposal, it will correspond to Europeans’ real needs and concerns”. The Association sees favourably the expansion of roles for EMA and the ECDC, with this last agency gaining more competencies also on non-communicable diseases. 

As for the possible creation of a European BARDA, this would prove beneficial to guide and advise member states with respect to pandemic preparedness and management, says EPHA, provided the new agency would prioritise public health needs and guarantee the affordability and availability of all end products. The think tank also commented other aspects of the State of the Union speech impacting on health, including financing and budget constraints, and the digital and Green New Deal transformations.

The EU’s Partnership Proposal for Health Innovation

Giuliana Miglierini
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The EU’s Partnership Proposal for Health Innovation

The proposal made by the European Commission of a Partnership for Health Innovation has been welcomed  by all the associations’ representatives of the pharma and medtech sector (including COCIR, EFPIA, EuropaBio, MedTech Europe and Vaccines Europe). Final target of the initiative is the optimisation of the new models for healthcare systems. “Investment in collaborative R&D can play a significant role in building health resilience, improving European health systems’ sustainability, addressing the needs of patients across Europe, and driving the region’s economic recovery from the Covid-19 crisis”, says the Joint statement signed by the Associations. The final version of the Partnership is expected to provide a harmonised set of rules for institutionalised partnerships across all Europe, while ensuring efficiency and flexibility for cross-sectorial collaboration.

How to support EU health innovation

Four key problem drivers have been identified to be addressed in order to optimise the impact of European research and innovation, starting with the need to better understand the mechanisms of health and disease, with a particular attention to the areas of unmet medical needs. A better collaboration between the academia and industry is also needed to transform research into real innovation. The different industrial sectors in the field of life sciences (i.e. pharma, medtech, vaccines, diagnostics, advanced therapies, imaging and digital industries) should establish more efficient models of collaboration, and many market barriers have still to fail in order to provide better incentives in support of innovation. According to the document, it would be important to rapidly act towards these goals to ensure the sustainability of the entire European healthcare system, which is being deeply impacted by the Covid as well as by the ageing of the population and the consequent increase of chronic and neurodegenerative diseases.

The document discusses data relative to the performance of the different industrial sectors and how the new IHI Partnership can be built and optimised upon the results obtained in the previous IMI and IMI2 initiatives.

The Partnership will also represent an important contribution to achieve many targets set forth by the von der Leyen Commission, especially with regard to the digitalisation of healthcare, a better involvement of SMEs in the creation of value for the European economy, and the achievement of the agendas relative to the European Cancer Plan, the EU One Health Action Plan and the European Green Deal.

Recommendations and objectives

The recommendations made in the draft proposal include the need for a substantial adaptation of the collaborative and funding model to ensure the active engagement of other industrial sectors together with the pharmaceutical industry, a better transparency and a change of the rules to calculate the in-kind contributions from non-European entities, and the Strategic Research Agenda (SRA) and call topics generation to reflect interests of stakeholders other than EFPIA. 

Six different specific objectives are considered, including a better understanding of the determinants of health and priority disease areas, a better integration of the yet fragmented health Research & Innovation efforts across sectors and technologies, the availability of tools, data, platforms, technologies and processes to improve prediction, prevention, interception, treatment and management of diseases. The feasibility of people-centred, integrated healthcare solutions along the health care pathway should be also demonstrated, exploiting the full potential of digitalisation and data exchange. The added value of the innovative and integrated healthcare solutions should be assessed using new and more comprehensive methodologies and models.

The draft proposal

The process for the elaboration of the draft Partnership proposal for Health Innovation started in autumn 2019 within the general framework of the planning of the new Horizon Europe framework research programme. All the potential partners forwarded their proposals to the Commission on the basis of a common template and the initial concepts highlighted by the early consultation phase. The current draft represents an intermediate stage in the discussions, before approval of the final document expected in Autumn 2020.

Each Partnership will follow an individual path of approval, during which the Commission Services will assess the respondence to the selection criteria issued by the Commission. The target is to enable the integration of cross-sectoral technologies, know-how, products, services and workflows to provide people-centred health care and timely and well-informed prevention, diagnosis and treatment. The exercise won’t be easy, says the document, as innovative health intervention may result complex to design and implement. Many silos have yet to be overcome in order to fully exploit the possible synergies between discovery and translational research, and academics and industry. These achievements are essential to strengthen the European position as a global leader in medical research, and they also require involvement of patients and other end-users during project design and implementation. 

Europe goes for real-world studies and GMO vaccines

Giuliana Miglierini
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Europe goes for real-world studies and GMO vaccines

The race to find a vaccine for the Sars-CoV-2 virus has encountered the first issue, as the development of the so-called Oxford vaccine (AZD1222) by AstraZeneca has now restarted after the short stop occured at the beginning of September following the observation of an unexplained possible severe adverse event occurred in the UK Phase 3 trial (see here AZ’s press release). Even if no further medical information will be disclosed, the sponsor communicated that trial investigators and participants will be updated with the relevant information to be disclosed also on global clinical registries, according to the clinical trial and regulatory standards. The decision to resume the trial was assumed on the basis of the considerations made by the independent committee called to review the data related to this event in order to establish if there is a cause relation with the vaccination. The AZD1222 vaccine is based on a replication-deficient chimpanzee viral vector using a weakened version of a common cold virus (adenovirus) containing the genetic material of the Sars-CoV-2 virus spike protein. The vaccination induces the production of the surface spike protein, which primes the immune system to attack the wild virus when it infects the body.

The EU Commission strategy for vaccines

The European strategy to accelerate the development, manufacturing and use of vaccines against Covid-19 was presented in mid-June by the European Commission. “Nothing is certain, but I am confident that we can mobilise the resources to find a vaccine to beat this virus once and for all. This vaccine will be a breakthrough in the fight against the coronavirus, and a testament to what partners can achieve when we put our minds, research and resources together”, said the European Commission president Ursula von der Leyen. The Commission’s expected timeframe for the availability of the new vaccine was between 12 and 18 months (thus up to end 2021). 

Quality, safety and efficacy is one of the main targets of the strategy, as for every new medicine under development. This shall parallel the swift and equitable access to vaccines for all EU’s Member States while taking also into account the solidarity needed at the global level.

Sufficient supplies to Member States shall be pursued by mean of Advance Purchase Agreements (APAs) closed with vaccine producers through the Emergency Support Instrument. APAs are to be signed directly with the single biopharmaceutical companies by the EU Commission on behalf of the Member States, and are based on the payment of part of the upfront costs of vaccines’ development in return for the right for governments to buy a specified number of doses in a given timeframe. To fund of this action the Commission is using part of the €2.7 billion Emergency Support Instrument, and a possibility to access loans from the European Investment Bank is also available.

Green light to GMO vaccines

In mid-June the EU Commission also proposed a new regulation “on the conduct of clinical trials with and supply of medicinal products for human use containing or consisting of genetically modified organisms intended to treat or prevent coronavirus disease”, which is part of the European vaccine strategy. The proposal was adopted by both the European Parliament and the European Council one month later, in mid-July (see here the final text).

The initiative is aimed to solve issues posed by the GMO legislation with respect to the possible use of vaccines against the Sars-CoV-2 virus and which may fall within the definition of GMO (as for example the above mentioned Oxford vaccine), as they are based on genetically modified viruses. The Commission aims to adapt the regulatory framework to ensure a rapid clinical development of Covid-19 vaccines while safeguarding safety and efficacy for the volunteers participating to the trials and for the entire European population. 

“The Coronavirus outbreak has created an unprecedented public health emergency. The development of vaccines and therapies against the virus is of major public interest and we are collectively called to make safe and efficacious medicinal products available to our citizens as soon as possible”, states the document. According to the regulation, Member States can authorise the supply and administration of medicinal products for human use (including those containing GMOs) even in the absence of a marketing authorisation in case of “urgent need to address the specific needs of a patient, for compassionate use, or in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation that could cause harm”. The protection of public health becomes in these instances the first priority, according to the Commission, and it must prevail over all other considerations. “In the situation of public health emergency created by the Covid-19 pandemic, there is an overriding interest in protecting human health”, states the document. 

The approved text allows to derogate the need of prior environmental risk assessment or consent (a normal request for GMO products) for most operations related to the conduct of Covid-related clinical trials. The regulation is in any case limited in time: it will apply up to when the WHO will declare finished the pandemic, or upon the validity into force of an implementing act by the Commission recognising a situation of public health emergency due to Covid-19 (see also RAPS Regulatory Focus).

EMA’s infrastructure to monitor real-world development

The rapid evolution of the many Covid-19 vaccines towards advanced clinical phases and the eventual administration of the approved ones to the general population needs a parallel deployment of resources from the regulatory point of view in order to carefully monitor their real-world efficacy and safety. The European Medicines Agency (EMA) has announced at the end of July the creation of a dedicated infrastructure to support the monitoring of the safety and efficacy of Covid-19 treatments and vaccines used in day-to-day clinical practice. The real-world phase of development will be monitored by some academic and private partners that signed with EMA three distinct contracts for observational research.

The Utrecht University and the University Medical Center Utrecht will act as the coordinators of the CONSIGN project (‘Covid-19 infectiOn aNd medicineS In preGNancy’), aimed to collect data on the impact of the disease in different trimesters of pregnancy and on neonates (see here more details). The ConcePTION consortium established under the IMI Initiative (and part of the COVI-PREG project and the International Network of Obstetric Survey Systems-INOSS network) will also participate to the project. A global regulatory workshop to discuss these themes was also organised at the end of July by EMA in collaboration with ICMRA.

The private company IQVIA will be responsible for the building of a framework for the conduct of multicentre cohort studies on the use of medicines in Covid-19 patients. Among the main goals are the identification of large national cohorts and appropriate comparator groups, the development of a protocol template for multinational studies and the establishment of a collaborative framework for researchers. The project will also see the participation of the IMI’s European Health Data & Evidence Network (EHDEN) consortium, led by the Erasmus Medical Centre (Rotterdam, NL) and under the research coordination by the University of Oxford.

The ACCESS project (‘vACcine Covid-19 monitoring readinESS’) is another EMA’s initiative aimed to run preparatory research into data sources and methods to monitor the safety, effectiveness and coverage of authorised Covid-19 vaccines in the clinical practice. The infrastructure established by the Utrecht University will provide EMA additional pharmacovigilance information from spontaneous reporting – on the basis of a Europe-wide network of data sources, including health insurance records, GP and hospital health records – to be used for the Pharmacovigilance Risk Assessment Committee (PRAC)’s post-authorisation evaluation of new vaccines. This shall also support the identification of possible adverse events of special interest needing extra consideration by PRAC.

The Agency is also working to optimise regulatory guidance to companies involved in vaccines and medicines development for Covid-19. Under its coordination, for example, the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has published the 8th revision of the ENCePP Guide on methodological standards in pharmacoepidemiology, which provides important highlights to plan Covid observational studies. ENCePP has also set up a dedicated Covid-19 response group; the advice is to enhance transparency through the registration of pharmacoepidemiological studies in the European Union electronic register of post-authorisation studies (EU PAS Register) and make study protocols and reports public.

Finally, EMA is also collaborating at the international level with the International Coalition of Medicines Regulatory Authorities (ICMRA) to improve cooperation in the areas of pregnancy research, building international clinical cohorts of Covid-19 patients and preparing a strong infrastructure for monitoring the safety and effectiveness of vaccines.

EFPIA on Covid-19 vaccine’s safety

The Federation of the European Pharmaceutical Industry Associations published at the end of August a statement to reassure on the attention producers are paying towards the safety of Covid-19 vaccines under study. The need to rapidly achieve the final goal and make a vaccine available is reflected by the fact that “work that would normally happen sequentially over time is now being run in parallel but never at the expense of safety or quality”.

Post-approval safety monitoring is already planned also from the producers perspective, and the administration of millions of doses around the world would make reasonable and possible that “some people receiving a Covid-19 vaccine will experience medical events following immunisation”. According to EFPIA, such an occurrence would be similar to all other medicinal products (including vaccines), as a result of the specific reactions that might affect single individuals. 

EFPIA’s statement indicates the will of the pharmaceutical industry to collaborate with governments to develop a system of compensation for the people that may result impacted by vaccine’s side-effects “Any system should aim to get the right level of compensation to the right patient when they need it, avoiding endless delays through prohibitively expensive litigation with uncertain outcomes”, states EFPIA. Discussions are ongoing to define the system’s mode of operation, says the statement. 

How the pharmaceutical market will look like in 2026

Giuliana Miglierini
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How the pharmaceutical market will look like in 2026

The pharmaceutical sector is one of the main actors in the play field of the Covid-19 emergency, as the race to find new treatments and vaccines is supporting new investments in R&D. But there is also another side of the pandemic to be considered, with many medical visits and hospital procedures cancelled or postponed, and many people at the four corners of the globe experiencing economic issues which might reflect on their possibility to access medicines. 

This persistent uncertainty impacts on the capacity of analysts to provide robust indications on the future evolution of the market. “The long-term impact of the pandemic on the biopharma industry is still largely unknown. As such, many of the forecasts in this year’s report will have been made in something of a vacuum”, wrote the authors of the EvaluatePharma World Preview 2020. 

The impact of the pandemic

Just four among the top 15 pharma companies are expected by the report to close the year with positive sales. The stand-by of many medical activities led to a generalised decrease of prescriptions. Looking at the different therapeutic areas, losses appear to be particularly relevant for CNS drugs, followed by Oncology, Musculoskeletal, Blood and Endocrine sectors. 

GSK should especially benefit from increases in sales of Tivicay (dolutegravir) to treat HIV (+ 5.2%) and Ventolin (salbutamol, +10.5%), while at the other end of the rank there is Merck experiencing losses for its leading products Keytruda (pembrolizumab, -3.1%), Bridion (sugammadex, -12.0%) and Gardasil (HPV vaccine, -2.6%). Gilead may benefit from the Emergency Use Authorisation received at the beginning of May for Veklury (remdesivir) to treat Covid-19. 

Trends for the next five years

The EvaluatePharma’s report expects a 7.4% CAGR (compound annual growth rate) increase of prescription drug sales for the period 2020-2026, supported mainly by the Oncology sector (21.7% of expected market in 2026) and orphan drugs (+10.8% CAGR). Prescription drugs sales are expected to reach $ 1.4 trillion in 2026, with Keytruda ($ 24.9 bln) almost doubling its competitors. 

Expected launches for 2020 include Palforzia (peanut (Arachis hypogaea) allergen powder-dnfp), Trodelvy (sacituzumab govitecan-hziy, for patients with metastatic triple-negative breast cancer) and Tukysa (tucatinib, for metastatic breast cancer), and the potential Covid’s treatments Veklury (remdesivir) and Actemra (tocilizumab).

More than 500 new molecular entities are expected to be approved by the FDA in the coming years. The sales of biotechnology products should grow $ 239 bln in 2026, compared to the values of 2019. This is paralleled by a possible $ 252 bln loss of sales due to patent expiry; this trend may impact especially anti-rheumatics.

Immunosuppressants are expected to grow 14.3% CAGR up to 2026; representatives of this therapeutic class include Dupixent (dupilumab, to treat atopic dermatitis), the products for psoriasis Otezla (apremilast) and Cosentyx (secukinumab), and the nephrology active ingredient bardoxolone methyl.

Roche is forecasted to maintain the leading position among top companies, before Johnson & Johnson and Novartis, thanks to its products Ocrevus (ocrelizumab, for multiple sclerosis), the oncology drugs Tecentriq (atezolizumab) and Perjeta (pertuzumab), and Hemlibra (emicizumab-kxwh, for hemophilia A), with a possible total sales volume of $25.4 bln in 2026.

Clinical trials are also delayed

The Covid-19 emergency also impacted on the regular prosecution of many clinical trials, thus slowing down the corresponding development projects. R&D expenditure is expected to grow 3.2% CAGR up to $232.5 bln in 2026. Roche ($ 12.9 bln), Merck ($ 11.00 bln) and J&J ($ 10.7 bln) should be the top investing companies in R&D in the next five years. GSK and Pfizer should increase their R&D spend by 0.9% and 0.7% respectively, while Eli Lilly and AstraZeneca are expected to reduce it by 5.2% and 4.6% respectively.

Looking at new products in the pipelines, oncology remains the leading therapeutic area; new approaches are expected to reach the market in the gastro-intestinal and cardiovascular sectors, and according to EvaluatePharma “blood products are most likely to be approved by the FDA with an average product-specific probability of technical and regulatory success (PS-PTRS) of 70%”.

Among the most interesting products in the pipelines, the EP World Preview 2020 mentions Eli Lilly’s anti-diabetic and obesity drug tirzepatide and The Medicines Company’s (part of Novartis) antihyperlipidaemic inclisiran. The small company Argenx is conquering the third place, thanks to the positive results of trials with its immunosuppressant efgartigimod in patients with generalised myasthenia gravis.

Biotechnological medicines shall represent up to 55% of top 100 global sales in 2026 (+12% vs 2012, + 9.6% CAGR 2019-2026), says the report. In this sector Roche may suffer the recent (2018-2019) patent expiration of its blockbusters Avastin (bevacizumab), Herceptin (trastuzumab) and Rituxan (rituximab); AbbVie is also expected to exit the top 10 position due to the loss of exclusivity of Humira (adalimumab) in 2023. 

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