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Giuliana Miglierini

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Finland: The pharmaceutical industry expects the future government to invest in health and research

Giuliana Miglierini
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Finland: The pharmaceutical industry expects the future government to invest in health and research

The debate on the future of healthcare is very rich and active in Finland, where the reduction of inequalities, the effectiveness of the system and new investments in health are among the main priorities that should be pursued according to the local Pharma Industry Association, Lääketeollisuus ry. “Adequate funding for health care and medical care must be secured and new, flexible financing models need to be developed, so all Finns will have equal opportunities for timely and optimal care regardless of their financial position or place of residence”, said the president of the Association, Sanna Lauslahti, commenting the objectives for the next government term. The next Parliament elections in Finland are due on 14 April 2019.

Improve the access of patients

In the commentary published on the Lääketeollisuus ry’ website, Sanna Lauslahti criticised the delays often observed by Finnish cancer patients and their neighbours to access new therapies, if compared to other European countries. Treatment options are also internally fragmented across different Finnish regions. Something that – according to president Lauslahti – is in contrast with the very good reputation of the welfare system of the Nordic country. The request for the new government is thus to provide adequate funding for health and medical care, together with new, flexible financing models. “Funding channels must not control access to care”, added Mrs Lauslahti.
According to Pharma Industry Finland, innovative and well-targeted treatments are not only important to improve patients’ health and quality of life; they may offer also many opportunities to better manage healthcare and social costs, as well as indirect costs related to labor or disabilities.
But the current Finnish model of evaluation of new medicinal products needs improvements to avoid the observed fragmentation: the suggestion for the new government advanced by Lääketeollisuus ry is to establish a single Health Technology Assessment body for hospitals, outpatients and vaccines.The medication reimbursement system should also discontinue the mutual valuation of diseases among different categories of compensation. “Resource allocation should increasingly be based on knowledge management, and treatments should be evaluated from the point of view of their effectiveness and value, not just through the costs generated. This requires that health data be utilised more and more effectively. We also need nationwide charters and impact indicators”, said Päivi Kerkola, the chairman of the Board of Directors of Lääketeollisuus ry.

The many opportunities for pharmaceutical R&D

Another main target for the new government suggested by Pharma Industry Finland is a major attention towards pharmaceutical R&D, in order to create an effective research ecosystem. The Health Sector Growth Strategy already adopted by the current Finnish government defined the pharmaceutical industry as the engine for health and economic growth in the country.

The Strategy sees the cooperation of the Ministries of Employment, of Economy, Social Affairs and Health and of Education and Culture and it extends more broadly to the entire life sciences sector. The establishment of a national cancer centre and genome centre are among current main investments, made by the funding parties (the Academy of Finland and the Finnish Funding Agency for Technology and Innovation-Tekes).
The Strategy is striving to reinforce the role in pharmaceutical R&D of the Finnish highly educated healthcare professionals and the activities for the recruitment of patients, in order to establish the country as a main location within Europe to run clinical studies. Many patient registries are already available in Finland, as well as a wide portfolio of blood and tissue samples collected by biobanks. This last sector is based on a legislation considered to be one of the most advanced worldwide, and which is due to be further revised and improved to ameliorate it. New steps in this direction that might be pursued by the new government might include amendments to make possible the information already contained in registries can be used for patient recruitment and registry-based research. Finland is also setting up a one-stop application and filing process which will considerably accelerate the current handling of applications. There is also a need for close cooperation between the research community, hospitals and healthcare companies, according to Pharma Industry Finland.

The importance to invest in real world data

Real world data (RWD) are the future of pharmaceutical research, as they allow to assess the effective behaviour of a medicinal product on the general population, outside clinical trials. A research report published on Lääketeollisuus ry’ website describes the finding of a survey run by MedEngine on behalf of the Pharma Industry Research Foundation and aimed to assess the current status of RWD research in Finland.
According to results, some more steps are needed in order to place Finland in a good position in the highly competitive scenario, starting with the need to approve the new law for the secondary use of health and social data. The culture of real world evidence has also to be improved among healthcare professionals and organisations, as well as the knowledge and understanding of the global operations and strategies typical of the pharmaceutical industry. A sufficient number of data scientists with expertise in health data analytics should be available, and expertise in artificial intelligence’s applications (i.e. machine and deep learning) would be also valuable. The attraction of international investments may help to expand the sector and create commercial value, and to establish Finland as a new first-class destination for effective drug development processes, new pricing models and improved and more effective approach to health management and treatment.

The FinnGen study

An example of the opportunities offered by the Finnish pharmaceutical R&D is given by the FinnGen study, that plans to analyse up to 500,000 unique blood samples collected by a nation-wide network of Finnish biobanks. The project is funded over six years by a current budget of € 59 million and aims to better characterise the unique genetic heritage of the 5,5 million Finnish population. Two thirds of the budget are expected to come from seven pharmaceutical companies participating to the project (Abbvie, AstraZeneca, Biogen, Celgene, Genentech, Merck and Pfizer) and one-third from Tekes.
The project is coordinated by the University of Helsinki and the Helsinki University Central Hospital, and sees the collaboration of many other biobanks and research organisations. The Finnish genetic heritage is much less heterogenous than those of other European populations, thus it “makes Finland a great testbed for genomic research”, according to Kimmo Pitkänen, director of the Helsinki Biobank, and can make the analysis of genomic data much more faster and effective. The ultimate goal of the project is to identify new therapeutic targets and diagnostics for treating numerous diseases. ”Tekes wanted to support the project, because of its potential to promote healthcare innovation and to support the growth andinterna- tionalisation of local businesses,” said Minna Hendolin, responsible for Health and Wellbeing at Tekes.

Hard Brexit, soft Brexit, no Brexit?

Giuliana Miglierini
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Hard Brexit, soft Brexit, no Brexit?

It is difficult indeed to summarise the hectic situation and the possible out comings of the Brexit procedure, as what we are writing today, December 11th, it might be completely outdated once this newsletter will be published at the end of the month. Yesterday UK Prime Minister Theresa May decided to postpone the vote of the Parliament on the withdrawal agreement negotiated with the EU, and already endorsed on November 25th on the European side during the special meeting of the European Council. Too many contrary votes were expected by PM May, officially attributed mainly to the difficulties to reach a clear agreement on the future management of the Northern Ireland borders. The backstop clause would not have been approved by the Parliament, claimed Theresa May.

All possibilities are open

But the situation is far more complex, just enough to say that the same day PM May made her announcement to postpone the vote, the European Court of Justice ruled the UK can unilaterally cancel the Brexit, without asking permission to the other 27 EU member States and without altering the terms of Britain’s membership to the Union. After the Court decision, the UK government confirmed by now the intention to proceed leaving the EU on 29 March 2019, under the terms of the EU’s Article 50 process.

But the process is very fluid, and as we are writing Theresa May is due to meet with several European leaders and EU officials to further – and urgently – negotiate the agreement. On the other side of the fence, the president of the European Council, Donald Tusk, said the EU would “not renegotiate” but just try to help “facilitate UK ratification“. It’s hard to say how the game will close, all possibilities are open by now, including a new referendum in UK or a “no deal” exit of Britain on 29 March 2019. We will keep readers posted in the new issues of the newsletter, as the date of the Brexit will become closer.

The political base of the withdrawal agreement

The European Council of 25 November also approved the political declaration on the future EU-UK relationship.  “The better deal possible”, according to Prime Minister Theresa May, and very favourable to the EU party. But in Britain many people would have preferred a more clear cut, as proved by the two UK ministers that resigned after the announcement of the withdrawal agreement.
According to the EU’s approved agreement, after 29 March 2019 a new transition phase would begin, extending at least up to 31 December 2020 (but it might be prolonged). Nothing would change at least up to the end of 2020, as UK would continue to follow all EU rules during the transition period in order to negotiate all details and prepare for long term changes.
The future interactions between the EU and Britain, according to the declaration, should be based on an “ambitious, broad, deep and flexible partnership”. Just focusing on science and innovation, being the central pillar of the biopharmaceutical industry, the “intended breadth and depth of the future relationship” should allow UK to continue its participation in Union programmes. “The Parties will also explore the participation of the United Kingdom to the European Research Infrastructure Consortiums (ERICs), subject to the conditions of the Union legal”, states the declaration. The identification of new opportunities of cooperation in science, innovation and education is also foreseen.
The document also recognises the “complex and integrated supply chains” existing between UK and continental Europe. The envisaged economic partnership should be “ambitious, wide-ranging and balanced”, and based on wider sectoral cooperation where it is in the mutual interest of both parties. The creation of a “free trade area, combining deep regulatory and customs cooperation” is expected to facilitate the movements of goods across borders. The declarations states that no tariffs, fees, charges or quantitative restrictions across all sectors should be put in place.
Regulatory aspects, particularly for disciplines on technical barriers to trade (TBT) and sanitary and phyto-sanitary measures (SPS), “should set out common principles in the fields of standardisation, technical regulations, conformity assessment, accreditation, market surveillance, metrology and labelling”. The declaration clearly states that it will be evaluated the possibility of cooperation of UK and EU agencies such as the European Medicines Agency (EMA) and the European Chemicals Agency (ECHA). “In this context, the United Kingdom will consider aligning with Union rules in relevant areas”, says the document, thus opening the door to the conservation of the current regulatory framework for pharmaceuticals.

Comments from the pharmaceutical world

Positive reactions came from the pharmaceutical industry after the endorsement of the Brexit withdrawal agreement by the European Council. EFPIA welcomed the transition period, the reference to the free trade area and the possible cooperation between the respective agencies, including EMA. “Our hope is that the deal is ratified and then immediate and intense focus is given to regulation and supply of medicines in the post-Brexit relationship. We, along with many others in the healthcare community and across the life sciences sector, believe that an explicit commitment to securing long-term, extensive cooperation around the regulation of medicines and medical technologies is in the best interests of patients and public health”, wrote EFPIA in a note.

The Federation of the European Pharmaceutical Industry Association released a new note to comment PM May’s decision to postpone the vote. “A disorderly exit from the EU by the UK has very real and tangible consequences for patient safety and public health in both the UK and across Europe. We hope that politicians in the UK take this into consideration when the vote occurs.”, said EFPIA’s director general, Nathalie Moll. From the pharma industry perspective, the provision of a transition period is critical to provide time for companies to adapt to the new regulatory requirements, manufacturing and supply issues including customs arrangements, as well as to manage the implications for the international staff.

A position paper describing the contingency plan and actions needed in the case of a “no deal” scenario for the Brexit has also been published by EFPIA. Among the main points of the plan shared with the Commission and Member States are the introductions of measures to recognise UK based testing at least until it can be transferred to the EU and to enable the continued UK participation in key data sharing platforms that protect public health and medicines safety. Discussions with relevant authorities are also envisaged to plan fast track lanes or priority routes for medicines into ports and airports. Custom exemptions should also be temporarily provided fort medicines and clinical trial materials, and paperwork and regulatory checks should to be completed away from the physical border. EFPIA also asked that the European Air Safety Authority (EASA) should recognise certificates issued in the UK to ensure that planes can continue to fly. A further discussion should better explore the possible exemption also for active pharmaceutical ingredients (API) and raw materials for medicines from border checks to ensure manufacturing of medicines continues with limited disruption.

The position of the UK pharma industry

The Association of the British Pharmaceutical industry confirmed with a note published after the decision to postpone the vote its commitment to work as closely as possible with the Government on ‘no deal’ planning and continue to look for further guidance on how medicines will be prioritised as new supply routes are put in place. “But we reiterate that a ‘no deal’ Brexit would present very serious challenges and this must be avoided.  Politicians need to find a way through the current impasse and reassure patients that medicines will not be delayed or disrupted come March 2019.”, said ABPI’s chief executive, Mike Thompson. The Association had a positive reaction to the endorsement of the withdrawal agreement made by the European Council, asking to move swiftly to confirm the closest cooperation in regulation and scientific research which will maximise Europe’s ability to compete globally. “Without this, the US and China will continue to attract the major share of new life sciences investment”, said Mike Thompson.

ABPI also commented on UK government contingency plan for a “no deal” exit, asking more details on how to manage the intention to prioritise the flow of medicines and vaccines announced by the government. “Pharmaceutical companies continue to do everything in their power to make sure that patients get access to medicines whatever the Brexit scenario. This includes duplicating processes, changing supply routes and stockpiling medicines in line with the Government’s guidance. However, we have been clear that there are things which are out of our control. Today’s update on potential border delays for six months in a no deal scenario is stark. Stockpiling more medicines is not the solution to this problem“, said Mike Thompson, asking for alternative supply routes between the UK and Europe.

A similar position on the government’s contingency plan has been expressed also by UK’s BioIndustry Association (BIA). “Today’s letter makes clear that the six-week stockpiling activities now need to be supplemented with additional actions. The letter states that there will be significantly reduced access across the shorts straits (Dover/Calais), for up to six months“, said BIA’s CEO Steve Bates. According to him, a ‘no deal’ Brexit would mean the biggest disintegration of the complex regulated medicines market across Europe in terms of regulation, cross border movement of goods, comparative pricing and intellectual property. “On behalf of patients we encourage all participants to be as prepared as possible for a scenario industry really does not want. We should be under no illusions that this will be easy or smooth and today the challenge of ensuring UK medicine supply through 2019 in a No Deal Brexit scenario got harder not easier.”, he added.

The desires of UK stakeholders for the future relationships with the EU have been also explained by a note signed by ABPI, together with the BioIndustry Association (BIA) and the National Health Service (NHS). Preventing fake or fraudulent medicines from entering the legal supply chain, sharing data and ‘signals’ between EU countries that flag potential problems with medicines, preventing and controlling infectious diseases across Europe, and ensuring the safety and supply of almost 1 billion packets of medicines are the main critical areas identified by the coalition. “It is vital that patients are a priority for discussions to ensure public health and patient safety are not negatively affected by Brexit – both day 1 post-Brexit and in the future.”, said BIA CEO, Steve Bates.

Niall Dickson, chief executive of the NHS Confederation, which represents organisations across the healthcare sector, added: “We understand that there is still much detail to be worked out on the future relationship between the UK and the EU, and we are pleased that the withdrawal agreement preserves key safeguards for patients during the implementation period. But we need assurances from the UK and the EU authorities that they will put patients first as they negotiate details of the long-term relationship”

EU: Quality of healthcare in the European Union

Giuliana Miglierini
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EU: Quality of healthcare in the European Union

The debate on the quality of healthcare in the European Union has made some new advancement, with the question for written answer posed last August by the Bulgarian member of the Parliament Ilhan Kyuchyuk and the publication of the report on the workshop held in May by the ENIVI Committee of the Parliament.

The tools to overcome fragmentation and inequalities

Mr Kyuchyuk was interested in knowing the means eventually available to the European Commission in order to establish differences in the quality of healthcare in the EU, and the measures proposed for countries with inferior quality healthcare, to help them catch up with Member States with high standards in health services. His question was based on the consideration of the existing fragmentation between European countries in the possibility to access quality healthcare. Inequalities arise most often from the differing quality of medical services — diagnostics, medicines, medical equipment and hospital infrastructure, wrote Mr Kyuchyuk in his question.

The answer by the EU Commissioner for Health and Food Safety, Vytenis Andriukaitis, came on 30 October.
According to Mr Andriukaitis, the Commission is responsible only to provide guidance and support to Member States, which remain in charge of the provision of their internal healthcare systems. The Commissioner recalled in his answer the twelve Member States that have received in 2018 a country specific recommendation regarding their healthcare system, and the fact the European Semester is the operative tool the Commission use to analyse the economic and social developments in the Member States, monitor relevant reforms and propose every year country-specific recommendations. The process of the European Semester also include the evaluation of access to timely, high-quality and affordable healthcare, one of the principles of the European Pillar of Social Rights, said Mr Andriukaitis.

The Commissioner also recalled in his answer several other instruments available to support the quality of healthcare, among which is the priority of knowledge-building. Member States also agreed a set of indicators that are now part of the Joint Assessment Framework (JAF) for Health, covering four dimensions: health outcomes, access, quality and non-health determinants. “The reading of these indicators is meant to provide a first-step quantitative screening to detect possible major challenges in each Member State’s health systems in the context of the Social Open Method of Coordination. Complementarily, the ‘State of Health in the EU’ cycle produced country profiles for all Member States in 2017”, said the Commissioner in his reply.
The Organisation for Economic Co-operation and Development (OECD) Patient-Reported Indicators Survey is also funded by the European Commission, and presents data useful to fill the knowledge gap on the quality of healthcare from the patients’ perspective. Finally, Mr Andriukaitis remembered the Commission’s Structural Reform Support Service, that can be activated on demand to provide technical support in order to raise the quality of healthcare.

The sustainability of health systems

A deep analysis and some examples of the sustainability of health systems has been been published by the Environment, Public health and Food safety (ENVI) Committee of the European Parliament, based upon the outcomes of a workshop held in May 2018 and intended to share the views of the Committee with those of representatives from the academia, international and national health organisations.

Among the main challenges to the sustainability of health systems, according to Dr Clare Bambra (Newcastle University), are the pervasiveness of inequalities in health and ageing. Death rate and life expectancy, for example, varies significantly between countries of East and West of Europe, or of the North and South of the continent. Not only: differences are also identifiable between neighbouring areas in the same city, e.g. Berlin, London and Paris, said the expert. Unemployment, healthcare services and housing, education, work, environment and health behavioural factors, such as smoking or drinking alcohol, are among the main factors determining the observed differences, together with politics and public policy.
According to Prof. Bambra, health inequalities have an estimated cost for the EU of € 980 billion per year, which is the equivalent of 9.4% of GDP. Health policies are also an important tool that may help influencing and reverting these inequalities; the European Social Charter, for example, can support issues related to the aging of the population. Reduction of the inequalities, said Mrs Bambra, requires policy cohesion across different sectors.

The access to new medical technologies is challenged by the the principle of universal healthcare, faced by the growing public spending and the consideration of the socio-economic costs of limiting access to health, said the co-chair of the workshop, MEP Mrs Cabezón Ruiz, being also the Rapporteur of the EP Report on EU options for improving access to medicines in the EU.
She said health expenditure represents the 15% of total public expenditure in OECD countries, with an increase of more than 70% since 1990. Projections show health expenditure might reach 9% of GDP by 2030 and 14% by 2060, compared to the 6% of 2014. This trend is supported by the ageing of the European population and the need of long-term care for chronic diseases, coupled to the raising costs of innovation and the high prices of pharmaceutical products. Only 3% of current health expenditure is currently being invested in health prevention and promotion in Europe, said Mrs Cabezón Ruiz. On the other hand, around 17% of health expenditure (approx. 1.41% of GDP) is due to pharmaceuticals, with expectations of growth by up to 7% in the next five years. The absence of new antibiotics is among the more urgent needs to be addressed.
The fundamental question, said Mrs Cabezón Ruiz, should be not why we need to reform health systems, but why we need to maintain the health systems of European member states. Quality and efficiency are characteristics typical of European healthcare systems, said the co-chair, and a return of about € 4.30 is estimated for each euro invested in health. Universality, equity and quality are also principles to be safeguarded, avoiding focusing the political debate only on controlling health expenditures. Education and socio-economic status also contribute to the observed health outcomes.
Access to medicines is another point of concern to be addressed. Mrs Cabezón Ruiz closed her presentation by illustrating several measures useful to support sustainability of health systems, as fiscal and budgetary-control measures at a national level, and reforms modelled on the example of Japan, that for example invested on primary care and prevention. Unmet needs remain also a central point of attention. Clinical trials, health prevention and promotion, intellectual property policy, research and innovation, and the concept of one-health are other important areas of intervention at the European level, according to the MEP.

Professor Barbara Prainsack (Univeristy of Vienna and King’s College, London) commented the theme of precision medicine as a possible tool to support sustainability of healthcare, instead of being looked as a cost driving and technology driven practice that would increase health inequalities. A change of paradigm that would require to rethink the very term of personalization and precision medicine, said the expert. Precision medicine today represent something that “encompass the collection and use of and all the individual patient information (e.g. genome, microbiome, and information related to lifestyles) and integrate them to create a map that gives the possibility of predicting when people will have a health problem”, is the new definition proposed by Prof. Prainsack. A definition that brings as a consequence towards a more holistic approach to the patient, based not only on the specific organ affected by the diseases: a shift would be need from symptomatic and ‘episodic’ medicine to continuous and pre-symptomatic medicine, said the expert.
A better data governance, and an increased attention to certain population groups and individuals, would be further outcomes of precision medicine, according to Mrs Prainsack. But a stronger framework for data protection and access would also be needed. Health in all policies is another measure strongly suggested by the expert, together with reducing harm and waste, for example through promoting low-cost interventions such as the ‘preventing over-diagnoses’ movement, or the realistic medicine initiative. Systematic exploration of low-tech and high-touch practices and their effects has been also suggested by Prof. Prainsack.

A direct comparison of the yet proposed Japanese model has been made by Dr Akiko Maeda, senior health economist at the Organisation of Economic Co-operation and Development (OECD). Life expectancy reached 83,9 years in Japan in 2015, paralleled by a very low incidence of obesity (3,7% vs 19.7% average OECD value) and a low ischemic mortality rate (34.1 for 100,000 people in 2015). On the other hand, dementia is raising in Japan (2,3% in 2017) due to the ageing of population. ‘Big items’ affecting the Japanese situation are, according to Mrs Maeda, the high per capita spending on health, high capital investment in the health sector, and a lack of efficiency in the use of hospitals. Japan is funding its healthcare expenditure through debt, thus greatly contributing the first global position of the country as for total debt (over 200% od GDP).
The new Vision 2035 indicates as priorities the tackling of fiscal deficits and ensuring economic stability. Healthy longevity is a field Japan wishes to act in as an authority at the global level. A complete new vision of the urban infrastructure is also envisaged, allowing for multi-generational living, a better social connectivity and improved coordination of medical care services, social services and long-term care. Healthcare, long term care and social services, housing and preventative care, and design of a system to promote wellbeing are the five step the Japanese government is planning in this direction, said Dr Maeda. An horizontal model for the healthcare system is the final goal, with engagement of all sectors through a shared vision and values. Investments in traditional high-knowledge fields of excellence of the Japanese industry is also being pursued, including stem cell research, cancer research, internet of things and robotics, this last one requiring also a deeper debate to solve ethical issues.

The final objective of a person-led heal-deal health support system that complements the professional-led cure-care system has been at the center of the intervention made by Dr Thomas Plochg, director of the Netherlands Public Health Federation. The Netherlands too are experiencing a transformative phase of their healthcare system. According to Dr Plochg, the current Dutch system is very successful at treating acute, single diseases, but it results unsustainable by design due to the high number of specialists and 70% of staff costs to treat a single patient. And all this different expertise are not of help to reach a coherent diagnosis and treatment, he added.
The values of the Dutch population and a more pro-active approach based on prevention is the picture envisaged by Thomas Plochg for the future of the Dutch healthcare system, based on a ‘zoom out’ vision in order to have a more holistic, integrative view of health. The idea of positive health might be part of this switching of perspective from the ‘care and cure’ to ‘the ability to adapt and self-manage in the face of social, physical and emotional challenges’. Health, and not diseases, should be the core interest of healthcare business models, added the Dutch expert, in a sort of business-to-consumer health relationship (e.g on the model of Spotify services). An approach that is not free from very dangerous aspects, especially for personal data protection.

The last intervention to the debate contributed the example of the Andalusian healthcare system. Dr Natividad Cuende, executive director of the Andalusian Initiative for Advanced Therapies, said the pharmaceutical and biotechnological sector should not be defended at the expense of health system sustainability. A balance between both interests must be found, she added, which protects health systems from the costs arising from monopolies on certain innovative drugs.
Dr Cuende illustrated the example of Andalusia healthcare system, that is the only one in Europe acting as ATMP manufacturer, clinical trial sponsor, healthcare provider and funding entity. According to the Spanish representative, the very high prices of advanced therapies – reaching a mean value of € 500,000 per treatment – are due to the complexity of the legislation governing this class of medicinal products. Member States may exert a hospital exemption clause to regulate non-industrially manufactured ATMPs. Public health systems, is the opinion of the expert, have already experience of several procedures used for cell and tissue donation and transplantation, and which are also used for ATMP manufacturing.

Dr Cuende also remembered that Spain is the leader in Europe of clinical trials in ATMP.
Andalusia is among the European regions with the lowest GDP per inhabitant and with the lowest number of hospital beds, but with a very high life expectancy. Andalusia spent a higher than average percentage of GDP on healthcare compared to other Spanish regions, but with the lowest healthcare expenditure per capita, she added. The rational use of medicines is promoted through the appropriate medicine prescription and competitiveness among pharmaceutical companies. This second objective is achieved through prescribing by active substance (rather than brand), the use of more efficient therapeutic alternatives, and public bids for the selection of the brand of medicines that pharmacists will use when dispensing by active substance. According to Dr Cuende, these measures allowed for 93.4% of medicines being prescribed by active substance in 2017, and to the lower hospital pharmaceutical spending in Spain.

ISO Excellence Award to five EMA’s experts for their achievements in the development of ISO IDMP standards

Giuliana Miglierini
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ISO Excellence Award to five EMA’s experts for their achievements in the development of ISO IDMP standards

The high quality level of the work done by the European Medicines Agency (EMA) has been confirmed once more by the ISO Excellence Award received by five members of its staff for their achievements in the development of the international standards for the identification of medicinal products (IDMP). Paolo Alcini, Sabine Brosch, Tim Buxton, Panagiotis Telonis and Ilaria Del Seppia have been awarded during the International Organisation for Standardisation (ISO) plenary meeting on 22 October 2018 held in Paestum, Italy.

The ISO Excellence Award has been created to recognise the contribution of individuals for recent achievements related to ISO’s technical work considered as a major contribution to furthering the interests of standardisation and related activities.
The five members of EMA’s team awarded have been supported in their activities by other EMA staff and experts from across the EU. IDMP standards are the result of a global collaborative effort led by ISO and involving medical experts from 32 participating and 27 observing countries.

Shared standards for the global exchange of information

Sharing of information about the regulatory processes involving medicinal products – from research to launch and post-marketing surveillance – is today a routine activity that requires all the stakeholders make use of a common language to facilitate the interoperability of data. This is the task of the international standards for the identification of medicinal products (IDMP), providing regulators, global sources of data and the pharmaceutical industry with a common base for the unambiguous identification of medicines along their entire life cycle.
IDMP standards (see here the dedicated page of the EMA website) have been developed to overcome the still fragmented regulatory scenario pharmaceutical companies have to face to obtain approval of their products in the different geographical areas, where different regulatory processes and operating models are in place.

A further level of complexity is represented by the many different languages that can be used in different countries, leading to a complex mix of terminologies and data models, as well as different technical standards for information exchange. The IDMP project provides standardised definitions for the identification and description of medicinal products, so to achieve the consistent exchange of information across all interested parties.
Four different domains of master data have been identified to implement IDMP standards in pharmaceutical regulatory processes: Substance, Product, Organisation and Referential master data, making all together the SPOR system. The use of IDMP standards is compulsory in the European Union according to Commission Implementing Regulation (EU) No 520/2012 (articles 25 and 26).

The five available ISO IDMP standards describes more specifically the substances used to manufacture the medicinal product (ISO 11238), the pharmaceutical dose forms, units of presentation, routes of administration and packaging (ISO 11239), the units of measurement (ISO 11240), the regulated pharmaceutical product information (ISO 11616) and the regulated medicinal product information (ISO 11615). All together, they provide the full description of the final product, including its name, marketing authorisation, clinical particulars and manufacturing.
ISO IDMP standards apply to all medicines for human use, including products under development, investigational products, products under evaluation and authorised products. The implementation of the common standards by the European Medicines Agency follows the phased implementation of the SPOR programme. The submission and maintenance of data on authorised human medicines is already mandatory since July 2012. Marketing-authorisation holders are up to now required to submit information on authorised medicines to EMA through the previous Extended EudraVigilance Product Report Message (XEVPRM) schema and using the specific XEVMPD Dictionary (see here the dedicated page of EMA’s website).
The common dictionary facilitates the reporting of adverse events, allows sharing and re-use of data for different regulatory submissions and among various regulators (subject to confidentiality restrictions) and improves the assessment and scientific evaluation of medicines during clinical experimentation. Application of IDMP standards to good manufacturing practice and inspections of manufacturing sites also facilitates the management of urgent situations involving defects and allows for a faster detection of falsified medicines.

The SPOR programme

EMA is implementing the ISO IDMP standards in phases through its SPOR programme, that applies to both human and veterinary medicines.
As said above, the SPOR systems identifies substance, product, organisation and referential data. For each domain, EMA is providing a specific SPOR service to communicate and manage master data:

  • Substance Management Service (SMS) – harmonised data and definitions to uniquely identify the ingredients and materials that constitute a medicinal product;
  • Product Management Service (PMS) – harmonised data and definitions to uniquely identify a medicinal product based on regulated information (e.g. marketing authorisation, packaging and medicinal information);
  • Organisations Management Service (OMS) – data comprising organisation name and location address, for organisations such as marketing authorisation holders, sponsors, regulatory authorities and manufacturers;
  • Referentials Management Service (RMS) – lists of terms (controlled vocabularies) to describe attributes of products, e.g. lists of dosage forms, units of measurement and routes of administration.

The first two services launched by EMA in June 2017 have been the Referentials Management Service and the Organisations Management Service. They can be already used for submitting applications to EMA and national competent authorities for initial marketing authorisations, variations and renewals for human and veterinary medicines. Once inserted in the system provided by EMA, the master data can be reused many times for regulatory purposes other than the original one.
The other two services – the Substance Management Service (SMS) and the Product Management Service (PMS) – are stil waiting for final implementation. Once they will be in place, the current data-submission format XEVPRM will be replaced with the new ISO IDMP compatible format.
The exchange of information will be based on the Fast Healthcare Interoperability Resources (FHIR, pronounced “fire”), as established in January 2018 by the EU Telematics Enterprise Architecture Board (EU TEAB). According to EMA website, the Agency and the US Food and Drug Administration will work together with Health Level Seven (HL7) to incorporate the ISO IDMP standards into the FHIR specification. This will allow SPOR to become compatible with HL7 standards while retaining flexibility in defining a new data model for ISO IDMP-based data. The last update from EMA on the progress made and next steps in the implementation of the SMS and the PMS is of July 2018.

The peril road of the SPC manufacturing waiver

Giuliana Miglierini
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The peril road of the SPC manufacturing waiver

The proposal of the European Commission of a regulation governing the SPC manufacturing waiver is currently under the scrutiny of the Council of Europe; new opinions from the relevant committees of the European Parliament have also been issued, and Commissioner Bieńkowska replied on behalf of the Commission to a question for written answer by deputy Brian Hayes.
Meanwhile, the generics producer’s association Medicines for Europe (MfE) expressed great concern about the undergoing discussions and claimed undue US inferences in the European legislative process. EFPIA’s director general Nathalie Moll reinforced from the Federation’s blog the point of view of the originators, asking for a waiver limited to the manufacturing for export.

Lobbying to sustain diverging interests

The proposal for an SPC manufacturing waiver sees the originators and generics industries on the two sides of the fence. Many are the opposing interests, starting from the originators trying to maintain the protection of their internal market and asking to limit the waiver just to the production of medicines for export in countries where the SPC is not in force or has already expired. The voice of the European Federation of the Pharmaceutical Industry Associations (EFPIA) has been confirmed by a post signed by EFPIA’s director general Nathalie Moll and published of the Federation’s website on 25 October.

On the other side, the genericists European association Medicines for Europe published two very hard communicates to complain about “vested interests” that are lobbying against the possibility to launch new generics and biosimilar medicines in Europe from day-1 after SPC expiry.
Both the parties are claiming an expected broad impact of the SPC manufacturing waiver on the European capacity to innovate and maintain a competitive position on the global scenario. EFPIA said originators are investing more than 35 billion euros in R&D in Europe every year, and employ over 750,000 people, with the ambitious goal to make the EU a world leader in medical R&D. According to Medicines for Europe, the extension of the SPC manufacturing waiver would contribute a € 9,5 billion economic value in revenues and would worth some 25,000 new jobs in the European Union.

The risk of “neuter” the potential benefits of the SPC manufacturing waiver

A comprehensive SPC manufacturing waiver is the final target for Medicines for Europe, representing the interests of the generics and biosimilar industry. According to the think tank, this approach would allow the European industry to better compete with extra-EU producers on the global markets. Furthermore, the inclusion of a Day-1 launch provision, the removal of anticompetitive requirements and the immediate applicability of the new regulation to existing SPCs would allow European patients to gain a broader access to medicines.
In a first post published on Medicines for Europe website on 11 October, the association denounced the “concrete risk that disproportionate influence on the Council of the European Union will hamper the progress of an effective, usable SPC manufacturing waiver and maintain the status quo”.

According to the genericists representative, “vested interests” would be active to exert pressure on the Council “to remove clauses or add new ones that will jeopardize the whole legislation in an attempt to limit competition in unprotected markets at the expense of European competitiveness and growth”. Delocalisation outside the EU is the risk recalled by the notice in the case the SPC manufacturing waiver would lose its potential benefits in the European contest.
The association asked for a clear provision for ‘Day-1 Launch’ to allow generic and biosimilar manufacturers to produce and stockpile in the EU to be prepared for launch immediately after the SPC expiry. The generics industry also expects the removal of the anticompetitive notification processes to EU intellectual property (IP) regulators foreseen by the Commission proposal, that would have “a significant dissuasive effect regarding the use of the manufacturing waiver”. Genericists also asked for the possibility to immediately apply the waiver to existing SPCs, in order to exploit the opportunities coming with the next significant “patent cliff”, due in 2020.
Medicines for Europe considers “highly regressive” the revisions proposed by the Austrian Presidency. “The proposals are detrimental. The EU’s status as one of the world’s leading pharmaceuticals centres will diminish, the European legislative framework today does not reflect the evolution of the industry since 1992, when the SPC was introduced. Europe is a pioneer in biosimilar and other complex medicines, we should preserve and boost our excellence”, added Mr van den Hoven.

A second, strong position from Medicines for Europe came on 22 October, with a post on its website denouncing alleged interferences from US governmental institutions on EU’s policymakers.
Reference is to a meeting said to have been organised on 23 October in Brussels by the representatives of the US patent and trademark office (USPTO), together with the US Trade Office (USTR) and the US Department of Commerce in order to express to EU legislators their position on the SPC issue. Contacted by Euractiv.com, a spokesperson from the US Mission to the EU, commented that the United States engages regularly with EU institutions, member states, and a wide range of stakeholders in Brussels on issues of shared interest, “just as they do in Washington.”
According to Medicines for Europe, the meeting would have pursued the US commercial interests to close the States internal market to biosimilar medicines.

The concerns of the originators

The reply of EFPIA on behalf of the originators industry came on 25 October with a post by director general Nathalie Moll, where she only refers to an “export manufacturing waiver to the SPC”, thus closing the doors to the possibility for genericists to manufacture, stockpile and enter the European market from day-1 of the SPC’s expiration date.

In any case, for EFPIA’s director general the waiver would represent a signal “that Europe is weakening its commitment to IP incentives and innovation”. Clear safeguards – i.e. transparence and legal certainty – would thus be needed in order to mitigate “potential spill-over effects that would further erode IP rights and could have the (perverse effect of) disincentivising investment in Europe, putting jobs and economic growth at risk”. A timely and fair notification system is among the requests made by EFPIA, together with labelling measures to prevent that products manufactured for export only would be re-directed back to the EU or would be launched on the EU market before SPC expiry. Mrs Moll also confirmed the request for a non-retroactive implementation and a limited scope of the regulation. “We believe these are sensible provisions to avoid weakening Europe’s IP framework further, particularly in today’s context of intense global competition for pharmaceutical research and development investment”, wrote EFPIA’s director general.

New opinions from the European Parliament

The Environment, Public Health and Food Safety (ENVI) Committee of the European Parliament published its draft opinion on 13 September.
Rapporteur Tiemo Wölken has highlighted the importance to balance the competitive scenario, as European manufactures of generics and biosimilar are currently greatly disadvantaged compared to extra-EU competitors. The document extends the purpose of the SPC manufacturing waiver not only for export, but also to “facilitating Day-1 entry within the Union”. The suggestion is to make possible a “stockpiling waiver, giving generic and/or biosimilar manufacturers more incentives to manufacture within the Union and not in third countries”. According to Tiemo Wölken, the SPC and stockpiling waiver would also allow to reinforce the EU’s position as a hub for pharmaceutical innovation and manufacture, especially in the field of biosimilars, and would help the reduction of prices of medicinal products and an improved sustainability of healthcare systems.

The Committee on International Trade (INTA) also published its opinion on 15 October, highlighting the importance of pharmaceutical products as one of the pillars of society, being not just commercial objects.
The Committee supports the possibility of a day-1 entry on the market for generics along the entire document, and adds a point in the preambles stating that “neither the production for export, nor the production for stockpiling purposes run counter to the legal objectives of the SPC system”. Furthermore, according to INTA the only effect of prohibiting stockpiling would be to boost the business opportunities of non-EU companies to the disadvantage of generic manufacturers established in the EU.
The Committee also rejected the Commission’s proposal to make public the commercial information related to the intention of genericists to enter the market and the compulsory use of a special labelling for products intended for export. The INTA Committee also supports the immediate application of the SPC manufacturing waiver, as soon as regulators will be ready to receive the “intention to make” notifications.

The Commission replied during Q&As

Commissioner to the Internal Market, Elżbieta Bieńkowska, participated on 8 October to the Q&A time at the European Parliament, replying to a question from deputy Brian Hayes.
According to Mrs Bieńkowska, the Commission proposal balances the interests of the whole spectrum of stakeholders, including patients as well as generic and originator companies. “Supplying the EU market as soon as the SPC expires will be facilitated by the existence of manufacturing facilities in the EU, set up in order to produce and export medicinal products during the term of the SPC”, said the Commissioner, according to which the proposal represents a “suitable compromise” between the diverging interests of SPC holders and the swift applicability of the waiver.

The use of real world data for R&D of pharmaceuticals

Giuliana Miglierini
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The use of real world data for R&D of pharmaceuticals

The increasing impact of smart technologies on everyday activities, including the ones directly related to the provision of healthcare services (e.g. electronic clinical records), results in the generation of a big quantity of “real world data“ (RWD). These data are under the attention also of regulators, as they may prove very useful to improve the effectiveness and efficiency of all processes related to the development and use of medicines, from research and development, to regulatory decision-making, from pricing and reimbursement to use in the medical practice.
A paper published in Clinical Pharmacology and Therapeutics analyses the possible use of real world data from a regulatory perspective. The paper sees also EMA’s general director Guido Rasi among the authors, together with the heads of three national EU agencies (Portugal, Germany and Denmark), and representatives from the academia, payer, and the Organisation for Economic Co-operation and Development (OECD).

A ‘learning healthcare system’

Machine and deep-learning algorithms play an essential role to analyse electronic health records and other routinely collected healthcare data. Algorithms are one of the central points towards the true implementation of personalised medicine; on the other hand, the continuous RWD flux entering the system ensures that with every new patient treated, the system itself is learning something new about the practice of medicine.
One of the most useful application of real world evidence is the filed of clinical trials, where it might be used to complement the traditional evidence arising from randomised clinical trials in order to speed development. According to the paper, there are still many barriers between the structured research setting and the everyday medical practice. This last one would assume a completely new role under the learning healthcare systems and RWD vision, as data gathered in everyday practice are critical for the generation of new knowledge and answer research questions.
A goal that would require a deep restructuring of healthcare systems in order to implement technologies needed to collect data and methodologies to analyse the gathered information. New models of governance are also needed to ensure a better control and protection of personal data, and to manage consent, ethics and data access. According to the authors, a coordinated, international effort including all stakeholders would be needed to accelerate the implementation of the new model of a ‘learning healthcare system’.

Best practice to generate evidence

Electronic health records are currently underperforming and would represent one of the first point to be addressed under the new vision, together with the infrastructures needed to analyse the big amount of collected data. According to the paper, science, informatics, incentives and culture should go together in order to join in a unique process the best practices and the supply of healthcare services. Under the new model, knowledge would be an outcome integral to the supplied experience, and each treated patient would represent an opportunity to learn something new to implement the system.
The authors say the barriers still existing between traditional, structured clinical trials and daily medical practice have been historically justified to protect patients from the unknown (and potentially dangerous) effects of the candidate medicines under experimentation. The availability of new data coming from the daily use of experimental drugs might prove useful to obtain insights on the effects on the real world patient population, which is usually very different from the selected cohorts typical of randomised clinical studies. The paper does not make any reference to healthcare and lifestyle data acquired through the use of smart devices.

The change in the research paradigm

Research setting is the current paradigm for the clinical development of new pharmaceutical products: detailed protocols based on specific targets established by researchers are at the base of each clinical study. According to the new model of learning healthcare systems, care-driven targets would prove more useful to understand the effects of a new drug on the real population. Complexity, costs and a long term perspective to generate data, together with the difficulty to identify rare adverse effects, are among the main limits of the traditional model, according to the authors.

Big observational studies would represent a much better tool to identify modest increases of a certain adverse event against the background noise.
This would be even more true in the case of innovative, advanced therapies, that are often subjected to post-approval monitoring as the result of the fast track procedures followed to quickly reach regulatory approval. Many cellular or gene therapies might be administered just one time to patients, and adverse effects might manifest even after many years, being thus very difficult to be identified. The use of real world data would allow for a better interception of such adverse effects. Variance analysis of outcomes of the therapeutic interventions across different patients would be also much easier using the real world approach, and it would support the improved identification of the potentially most responsive patients to a certain treatment.

Data protection is still fragmented

An international effort would be needed, according to the paper, in order to overcome the current fragmentation of rules on data protection, informed consent, data access and their ethical use. Secondary use of healthcare data is one of the main issues to be solved, say the authors. All stakeholders should be part of this effort, including regulators, legislators, industry, payers, patients and healthcare professionals.
Three possible lines of action are suggested to reach a rapid implementation of the new model, starting with a deep and multi-level debate among the stakeholders, including also resistance elements that are slowing down the transition. Best practices might also be shared at the international level, with a particular attention to the ones in used in countries more advanced in the implementation of the learning healthcare system model.

The business of AI-based sharing of healthcare data

Giuliana Miglierini
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The business of AI-based sharing of healthcare data

Artificial intelligence (AI) is booming, and there is no day without a new application being announced also in healthcare. Recent examples see the use of blockchain technologies for the acquisition of consent or to collect, store and manage genomic data of wide populations to run R&D activities. On the other hand, the legislative framework regulating this potentially disrupting innovation is still far to accommodate issues related to the acquisition of data and the possibility for third parties to access them for secondary use.

The perception of this approach among the general public is still widely anchored to a more traditional vision, according to a survey run in the UK by KPMG; some observers also highlight the hidden dangers of a possible decline of democracy in favour of mass control using AI-based applications…the Big Brother might turn to become real, tells The Medical Futurist, highlighting how autocracies might misuse the power of data and digital transformation.

EU’s policies for the digital transformation of healthcare

The European Economic and Social Committee (EESC) adopted on 17 September 2018 a positive opinion on the EU Commission’s Communication ‘Transformation of Health and Care in the Digital Single Market, empowering citizens and building a healthier society’. According to the EESC, the impact of the digital transformation will significantly change the intrinsic nature of medical work, as well as that of other healthcare professionals. Machine- and deep-learning algorithms in the next future will represent a fundamental player of the decisional process for diagnosis and treatment, supporting doctors on the base of the great amount of knowledge accumulated through the analysis of big data. This new digital approach is expected to allow doctors to dedicate more time to their patients, suggests the EESC, and patients will remain in any case at the centre of every new healthcare policy.

Of course, a big effort to educate and train healthcare professionals to acquire the new skills linked to AI is paramount. The European Economic and Social Committee also highlights the need to completely rethink the organisation of healthcare systems in order to accommodate the potentialities offered by digital technologies. Interoperability across the eHealth European network is particularly important from this point of view, especially in view of a closer cross-border cooperation as indicated by EU’s Directive 2011/24/EU.

A long-term personal service

According to EESC’s opinion, care is due to become a long-term personal service expected to supporting the increasing impact of ageing and related chronic diseases. A critical issue of the digital transformation relates to the fair access and control of each individual’s personal data and with whom their are shared. A “right to (free) copying” is the suggestion advanced by the Committee, representing an active form of protection of data that users generate while interacting with healthcare digital platforms. The original data conferred through the platforms should be considered as an original product created by the user, and thus protected according to the intellectual property legislation, says the EESC.

Data mining is another issue that would require the adoption of new ethical, legal and social framework, according to the opinion. Actions to rebalance the current socioeconomic asymmetry typical of data driven economies would also be needed; this might be pursued working to the development of safe platforms and providing support to not-profit, cooperative organisations to manage the storing, management and sharing of copies of the acquired personal data.

The perceived impact on the population

The EESC’s opinion also refers to data from the European Commission telling that around 90% of European citizens would agree with the possibility to digitally access their health data. 80% of the EU’s population would also agree to share their data, provided a guarantee of privacy and security, and it would be available to provide feedback on the quality of this sort of instruments.

(source: EESC-European Commission)

In the UK, the estimated perception of the digital healthcare transformation among the wide public appears by now to be much lower, according to KPMG’s analysis “How the UK can win the AI race”, drafting the roadmap for the country’s post-Brexit policies to 2030 for the implementation of artificial intelligence.

Around a third (32%) of the 2,000 British citizens included in the survey thinks to already posses the digital skills needed to use AI technologies, while for another 61% there is need to acquire new competences and skills. Confidence on the potential impact of AI to improve the performance of the National Health Service (NHS) falls to just 53% of respondents, and 56% is available to provide its own data to the NHS in order to achieve this goal. Not so much, but in any case far better than the trust in other types of organisations potentially interested in the collection of personal health data, such as for example the pharmaceutical industry (15%), charities (11%) or internet and communication companies (8% each). It is significant to note that around a quarter of the sample (24%) would not confer its personal data to any kind of organisation, including the government, the police or banks.

According to KPMG, the amount of health data stored by the NHS should be considered as a national asset, able to open the door to an AI healthcare industry able to conquer the global leadership. Trust is one of the main barriers that still need to be shot down, and privacy represents an issue for 51% of respondents. Just 31% of the sample thinks AI might contribute to better informed decisions, able to decrease the errors intrinsic to human decisions.

The evolution of the world wide web

Data protection and sharing it’s not a worry just for common people, and many new initiatives are emerging trying to develop an improved framework to provide consent and control access to each individual’s personal data. “I’ve always believed the web is for everyone. That’s why I and others fight fiercely to protect it. The changes we’ve managed to bring have created a better and more connected world. But for all the good we’ve achieved, the web has evolved into an engine of inequity and division; swayed by powerful forces that use it for their own agendas. Today, I believe we’ve reached a critical tipping point, and that powerful change for the better is possible – and necessary”, writes the inventor of the world wide web, Sir Tim Berners-Lee, in a letter presenting his new project Solid (“Social linked data”).

The open-source project aims to change “the current model where users have to hand over personal data to digital giants in exchange for perceived value”. Berners-Lee’s new platform should represent, in the mind of its inventor, the natural evolution of the web able to provide the possibility to keep control over any kind of digitally shared data, while neutralising data silos and incompatibility issues. According to its website, the project shall focus on the proposal of a set of conventions and tools for building decentralised social applications based on “linked data” principles. One of these is the principle of “personal empowerment through data”, that shall become fundamental according to Tim Berners-Lee. The Solid project would provide users with a choice about where their data are stored, and who may access select elements. Authorised apps might also share the conferred data, providing a completely new experience for the user and opening to “multiple market possibilities, including Solid apps and Solid data storage”, writes Tim Berners-Lee. The development of the Solid platform infrastructure is managed by the startup company inrupt, founded by him together with John Bruce, previously founder and CEO of Resilient.

Blockchain to acquire (and monetise) consent

Sir Tim Berners-Lee is not the only one working to decentralise consent, access and control of personal data. Hu-manity.co, for example, is a US company using blockchain to allow people to manage their “31st human right”, the property of their personal data. The mission itself of the company is focused on “developing human rights and corollary sovereign laws in a decentralised manner on blockchains”. Something that sounds at least ambiguous, if we considered the private nature of the company, compared to the official 30 human rights that were established in 1948 by an intergovernmental institution, the United Nations. Empowered communities are in this case too at the centre of action as, according to hu-manity.co’s vision, they should represent the driven force for the next generation of human rights and policies emerging from a balance of centralised power and decentralised technologically empowered communities. To achieve this challenging goal, the company is flanked by the Hu-manity.science research foundation, those activities are more focused on the convergence of social policy and technological innovation to catalyse socioeconomic impact.

The creation of a global inherent Human Data Consent and Authorization Blockchain is the core business of Hu-manity.co; a blockchain that might be accessed by interested individuals through the dedicated app “#My31”, developed in collaboration with IBM and launched at the beginning of September 2018.

The company expects the app to become a reference point to confer personal data, especially the healthcare ones, provide consent for their usage and control on their sharing. Options to provide compensation for users who agree to share their data with, for example, pharmaceutical companies are also planned to become operative in future.

AI and blockchain-based genomic platforms for the new R&D

Traditional and new players are starting to implement projects that might revolutionise the way new medicines are discovered and R&D activities are run.

GSK, for example, signed last July a multi-year collaboration with 23andMe, a consumer genetics company providing genetic profiling services to over 5 million people. GSK has also made a $ 300 million equity investment in 23andMe, and the two companies said they will share 50% the costs of the agreed research programmes. 23andMe genomic and phenotypic information is expected to prove useful to generate new insights for the identification of novel drug targets under the personalised medicine approach, tackle new subsets of disease and enable rapid progression of clinical programmes. According to the companies, 23andMe customers will be able to choose if to contribute their information (in an aggregate and de-identified form) to a unique and dynamic database for research purposes; more than 80% of 23and Me customers would have already voluntary consented to use their data, said the company. The resulting genetic and phenotypic resource would allow to better identify patient subgroups more likely to respond to targeted treatments and a more efficient enrolment for clinical trials. GSK’s first programme to enter this development platform should be LRRK2 inhibitor, which is currently in preclinical development as a potential treatment for Parkinson’s disease, said the multinational.

In Indian State Andhra Pradesh, Shivom has started its pilot blockchain-backed programme targeted to use genomic data for diagnosis and treatment of type 2 diabetes. The company will collect, sequence and analyse DNA of thousands of patients as well as control healthy people, working in collaboration with Genetic Technologies Limited. Collected genomic data will be extracted, analysed and secured on Shivom’s blockchain-based genomics datahub, to be then anonymised and analysed to develop a diagnostic SNP panel specific to the Indian population. According to the company, patients maintain control of their data, and can withdraw it from the database when they want. Anonymised data might be easily shared and interoperable across technological boundaries, adds the company, and patients might be initially compensated with health insights and benefits, while in a compensation option for data use in trials is planned for the future.

Brexit: EU Commission warns on possible issues regarding clinical trials

Giuliana Miglierini
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Brexit: EU Commission warns on possible issues regarding clinical trials

In preparation to the Brexit due on 30 March 2019, the Directorate for Health and Food Safety of the European Commission released a Notice to stakeholders to provide guidance in the field of clinical trials as a consequence of UK leaving the European Union to become a third country.

The transformation of UK’s legal status may imply legal repercussions also on the field of how clinical trials are planned, organised, managed and reported. Sponsors (both academic researchers and pharmaceutical companies) – as well as investigators and other persons involved in the preparation and conduct of the studies – need to carefully consider all possible issues raising from the Brexit in order to plan and implement the activities needed to mitigate the impact of the leave.

Considerable uncertainties are expected

The Notice to stakeholders highlights the many uncertainties that might go with the cessation of all Union’s primary and secondary laws from the withdrawal date. No withdrawal agreement has been signed up to now between the UK’s government and the European Union, and it is far to be certain any agreement might be reached in time before the end of March next year. This means that from 30 March 2019 EU’s rules on clinical trials will no longer apply in the UK. In particular, the European regulatory framework still refers to Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, as the more recent EU Regulation 536/2014 on clinical trials on medicinal products for human use is not going to apply before the withdrawal date.

The consequences for clinical studies

Three main consequences impacting on clinical trials are expected by the European Commission following the Brexit, the first of which relates to the supply of investigational medicinal products from the UK, that will become subjected to the holding of an authorisation for import in the EU.

This apply also to manufacturing processes only partially performed in a third country, for example the packaging or repacking which is part of blinding activities. All manufacturing activities and batch release for investigational products, including those based in the third country, have to be checked and validated in accordance with the clinical trial authorisation by a qualified person located in the EU and responding to the authorisation holder. Good manufacturing practices must apply as standards of at least an equivalent quality to those laid down in the EU.

Comparator investigational medicinal products authorised in a third country have also to be verified by the qualified person, called to ensure that each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality. It is worth to note that retesting in the EU is not mandatory if the analytical controls have been already carried out in the third country, according to art. 11(2), second subparagraph, of the Directive 2003/94/EC5.

The second consequence impacts on legal requirements for the sponsor or legal representative of the clinical trial, as from 30 March 2019 they also must be established in the EU. This implies that if the sponsor is currently based in the UK, it should promptly act in order to ensure that after the withdrawal a new sponsor or legal representative will be available within the EU-27. The regulatory procedure is a substantial amendment, thus requiring notification to the competent authority and information of the Ethics Committee.

Finally, it should also be considered the impact of the UK’s leave of the flux of information to be transmitted to EudraCT, the EU clinical trials database. In particular, from the date of the Brexit protocol-related information on UK-specific trials will no longer have to be submitted to the database, except when the trial is part of an agreed Paediatric Investigation Plan and the UK is the only country in which the protocol has been submitted.

Submission to EudraCT have also to be run for the results of studies conducted in UK and completed before the withdrawal date, if the reporting of these results is due before the withdrawal date. Furthermore, the submission to EudraCT continues to be required also after the withdrawal date for results of clinical studies conducted in the UK only, and for multi-country trials where the UK was the only EU/EEA Member State where the clinical trial was conducted, if this is required for non-EU/EEA studies (i.e. if the trial is part of an agreed Paediatric Investigation Plan or falls in the scope of art. 46 of Regulation EC/1901/2006).

The UK as source of medicinal products used in bioequivalence studies

Point 11 of the Q&A document “related to the United Kingdom’s withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the Centralised procedure” (released by the EU Commission and EMA on 19 June 2018) discusses the possibility to source from the UK innovator pharmaceutical products to be used in bioequivalence studies of generics outside UK.

This typology of bioequivalence studies can be used in generic/hybrid marketing authorisation applications only if the marketing authorisation for that application will be granted before 30 March 2019, date of the Brexit. The document refers to art. 10(1) of Directive 2001/83/EC or art. 13(1) of Directive 2001/82/EC, stating that the applicant can submit an abridged application if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised in the EU or EEA for not less than eight years.

The Q&As also recall the definition of “generic medicinal product”, i.e. a product which has the same qualitative and quantitative composition in active substance and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. As a consequence of the above and without the possibility of a withdrawal agreement, generic dossier holders will have to reinvest an accountable budget and considerable submission time to perform new BE studies for their products using EU innovators to support their ongoing and upcoming submissions.

A consultation on the “no deal” scenario in the UK

On the other side of the Channel, UK’s Medicines and Healthcare products Regulatory Agency (MHRA) launched on 4 October an open consultation on how its legislation and regulatory processes would have to be modified in the event of a “no deal” exit from the European Union. The consultation is open up to 1st November 2018 and it can be accessed online from this link.

MHRA said to be still “committed to reaching agreement on the Withdrawal Agreement and Future Framework in the autumn”; nevertheless, it comes under its responsibility to prepare also for the worst-case scenario, making the needed contingency plans to make sure the UK’s regulatory processes for medicines, clinical trials and medical devices “are legally coherent on exit day”. Under this worst-case hypothesis, the MHRA would become a stand-alone regulator, taking any decisions and carrying out any functions which are currently taken or carried out at EU-level.

The consultation covers four different Statutory Instruments (SIs) currently available in the UK: the Medicines for Human Use (Clinical Trials) Regulations 2004, the Medical Devices Regulations 2002, the Human Medicines Regulations 2012 (HMRs) and the Medicines (Products for Human Use) (Fees) Regulations 2016. Many are the technical changes to such regulations that would be due in order to eliminate references to the EU and insert those to UK, but other suggestions might be considered provided they fulfil a pragmatic and proportionate approach in establishing UK regulatory requirements, allow MHRA to take regulatory action to protect public safety and provide minimum disruption and burden on companies.

Commenting the initiative, the Association of the British Pharmaceutical Industry (ABPI) said that pharmaceutical companies continue to plan for all possible outcomes of negotiations, in close collaboration with the government. “But we have been very clear that the best way to protect patients and public health in the UK and in the EU is to agree future cooperation between the MHRA and the EMA on the regulation of medicines”, said ABPI’s Deputy Chief Scientific Officer, Dr Sheuli Porkess.

How technologies for the screening of new drugs are changing

Giuliana Miglierini
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How technologies for the screening of new drugs are changing

The increasing availability of artificial intelligence (AI) and deep-learning algorithms able to analyse from many different perspectives the huge amount of R&D data already available in public and private research labs and databases are changing the way drug discovery and development is run. A recent review published in SLAS Discovery and signed by a group of AbbVie’s R&D scientists discusses the many new and emerging approaches to evaluate off-target toxicology from an industrial perspective. Many innovative AI-based companies are also playing an increasing role in supporting traditional pharmaceutical companies in the identification of new, promising therapeutics. We summarise the main features and the many tools discussed in the review and provide some not-exhaustive examples of new business models emerging in the pharmaceutical sector.

The integrated screening paradigm for off-target toxicity

The integrated screening paradigm may support the early identification of off-target toxicology and safety issues, a challenge that is still hard to estimate due to the difficulties to translate observed data from animal to humans and the possible inability to recognise potentially susceptible human subpopulations, argues AbbVie’s group of scientists in the in SLAS Discovery paper.

It is not possible to completely avoid off-target toxicity, especially when small molecules are concerned: an optimised lead may bind to several different targets, a phenomenon which impacts on the observed toxicity profile. Exposures in the in vivo populations represent another bias, according to the review, as many factors might alter this parameter in certain subpopulations of patients.

Gene expression profiling and mapping

Many new analytical tools are available, according to AbbVie’s scientists, to support the elucidation of target and off-target interactions of small molecules, such as for example the L1000 gene expression profiling. The method – born from a collaboration between the MIT’s Broad Institute, Harvard University and Genometry – is based on a high-throughput gene expression assay that measures the mRNA transcript abundance of 978 “landmark” (the “L” in the name) genes from human cells, coupled to the measure of expression of 80 control transcripts chosen for their invariant expression across cell states. Readings are performed on crude lysates of human cells, obtaining an output dataset of expression values for 22,000 genes × 380 samples, suited to be used by machine-learning algorithms and AI-guided drug discovery. The method might be applied, for example, to evaluate the broad impact of the small molecules on cells and identify common and targeted mechanisms of action.

The Broad Institute is also the creator of the Connectivity Map (CMap), a comprehensive catalog of cellular signatures representing systematic perturbation with genetic (reflecting protein function) and pharmacologic (reflecting small molecule function) perturbagens. The library currently contains over 1.5 million gene expression profiles from about 5,000 small molecule compounds and 3,000 genetic reagents, tested in multiple cell types. The database is hosted in the cloud-based infrastructure CLUE (CMap and LINCS Unified Environment), from which researchers can access and manipulate CMap data and integrate them with their own.

L1000 gene expression profiling is also at the base of the National Health Institute (NIH) Library of Integrated Network-Based Cellular Signatures (LINCS) program, an open resource containing assay results from cultured and primary human cells treated with bioactive small molecules, ligands such as growth factors and cytokines, or genetic perturbations. The program aims to better understand the functioning of cell pathways and to support the development of therapies able to restore perturbed pathways and networks.

Phenotypic profiling and CRISPR libraries

The BioMAP human primary cell phenotypic profiling services provided by DiscoverX/Eurofins is another useful tool to determine the efficacy, safety, and mechanism of action of small molecules, say the review’s authors. The system is based on over 60 human primary cell-based models of tissue and disease biology, coupled to a reference benchmark database of more than 4,500 reference compound profiles. Bioinformatic tools associated to the system provide the desired insights.

Screening of CRISPR-generated libraries is another tool complementary to the above mentioned ones; according to the review, this approach allows to study either activating (CRISPRa) or inhibiting (CRISPRi) genes using gene editing. CRISPRa techniques are also useful to assess gain of functions and survival of cells under specific conditions (e.g. the presence of the candidate substance), says an article published in the Journal of Human Genetics, while CRISPRi is a more powerful tool than RNA interference (RNAi) libraries in screening for loss of functions and it can be used also to assess synthetic lethality interactions.

Cellular thermal shift assay mass spectrometry (CETSA-MS) is another recent label-free, biophysical assay based on proteomics useful to evaluate target engagement of a candidate molecule. The method invented at the Swedish Karolinska Institute (which founded the startup Pelago Bioscience to exploit it) allows for the direct measure of ligand-induced changes in protein thermal stability both in living cells and tissues (read here more details).

In vitro ligand binding assays

In vitro panel ligand binding assays can be run using pharmacological targets similar to the one of interest or against off-targets known to be associated with adverse side effects, suggested the SLAS Discovery’s review. According to the recent US regulations on abuse potential of new drugs, assays for neuronal systems related to drug abuse potential and transporters might also be included, suggest authors.

Many assay panels are also commercially available to test kinase activities and interactions with small molecules. More complex is the elucidation of the possible interactions with microtubules and the electron transport chain components: the suggestion in this case is to approach it through routine assessment in advanced mitochondrial cell health assays. Label and label-free technologies can also be used to determine binding with small molecules; the review provide a wide list of both types of methodologies to be used to better assess target deconvolution.

Computational off-target prediction methods

The interaction of small molecules with biological receptors can also be assessed using computational analysis of structure-activity relationships (SAR, or QSAR in the case of quantitative measures). The exercise can be approached under a target-centric vision focused on the target protein, or a ligand-centric vision focused on the small molecule. According to the review, automated molecular docking tools such as Glide and AutoDock are useful to assist the computational lead identification and optimization. The second one is a free tool developed by the Scripps Research Institute. The review also list a wide group of commonly cheminformatics tools and target based off-target prediction methods.

Toxicogenomics and other omics technologies

Toxic substances up- or down-regulating the transcription process may be identified using key mRNA as “gene signature” to be compared against reference toxicological databases. According to the AbbVie’s specialists, this approach is useful to estimate drug safety through the induction of several substances typically produced by the liver, e.g drug-metabolizing enzymes, phase II enzymes, and transporters.

Useful database in this instance are DrugMatrix, released by the U.S. National Toxicology Program, and TG-GATEs. The first one contains results of thousands of highly controlled and standardised toxicological experiments on rats or primary rat hepatocytes, including large-scale gene expression data. The second database is the result of the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system jointly run by Japanese’s National Institute of Biomedical Innovation and National Institute of Health Sciences and 15 pharmaceutical companies. TP-GATEs also focuses on data originated in rats and primary cultured hepatocytes of rats and humans following exposure to 150 compounds. The second phase of the project (TGP2, Toxicogenomics Informatics Project) discovered over 30 different safety biomarkers, which have been incorporated into TG-GATEs.

In vitro transcriptomics on single cells or co-cultures is also a useful tool, according to the review, in order to directly test human tissues, especially when their availability is limited or when small quantities of the drug candidates are available. Furthermore, toxicogenomics often pairs with other types of -omics technologies – i.e. proteomics, metabolomics, and lipidomics – in order to obtain a more comprehensive picture of the cell environment and of the impact of small molecules.

Microfluidic organs-on-a-chip

A rapidly emerging technology to facilitate toxicity evaluation are microfluidic “organs-on-a-chip”, which for example can be organised in series to test different types of tissues or cellular systems. Examples cited by the review are liver- and gut-on-a-chip, but labs are continuously producing new systems reproducing a wide range of tissues and biological processes (e.g. inflammation or tumoral tissues), mimicking both health and disease conditions. Small molecules are fluxed through the nano-channels of the devices, with or without presence of other substances such as cells’ nutrients or metabolites. Organoid models are more complex types of organs-on-a-chip containing different types of cells to reproduce as close as possible the situation of the real organ under exam. According to AbbVie’s scientists, a better qualification of this approach is still needed for a wider application in the pharmaceutical field, where it may result useful for the identification of mechanisms of toxicity and early screening for liabilities not easily or well tested by other in vitro methods.

The emerging technologies

Chemogenomics, high-throughput (HTS) and high-content screening (HCS) are other techniques useful to expedite the identification of good candidate molecules. Toxicology in the 21st Century (Tox21), for example, is a collaboration between four different US federal agencies which makes available different AI-tools for data analysis, and the possibility to access and visualize the Tox21 quantitative high-throughput screening (qHTS) 10K library data, that can also be integrated with other publicly available data.

Toxicity Forecaster (ToxCast) is another high-throughput screening tool created by the US’s Environmental Protection Agency (EPA) which contains data for approximately1,800 chemicals from a broad range of sources, screened in more than 700 high-throughput assay endpoints covering a range of high-level cell responses.

High-content screening (HCS) is based on the combination of molecular tools with a pool of automated imaging and visualisation techniques (e.g automated digital microscopy and flow cytometry) and aims to quantitatively analyse images from high-throughput screenings in order to identify particular patterns, such as for example the spatial distribution of targets and individual cell or organelle morphology.

New integrated approach to drug discovery and development

If the above is a description of single instruments available to drug developers, viewed under the perspective of scientists working for a big “traditional” pharmaceutical company, many are the innovative companies deeply investing on artificial intelligence to create a completely new business model for the R&D process.

Historically, newcos born from IT giants, such as Verily Life Sciences (Google) or IBM Watson have pioneered the new era. Watson for Drug Discovery (WDD), for example, is a cognitive platform collecting more that 25 million Medline abstracts, plus over a million scientific articles and 4 million patents: a knowledge that can be integrated with private data and searched using seven different modules to better define the query. Leader pharma companies such as Pfizer and Novartis have already closed collaboration agreements with WDD to improve the possibility of success of their screening strategies.

New not-conventional players include for example Cota Healthcare, a platform for personalised medicine specialised in the stratification of patients on the base real-world evidence generated insights of personal and clinical data. Its Cota Nodal Address technology allows to classify patients and their disease using a concise digital code, thus enabling a detailed analysis of outcomes, toxicities, practice patterns, and cost.

Deep convolutional neural network is the core technology used by Atomwise to predict the characteristics of the binding between small molecules and target proteins using the proprietary algorithm AtomNet. The core database contains millions of affinity data and measures and it can be searched to screen for potency, selectivity and polypharmacology, as well as against off-target toxicity. The company has already in place more than 60 collaborations, including multinational companies such Pfizer, AbbVie, Merck or Bayer.

The complete development cycle typical of a pharmaceutical business, from lab to market, is the focus of a network of companies comprising Insilico Medicine, Juvencescence.ai and Netramark. The first one is focused on the identification of new therapeutic approaches to treat ageing and related diseases (including identification of novel biomarkers), and also provides services for drug discovery and development. Its AI-based infrastructure uses a complex mix of -omics and chemical databases screened by artificial intelligence tools to identify the “signature” for diseases.

Juvenescence.ai is responsible for the development of drug candidates for ageing identified by the artificial intelligence used by Insilico Medicine, while Netramark uses it proprietary algorithm NetraPharma to match therapeutics with patients’ sub-populations and identify new possibilities for molecules that have already failed development.

The concept of “Interrogative Biology” is at the core of Berg Health’s business model, upon which the development of new personalised interventions starts from the biology of the single patient to be treated. In this case too, artificial intelligence is used to analyse data from biological samples acquired using wide set of technologies (e.g. high performance mass spectrometry, genomics, proteomics, lipidomics and metabolomics, oxidative stress, mitochondrial function, ATP production, etc). Each sample can generate million of data, that are matched with phenotype and clinical information on the single patient. Machine- and deep-learning algorithms are used to identify the therapeutic approach most suited to each clinical case, as well as the biomarkers that may be used. Berg Health is collaborating with several pharmaceutical companies, among which are AstraZeneca, Sanofi-Pasteur and Becton Dickinson.

EU: The amended HTA regulation approved in first reading by the EU’s Parliament

Giuliana Miglierini
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EU: The amended HTA regulation approved in first reading by the EU’s Parliament

The new health technology assessment (HTA) regulation, first proposed by the European Commission on 31 January 2018 (we wrote about it in the June newsletter), is continuing its trip towards final approval expected by 2019.

After the issuing of the final opinions from the relevant Committees (see below), the consolidated text of the regulation (see here the final report of 24 September 2018) was voted in first reading during the plenary sitting of 3 October 2018 and adopted with 576 votes to 56, and 41 abstentions. The next step of the procedure will see the Parliament dealing with the negotiations for a first reading agreement with EU ministers once they set their own position on the file.

The approved text substantially reflects the proposed amendments of the EP’s Committees: one of the main features of the new legislation is the distinction made between “assessment” and “appraisal” of the new technologies. The first one (which is the object of the new HTA regulation) is based on the scientific clinical evidence available at the time of the marketing authorisation and it is just intended to determine the “added value” of a new technology. Appraisal will continue to be run independently by each Member State, it can include both clinical and non-clinical information and data, and it is intended to provide access to treatments on a national basis and to determine price and reimbursement according to each country specific characteristics and policies.

We provide a summary of the main points of the approved document.

Amendments adopted by the European Parliament

The new recital 1(a) details data on the economic impact of the expenditure on medicines in Europe, representing 1,41% of GDP in 2014 and accounted for 17,1% of overall health expenditure; this last equals 10% of GDP, i.e., € 1,300,000 million per annum, € 220,000 million of which for pharmaceutical expenditure and € 110,000 million for medical devices.

The many barriers still preventing access to patients, including the “lack of new treatments for certain diseases and the high price of medicines, which in many cases do not have added therapeutic value”, are another problem addressed by the new regulation. New recital 1(c) adds that Joint clinical assessment (JCA) bodies normally take into consideration comparative effectiveness, but these sort of studies are not usually part of the marketing authorisations procedures.

As for Joint scientific consultations, recital 20(a) specifies that they should address transparently the clinical study design and the determination of best comparators, on the base of best medical practices and in the interest of patients. To ensure confidentiality of data – while making them as open as possible in order to preserve the public interest – recital 21(a) states that commercially sensitive data are shared in an anonymised format for the redaction of reports before publication. “Public health should always prevail over commercial interests”, further adds recital 21(b) with respect to the disclosure of data impacting on the health of individuals.

HTA is defined as a scientific evidence-based process focused specifically “on the added therapeutic value of a health technology in comparison with other new or existing health technologies”. Comparative assessment based on comparative trials against the current best proven intervention (‘standard treatment’) – or against the current most common treatment where no standard treatment exists – is the instrument of choice to perform the assessment, according to recital 3(a).

JCAs shall apply also to “certain medical devices within the meaning of Regulation (EU) 2017/745 […], given the need for greater clinical evidence concerning all of those new health technologies” (rec. 12). The tool of HTA should support the universal health coverage, as stated by the World Health Organisation (WHO) in May 2014 (rec. 2(a)). It might also be extended, suggests recital 4(b), to areas such as diagnostics used to supplement treatment, surgical procedures, prevention, screening and health promotion programmes, information and communications technology (ICT) tools, health-care organisation plans and integrated care processes.

HTAs shall be run according to the nine ‘HTA Core model’ domains identified under the EUnetHTA Joint Actions, four of which are clinical and five non-clinical. The first ones include the identification of the health problem and currently available technology, and the examination of the technical characteristics, safety and relative clinical effectiveness of the new technology under assessment. The second ones include cost and economic evaluation, ethical considerations and organisational, social, and legal aspects.

The summary report, according to article 6.1.2, shall contain at least the compared clinical data, the end-points, the comparators, the methodology, the clinical evidence used, and conclusions as regards efficacy, safety, and relative efficacy. It shall discuss also the limits of the assessment, diverging views, and report a summary of the consultations carried out, and the observations made.

Article 6.2 lists the documentation to be submitted by developers, that shall include all data and studies, including negative results. Other relevant complementary data and information may be obtained from public databases and sources of clinical information, such as patient registries, databases or the European Reference Networks. As for orphan medicines, article 6.2(a) specifies that the Coordination Group may “justifiably consider that there is no substantive reason or additional evidence to support further clinical analysis beyond the significant benefit assessment already carried by the European Medicines Agency”.

A seven day period is suggested for the developer of the technology under exam to object in writing to the conclusions of the JCA report and summary report; the Coordination Group is granted another seven days to respond to such observations. A system of charges for health technology developers requesting both joint scientific consultations and JCAs for research on unmet medical needs shall be put in place by the European Commission, according to rec. 27. The Commission is also called to reach a common agreed definition of what constitutes “high-quality innovation or added therapeutic value” (rec. 28 (b)). The Coordination Group shall issue the methodologies needed to run the assessments and consultations by no longer than six months from the final approval and entry into force of the new HTA regulation.

Other expected outcomes of the new legislation are a common “POP” database for sharing projects Planned, Ongoing or recently Published by individual agencies. Another database shall store the information and the stage of assessment of new emerging and promising technologies, as well as the request for supplementary studies arising from the HTA.

The time proposed to publish JCAs’ reports and summary reports is not less than 80 days and not more than 100 days, except in justified cases (art. 6.14(b)). To avoid conflicts of interest, distinctive mandates of the Coordination Group’s sub-groups conducting the joint clinical assessments and the joint scientific consultations should be considered.

The IMCO opinion

The Committee on the Internal Market and Consumer Protection (IMCO) published its final opinion on 20 July 2018. Among others, the Committee indicated the need to consider health technologies a key factor to improve health policies, as they would allow to increase “access to more progressive health technologies, and thus achieving a high level of health protection”. The Committee also underlines patients’ rights to be protected “against the financial, social and medical consequences of a disease”, and to have unrestrained access to the latest therapeutic discoveries, “which should be guaranteed by law in all Member States”.

IMCO asked for joint clinical assessments to be carried out on all medicinal products undergoing central marketing authorisation and incorporating a new active substance, and in case of subsequent authorisations for new therapeutic indication. Some types of high-risk medical devices should also had been included in the purpose of the new regulation. The Opinion clarifies that JCAs should focus on the factual review and analysis of available evidence at the time of regulatory approval of the product, thus the two procedures should be run in parallel. Furthermore, the assessment “excludes any valuation (i.e. setting a value) of a product, as this step is called appraisal and remains the full prerogative of Member States”. The HTA analysis should include all “patient-relevant health outcomes”, i.e. data that captures or predicts mortality, morbidity, health-related quality of life and adverse events. All these points are present in the consolidated text approved by the Parliament.

Synergies and conditions for the updating of assessments are also needed, according to IMCO, in order to avoid duplication of efforts between the European Medicines Agency (EMA) and JCA bodies. These last ones are expected to cooperate on the base of principles of good governance, objectivity, independence and transparency. Member States shall maintain the right to complement joint clinical assessments with additional clinical evidence, where needed. The opinion confirms that certain Member States can start clinical assessments “even before the marketing authorisation has been granted by the Commission”, and the process should be completed in any case by the time of the publication of the Commission decision granting MA. Assessment of medical devices should occur after their launch on the market, and “if possible, in the presence of producers”, was the suggestion made by IMCO.

The Committee also highlighted that joint clinical assessment of vaccines should be also accomplished, in order to consider their preventive nature “that brings benefits to individuals and populations over a long time horizon”.

Results of the work already undertaken in the EUnetHTA Joint Actions, and in particular the methodological guidelines and evidence submission template, should be used to create the common procedures for joint clinical assessments and joint scientific consultations.

The Commission and the Coordination Group would be responsible to establish the updating frequency for HTA parameters and procedures, and should set a flexible framework to accommodate the special features characterising some types of products, e.g. advanced therapies. The Coordination Group shall reach decisions on the base of consensus, with a two-third majority of votes (one for each Member State; the Commission shall have no right to vote). Regular consultations with stakeholders, including patient organisations, health professionals and clinical experts had been also suggested, and have been included in the approved text.

The ITRE opinion

The final opinion of the Committee on Industry, Research and Energy (ITRE) was published on 12 September 2018, highlighting the importance of a reinforced cooperation in the European healthcare sector to boost its global competitiveness.

The document confirmed the lack of a clear definition of the methodologies within the proposal, something to be addressed on the base of top level scientific evidence. Areas of action for the Coordination Group shall include JCAs of the most innovative health technologies, having the highest potential impact for patients, joint scientific consultations to obtain advice from HTA authorities, early stage identification of emerging health technologies and voluntary cooperation in other areas. A structured involvement of patient organisations, industry and other stakeholders is also envisaged, as well as the sharing of HTA research outcomes, both negative and positive ones. The assessment report shall include details on votes underlying decisions, together with dissensions and minority opinion, that shall be always motivated.

The ITRE stressed the importance of the mandatory uptake of JCAs in order to avoid duplications, and once more the distinction between the assessment of available scientific evidence run at the European level and the appraisal run by each single Member State, that leads to decisions on access, price and reimbursement.

According to the Committee, medical devices should not have been included in the scope of the HTA regulation, as national HTA bodies can already use other useful tools to evaluate them. Furthermore, the new Regulation (EU) 2017/745 will not enter into force until 26 May 2020: “It thus would be premature to refer to those medical devices subject to the scrutiny procedure when it is still unclear which devices would eventually be CE-marked under the scrutiny procedure”, wrote the rapporteur.

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