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Giuliana Miglierini

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The importance of IP to boost company’s success

High-growth firms (HGFs) are defined as small and medium enterprises (SMEs) experiencing an annual growth of at least 20% for at least three consecutive years. The origin of their success is the very strong intellectual property (IP) rights on patents, brands, design they own, says a joint study from the European Patent Office (EPO) and the European Union Intellectual Property Office (EUIPO). Innovation and the focus on scaling up HGFs’ activities at the international level are indicated as the main drivers of their growth.

SMEs are critical for the EU economy

Small and medium enterprises represent 99% of the EU business and produce 57% of the Union’s GDP. High growth firms are just a small proportion of this universe (6%), but their role to boost the entire European economy is critical, according to the study, as they act as a major element of the European innovation ecosystem, together with the academy. In 2016, SMEs were more than 179,000 in the EU 28 (+24% compared to 2014; two thirds located in Germany, UK, Spain, France, Italy and Poland), with a three-year average growth rate in employment of at least 10%. HGFs contribute 28% of the European net job creation, says the study, that analysed data linking demographic information on European SMEs in manufacturing industries from 2005 to 2010 with those of the national and European registers for patents, trademarks and industrial design rights.
A fifth (20%) of all patent applications received by the EPO are originated by SMEs or individual entrepreneurs; a percentage that is even increasing for trademarks and design application managed by the EUIPO. It is thus easy to understand why HGFs are a priority target for policymakers. Intellectual property rights are fundamental intangible assets for this type of business: patents and trademarks allow to secure ideas and obtain higher returns on the investments. On the other hand, HGFs often lack physical assets or non-core skills, and they rely more on risk-oriented finance than on the classical bank loans. A modality of financing that may expose them to higher risks, as investors are willing to rapidly return from their investments. Partnerships with start-ups and SMEs based on collaboration and/or licensing agreements for new technologies are, for example, the current most diffused model to run R&D projects. According to the study, SMEs are more prone to accept higher entrepreneurial risks, thus they act as agents of change and indicators of the ability of the European industrial framework to compete on global markets.

How to better exploit IPRs to become a HGFs

According to EUIPO data (2015), just a small proportion (9%) of European SMEs – usually the most innovative ones – have registered IP rights, compared with 40% of large companies. And only the 0.3% of SMEs own European patents. The early identification of the correct strategy to manage intellectual property rights is an essential requirement to support the high growth of a start-up and create strong IP assets. According to the study, the interplay between IP management and commercial success should be early addressed to avoid any subsequent issue in funding, partnerships or litigations.
Data reported by EPO shows that even innovative SMEs are not always seeking IP protections of their innovations, often due to a lack of awareness of the benefits, high costs, length and complexity of the related procedures. Just 30.4% of innovative SMEs are using patents, compared with 52.8% for large companies (data Community Innovation Survey, CIS, 2012). Self-acknowledgment of the “innovative” profile of a SME is very high (80%) for companies that have registered IPRs, much less (53%) for those that do not register IPRs (data SME Scoreboard, EUIPO, 2016). And SMEs with registered IPRs benefit from 32% higher revenue per employee than those that do not consider important to protect their intellectual property (data EUIPO, 2015).

According to EPO and EUIPO, a SME detaining at least one IPR have 21% more probability to experience a subsequent growth period, and is 10% more likely to become an HGF. Possible growth is 9% higher for SMEs that possess at least one patent, and 13% higher for those that have led at least one trademark. A similar pattern is shown for companies filing a European IPR (26% growth, 17% high growth), representing for EPO an indicator of SME’s readiness to scale up business to the European level.
As can be expected, high-tech SMEs focused on the exploitation of their property rights are more likely (+110%) to experience high growth. This group includes companies manufacturing pharmaceuticals, computers, electronics, optical products, and air and spacecraft. The percentage is even greater (+172%) for low-tech companies, where patents are not so common assets to be found. European trademarks are particularly important for high growth of consumer non-durable SMEs (+62%), while national trademarks are more relevant (+49%) for consumer durable industries.
Furthermore, holding more than a single IPR boosts the likelihood to achieve high growth. Trademarks (TMs), in particular, are critical assets within an IP bundle, with a potential growth of 27% for the combination design+TMs, compared to 10% for just TMs and 16% for patents+TMs; and all the three combined determine +33% potential odds of high growth. Other non-formal types of IPRs may be also exploited in conjunction with patents, trademarks or designs, i.e. the use of confidentiality (42% of surveyed SMEs), the complexity of product design (29%), a faster time-to-market (24%), or complementary assets (23%) to protect the intellectual assets.

Patents to improve growth

Patents are the typical form IPRs assume within the pharmaceutical industry and all other regulated sectors characterised by long product cycles to protect innovation from being copied. Once granted, this exclusive right is limited in time: typically, patent protection lasts 20 years from the date of the application. It is also limited in space, i.e. only within the jurisdiction of the granting state.

Trademarks and industrial designs often represent a key communication element towards consumers and are more focused on the protection of the investments (i.e. product quality, service or advertising) on which the reputation of firms is based, explains the report. Trademarks can be protected on the basis of either registration, or through their actual use in the marketplace.
Patents are essentially filed for reasons of “commercial exploitation” or “prevention of imitation”, added the experts from EPO and EUIPO. They also support the company’s freedom to operate (FTO) by protecting on-going or future development of its products/services, representing a lever to negotiate cross-licensing agreements in the case of infringement of third-party IPRs. Licensing out is the preferred destination for up to 48% of patents hold by European SMEs (closing a true deal in one third of cases), says the study, compared with 16% (9% closed deals) for large companies.

EMA’s updates on the business continuity plan and preparation for the Brexit

After the European elections, the new representative of the European Parliament – Matthias Groote, previously president of the ENVI Committee of the Parliament – entered the Board of the European Medicines Agency (EMA) during the last meeting in June. The Board discussed the current situation of EMA’s internal organisation after the move to Amsterdam and updated the preparations for the Brexit.

Loss of staff is an issue

Loss of staff is higher than expected after the move of the European Medicines Agency to its new – but still temporary – buildings in Amsterdam Sloterdijk. The Board indicated an estimate of 20-25% of workers expected to leave the Agency as a consequence of the transition to Holland. It has been confirmed that the final building in Amsterdam Zuidas is expected to be completed by November 2019, with the final relocation starting from 1° January 2020.
The move of EMA’s staff to the Sloterdijk building is not yet complete, and while some 464 resources are already at work in Amsterdam, some other 312 are still tele-working from London (data referred to mid June); there were 901 people working at EMA before the Brexit. According to the last Board meeting, the Agency does not anticipate reaching its previous headcount, despite the ongoing selection procedures to recruit new staff members.

Many activities remain on hold

Staff constraints and the further pressure resulting from the need to address additional workload to handle the Brexit are at the basis of the Board’s decision to keep on hold many activities that were suspended during the relocation from London to Amsterdam according to EMA’s business continuity plan.
Actions needed to guarantee the long-term efficiency of the Agency should be the first to be resumed, including the creation of a new IT platform supporting the evaluation process for medicinal products and the digitalisation of administrative activities. EMA released an updated table summarising all not priority (category 1) activities that will continue in 2019 (download it here).

According to the table, the availability of internal resources will impact on the effective capacity to run some of the activities scheduled for Q3-Q4 2019, i.e. those relating to EC/EMA Action Plan on the 10-year report on the Paediatric regulation, initiatives relating to the Regulatory Science Strategy and the preparation of the EU Medicines Agencies Network Strategy to 2025. Other activities that may be delayed include the preparation for implementation of the new veterinary, GDPR and medical device legislations and the availability of veterinary medicines. According to staff availability, also activities relating to EC’s report to improve product information and those relating to the International Coalition of Medicinal Regulatory Authorities (ICMRA) might be activated in the second half of 2019.
The development of new guidelines, meetings of some working groups, EMA’s participations to international activities and the pro-active publication of clinical trials results are among the still delayed activities.

An additional issue that, according to the Board, has mined EMA’s operative capacity is represented by the many new pieces of European legislation that have impacted on the Agency workload. The new Medical Device and In vitro Diagnostics regulations, the GDPR regulation on data protection and the new legislative framework for veterinary health all requires some sort of activities to be run by EMA. Preparations to handle this additional workload are expected to start immediately, but their effective implementation will depend on the concrete availability of the needed resources, both at the human and financial level.

The last data on the preparations for the Brexit

Just three months are left to the 31 October, the current date for the Brexit; EMA’s Board released in June the last updates on the regulatory procedures needed to face the exit of UK from the European Union. The transfer of marketing authorisations from UK to an EU-27 country is almost completed (397/400), as well as that of the sites for batch release (95/119, 80%), the Qualified Person for pharmacovigilance (72%) and the pharmacovigilance system master files (83%).

Among other issues discussed by the June Board of EMA, the approval of the 2018 Annual Report. Significant achievements were made last year in relation to orphan medicines, with the activation of the IRIS web platform to manage submissions to the Agency, and the advances of the Clinical Trials Information System (CTIS) to be implemented according to the Clinical Trial regulation. Some “product owners” have been named to represent member states and stakeholders in the management of the IT infrastructure, being responsible to monitor the respective expectations are considered in its development. A first test run of the CTIS system has been achieved in spring 2019. According to EMA’s Board, a first, preliminary release of the platform should have occurred in June, in order to prepare the audit of the system.

Trends for the global pharmaceutical market to 2024

Many opportunities should open in the next five years in the pharmaceutical market, and sales volumes might reach $1.18 trillion in 2024. The main drivers are the increasing convergence of technologies and health and new models for the treatment of many diseases based on advanced therapies. Pending issues pertains the revision of the current models for pricing and reimbursement to adapt to new generation technologies, says the EvaluatePharma report “World preview 2019. Outlook to 2024.

The market for prescription medicines

Forecasted sales to 2024 are seeing the programmed cell death protein 1 antibody Keytruda (Merck and Otsuka, +15.4% CAGR (compounded average growth rate)) conquering the first place, leaving behind Humira (AbbVie and Eisai, -8.0%), an TNFa antibody. The analysts expect also a strong improvement in the sales of Bruton’s tyrosine kinase inhibitor Imbruvica (AbbVie and J&J, +13.5%) and the cyclin-dependent kinase 4 inhibitor Ibrance (Pfizer, + 14.2%). At the tenth position enters Gilead’s HIV-1 integrase inhibitor and nucleoside reverse transcriptase inhibitor Biktarvy, with projections of a +34.3% in sales.

The increasing number of regulatory approvals (62 by the FDA in 2018 vs 55 in 2017) are supporting a 6.9% CAGR expected growth of the prescription drugs market in the period 2019-2024. Orphan medicines and immuno-oncology should remain the favorite areas of innovation, in the second case seeing many line extensions for products already on the market. Oncology shall represent the 19.4% of the market in 2024 ($237 bln), while orphan drugs are expected to generate additional sales for $109 bln in 2024 vs 2018.
The report also indicates an increased competition in the anti-rheumatic field (-1,0% CAGR in the period 2018-24) and poses the question of the real interest in pursuing the development of new cardiovascular medicines, considering the risk of failure, the big dimensions of clinical studies and development costs in the order of a billion dollars. In comparison, the development cost for a new oncological product is “just” $0.7 billion.

Uncertainties linked to US’s president Trump intention to revise health policies on one side, and the launch of new products on the other are indicated by the analysts as possible factors that might influence the market. Among the more interesting and recently approved products, the report remembers Ultomiris-ravulizumab (Alexion Pharma) for adult patients living with paroxysmal nocturnal hemoglobinuria and Takhzyro-lanadelumab-flyo (Takeda) for routine prevention of recurrent attacks of hereditary angioedema in patients aged 12 years and older.
Pfizer, Novartis and Roche will remain the markets leaders, fighting for the first position; Takeda is expected to gain positions thanks to the acquisition of Shire, while BMS is suffering the competition of Keytruda (pembrolizumab) to its product Opdivo (nivolumab) to treat various types of cancers. The acquisition of Celgene may offer BMS an opportunity to access again the top 10 positions of the ranking. AstraZeneca is currently holding the 10th place, and its growth should be supported by the strong presence on the Chinese market and sales of the two oncological products Tagrisso (osimertinib) and Lynparza (olaparib).

The patent cliff and the new products from pipelines

According to the report, sales should decrease (-$198 billion) as the consequence of the expiration of many patents. One of the main products facing the patent cliff is Humira-adalimumab. On the other hand, analysts expect some 400 new products exiting the pipelines, even if R&D investments in proportion to sales of Rx medicines is due to diminish to 18% (from 21.6% in 2018). R&D expenditure reached $179 bln in 2018 (+6.5% vs 2017), and it is expected to increase 3% CAGR up to 2024.
According to the analysts, the forecasted reduction in R&D spend after 2019 may be an indication the investments to improve the future R&D efficiencies of the companies – i.e. real world data combined with machine learning techniques and collaborative R&D programs – might be well advanced. Another explanation is that less revenue is being reinvested in new R&D activities to enrich pipelines.
GlaxoSmithKline is expected to have the highest growth in pharma R&D spend (+5,3%), in a ranking seeing J&J and Roche as the leaders, with $9,9 bln R&D spend each. Johnson & Johnson and Merck should lead the investments ranking, before Novartis. Among promising products under development and that should reach approval in the next few years are the triple combination VX-659/VX-445+tezacaftor+ivacaftor for the treatment of cystic fibrosis, currently in phase 3 (Vertex), the Jak1 kinase inhibitor upadacitinib (Abbvie) to treat ulcerative colitis and rheumatoid arthritis (under approval) and the oncological anti-Her2 DS-8201 antibody currently in phase 3 (Daiichi Sankyo).

Biological medicines are the new king of the market

Small molecules are the past of the pharmaceutical industry, the present and the future being represented by biological medicines. This type on medicinal products currently represents 66% of the ten most sold drugs; if looking at the the top 100 ranking, says the report, biotech and conventional products should gain each 50% of the market in 2024.
Roche is maintaining its leading position, while Merck is rapidly growing (10.9% CAGR) and it is expected to reach the second position. Eli Lilly is also increasing its market shares thanks to its anti-diabetic product Trulicity (dulaglutide). The less performing company is expected to be AbbVie (-4.9%), suffering for the expiration of Humira’s patent.

Italy: The 2019 AFI Symposium

As every year, June saw the annual meeting of the Italian pharmaceutical community in Rimini, to attend the 59° AFI Symposium. This year the symposium counted about 1,300 participants, many from Italian scientific, trading and entrepreneurship associations invited and collaborating with AFI, and 110 sponsors showing their technologies in the exhibition area. Numbers that make the AFI Symposium the most important meeting in Italy for the professionals working in the pharmaceutical industry. Students can attend the entire Symposium free of charge, and free is also the access to the exhibition area.

The theme chosen by the Associazione Farmaceutici Industria for 2019 was “Innovation and globalisation strategies for the pharmaceutical industry”: three days of debates on the impact of advanced technologies on research, manufacturing and therapeutic applications, and the consequent need of developing new business strategies and competencies, as well as new forms of investment in material and human resources.

The global scenario of advanced therapies (ATMPs) is rapidly evolving, and it is critical for the biopharmaceutical industry to keep up with these changes. Choices are strongly determined by the global market, and the ability to successfully manage competition involves at the same time the consideration of both emerging countries (for economic reasons) and small innovative companies (especially in the biotech sector).

A rich program and many opportunities for networking

The AFI Symposium counted this year, as usual, a lectio magistralis and a plenary session; the first speech was given by Maurizio De Cicco, CEO of Roche Italy, discussing the many challenges companies have to face to maintain their competitiveness in the above mentioned rapidly evolving scenario. Future opportunities for the governance of the pharmaceutical expenditure was discussed during the plenary session, that saw experts debating the possible ways to ensure sustainability for healthcare systems in the era of personalised medicine.

The program of the Symposium also included 17 technical sessions, covering all aspects of the development and production of medicinal products. Many hot topics have been considered from different points of view in more than one session, i.e. issues in the field of manufacturing (mainly serialisation and innovative processing), regulatory and pharmacovigilance, the implementation of new technologies and drug delivery systems, the problems linked to quality compliance, supply chain and GDPs, the evolving scenarios for clinical trials, ATMPs and biotechnologies and, finally, the preparation to the entry into force of the Medical Devices new regulation. Sponsors – carefully selected among those able to present innovative solutions, products or services – had the opportunity to present their activities during 14 dedicated workshops.

Many special initiatives to expand the network

The “Start-up square” is the annual meeting where new, innovative companies can present their activities and projects: an important opportunity for networking with other stakeholders to exchange views and build partnerships with investors, industrial partners or customers. The commitment to develop innovative technological solution to support pharmaceutical activities was rewarded with the formal recognition of the Innovation Prize to the best technological solution. Another prize was assigned to the best poster presented among the 30 participating to the Poster session of the symposium.
The working opportunities opened in the pharmaceutical industrial sector for young graduates in life sciences disciplines were discussed in three sessions specifically dedicated to students, new graduates and PhDs, during which they had the opportunity to meet with experts from industry and research institutions. In particular, AFI experienced members outlined the professional profiles which are required today by the pharmaceutical industry, and the trends expected for the next few years.

EIPG at the 59° AFI Symposium

EIPG president Claude Farrugia was invited to attend the AFI Symposium. He contributed to the debate with a presentation on the “Impact of the last mile”, given within Session I, centred on the serialisation process.
EIPG is expected to play a more pro-active role in the organisation of the next edition of the AFI Symposium, in 2020, that will correspond to the 60th anniversary of AFI foundation. In fact, during this year meeting it was agreed that EIPG will act as the connection point to invite representatives of other European associations, with the ambitious goal to make the AFI Symposium more European.

The WHA has approved the resolution on transparency of drug prices

After very complex negotiations, the World Health Assembly (WHA) approved at the end of May the resolution to support greater public disclosure of prices and R&D costs for medicines and other health products (find here the document).
The initiative was launched in February by the Italian Ministry of Health, and it has finally found the agreement of another twenty-two countries (Algeria, Andorra, Botswana, Brazil, Egypt, Eswatini, Greece, India, Indonesia, Kenya, Luxembourg, Malaysia, Malta, Portugal, Russia, Serbia, Slovenia, South Africa, Spain, Sri Lanka, Uganda and Uruguay). Some others – i.e. Germany, Great Britain and Hungaryhave dissociated from the final document approved by the WHA, arguing that the time had not been enough to deeply evaluate its complex implications (read here more on Health Policy Watch).

Our proposal represented a challenge towards a fair access to healthcaresaid the Italian minister of Health, Giulia Grillo, commenting on the approval -. Now countries have committed to adopt its principles so that no more barriers to the right to health will exists”.

But the resolution approved by the WHA may turn out to exert a far less deep impact on price negotiations for new drugs than expected, as in the final text transparency has become just a declaration of principle, without any compulsory action for the disclosure of costs elements contributing to price calculation.

A voluntary adoption

According to Italian minister of Health, the resolution on price transparency is opening a new way for such negotiations, as more complete information is expected to be available that should improve the dialogue with the industry. The final goal is a more competitive and innovative market for pharmaceutical products, and the possibility for governments to buy “more health” with the same economic resources.
According to the compromise text agreed by the WHA, each country remains free to voluntarily adhere to the indications set forth by the resolution. These include the public sharing of information on net prices of healthcare products, i.e. the price received by the company after deduction of discounts, rebates and other incentives. Access to aggregate data on results of clinical studies is also expected to improve, limited to those data already publicly available or that the companies may provide under a voluntary basis. The same applies to costs for human clinical studies, independent from their results or filing for regulatory approval.
A greater collaborative effort should be put in place, according to the resolution, to improve transfer along the supply chain of information on prices, sales volumes, marketing costs and received incentives. An important goal of the final text approved by the WHA is the increase of publicly available information on the intellectual property and regulatory status of a certain medicinal product. The resolution also targets a better use of international cooperation tools and open and collaborative research to support the development of healthcare products in low and medium income countries.

Requests for WHO’s executive director

Together with the above mentioned indications, the resolution on price transparency also addresses some requests directed to the WHO executive director. The World Health Organisation should provide support to member states, if required, to collect and analyse the economic data – together with all other data relevant for the development of new policies to reach universal health coverage – along the entire value chain.
A particular attention should be paid to low and medium income countries, to help them in the development and implementation of policies supporting a better transparency of markets and local productions, an improved adoption of biosimilars and to help solving critical issues in the healthcare field. The WHO should also monitor the impact of price transparency on availability and sustainability of medicinal products in the different markets, at the global level. To reach this objective, the suggestion is to analyse input data along the value chain and to run a feasibility study on the possible use of web-based tools to facilitate sharing of all information needed to support transparency. The WHO’s biannual forum on Fair Pricing is expected to continue being a privileged location to discuss with stakeholders all issues on these themes.

A complex negotiation

When we started working at the text of the resolution, very few believed we would have reached the end. Many people called us visionaries, dreamers. Today, I clearly state that without a dream, a vision, no change is possible”, said Italian Health minister Giulia Grillo commenting on the approval of the resolution. The executive director of the Italian Medicines Agency (AIFA), Luca Li Bassi, played a central role in the negotiations, as he led the team involved in reaching a tentative agreement the week prior to the World Health Assembly. In a first phase of the negotiation there were ten countries supporting the Italian proposal, a group reaching the final number of 22 after convergence on the final text (see more here and here).

Sharing and transparency on R&D costs has been one of the mostly opposed points of the documents. According to Health Policy Watch (HPW), the UK representative, Julian Braithwaite, would have expressed concerns on the possible impact of the resolution on differential prices that are today applied to facilitate access to medicines in low income countries (see also The Guardian).

HPW says Germany also criticised the resolution in that it did not undergo a formal preventive scrutiny by the WHO Executive Board. On the other hand, positive comments came from African countries and from the US representative, Garett Grigsby.

IFPMA commented from the industrial perspective

The International Federation of the Pharmaceutical Manufacturers Associations (IFPMA) released a statement commenting on the approval of the resolution by the WHA, showing concerns that “some proposals in the Roadmap and at this Assembly focusing on transparency and intellectual property would deter from holistic and sustainable solutions to access”. The industrial federation has asked once more for the promotion of sustained investments in health systems as the way to support long-term solutions for access, together with an innovation ecosystem to incentive research in new products.
According to IFPMA, the issue of transparency would have been already addressed on the industrial side, for example through the IFPMA’s Principles for Responsible Clinical Trial Data Sharing and the Pat-INFORMED initiative to facilitate access to medicine patent information.
We urge Member States to carefully consider potential risks to patients, particularly in less developed countries, of sharing outcomes of confidential prices negotiations across countries. We also caution against disclosure requirements on R&D costs that underscore ‘cost-plus’ models. Prices should reflect the therapeutic value of medicines and positive outcomes for patients and society, rather than simply the cost ‘input’ of a individual medicine”, is the position of the industry reported in the statement.

The top priced new treatment for spinal muscular atrophy

While the WHA was debating to find agreement on the final text of the resolution, AveXis’ (part of Novartis) cutting edge one-time gene therapy Zolgensma (onasemnogene abeparvovec-xioi) received approval from the US Food and Drug Administration to treat spinal muscular atrophy (SMA). A single treatment costs $ 2,1 million, establishing the new therapy as the more costly worldwide (see more here and here). The current annualised costs of the treatment is USD 425,000. To ease patients’ access, Novartis has announced AveXis is working to create 5-year outcomes-based agreements and novel pay-over-time options.

Zolgensma is targeted to treat pediatric patients less than 2 years of age affected by SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. AveXis also announced the OneGene Program for patients, providing a personalised support team to address the needs of each family throughout the treatment journey, including reimbursement assistance and coordinating financial assistance programs for eligible patients.

We have used value based pricing frameworks to price Zolgensma at around 50% less than multiple established benchmarks including the 10-year current cost of chronic SMA therapy – said Vas Narasimhan, CEO of Novartis. – In addition, the price of Zolgensma is expected to be within the range of traditional cost-effectiveness thresholds used by ICER when updated for its full labeled indications. We believe by taking this responsible approach, we will help patients benefit from this transformative medical innovation and generate significant cost savings for the system over time.”
The current chronic therapy to treat SMA is given over the patient’s lifetime, with costs that can often exceed the estimated $ 4.1 million in just the first 10 years of a young child’s life, according to AveXis. Also, further savings are expected on the side of recurrent healthcare costs upon adoption of the new gene therapy. Treatment costs for other genetic pediatric ultra-rare diseases, reports the company, are also estimated to reach $ 4.4 – 5.7 million.

EMA opens the early dialogue to the development of anti-infective therapeutics

Access to the Innovation Task Force (ITF) established by the European Medicines Agency (EMA) has been expanded: it is now possible (see here) to seek early dialogue for pharmaceutical companies and other developers working on the identification of new therapeutic approaches for the treatment or prevention of bacterial and fungal infections.

Early contact to optimise development

The final goal is to improve the process to make available new options to fight anti-microbial resistance, a threat to public health that continues to pose many challenges to governments and healthcare systems.
Interested parties can initially start the dialogue process by filling the ITF briefing meeting request form, and send it to the e-mail address itfsecretariat@ema.europa.eu.

The service is provided by the ITF for free, and it can now be access by all new medicinal products targeted for the treatment of life-threatening bacterial or fungal infections, or conditions resulting in a severe debilitation of patients. The early dialogue tool was up to now reserved just for the development of innovative products; the current expansion reflects EMA’s intention to find more answers to an area of primary health need.
The Agency expects the initiative to boost the discussion between EMA and innovators in order to optimise the development of new products from the very early phases according to the indications of the regulatory authority. Among expected results is an improved access to other, more formal, regulatory tools, i.e. the scientific advice.

The WHO report on the future of drug-resistant infections

EMA’s decision to open the ITF early dialogue to the development of anti-infective medicines follows the report published in April by the Inter-Agency Coordination Group (IACG) on antimicrobial resistance of the World Health Organisation (WHO).
According to the document, there are currently more than 700 thousands death each year at the global level due to resistant infections, 230 thousands of those due just to multi-resistant tuberculosis. The warning advanced by the report is that if there is no action, by 2050 the total number of deaths might reach 10 million/year, with an impact on healthcare expenditure that might be similar to the one of the 2008-2009 economic crisis. Without the sustained effort to contain antimicrobial resistance, the WHO expects 2,4 million people might die in high-income countries in the period 2015-2050.
The problem is always the same, the inefficacy of the current, quite old generation of antimicrobial treatments to be used not only in humans, but also on animals or plants. According to the report, this trend poses a challenge to achieving Universal Health Coverage and the Sustainable Development Goals. The impact is not only directly on human health, but also involves the availability of clean water, food quality and safety and sanitation and hygiene in health care facilities, farms, schools, households and community settings.

The action suggested by the report

The picture depicted by the IACG report is dramatic, and it should be faced through a sustained “One Health response” and National Antimicrobial Resistance Action Plans are suggested in order to engage all stakeholders around a shared vision and goals. A limiting factor is currently represented by the economical constraints experienced by many countries around the world. The suggestion coming from the IACG calls for public, private and philanthropic donors and other funders to increase investments and innovation in quality-assured, new antimicrobials (particularly antibiotics), diagnostics, vaccines, waste management tools, and in implementation and operational research.
Suggestions advanced by the document include strengthening infection prevention and control, an improved surveillance and regulatory frameworks, with oversight of antimicrobial prescription and use. Antimicrobials on the WHO List of Highest Priority Critically Important Antimicrobial Agents for Human Medicine, in particular, should be immediately dismissed as growth promoters. A One Health Global Leadership Group on antimicrobial resistance should also be established, supported by a Joint Secretariat managed by the Tripartite agencies (FAO, OIE and WHO).
Stronger political leadership, advocacy, coordination and accountability are needed to reach the goal of a more equitable and affordable access to quality antimicrobial agents. All players should be involved in the process, including governments, financial multilateral institutions and banks, the civil society and the private sector. Antimicrobial resistance should be given priority in resource allocation, suggests the report. An Independent Panel on Evidence for Action against antimicrobial resistance in a One Health context should be also established to monitor and provide member states with regular reports on the science and evidence related to antimicrobial resistance, its impact and future risks, and recommended options for adaptation and mitigation. This should be flanked by an improved effort of the Tripartite agencies and UN Environment to reach the goals of the 2015 World Health Assembly resolution on antimicrobial resistance (WHA68.7).

The Exploitation Strategy and Innovation Consultants network (ESIC)

Pharmaceuticals are among the most innovative field of science, but running pharmaceutical and biotechnological research is also one of the most costly areas in which to invest. According to the latest estimates from the Tufts Center for the Study of Drug Development, a new prescription medicinal product requires $2.6 billion investment, more than triple the sum needed in 2003 ($802 million) and double with respect to 2013 ($1 billion) (see here Policy & Medicine for more details).

It is thus understandable the importance the pharmaceutical industry gives to the protection of intellectual property (IP). Innovators can experience a theoretical twenty years exclusivity on the market for new products provided by the corresponding patent, decreasing to 10-15 years at the best if taking into consideration the time needed to develop and register the product. Some other years of exclusivity (usually five) can be granted by the Supplementary Protection Certificates (SPC) or orphan drug designation.

New collaborative models for R&D are giving the academia and small, innovative biotech companies the role of leaders in the identification of new ideas and methodologies (we spoke about this in the April newsletter). Basic and early phase research is often run by start-up companies that are rich in ideas and patents, but that might experience some difficulty in finding a proper source of financing in order to translate their innovative potential into a real product able to reach the market. This issue has been addressed by a post on EFPIA blog signed by Ari-Pekka Laitsaari, an expert in innovation financing at the European Investment Bank (EIB).
The EIB is one of the institutions part of the Exploitation Strategy and Innovation Consultants network (ESIC), established by the Industrial Technologies (NMP) programme.
The ESIC network provides consultancy to the European Commission in the field of technological innovation and industrial technologies, with the goal to bridge the gap between the scientific and technical performance of funded projects and their socioeconomic performance. ESIC gives project partners the opportunity to work with a consultant to better identify risks and determine a strategy to maximise results. We offer readers a brief summary of the different areas of specialisation of the ESIC partners.

The role of the EIB in support to life sciences

The European Investments Bank (EIB) is the main provider of funding for innovative EU-based SMEs in the growth stage of development, providing about €700 million each year in venture debt, explains Laitsaari from EFPIA’s blog.
Companies receive a “venture debt” that they can use to alleviate immediate debt repayment pressures, so to better face the rounds of financing typical in the life of startups. An advantage offered by the EIB, according to its expert, is that contrary to traditional venture capitals and other types of investor, it does not require any share or seat on the board of the participating company. “Crucially, it gives them space to focus on the science and develop their products without diluting the value of the company.”, writes Laitsaari, also highlighting the possible reassuring role the EIB participation might play with respect to other interested investors or partners.
IP protection is another fundamental asset that marks a distinction with other highly innovative sectors. Patents might not be seen as so relevant by many technological companies, while they are the center of the business in the biopharmaceutical field. This is why the analysis of applications run by the EIB considers also the robustness of the patent portfolio for life science startup companies and the possibility for competitors to patent derivative molecules.

This is also why the EIB looks favourably at incentives like the SPC or the orphan drug designation to sustain the innovator industry: “Despite the uncertainties associated with clinical trials and securing marketing authorisation, it offers a degree of reassurance that successful products will recoup investment”, writes Laitsaari.

Venture debt is not the only form of lending made by the EIB: the Bank offers a wide array of tools able to adapt to each different need and size of the funded company. The Project loans, for example, are targeted to individual projects with total investment costs of more than € 25 million. Midcap companies with up to 3,000 employees may sometimes access this tool, where the loan volume requested is in the range € 7.5 – 25 million. Intermediated loans are directed to local banks and other intermediaries which subsequently “on-lend” to the final beneficiaries; they are intended to pursue at least one of the public policy goals established by the EIB.
The European Investment Fund (EIF) is also part of the EIB group; it focuses on establishing a sustainable venture capital ecosystem in Europe, and provides funding to venture capital funds. These act in turn as intermediaries that invest into innovative high-tech small and medium sized enterprises in their early and growth phases. Micro firms are a peculiar kind of entrepreneurial activity needing targeted resources; the Microfinance tools from the EIB are directed to companies employing fewer than 10 people, with up to € 2 million/year balance sheet.

The reference point for SMEs

The Executive Agency for Small and Medium-sized Enterprises (EASME) is an initiative of the European Commission to help manage several EU programmes in the field of SME support & innovation, environment, climate action, energy and maritime affairs. EASME is responsible for the management of significant parts of the COSME, LIFE, Horizon 2020 and EMFF programmes. With respect to H2020, for example, the agency has been involved in actions to develop the “Industrial leadership” action, the INNOSUP programme exploring new modalities and funding opportunities for clusters, innovation agencies and other SME intermediaries and several actions within Part III “Social challenges”.

A partner to provide coaching and support

Gate2Growth is a private Danish company member of the ESIC network providing services for EU projects and societal challenges across many industry and business sectors. It usually acts as the “business development, funding and exploitation” expert partner of the projects, with experience in more than 25 European countries. Among the areas of expertise are commercialisation processes, business model development, internationalisation and raising finance, value chain modelling, Term Sheets and Shareholder Agreement negotiations, the raising of capital for high-tech ventures and private-public partnerships, the identification of strategic partnerships for spin-offs from universities and research institutions and coaching activities on various aspects of Horizon 2020.

The voice of private equity

Invest Europe is the European association of private equity, venture capital and infrastructure sectors, and their investors. Its main target is long-term investment in privately held companies of any size to support strong and sustainable growth. Investor members of the association adhere to the professional standards laid down in the Invest Europe Handbook.
Political advocacy is among its core services: the association acts as a counterpart of European legislators to discuss policies affecting private capital investment in Europe; it also elaborates studies and provides public information on the sector. Invest Europe Library and Research Helpdesk provides the members with industry data and information. Promotional activities focus in building a better understanding and awareness of private equity at various levels are pursued by an extensive networking activity and conference organisation.

The CIP financial instruments and COSME programmes

The Competitiveness and Innovation Framework Programme (CIP) was an initiative of the European Commission aimed to provide SMEs with better access to finance, support for innovation, and regional business support. The programme ran in years 2007-2013 with a total budget of € 1 billion, and according to its website some financing is still available through financial intermediaries that have been recently selected and approved.

The EU programme for the Competitiveness of Enterprises and Small and Medium-sized Enterprises (COSME) has now replaced CIP. The new programme support SMEs’ access to finance in all phases of their lifecycle, from creation to expansion and business transfer. Under COSME’s tools, the EU ‘financial instruments’ are channelled through local financial institutions in the different European countries, that can be found through the Access to Finance portal.

The European IP Helpdesk

As mentioned above, intellectual property plays an extremely crucial role for the success of a biopharmaceutical business. The ESIC network includes a specific tool, the European IP Helpdesk, to provide first-line, free of charge support to beneficiaries of EU-funded research projects and EU SMEs involved in transnational partnership agreements.The IP SME Corner, for example, is the reference contact point for smaller companies, often lacking internal competences on IP issues. The Corner offers a selection of publications to support the easy and rapid understanding of the possible impact of IP on the company’s activities.

The IP Helpdesk is managed by EASME, under the guidance of the Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs (DG Grow) of the EU Commission. Its services are aimed to cover all different IP practices, from awareness to strategic use and successful exploitation. Upon registration, it is possible to receive a consultancy on specific IP issues – under strict confidentiality – from a team of experienced legal specialists within no more than three working days.

The European Patent Office

For companies ready to make the big jump and file a patent, the main reference is the European Patent Office (EPO). The Office is responsible for the examination of all European patent applications and manages the database of patents valid in the territory of the European Union. The protection obtained from EPO is not limited to the EU, as patents granted by EPO are valid in up to 44 different countries through a centralised and uniform procedure that requires just one application. All services are provided in accordance with the European Patent Convention.

Hungary: The new EU MDR raises a lot of uncertainty and concerns for manufacturers

In less than a year, the 26 May 2020, the new European Medical Device Regulation (MDR, (EU) 2017/745) will fully enter into force, after the three years transition period from its approval on 5 April 2017; the other new regulation (EU) 2017/746 on In vitro diagnostic medical devices will also come into force on the same date. A full guidance to the different aspects of the new framework, together with relevant links to explanatory documents, can be found on the dedicated webpage of the European Commission.

Compliance with the new rules to obtain the CE certification will become compulsory from 26 May 2020; previously released CE certificates will maintain validity for five years from their issuance, and devices already on the market at this data can be sold up to 25 May 2024, when their CE certificates will loose validity. But in case of “significat changes” to the devices after May 2020, the passage to the new regulation shall occur immediately.

The reasons for a new regulation

The adoption of the new rules has completely redefined the framework for the development, production and distribution of medical devices in the European Union. The new vision has tried to capture the rapidly evolving field of medical technologies, that includes a very big variety of different products, each one with its own peculiar characteristics. The final objective is double: improving the overall safety of the devices marketed in the EU, as well as boosting the competitiveness of the European medtech industry globally.
Even if the picture is quite clear and the Medical Device Coordination Group (the MDCG) – an expert group made up of experts of the national competent authorities – is supporting the EU Commission and member states in the implementation of both regulations, many details are not yet fully published. This uncertainty reflects on the industry to be able to prepare in advance for the final transition to the new legislation.

The main features of the new MDR regulation

A regulation, and no more a directive: the EU Commission has selected this type of legislative tool so that it has to be automatically implemented by member states without the possibility of modification. The different interpretations at the national level of the previous directives were one of the main issues limiting their standardised application across Europe.
The new regulations have reclassified both medical devices and in vitro diagnostics. Stricter ex-ante control via a new pre-market scrutiny mechanism with the involvement of the MDCG has been put in place for high-risk devices. The criteria for designation and oversight of Notified Bodies have been revised; according to Commission Implementing Regulation (EU) 2017/2185, starting from 26 November 2017 conformity assessment bodies have to apply for designation as notified bodies under Regulations (EU) 2017/745 and 2017/746.
A better transparency of the development process for a new device has been pursued by the reinforcement of rules on clinical evidence and product traceability (referred to some aesthetic devices with the same characteristics and risk profile as analogous medical devices, e.g PIP silicone breast implants). An EU-wide coordinated procedure for authorisation of multi-centre clinical investigations and the strengthening of post-market surveillance requirements for manufacturers – including an improved coordination mechanisms between member states – are expected to support this new vision both in the pre- and post-launch phases of the devices’ life cycle.
The establishment of a comprehensive EU database on medical devices and the use of the Unique Device Identification system (UDI) to trace the products are the basis of the improved coordination mechanisms between different countries. All information on implanted devices are now provided to patients by the “Implant card”.

Open questions looking for answers

In a post on Greenlight Guru, Jon Speer defined the fundamental questions that companies should keep in mind while affording the transition to the new rules governing medical devices.
Starting from the need to update the legislation to new and emerging technologies: the old MedDev directive dated 1992, when apps and advanced software solutions were not available. The ageing of population was also not so dramatic at that time. The increasing complexity of both the technology and the society is reflected in a much more complex structure of the new MDR compared to the 1992 directive. The previous Active Implantable Medical Devices Directive (AIMD), for example, is now included in the regulation. The picture is further complicated by the subsequent publishing of 42 implementing acts and 12 delegating acts, aimed respectively to clarify and amend certain aspects of the regulation.

Not only softwares intended for medical applications are now considered medical device: the MDR extends the definition to certain products used to clean, disinfect, or sterilise medical devices, and products used to control and support conception. It may prove hard – on this basis – to correctly classify a new product under development. In this respect, Annex XVI of the MDR lists some groups of products without an intended medicinal purpose but that are now considered medical devices ex article 1.2: contact lenses, for example, substances or items for facial dermal filling (both of them being previously considered simple cosmetic products), or equipment intended for brain stimulation.
Only Class I devices are exempted from the auditing of their Quality Management System (QMS) by a notified body. The QMS shall comply to the requirements listed under the “General Obligations” specified by article 10 of the MDR, and shall be supported by the availability of a quality manual and all other documentation demonstrating auditing and validation activities. The QMS has to be verified and certified by a notified body, and it shall be fully applied starting from 26 May 2020. The ISO 13485:2016 standard on Quality Management Systems for medical devices offers manufactures a full picture to help them structure the new QMS. The Medical Device Single Audit Program (MDSAP) is another useful tool offered by many notified bodies, and it allows to access different markets with just one audit.
The device identifier (DI) and the production identifier (PI) are used to identify each batch of a certain device. Data on product registration, clinical studies and post-marketing surveillance will feed the centralised EUDAMED database of medical devices marketed within the EU.

Other changes derived from the MDR

The equivalence criteria to other similar devices already on the market can no longer be used by manufactures, explains Kim Trautman, NSF International executive vice-president, in an interview on Verdict Medical Devices. The result is that more clinical experimentation shall be needed, as it will no longer be possible to refer to data published in the literature and referring to competitors.

Issues might arise from the application of the risk management criteria required by the MDR, as if it would not be possible to reduce “as much as possible” the risks connected to a certain device, they have to be listed in the labelling or in the instructions for use. Reporting the clinical outcomes in the post-marketing phase may also pose some challenges to manufactures. “To meet these new requirements, manufacturers must break down the silos that traditionally exist between regulatory affairs and quality assurance”, says Trautman in the interview. This task may be difficult to achieve for many medtech companies, that are traditionally less structured compared to the very highly regulated environment typical of the pharmaceutical industry. Thus, a strategic decision may be to outsource some activities, or to keep all the process within the company.

Biosimilars: the strategic imperative to balance between the needs for innovation and a sustainable solution

Biosimilars are not just generic copies of biological medicinal products, as the natural variability of their protein structures and the complex manufacturing processes allow to achieve just a high “similarity” with the originator in terms of structure, biological activity and efficacy, safety and immunogenicity profile, while it is impossible to exactly replicate the molecular micro-heterogeneity of the reference product. The first biosimilar was approved in 2006 by the European Medicines Agency (EMA); there are currently 67 biosimilar approved by EMA. Europe has been the pioneer in the field, far ahead the US where just 19 products have been approved by now by the FDA (three of which in 2019).

The number of biosimilar medicines shall greatly increase in future years, following the expiry of many patents for biological molecules. Innovative medicines too are mainly biologicals, which replaced the development of small molecule new chemical entities more typical of the ‘900. This indicates a further explosion of the biosimilar market in the next two to three decades, upon the progressive ending of the protection of the intellectual property.

A different framework in the EU and US

As said, Europe is the cradle of biosimilars, characterised by a strong, science-driven, knowledge-based approach and regulatory framework supporting the development and commercialisation of this type of medicines.
Very different is the situation in the US, where this sort of development target is still often seen as a true challenge: the first biosimilar was approved by the FDA ten years after Europe, in 2015, and just seven products are currently available on the market, reports Karen Langhause from Pharma Manufacturing columns. But this might turn to be an advantage, adds Mrs Langhause, as US companies may now benefit of “10-plus years of market data available, courtesy of Europe”.

The challenge of interchangeability

As a matter of fact, the safety and efficacy of biosimilar medicines are currently acknowledged mainly by their very extensive use in the European markets, totally counting for 700 million patient days of safe clinical experience since 2010 (source: International Generic and Biosimilars Association, IGBA).
Being slightly different in structure with respect to the reference product means that a biosimilar cannot be automatically interchanged to substitute the originator, as the efficacy and safety profiles may also result not exactly superimposable. In the US, the FDA clearly distinguishes between biosimilars and interchangeable medicinal products, with additional requirements and a second regulatory approval procedure to prove that the interchangeable product is expected to produce the same clinical result as the reference product in any given patient. The final guideline explaining FDA’s “Considerations in demonstrating interchangeability with a reference product” has been just released by the Agency and it can be dowloaded here.

In the case of several administrations of the medicines to a patient, according to the Biologics Price Competition and Innovation Act, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable product and a reference product has to be evaluated. The complexity and costs of this double regulatory approval, explains Pharma Manufacturing’s article, results in no interchangeable product being approved so far by the FDA. This barrier does not exist in Europe, where biosimilars are automatically interchangeable upon approval by EMA.

A useful tool to reduce costs

According to IGBA, the potential addressable biosimilars market would account for $ 250 billion potential savings in the US, plus $ 50 billion in the combined top 5 EU markets (Germany, France, UK, Italy and Spain). These savings may represent a fundamental tool to support the long-term sustainability of healthcare systems, but a better competitive scenario is still needed to fully exploit this opportunity.
Biosimilars are expected to give a great contribution to control costs, as their price is significantly lower than the one of the corresponding branded reference products. But the challenge of interchangeability and the dynamics of market penetration are slightly different for biosimilars compared to generic medicines (that are automatically dispensed at the pharmacy level in substitution of the originator). The result is that, while generics may rapidly conquer very broad market segments (up to 90%), the entry of a new biosimilar on the US market may be greatly delayed, as acknowledged by the case of Zarxio (filgrastim-sndz), reaching just 35% of the US filgrastim market after three years from approval. A reason for this is attributed by Karen Langhause to the request of the FDA to add the four letter code to the non proprietary name of the biosimilar product to better identify it, a provision not considered by the other pharmaceutical regions and that may impact on the ease of substitution of the products.
Many anti-competitive behaviours to slow down biosimilars penetration are cited by the Langhause article, including very high rebates for the originator products upon commercialisation of the corresponding biosimilar, and the possible bundling of all products of a certain company to the possibility to obtain a price rebate.

The challenge of innovation

Eight prominent biological medicines became off patent between 2015 and 2020 (adalimumab, insulin glargine, etanercept, infliximab, rituximab, peg-figrastim, trastuzumab and follotropin alfa), thus opening a total annual market value of $ 47,3 billion (2015 values, US + EU top 5 markets, source IGBA), opening space for interesting opportunities of potential savings in healthcare costs (figure).

(source: IGBA)

Biological medicines are usually protected by a very thick fence of “follow-on” patents in order to extend the market exclusivity over the 20 years of life of the original patent. Challenging these patents in Courts may prove very expensive and time consuming, and it can represent a deterrent to biosimilars competition, according to the Pharma Manufacturing article, which specifically discusses the US scenario.
Innovation in the biopharmaceutical sector is a feature characteristic of the highly dynamic, smaller biotech companies, those products are then acquired or licensed in by big pharma companies. Many of the current top level innovator products, like Abbvie’s Humira and Merck’s Keytruda, were sourced externally, and together accounted for a $21.1 billion US sales in 2018, reports EvaluatePharma: a trend that is expected to continue in future.

The market opportunity

Emerging markets are also expected to play an active role in the growth of the biosimilars sector, with companies from China and India manufacturing and launching their products also in the regulated Western countries. A recent example is Indian Biocon, that according to the Economic Times should launch the biosimilar version of Roche’s trastuzumab on the US market in 2019. The relevant impact that biosimilar and biologic manufacturing, together with R&D services, may play for Asian companies is acknowledged by the 64% increase reported by Biocon for Q1 2019. Earnings are expected to growth 45% in the period 2019-2021. The Indian company already launched in the US the biosimilar of peg-filgrastim at a price, according to the Economic Times, of one-third the one of the originator, resulting in a penetration of 15% of the market share.

Data for year 2018 shows that a pure generic and biosimilar company such as Sanofi improved one position in the ranking vs the previous year, reaching $ 111,3 billion market cap and $ 42,1 billion revenues (source: GlobalData). A positive trend, considering that four of the top 20 companies considered by the GlobalData survey showed a negative growth and six saw their market cap fall by more than 15%.

Life sciences should remain one of the leading industrial and economical sectors also in the next decade. An analysis commissioned by the Association of British Pharmaceutical Industry (ABPI), for example, indicates that the sector may add an extra £ 8.5 billion of growth to the UK economy by 2025, plus an additional 31,400 more jobs. A strong framework for R&D investment and a highly skilled workforce are the requests to the UK government advanced by ABPI to fully exploit this potential; the industrial association also called on to improve efforts to reach the target of 2.4% of GDP spent on R&D by 2027.

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