Bianca Piachaud-Moustakis is lead writer at Pharmavision, Pharmavision.co.uk.

Bianca Piachaud-Moustakis

On 22 March 2023, the government of the United Kingdom (UK) published its strategy to promote cyber resilience across health and social care by 2030. The Cyber Security Strategy for Health and Adult Social Care denotes that cyber security is a key aspect of improving patient care and the safety of frontline staff, designed to build trust and in turn, foster innovation (1).

Given that cyber security underwrites public trust in digital services and technologies, the new cyber strategy sets out a vision for reducing the cyber security risk to health and social care organizations across the Department of Health and Social Care (DHSC), National Health Service (NHS) organizations, local authorities, independent social care providers, and suppliers—which includes pharmaceutical manufacturers. The strategy aims to protect patient, service user, and staff data, as well as implement measures to ensure organizations can recover quickly from cyber-attacks when they do occur.

As contained in the government’s policy document, the strategy includes the following five key pillars:

—identifying the areas of the sector where disruption would cause the greatest harm to patients, such as through sensitive information being leaked or critical services being unable to function.

—uniting the sector so it can take advantage of its scale and benefit from national resources and expertise, enabling faster responses and minimizing disruption.

—building on the current culture to ensure leaders are engaged and the cyber workforce is grown and recognized, and relevant cyber basics training is offered to the general workforce.

—embedding security into the framework of emerging technology to better protect it against cyber threat.

—supporting every health and care organization to minimize the impact and recovery time of a cyber incident (2).

The pillars and this strategy’s implementation plan are underpinned by the Cyber Assessment Framework (CAF) (3), which is the National Cyber Security Centre’s (NCSC) standard, designed for organizations responsible for vitally important services and activities.

The growth of technology and the crucial role of effective cyber resilience

In an increasingly digitized health and social care system, technology is transforming how people access health and care services, as well as information. In primary care, technology includes patient booking systems, call and recall facilities, and electronic prescription services. In secondary care, technology includes diagnostic machines such as imaging scanners, and electronic systems that inform hospitals of the number of free beds available. For adult social care organizations, it is technologies such as digital care records and acoustic monitoring systems that facilitate more integrated care.

The DHSC estimates that, in England, there are approximately 950,000 general practice appointments conducted daily, 45,000 major accident and emergency (A&E) department attendances, and 137,000 imaging events recorded (2). Furthermore, it also estimated that more than 40 million people in the UK now have an NHS login, which helps them to book appointments, track referrals, and order medications online; while over 50% of social care providers use a digital social care record, that enables staff to share vital information about the people they care for (1).

While it is unlikely that a cyber incident would bring down all the hundreds or even thousands of separate systems that support direct care, interdependencies between systems imply that the UK government must account for at least some degree of cascading risk, since the scale of impact—both direct and indirect—from a cyber-attack on the health and social care sector has the potential to be far-reaching and large in nature.

Threats to England’s health and social care sector

The Department for Science, Innovation and Technology’s Cyber Resilience Policy defines cyber resilience as “the ability for organizations to prepare for, respond to and recover from cyber-attacks and security breaches … with cyber resilience the key to operational resilience and business continuity” (2).

The health and social care sector encounters cyber threats every day, which include phishing and other malicious emails, automated scanning for common software vulnerabilities, and attempted fraud (4). Of these, phishing and malware are recognized as low-sophistication ‘commodity attacks’ that are used by a wide range of cybercriminals. Data derived from NHS England’s Cyber Security Operations Centre (CSOC), which provides real-time protection against any suspicious activity to approximately 1.7 million devices across the NHS network, estimates that approximately 21 million malicious emails are blocked every month (1).

However, the most significant cyber threat the healthcare sector faces is ransomware, which is used in profit-seeking attacks, often staged by organized criminal groups or state actors (3). Such attacks can cause a complete loss of access to clinical and administrative information technology (IT) systems, resulting in significant disruption in day-to-day operations. This, together with the increasing proliferation and commercial availability of ‘ransomware as a service’, now implies that attacks are not just limited to sophisticated groups. According to the NCSC, ransomware attacks are increasingly seen to include data theft and extortion with a threat of data leaks (3). Furthermore, ransomware and other cybercrime have also become a significant threat to third-party suppliers (which includes pharmaceutical manufacturers), an attack on whom can cause as much, or more damage and disruption as an attack directly on a health or care organization (3). For example, in October 2020, Philadelphia-based company eResearchTechnology, which manufactures software used to develop COVID-19 vaccines and treatments was hit by a ransomware attack (5). Employees were locked out of systems and the attack had a knock-on effect that was felt by IQVIA, the research organization assisting UK pharmaceutical firm, AstraZeneca’s COVID vaccine trial, and US pharmaceutical major, Bristol Myers Squibb, which was involved in the development of a quick test for COVID-19 (5).

According to the UK government’s recently published policy paper outlining the new cyber security strategy, “all these threats pose risk not just to patient and staff safety, but also to public trust in a health and social care system that can and must safeguard people’s data” (2). It is therefore vital that the sector continues to adapt and improve its cyber resilience against these evolving threats and retain the confidence of the public.

The strategy also identifies several other challenges, including:

 The healthcare sector comprises varying working environments and high operational demand with many systems required to run 24/7, presenting a challenge of how to address competing risks, priorities, and pressures.

 The size and diversity of the sector make it challenging to set standards that can be applied uniformly.

 The health and social care supply chain are complex because providers each use many suppliers, who in turn have their own supply chains, thereby creating multiple layers of risk.

Unclear accountability and ability to influence.

 Where accountability for cyber risk is unclear, there must be clear messaging to boards and leaders that they are accountable for their organization’s cyber security, while at the same time, highlighting the responsibility that cyber professionals have for delivering in this space.

 A UK-wide shortfall of cyber professionals makes it challenging to hire and retain the experts that are needed to support leaders and staff in improving their organizations’ cyber security.

 The pace of growth and development in the digital, data, and technology space makes it challenging to assure the effective cyber security of new products.

 As new technology is developed; it can be challenging to monitor and replace older technology as it becomes outdated and more vulnerable to cyber-attacks (2).

Later this year, a full implementation plan will be published setting out activities and defining metrics to build and measure resilience over the next two to three years. National cyber security teams will work closely with local and regional health and care organizations to achieve the visions and aims of the strategy. The work will include enhancement of the capabilities of NHS England’s CSOC; publication of a comprehensive and data-led landscape review of cyber security in adult social care; and an update to the Data Security and Protection Toolkit to empower organizations to own their cyber risk.

Government Sets Out Strategy to Protect NHS from Cyber Attacks

, Press Release, 22 March 2023.
2. DHSC. 

A Cyber Resilient Health and Adult Social Care System in England: Cyber Security Strategy to 2030

. Published 30 Sep. 2019. Reviewed 11 April 2022. Version 3.1.
4. Ghafur, S.; Fontana, G.; Martin, G.; et al. Improving Cyber Security in the NHS. Institute of Global Health Innovation. Imperial College London, 2019.
5. Tambe, D. Major HNS Supplier hit by Ransomware Attack. 

When referring to this article, please cite it as Piachaud-Moustakis, B. Protecting the NHS from Cyber Attacks. 

Articles

A strategy on cyber resilience for health and social care organizations has been set out by the UK government.

Protecting the NHS from Cyber Attacks

In February, the Spanish Government released its Annual Regulatory Plan for 2023, which presents important regulatory changes and developments relating to legislation governing pharmaceuticals and healthcare. The country’s Ministry of Health has proposed three laws and three regulations—of particular note are the amending law on guarantees, the decree on pricing, and the decree on the assessment of health technologies.

Law amending the revised text on guarantees and rational use of medicinal products and medical devices

Amendments are to be made to the Law on Guarantees and Rational Use of Medicinal Products and Medical Devices aimed at updating the consolidated text in line with changes that have taken place in recent years. Modifications will therefore be made to the consolidated text of the law (RDL 1/2015), signed into law on 24 July 2015 (1).

The amending law aims to bring the current text up to date to meet the requirements and developments that have taken place in the field of human and veterinary medicinal products, medical devices, cosmetics, biocides for personal use, and personal care products, at both the national and European level (2). The aim is to also harmonize the legislation with the different European regulations that have been approved in recent years regarding products regulated by this law. Although further details are presently lacking, the law entails the “incorporation of new perspectives related to the public funding of medicinal products, rational use of medicinal products, and structures of governance bodies” (3).

Royal Decree regulating the funding and pricing of medicines and health products

Royal Decree 271/1990, passed on 23 February 1990, states that the “maximum ex-factory price of a reimbursed medicinal product should be equal to the cost of the product plus a given margin (12% to 18% on capital allocated to exploitation)” (4). However, in practice, it has been found that setting the price of a reimbursed medicinal product involves negotiating the price with the public authorities.

The proposed amendments to the Royal Decree regulating the funding and pricing of medicines and health products and their inclusion in the pharmaceutical provision of the National Health System (NHS) will therefore aim to develop the following aspects:

inclusion of medicinal products and new indications for medicinal products in the pharmaceutical provision of the NHS

special reserves and special conditions for the reimbursement of medicinal products

industrial price review regime for medicinal products, to be included in the pharmaceutical provision of the NHS new drug indications

funding medicines available in special situations; supply of medicines in the pharmaceutical provision of the NHS

exclusion of medicines from the pharmaceutical provision of the NHS

reimbursement of medicinal products available under early access programmes

inclusion of medical devices in the pharmaceutical provision of the NHS

Information systems for the supply of medicines and monitoring of their funding in the NHS (3).

Royal Decree regulating the assessment of health technologies

A further Royal Decree regulating the assessment of health technologies will seek “to regulate an independent, transparent, and participatory system for the evaluation of the therapeutic positioning of health technologies by means of a scientific process based on contrasted data that makes it possible to determine the relative efficacy and efficiency of existing or new health technologies in comparison with others” (5).

The Royal Decree aims to include the involvement of different actors in this assessment (such as lay members representing the interests of patients), as well as develop those aspects that are not covered by the Health Technology Assessment (HTA) Regulation. It also aims to introduce modifications and incorporate new perspectives related to the public financing of medicines, their rational use, and structures of governance bodies. Additionally, the Royal Decree also aims to bring the system into line, as far as applicable, with the provisions of Regulation (EU) 2021/2282 of the European Parliament and of the Council of 15 December 2021 on Health Technology Assessment and Amending Directive 2011/24/EU (6).

As part of Spain’s overhaul of its HTA system, the Spanish authorities will draw on the experience of the United Kingdom’s (UK’s) National Institute for Health and Care Excellence (NICE) system, to speed up its own HTA process. The principal reason cited for this move is that the Spanish Ministry of Health does not believe it has sufficient resources to prepare adequate economic evaluations of the new medicines that are marketed in Spain (7). For this reason and following in the footsteps of other European countries, including the UK, the Spanish authorities will ask pharmaceutical companies to submit health economic evaluations for review.

According to Carlos Martín Saborido, advisory member of the General Directorate of Common Portfolio of Services of the SNS (Sistema Nacional de Salud) and Pharmacy, holders of Marketing Authorization (MA) will soon be asked for these pharmacoeconomic studies. In addition, the Ministry of Health is currently working on guidelines stipulating the characteristics of these evaluations, which will then be verified through published checklists to ensure they are “faithful to the methodology” in the name of transparency (7).

Of notable consideration, the government plans to make “substantial reforms to early access (before and after authorization) to establish rapid decision-making procedures for drugs that offer greater potential for improvement and mechanisms to manage uncertainty in access to funding and price” (3).

In July 2022, Spain’s pharmaceutical industry association, Farmaindustria, published a document outlining various proposals for the Spanish government to consider, aimed at increasing access to medicines across the country. These proposals include:

modifying the pharmaceutical contribution system to achieve a better redistribution of the economic burden derived from the pharmaceutical co-payment, based on the socioeconomic level of the citizen

pursuing a fairer model that guarantees more equity in access to medicines

modifying the reference price system by introducing elements that increase competition and value the contributions that represent an incremental benefit in the use of medicines

modifying the system to calculate the four-monthly contribution made to the SNS by manufacturers, importers, and suppliers of medicines and health products financed with public funds (3).

Delays in approval and the availability of medicines in Spain have increased in recent years, leading it to lag regional peers such as Germany, France, Italy, and the UK. As such, Spain is regularly criticized for its slow reimbursement times for innovative medicines, particularly for orphan drugs. For pharmaceutical manufacturers, market access delays translate directly to reductions in revenue as reimbursement often cannot be secured until the IPT (Informes de Posicionamiento Terapéutico) process is complete.

Research conducted by Fitch Solutions for H122 found that “the average time taken to complete an ITP was 362 days, while for medicines taking part in the pilot project for the new ITP method, the process took between 297 and 780 days” as opposed to the target of 93 days (8). In February 2023, the Spanish Association of Orphan Drug Manufacturers (AELMHU) released its Annual Report on Access to Orphan Drugs in Spain 2022, which shows that just 23% of orphan drugs with a centralized MA have full, unrestricted reimbursement in the country (9). In response, Farmaindustria has called for an in-depth reform of the pricing and financing system, a review of the ITP system, and the implementation of early access schemes for drugs that provide greater clinical benefit to patients (8). The association has also proposed 12 measures aimed at improving access for patients with rare diseases to new treatments. It is therefore important that the pharmaceutical industry follow these initiatives closely and begin thinking about how organisations can adjust to the proposed processes and strategies.

1. Osborne Clarke. Amendment of the Law on Guarantees and Use of Medicines and Medical Devices. 

, Article, 20 July 2022.
2. Abad, A. Major Regulatory Changes in Pharmaceutical Laws, and Regulations in Spain for 2023. Hogan Lovells, 8 Feb. 2023.
3. Eversana. Spain to Pass New HTA Legislation in 2023. 

, 2 Feb. 2023.
4. Faus, J.; Moliner, X.; Rodellar, E.; et al. Medicinal Product Regulation and Product Liability in Spain: Overview. 

, Country Q&A, 1 Aug. 2021.
5. Grubert, N. Spain Will Pass Major New Legislation on Drug Pricing and HTA in 2023. LinkedIn Post, February 2023.
6. EC. Regulation (EU) 

2021/2282 of the European Parliament and of the Council of 15 December 2021 on Health Technology Assessment and Amending Directive 2011/24/EU (Text with EEA relevance)

, 22 Dec. 2021.
7. Rudd, A. Spain’s Ministry of Health copies NICE, and Asks Pharma for their Economic Evaluations. Remap Consulting, 17 Feb. 2023.
8. Fitch Solutions. Spain’s Pharmaceutical Industry Calls for Pricing System Reform as Market Access Delays Persist. Article, 2 Sep. 2022.
9. AELMHU. 

Annual Report on Access to Orphan Drugs in Spain 2022

When referring to this article, please cite it as Piachaud-Moustakis, B. Changfes Afoot in Pharmaceutical Laws and Regulations in Spain. 

Proposed regulatory changes signal a major overhaul of legislation governing pharmaceuticals and healthcare in Spain.

Changes Afoot in Pharmaceutical Laws and Regulations in Spain

It has been reported that interest in the gut microbiome and its relevance to human health has increased significantly over the past decade (1). As noted in a recent article by James McIlroy—who has been cited on the Forbes 30 Under 30 Europe Healthcare and Science list (2)—founder and CEO of EnteroBiotix, a clinical stage microbiome therapeutics company, “Instead of viewing bugs as bad, we’re embracing them as being part of a symbiosis” (1).

EnteroBiotix is a clinical-stage microbiome therapeutics company which leverages the gut microbiome to develop novel medicinal products that restore health and prevent disease, with a specific focus on drug-resistant bacterial infections and gastrointestinal conditions. Established in 2017, EnteroBiotix is headquartered in Glasgow, United Kingdom, and operates research laboratories and Medicines and Healthcare products Regulatory Agency (MHRA)-licensed good manufacturing practice (GMP) pharmaceutical manufacturing sites in Glasgow and Aberdeen, UK.

The company has developed a differentiated platform manufacturing technology that has broad potential applicability across the spectrum of microbiome therapeutic approaches. EnteroBiotix have created a trademark-protected donor brand and online portal called the ‘Number 2 Donor Programme’ for recruiting healthy donors (3). The company’s MHRA-licensed cleanroom facility in Aberdeen ensures that starting material is accepted, tested, and processed in a regulatory compliant manner. The platform delivers investigational medicinal products that contain diverse and viable communities of donor-derived microorganisms which target multiple functional pathways.

Enterobiotix’s competitors include Evolve Biosystems Inc. (United States), Ilya Pharma AB (Sweden), Novome Biotechnologies Inc. (US), and RedHill Biopharma (Israel). EnteroBiotix ranks 19th among 169 active competitors according to data published by Tracxn Technologies (4).

Diseases and conditions linked to the human microbiome

Research shows that imbalances within the gut microbiome may be associated with a wide range of medical ailments ranging from acute intestinal infections such as those caused by the bacterium 

, to complex chronic conditions like inflammatory bowel disease and colorectal cancer (5). However, it is thought that modulation of the microbiome offers an exciting and largely unexplored therapeutic avenue to treating an array of infectious intestinal diseases and Multidrug Resistant Organism (MDRO) infections, as well as conditions linked to the brain and liver, metabolic diseases, and those in immuno-oncology.

EnteroBiotix, therefore, believes that one of the best established and most powerful means of modulating the microbiome is through Intestinal Microbiota Transfer (IMT), which involves the transfer of microbiome communities from a healthy person into the intestinal tract of another person suffering from a microbiome mediated condition (6). The company produces capsules that contain diverse ecosystems of microbiota obtained from healthy and rigorously screened donors, which provide a compositionally consistent, safer, and non-invasive alternative to current methods for transferring microbiota from donors to patients (1).

IMT is a gold-standard therapeutic intervention for patients suffering from recurrent 

 infection (rCDI) and has shown promise in other diseases areas associated with substantial unmet clinical need (7). For example, this has also been demonstrated in indications that affect the liver such as liver cirrhosis, hepatic encephalopathy, and hepatitis (6). Globally, more than 90 randomized controlled trials (RCTs) investigating the therapeutic utility of IMT have been conducted in a wide array of patient populations suffering from extra-intestinal and intestinal diseases, all of which have consistently reported good efficacy and safety supporting this route of treatment (8).

EnteroBiotix has raised total funding of US$24 million (€22.5 million) over four rounds (4). In September 2021, the company secured US$21.5 million (€20.3 million) in a series A financing round to advance a pipeline of drugs targeting the microbiome (9). The funding round was led by Scottish investment firm Thairm Bio with investments from Scottish Enterprise, SIS Ventures, and US-based Kineticos Ventures. With these funds, EnteroBiotix will expand its headcount to 50, and advance its pipeline for multiple disease areas, as well as develop its in-house manufacturing capabilities. According to data derived from Crunchbase, venture capitalists invested US$1 billion (€94.3 million) into microbiome start-ups between 2015 to 2020 (10).

In October 2022, EnteroBiotix announced that it had been granted a manufacturer’s licence for Investigational Medicinal Products (IMP) by the MHRA to manufacture microbiome product candidates for clinical trials (11). Located at the Strathclyde Business Park in Glasgow, the 20,000-square-foot facility incorporates an in-house quality control (QC) hub and analytical department that is designed to meet regulatory biologics requirements and product analysis while providing the company end-to-end control of its supply chain (12).

EnteroBiotix’s manufacturing capabilities include its novel proprietary AMPLA platform that enables the rapid preparation of dry powder from hydrated starting material at static temperature (11). The company believes this technology has potential applicability across the entire spectrum of microbiome therapies that are currently dried using traditional methods, including lyophilization, making this approach superior to others being currently pursued. The GMP-certified manufacturing facility is the most advanced of its kind in Europe and is designed to operate as a flexible and scalable manufacturing centre. According to Douglas Thomson, non-executive chairman at EnteroBiotix, “The board has backed the vision of establishing control of the supply chain and to develop in-house manufacturing and analytical capabilities as a strategic asset” (13). Looking ahead, the company is aiming to initiate a Phase II clinical trial for its lead microbiome therapeutic asset, EBX-102, in patients with liver cirrhosis by the end of 2022.

Partnership with Imperial College London

In November 2022, EnteroBiotix entered into a collaboration with Imperial College London (ICL) to assess the potential of IMT administration in patients with blood cancer prior to bone marrow transplant as a means of altering their gut microbiome with the aim of achieving improved outcomes. The Phase IIa, investigator-initiated trial, will evaluate how EBX-102 impacts the outcomes of bone marrow transplant patients with blood cancer. This trial forms part of the Microbiota Transplant Prior to Allogeneic Stem Cell Transplantation study, that is being conducted across six of the UK’s leading blood cancer centres including, Imperial College, University College London Hospitals, the Royal Marsden, King’s College London, Leeds Teaching Hospitals, and University Hospitals Birmingham (14).

According to Professor Julian Marchesi of ICL, Department of Metabolism, Digestion and Reproduction, “Patients with blood cancers are a group whose gut microbiome is particularly under attack … as they often receive strong chemotherapy, which has side effects of mouth ulcers and gut inflammation” (14). These patients receive antibiotics frequently due to their high rate of infections, with many inevitably being colonised with antibiotic-resistant bacteria. As a result, patients are at high risk of getting an infection which is untreatable. The products developed by EnteroBiotix hold the promise of manipulating the gut microbiome in such patients, thereby reducing the need for antibiotics and improving health outcomes.

The clinical trial, which is funded by the Medical Research Council and supported in-kind by EnteroBiotix, will build on Imperial’s successful pilot study (in the same patient population) which demonstrated preliminary data suggesting that IMT can reduce complications and improve survival rates (14). Through this partnership, Imperial will increase its exploration into the efficacy of this approach for a range of diseases and will aim to strengthen the pathway to commercialization through the conduct of systematic research.

In addition to helping explore the safety, tolerability, and efficacy of IMT-based drugs for a range of conditions, the partnership between Imperial and EnteroBiotix is expected to help place microbiome research onto a sounder footing, supported by systematic learning about the gut microbiome and the very specific mechanisms that make microbiome treatments work in patients with variable gut ecologies. Microbiome therapeutics have the potential to provide short- and long-term changes to the gut and liver, and may provide an alternative means of treating disabling and life-threatening conditions such as inflammatory bowel disease, colorectal cancer, and liver cirrhosis, in the near future.

1. Silverman, D. Imperial Partnering with EnteroBiotix to Advance Microbiome Medical Treatments. 

, 10 Nov. 2022.
2. Jennings, K.; Pratap, A.; Valet, V.; Conklin, J. Under 30 Europe 2022: Meet the Entrepreneurs Innovating from the Microbiome to the Psyche. 

, 3 May 2022.
3. EnteroBiotix. Number 2 Donor Programme. 

 (accessed 21 Feb. 2023).
4. Tracxn. EnteroBiotix. 

, 21 Feb. 2023 (accessed 21 Feb. 2023).
5. Guinane, C.M.; Cotter, P.D. Role of the Gut Microbiota in Health, and Chronic Gastrointestinal Disease: Understanding a Hidden Metabolic Organ. 

, 6 (4), 295–308.
6. EnteroBiotix. Intestinal Microbiota Transfer (IMT). 

 (accessed 21 Feb. 2023).
7. Quraishi, M.N.; Widlak, M.; Bhala, N.; et al.Systematic Review with Meta-Analysis: The Efficacy of Faecal Microbiota Transplantation for the Treatment of Recurrent and Refractory Clostridium Difficile Infection. 

, 46 (5), 479–493.
8. Cammarota, G.; Masucci, L.; Ianiro, G.; et al. Randomised Clinical Trial: Faecal Microbiota Transplantation by Colonoscopy vs. Vancomycin for the Treatment of Recurrent Clostridium difficile Infection. 

, 41 (9), 835–843.
9. Lucas, E. EnteroBiotix Secures $21.5M Series A to Advance Microbiome Drug Pipeline. 

, 8 Sep. 2021.
10. Hall, C. Startups Focused on Gut Microbiome for Health Clues Raised $1B in VC Funding. 

. 8 Dec. 2020.
11. EnteroBiotix. EnteroBiotix Receives MHRA MIA (IMP) Licensure of State‑of-the-Art GMP Manufacturing Facility for Producing Microbiome Therapeutics. Press Release, 11 Oct. 2022.
12. Keenan, J. EnteroBiotix Completes New Manufacturing Facility Focused on Gut Microbiome Therapies. 

, 27 Oct. 2021.
13. Laws, L. License Granted to EnteroBiotix for Manufacture of Microbiome Product Candidates. 

, 11 Oct. 2022.
14. EnteroBiotix. EnteroBiotix Partners with Imperial College London to Develop Microbiome Therapeutics. Press Release, 10 Nov. 2022.


Vol. 35, No. 3
March 2023
Pages: 12–13, 15

When referring to this article, please cite it as Piachaud-Moustakis, B. Frontrunner in Microbiome Therapeutics. 

EnteroBiotix is harnessing the power of the microbiome to target an array of diseases.

Frontrunner in Microbiome Therapeutics

In June 2019, it was announced that a targeted recalibration of certain aspects of patent and supplementary protection certificate (SPC) protection aimed at boosting the competitiveness of regulated industries such as the pharmaceutical industry would commence under the auspice of the European Union’s (EU’s) Single Market Strategy (1). While the European Commission (EC) believes that overall, the current legislation on SPCs is fit-for-purpose, its fragmentation has been noted as an issue that needs to be addressed. To this end, the commission believes that the creation of a unified SPC grant procedure and a unitary SPC would not only strengthen the single market for pharmaceuticals, but also align SPCs more harmoniously with the EU’s twin objectives of achieving digital and green transition (2). Against this background, the EC closed a call for evidence on proposals to introduce a single procedure for granting SPCs across the EU in April 2022, to prepare an impact assessment and any necessary legislation. This initiative is aimed at amending the EU’s founding legislation on SPCs for medicinal products (Regulation (EC) No 469/2009) formulated in June 2009 (3).

An SPC is a “European Intellectual Property (IP) right granted on a national basis that provides protection for a patented active ingredient or combination of active ingredients of an authorized medicine or plant protection product after expiry of the patent … and is intended to compensate delays in gaining regulatory approval and the resulting curtailment of the duration of effective protection under the patent” (4).

SPCs form a critical component of the European IP rights framework and have played a critical role in the development of innovative medicines for European Patents. European SPCs can extend the term of a medicinal or plant protection patent by up to five years, with the possibility of a further extension period of six months, dependant on circumstances (5). SPCs are designed to ‘compensate’ a patent owner to a degree, for some of the patent term that is effectively lost during the clinical trials and approval process and are available as European patents granted by the European Patent Office (EPO), or as national rights that need to be applied for via the national patent office of each member state where at least one suitable patent extension is sought (6). Once an SPC expires, innovative medicines lose their exclusivity period and become generic.

An SPC may be based on any patent which protects:

the active ingredient(s) of the authorized medicinal or plant product

a method of producing the active ingredient(s)

an application of the active ingredient(s)

a preparation containing the active ingredient(s), a condition which is more applicable to plant protection products.

To qualify for an SPC, the patent must be in force in the country where the SPC is sought at the time the SPC application is made. The scope of SPC protection is limited to the product for which a marketing authorization (MA) has been granted.

On 25 Nov. 2020, the EC published its new IP action plan, in which, one of the key objectives was to improve the protection of IP rights by modernizing existing systems or reducing the complexity of existing legislation (7). The findings of the document subsequently decried the fragmented nature of the regulatory framework governing SPCs that, according to the commission, “translates into inefficiencies and a lack of transparency and predictability, which hampers innovators and generic producers, and eventually harms patients” (8).

As such, the commission is proposing legislative changes to set up a centralized SPC system that could encompass a ‘unitary’ SPC to extend the protection of unitary patents; a unified procedure for granting a bundle of SPCs covering multiple territories (equivalent to a European Patent); or a combination of the two (9). However, it is unclear which option maybe pursued.

While the conditions for obtaining SPCs are governed by the same regulations (EC) No. 469/2009 (for medicinal products) and (EC) No. 1610/96 (for plant protection products) in all EU countries, in practice, the application of these regulations often differs, thereby leading to disparities among the different member states. For example, this variance may be in relation to the granting of procedures, the length of the examination period, the SPC expiry date, and/or the outcome of the examination which may also differ from one country to another (10). To illustrate, an SPC application was refused for the combination Zetia (ezetimibe) plus Lipitor (atorvastatin) in France, whereas an SPC was granted for the same combination in Belgium (10).

Disparities also exist between member states in relation to health products that are based on innovative technologies, such as medical devices. For example, patent offices in Denmark, France, Italy, Poland, Portugal, Spain, and the United Kingdom (UK) consider medical devices as products that do not fall within the jurisdiction of SPC Regulation, whereas in Germany and the Netherlands, SPCs have been granted for such products (11). Furthermore, the question as to whether third-party observations are considered also differs from one member state to another (11). For example, French Law does not allow third-party observations for SPC applications, whereas the same is permitted by patent offices in the UK, Germany, and Denmark. With these disparities in mind, it is thought that a unitary SPC would simplify the existing system and ensure consistency between all member states of the EU.

The impetus for this initiative is the approaching opening of the Unified Patent Court (UPC), scheduled for 1 April 2023, which will offer patent protection in up to 25 EU member states and which will allow for the granting of a unitary European patent in the participating countries. The new UPC will have exclusive jurisdiction over unitary patents and all European patents designated to participating EU member states, unless these have been opted out of its jurisdiction (12). Unitary patents will provide patent protection through a single request to the European Patent Office (EPO) and will build on European patents granted by the EPO under the rules of the European Patent Convention.

Although details of how a new system would operate are yet to be determined, the EC has suggested one option comprising a ‘virtual’ examining office, made up of SPC examiners from national patent offices of member states, designed to perform the functions of a regional office (5). Another possibility is for the ‘virtual’ body to perform the functions of an international organization like the EPO, or as an EU agency such as the European Union Intellectual Property Office, which currently only deals with trademarks and designs but not patents or SPCs (9).

The ‘call for evidence’ study conducted by the EC in April 2022 does not recommend substantive amendments to the legislation. Rather, it acknowledges that a more streamlined process for granting SPCs should rationalize diverging practices and decisions, thereby providing greater commercial certainty for manufacturers of medicinal products.

Regulation (EU) 2019/933 of the European Parliament and of the Council of 20 May 2019 Amending Regulation (EC) No 469/2009 Concerning the Supplementary Protection Certificate for Medicinal Products

Revision of the Legislation on Supplementary Protection Certificates (Refit)

. European Parliament, Legislative Train Schedule, 15 Dec. 2022.
3. EC. 

Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 Concerning the Supplementary Protection Certificate for Medicinal Products (Codified Version)

. 16 Jun. 2009 (Current Consolidated Version, 1 July 2019).
4. Mathys & Squire. What is a Supplementary Protection Certificate? 

Mathys-Squire.com/intellectual-property-services/patents/spcs

 (accessed 18 Jan. 2023).
5. Penningtons, Manches, Cooper LLP. Unitary Supplementary Protection Certificates (SPCs) May Become a Reality. 

, 27 Apr. 2022.
6. Mewburn Ellis. Supplementary Protection Certificates (SPCs) and Patent Term Extensions (PTEs). 

Mewburn.com/law-practice-library/supplementary-protection-certificates-patent-term-extensions

 (accessed 18 Jan. 2023).
7. EC. Document 52020DC0760. COM/2020/760 Final. 

Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions. Making the Most of the EU’s Innovative Potential: An Intellectual Property Action Plan to Support the EU’s Recovery and Resilience

 (25 Nov. 2020).
8. Van Bael and Bellis. European Commission Looks to Harmonize Rules Governing Supplementary Protection Certificates for Medicines and Plant Protection Products. 

, 25 Mar. 2022.
9. Weekes, C.; Fabre, J. European Commission Publishes Study on Options for a Unified SPC System. 

, 1 Nov. 2022.
10. Labarre, I.; Touati, C. Supplementary Protection Certificates (SPC): A New IP Right to Come? 

, 22 Feb. 2022.
11. EC, Directorate-General for Internal Market, Industry, Entrepreneurship, and SMEs, Romandini, R.; Slowinski, P.; Wright, G.; et al. Study on the Legal Aspects of Supplementary Protection Certificates in the EU: Final Report. Publications Office, May 2018.
12. EPO. Unitary Patent. 

EPO.org/applying/european/unitary/unitary-patent


Vol. 35, No. 2
February 2023
Pages: 7–8

When referring to this article, please cite it as Piachaud-Moustakis, B. Harmonizing Rules Governing SPCs for Medicinal Products. 

A new unified initiative for patent protection in the EU to boost the competitiveness of the pharma industry is nearing completion.

Harmonizing Rules Governing SPCs for Medicinal Products

On 11 Aug. 2020, the European Commission (EC) published its evaluation on the legislation for medicines for rare diseases and for children (1). This marked the first comprehensive evaluation of the Orphan Regulation (Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on Orphan Medicinal Products) since its adoption in 2000 (2).

The purpose of the Orphan Regulation is to “lay down a community procedure for the designation of medicinal products as orphan medicinal products and to provide incentives for the research, development and placing on the market of designated orphan medicinal products” (3). Within the European Union (EU), a disease is defined as rare when its prevalence does not exceed the threshold of five in 10,000 people (4). However, despite the low prevalence, more than 6000 different rare diseases have been identified, affecting approximately 30 million people across Europe (5). Many of these rare diseases (80%) are genetic in origin and are often chronic and life-threatening.

The evaluation of the Orphan Regulation was conducted in line with the European Commission’s (EC’s) 

, which was used to assess the regulation’s strengths and weaknesses. The principal objectives of the Better Regulation agenda are to ensure that EU policymaking is based on evidence, to make EU laws simpler and better, and to involve citizens, businesses, and stakeholders in the decision-making process (6).

Taken within this context, the evaluation consisted of several stages, including the publication of a roadmap, assessing various recent studies on the functioning of the regulation on medicines for rare diseases, and the extensive consultation of stakeholders—which was aimed at collecting views and opinions on the implementation of the Orphan Regulation, to gather factual information on what works well and where there is still room for improvement, and to gather data and knowledge about the impact of the legislation (7). The impact assessment formally ended on 31 July 2021.

The current framework for orphan medicines has delivered significant societal benefits, with more than 207 orphan medicines gaining approval from the European Medicines Agency (EMA) since 2000, 38 extensions of indications being granted, and patient access across the EU accelerating by nine months on average (8). This progress has been achieved by a stable regulatory framework, which incentivises increased investments into R&D for treatments for rare diseases, and especially ultra-rare diseases.

Nevertheless, the commission’s Staff Working Document (SWD) published in 2020 has highlighted that the current legal framework presents several shortcomings, including insufficient flexibility in supporting scientific developments and R&D in the context of unmet needs. The document notes that at present, no authorized treatment is available for 95% of rare diseases. It also identifies the excessive burden and inefficiency of some procedures, including within EMA itself, and points out that legislative frameworks need to be adapted considering the scientific progress being made in areas such as personalized medicine and the use of biomarkers (9). As such, the EC has reviewed the legislation to assess whether reform is necessary and gauge what this could consist of.

Key areas of potential legislative change

Conditionality of Intellectual Property (IP). Under the conditional system, companies might obtain and maintain their IP rights based on two conditions:

companies must launch the product in most, if not all 27 EU Member States

R&D expenditure must be transparently reported.

Both conditions are far reaching and create additional risk for companies when launching their orphan medicinal products given that most developers tend to initially focus on the big five markets in Europe (Germany, France, Italy, Spain, and the United Kingdom). By incentivising broader launches, this increases the burden on companies to manage 27 different market access strategies, and for public authorities who will be required to assess pricing and reimbursement applications for medicines they may not even have a patient population for.

The requirement to transparently report R&D expenditures could also be viewed as a huge threat to the industry who might find themselves in a position where they are compelled to reveal confidential trade secrets. This could be further confounded by the lack of agreed standards on what constitutes ‘cost’. Therefore, if cost is the primary consideration, it may not be possible to achieve a viable price that fully reflects the risks and probabilities of achieving clinical success and market access for the product (10).

Reducing market exclusivity. Another potential incentive under consideration to combat unmet medical need and encourage broader patient access is the reduction of market exclusivity for orphan products by half, from 10 to five years. Currently, the 10-year market exclusivity period safeguards a company from having a similar product for the same indication being submitted for approval. Additionally, if a product works in two completely different indications, the developer can obtain a second or even a third orphan exclusivity designation, which helps stimulate investment in new indications. Nevertheless, the EC is considering reducing the market exclusivity period for new indications and hypothetically giving orphan exclusivity only to products defined as addressing unmet needs (11). It could therefore be argued that if the probability of attaining orphan drug designation decreases, this could directly affect the willingness of companies to invest in the orphan medicines space (10).

Concerns of potential legislative changes

A publication of draft impact assessment by Politico Europe renewed concerns that the commission’s revision of the Orphan Regulation may upset the delicate balance between academia, start-ups, and well-established companies that work together to bring new therapies and solutions to rare disease patients. In her commentary, Claire Skentelbery, director of EuropaBio, noted that “while political priorities of affordability and accessibility are shared by all stakeholders including industry, these must be balanced with the need for innovation and competitiveness in Europe, especially as revision of the Orphan Regulation will shape the regulatory environment for orphan medicine development in Europe for the next 25 to 30 years” (12).

The author argues that any move to lower and restrict incentives could jeopardize the ability of orphan drug developers to attract investments that enable them to continue with their product development programmes. This argument is especially pertinent to Europe’s small and medium-sized biotechnology companies as a reduction in incentives would hinder their ability to raise capital, decrease their value, and could even drive innovation out of Europe (12).

Skentelbury wrote in her commentary that, “Preserving and building upon the stability and predictability of orphan designation, approvals, marketing exclusivity, and regulatory data protection are essential ingredients to bringing further innovation to market and in supporting the rare disease ecosystem” (12).

The issue of addressing unmet needs requires all stakeholders to imagine different ways of partnering and collaborating to bring about sufficient levels of R&D, as well as to reach actionable solutions that address the fundamental questions that have now been raised. It is therefore critical that industry stakeholders share their insights and experience, whether directly or through trade associations, to ensure that the resulting legislation is not only coherent but is also beneficial to all parties concerned, thereby serving to strengthen rather than undermine the achievements that have been made to date.

Taking a broader perspective, it is also vital that the Orphan Regulation review adopts a ‘global perspective’ and considers the interplay between the European framework and the incentive environment for the development of rare disease therapies in other geographies to create a system that attracts investment in rare disease innovation in Europe, which should form the core elements of the legislative review process (11).

Joint Evaluation of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on Medicinal Products for Paediatric Use and Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 o

 Commission Staff Working Document: Part 1/6 (August 2020).
2. EC. 

Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products

EMA.europa.eu/en/human-regulatory/overview/orphan-designation-overview

Eurordis.org/information-support/what-is-a-rare-disease/

Commission.europa.eu/law/law-making-process/planning-and-proposing-law/better-regulation_en

Evaluation of the Medicines for Rare Diseases and Children Legislation

Health.ec.europa.eu/medicinal-products/medicines-children/evaluation-medicines-rare-diseases-and-children-legislation_en

Orphan Medicinal Product Designation: Overview 2000–2021

EMA.europa.eu /en/documents/other/orphan-medicines-figures-2000-2021_en.pdf

The Revision of the EU Regulations on Medicines for Children and Rare Diseases: Background and Discussion

, March 2022.
10. Berdud, M.; Garau, M.; O’Neill, P.; Rozanova, O.; Bell, E. 

Economic and Financial Challenges of Developing Orphan Medicinal Products. Does the European Regulation Tackle them?

 Office of Health Economics, February 2020.
11. EUCOPE. 

The Orphan Medicines Regulation: The Way Forward

, July 2021.
12. Skentelbery, C. The Revision of the Orphan Medicines Regulation is an Opportunity: Will Europe Seize it? 


Vol. 35, No. 1
January 2023
Pages: 7–8

When referring to this article, please cite it as B. Piachaud-Moustakis, “Revision of the Orphan Medicines Regulation,” 

Does the new regulatory framework have the potential to incentivise R&D investment in rare diseases?

Revision of the Orphan Medicines Regulation

On 30 May 2022, the Parliament of the European Union (EU) adopted the revised European Data Governance Act (DGA), which builds on the previous Regulation (EU) 2018/1724, which was designed to establish a single digital gateway to provide access to information (1). The DGA entered into force on 23 June 2022 and, following a 15-month grace period, will be applicable to all member states from September 2023. It forms part of the broader context of the European Commission’s (EC’s) action plan to ensure Europe’s digital sovereignty by 2030 and is complementary to the European Artificial Intelligence (AI) Strategy. The aim of the law is to create a single European market for data, while seeking to increase trust in data sharing by companies, individuals, and the public sector as well as strengthen mechanisms to increase data availability and overcome technical obstacles to reuse data.

The DGA applies to data defined as “any digital representation of acts, facts, or information and any compilation of such acts, facts, or information, including in the form of sound, visual, or audio-visual recording that is held by public sector bodies that is not subject to the Open Data Directive but is subject to the rights of others” (2). This may include personal data, including special categories of data, such as health data, statistically confidential data, trade secrets, and data that are subject to intellectual property rights.

The DGA aims to ensure a better distribution of the value derived from the use of personal and non-personal data between the actors of the data economy, particularly in relation to the use of connected objects and the development of the Internet of Things (IoT) (3). The proposed DGA therefore aims to:

facilitate the sharing of data between companies (B2B) and with consumers (B2C)

re-use public sector data subject to the rights of others

facilitate the switching of data processing services (cloud and edge computing)

provide for the development of interoperability standards for data and its re-use across sectors

put in place safeguards against unlawful access to non-personal data in the cloud by third country governments.

The DGA also supports the establishment and development of common European data spaces in strategic domains that involve both private and public players, in sectors such as health, environment, energy, agriculture, mobility, finance, manufacturing, public administration, and skills.

In the context of health, a document published by the EC believes that data-driven innovation will bring benefits to companies and individuals alike by creating efficiencies through “improving personalized treatments, providing better healthcare, and helping cure rare or chronic diseases … while providing efficiencies in health data will save approximately €120 billion a year in the EU health sector” (4).

Member states will have to set up a single information point to support researchers and businesses in identifying suitable data, while the EC will establish a European single-access point consisting of a searchable electronic register of all data available in each of the national single information points.

Re-use public sector data subject to the rights of others

This re-use of data concerns commercially confidential data (such as business trade secrets), statistically confidential data, data with intellectual property rights and personal data that are protected by the General Data Protection Regulation (GDPR) (5). If public sector bodies choose to share their data, it is conditional that they introduce harmonized basic conditions that will support this re-use. Technical measures that ensure the protection, privacy, and confidentiality of the data, through anonymizing or pseudonymizing the data before sharing and re-use must also be taken. It is also incumbent upon public sector bodies to verify the results of the data processed by the re-user, and they have the power to prohibit the use of the results if it believed that the rights and interests of third parties are being jeopardized (5). Under the terms of the DGA, exclusive arrangements are prohibited, although exceptions for a maximum of 12 months are possible under certain conditions.

The DGA has also defined a new business model for data intermediary services. These are services that act as a data hosting marketplace platform that enables the sharing of data but does not process or utilize the data. These intermediaries will be required to notify supervisory authorities of their intention to perform these services, and a license will be required to perform such services. To achieve this, a licensing regime will be put in place by supervisory authorities to ensure that the intermediary service is sufficiently independent and has appropriate security measures to protect privacy and confidentiality (2). Once a licence has been obtained, the data intermediary will be permitted to use a common logo that signifies it is compliant with DGA regulations and is a trusted entity. These intermediaries are permitted to charge a reasonable fee for the provision of the data intermediation service but are not authorized under any circumstance to use the stored data for their own purposes or profit.

The DGA seeks to increase trust in data sharing, strengthen mechanisms to make data more available, and overcome obstacles to the reuse of data, which are vital ingredients to the intersectoral use of health data.