Cheryl Barton is director of PharmaVision, 

Cheryl Barton

For several years, manufacturers have been developing organs‑on‑a-chip (OoC) technology, whereby engineered or natural tissues are grown inside microfluidic chips allowing them to maintain tissue-specific functions. Today, OoCs encompass an array of tissues and organ functionality including the blood-brain-barrier (BBB), central nervous system (CNS), heart, intestine, liver, lung, kidney, muscle, and skin to allow pharma to better understand the underlying pathophysiology of diseases and to determine the effect of drugs 

Advances in tissue engineering, microfabrication, and biocompatible microfluidic chambers alongside the governmental (2) and regulatory (3) appetite to seek animal-free innovations in the drug development process has fuelled further interest and investment in this marketplace. According to market research, the global OoC market is forecast to be worth US$388 million (€354 million) by 2028 increasing from US$82 million (€75 million) in 2023, with a compound average growth of 36.4% from 2023 to 2028 (4).

Market leaders carving out a niche in the OoC market

Several players have already carved out niches in the OoC field. CN Bio Innovations, a spin-out from Oxford University in the United Kingdom, was founded in 2008 and became one of the first companies in this space with OoC technology licensed from Massachusetts Institute of Technology and Vanderbilt University. CN Bio has developed a range of single OoC technologies including the gut, liver, or lung, and recently launched the PhysioMimix platform, a system that can co-culture human cells (e.g., gut/liver) in open-well plates to recreate human organs. Importantly, multiple devices can be connected together to generate a ‘body-on-a-chip’ device whereby microchannels allow different organs to interact with one another (5).

Another player in the field of OoC, TissUse, was founded in 2010 and is a spin-off from Technische Universität Berlin. The biotech company produces models of human organs for preclinical drug testing based on this patented technology. Like CN Bio, TissUse has developed a multi-organ system or human-on-a-chip technology to allow potential interaction of one organ with another. This technology has been used in drug development, consumer products, cosmetics, and food and nutrition products to help predict absorption, distribution, metabolism, and excretion (ADME) and toxicity (6).

Netherlands-based Mimetas was founded in 2013 and has raised more than US$25.2 million (€23 million) in series A and B funding (7). In March 2022, it launched a three-dimensional (3D) OrganReady Coco-2 assay consisting of 38 intestinal tubules that facilitate the pre-clinical assessment of ADME, safety, and toxicology of new chemical entities (NCEs) and later the same year won the Dutch Innovation Award in recognition for its innovative technology (8). In July 2021, it entered into a strategic partnership with Roche to develop 

 models of inflammatory bowel diseases and hepatitis B viral infections, which it successfully completed in March 2023. Mimetas has also teamed up with Astellas Pharma to utilize its Organoplates for high throughput (HT) 

 screening of Astellas’ next-generation immune-oncological therapies (9). Mimetas continues to push the frontiers of OoC and recently launched its off-the-shelf solution, OrganoReady consisting of 3D Adult Stem Cell (ACS)-derived tubular organoid assay derived from either the colon or kidney for use in preclinical research (10).

In the United States, microfluidic start-up Emulate was established in 2014 and became one of the first companies to develop the Liver-Chip for predictive toxicology (11); the technology was developed at the Wyss Institute for Biological Inspired Engineering at Harvard. Like other OoC companies, Emulate is now researching personalized medicines through a human-on-a-chip approach. New York-based TARA BioSystems was also created in 2014, a spin out from Columbia University and became one of the market leaders in heart-on-a-chip technology. It was recently acquired by Valo Health in April 2022, enabling it to expand its cardiac disease modelling capabilities (12). Meanwhile, Florida-based Hesperos a global contract research organization (CRO) has ventured into the OoC space and now offers clients inhouse safety and efficacy testing services. It has developed a multi-organ 

 platform, ‘human-on-a-chip’ technology, to allow drug developers to investigate patients’ response to drugs during pre-clinical and clinical development. Hesperos has forged collaborations with Roche and Sanofi to pre-clinically evaluate NCEs for ADME and toxicity; these data have been used to support investigational new drugs (IND) files (13,14).

Newcomers in the OoC field attracting investor attention

As the field of OoC moves forward at a pace, several European start-ups have recently entered the arena and gained investor attention.

In March 2022, Lyon-based NETRI, attracted €8 million series A funding to help develop its novel high throughput (HT) compartmentalized microfluidic brain-on-a-chip and skin-on-a-chip technology for use by the pharma and cosmetic industry (15). The NeoBento HT 96-well plate contains between 16 and 24 chips that are interconnected by microchannels (e.g., tunnels or grooves) allowing cells to be co-cultured and recreate physiological interactions. Unlike other OoC technologies, the microchannel grooves allow continuous connection between compartments allowing research to study axotomy, the gut brain axis, the neuromuscular junction, and innervated skin and evaluate therapeutic agents for neurological conditions such as multiple sclerosis and neuropathies. NETRI’s microfluidic chips can also be used to mimic physiological barriers such as cell membranes to allow companies to assess how substances are transported across the cell membrane including the blood brain barrier.

In September 2022, NETRI teamed up with Axion Biosystem to develop a HT microchip that is compatible with multielectrode arrays (MEA) (16). In March 2023, the companies launched the NeoBento MEA a HT 96-well plate that enables electrophysiological recording of cells 

; this allows pharma to remotely stimulate the cell and monitor synaptic activation in isolated cell populations (17). The technology is currently designed for use in peripheral nerve injury (peripheral neuropathic pain and allodynia, nociceptive pain) and sensitive skin syndrome as well as the evaluation of neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease) and other neurological disorders. NETRI has adopted a modular approach that allows the OoCs to be combined to create multi‑organ or multi‑organoid formats and these can be customized to clients’ requirements, enabling them to rapidly and cost‑effectively screen NCEs and select the most appropriate drugs to move forward into clinical development (

NETRI high throughput organs-on-chip platform, NeoBento, for drug discovery and cosmetic testing. 

In March 2022, Netherlands-based Bi/ond, secured US$4 million (€3.6 million) investment from leading industrial venture firm FORWARD.one to develop its proprietary inCHIPit and the reusable comPLATE platforms that combine 3D microfluidic cell culture within a microchip for applications in kidney research, oncology, and cardiac simulation (19). The inCHIPit is an open well system that can be loaded with a variety of cells or tissues (e.g., pluripotent stem cells, organoids, 

 tissues, spheroid, or microtissues) and each well is connected to microfluidic channel via a porous membrane, which allows cells to be stimulated 

 and viewed optically. Bi/ond is currently evaluating its technology to predict treatment response and personalize therapy. For instance, the company has forged a collaboration with the Leiden University Medical Centre (Netherlands) to culture heart OoCs so that patients’ response to therapy can be predicted, and the company is working with the Erasmus University Medical Center (Netherlands) to generate OoCs containing patient tumour tissues to assess their response to chemotherapy (19).

As OoC manufacturers continue to embrace the adoption of new biomaterials and fabrication techniques such as lithography and 3D bioprinting this will allow companies to increasingly customize multi-OoC systems with the desired functionality and will provide high content imaging and/or electrophysiological readouts (1). To date, the use of OoCs has primarily focused on drug development; however, they also offered considerable potential throughout preclinical and clinical development, providing new ways to model diseases, including rare disorders, monitor pharmacokinetic and pharmacodynamic properties of NCEs, and guide the personalization of treatment in the clinic based on genotypic-phenotypic characteristics. Given the recent regulatory move to reduce animal testing (3) the field of OoC looks ripe for innovation and further investment.

1. Leung, C.M.; de Haan, P.; Ronaldson-Bouchard, K.; et al. A Guide to the Organ-on-a-Chip. 

, 2, 33.
2. European Commission. JRC Supporting Alternatives to Animal Testing. 

, News Release, 7 April 2022.
3. Wadman, M. FDA No Longer Needs to Require Animal Tests Before Human Drug Trials. 

, Article, 10 Jan. 2023.
4. Market Data Forecasts. 

Global Organ-on-Chip Market Size, Share, Trends, COVID-19 Impact and Growth Analysis Report—Segmented by Type (Heart-on-chip, Human-on-chip, Intestine-on-chip, Kidney-on-chip, Liver-on-chip and Lung-on-chip), Application and Region (North America, Europe, Asia-Pacific, Latin America, Middle East and Africa)—Industry Forecast from 2023 to 2028

. Market Report, March 2023.
5. CN-Bio. PhysioMimix OOC Microphysiological Systems. 

, accessed 3 April 2023.
6. TissUse. Technology. 

, accessed March 2023.
7. Mimetas. MIMETAS Secures 20 Million Dollar Series B Financing. 

, Press Release, 11 April 2018.
8. Mimetas. MIMETAS Elected Most Innovative Company of the Netherlands. 

, Press Release, 2 Nov. 2022.
9. Mimetas. MIMETAS and Astellas Enter into Strategic Partnership on Immuno-Oncology. 

, Press Release, 28 March 2023.
10. Mimetas. MIMETAS Launches Ready-to-Use 3D Adult Stem Cell Organoid Tubules. 

, Press Release, 7 March 2023.
11. Ewart, L.; Apostolou, A.; Briggs, S.A.; et al. Performance Assessment and Economic Analysis of a Human Liver-Chip for Predictive Toxicology. 

, 2, 154.
12. Valo. Valo Health Acquires TARA Biosystems Creating First of its Kind Vertically Integrated Cardiovascular Platform. 

, Press Release, 5 April 2023.
13. Hesperos. Hesperos Shows Potential for 

 Approach to Replace Conventional Animal Efficacy Studies for Rare Neuromuscular Disorders. 

, Press Release, 19 April 2022.
14. Hesperos. The Original Human-on-a-Chip Company. 

, accessed 3 April 2023.
15. NETRI. Lyon-Based Industrial Start-Up NETRI is Finalizing an €8 million Series A Funding Round. 

, Press Release, 3 Mar. 2022.
16. NETRI. NETRI and Axion BioSystems Announce Organs-on-Chip Collaboration. 

, Press Release, 8 Sep. 2022.
17. Business Weekly. Axol Bioscience and French Partner Unveil Organs-on-Chip Innovation. News Release, 3 Jan. 2023.
18. NETRI. Modular Integration. 

, accessed 3 April 2023.
19. Bi/ond. Bi/ond Secures Over $4M in Funding—Bi/ond. 

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.


Vol. 35, No. 5
May 2023
Pages: 16–17, 30

When referring to this article, please cite it as Barton, C. Frontrunner in Organ-on-a-Chip. 

Articles

Competition in the organ-on-a-chip market increases as NETRI enters the arena.

Frontrunner in Organ-on-a-Chip

On 6 Feb. 2023, the European Medicines Agency (EMA) issued new European Union (EU) guidance for drug developers regarding the conduct of paediatric investigation plans (PIPs), particularly when clinical information is limited (1). EMA defines a PIP as “a research and development programme aimed at ensuring that the necessary data are generated determining the conditions in which a medicinal product may be authorized to treat the paediatric population” (1). Ideally a PIP should be submitted to the Paediatric Committee (PDCO) at the EMA following pharmacokinetic studies in adult humans and are reviewed under regulation (EC) No 1901/2006 (Paediatric Regulation) (2) and regulation (EC) No 19032/2006 (Paediatric Regulation) (3).

In 2017, the European Commission (EC) published its 10-year report on the implementation of paediatric regulation where it highlighted five areas that remained a challenge or lagged behind adult regulations. These included identifying paediatric medical needs, strengthening of cooperation of decision makers, ensuring timely completion of PIPs, improving the handling of PIP applications, and increasing transparency around paediatric medicine (4).

Steps taken to address shortfall in paediatric regulation

To address these issues, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and European Forum for Good Clinical Practice (EFGCP) organized a multi-stakeholder workshop with EMA in 2019 to help define paediatric unmet medical needs (5). Furthermore, Accelerate, in collaboration with EMA, held various meetings on topics related to children and adolescent therapies (6), and the results of these interactions were published in the scientific literature to raise awareness.

Similarly, EMA’s Paediatric Committee (PDCO) strengthened its collaboration with the Clinical Trials Coordination Group (CTGC) and improved harmonization of pedantic regulations through EMA/US Food and Drug Administration cluster activities (7) and establishing the EMA/PDCO PIP assessment process. The European network of paediatric research and EMA (Enpr-EMA) also established an international working group to work on a white paper to provide recommendations on international standard for sustainable paediatric clinical trial sites (8).

In terms of ensuring timely completion of PIPs, EMA published a reflection paper in 2018 on the use of extrapolation in the development of medicines for paediatrics (9) and the Enpr-EMA published a framework about paediatric clinical trial preparedness in 2020 (10). This framework provided developers with further clarity around the extrapolation of data and additional guidance on the implementation of paediatric clinical trials.

To improve the handling of PIP applications, the EMA/PDCO has developed a framework for a “stepwise PIP” (sPIP) approach, which aims to simplify the administration of PIP submissions and procedural aspects of PIP compliance and allows changes to be made to PIPs as more evidence becomes available (1).

On 6 Feb. 2023, EMA launched the sPIP pilot programme, and eight sPIPs are due to be adopted and opinions gathered to help mould the process and inform decision-making for its future use. At the current time, EMA does not anticipate a sPIP approach will be warranted in most cases, but a dedicated pre-submission meeting with the Paediatric Medicines (PME) Office is recommended to determine if an sPIP approach is justified (1).

However, a sPIP submission may be justified in cases where there is limited scientific knowledge, for instance, the development of a first-in-class drug to treat a rare paediatric disease, when the mechanism of action of a drug is not fully characterized and may impact ontogeny-related changes in an individual or a medicine addresses significant unmet needs in several indications where adult data are lacking. Applicants may participate in the sPIP pilot programme on a voluntary basis and may consider this option if the study design, population, and main objectives of a study are not well‑defined (1).

When a developer chooses to submit a sPIP they do so using the same template as a conventional PIP but the content included in part B and D will differ. 

a valid scientific justification to support a sPIP approach in the development in all paediatric ages or in certain age subgroups

information and explanation regarding information gaps and why some studies cannot be planned or aspects of the clinical studies cannot be determined or estimated at the time of the initial application

a detailed discussion on existing information (or lack thereof).

a high-level, overall plan and strategy for paediatric development (e.g., the condition, preliminary outline of planned studies based on available evidence and a PIP completion date)

milestones/timelines for subsequent PIP modification(s) and outline of how the missing data will be generated and the PIP fully completed

open sections to discuss and agree future modification procedures to develop the final full PIP.

If additional information becomes available during the sPIP, the application can be modified via the established modification procedure used in the traditional PIP approach. Not all elements need to be modified at the same time, but multiple modifications should be avoided and streamlined/or bundled where appropriate. If applicable, timelines/milestones can be updated during the modification procedure. In cases where significant updates to the sPIP are requested, a pre-submission meeting with the PDCO assessment team is strongly recommended. The same compliance checks apply to sPIPs as conventional PIPs.

The EMA is also working to increase transparency around paediatric medicines and is updating the Community Register of medicinal products with paediatric information and a public register regarding paediatric trials is under development.

It is clear that EMA has taken great strides to address the challenges and areas of paediatric medicines that lagged behind adult medicines. The implementation of sPIPs is one way to promote paediatric drug development and better aligns the data requirements between decision-makers and the regulators. The sPIPs should enable developers to move paediatric medicines forward with a minimum set of data and allow sPIPs to be refined as more data becomes available.

Overall, the EMA-EC paediatric plan taken together with the Orphan Drug Regulation should help to provide a framework to improve the implementation of Paediatric Regulation where all stakeholders can collaborate and help to improve the efficiency of the process so that developers continue to target areas of high unmet medical need and increase the number and speed to market of paediatric medicines that can benefit future generations.

Regulation (EC) No 1901/2006 of the European Parliament and of the Council on 12 December 2006 on Medicinal Products for Paediatric Use and Amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No. 726/2004

Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 Amending Regulation 1901/2006 on Medicinal Products for Paediatric Use

 (December 2006).
4. EMA. EMA/635567/2022, 

Boosting the Development of Medicines for Children

EFPIA and EFGCP Multi-stakeholder Workshop on Paediatric Unmet Medical Needs

, 12 Dec. 2019.
6. ACCELERATE. ACCELERATE Platform—Innovation for Children with Cancer. 

FDA/EMA Common Commentary for Submitting an Initial Pediatric Study Plan (iPSP) and Paediatric Investigation Plan (PIP) for the Prevention and Treatment of COVID-19

European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)

 (accessed 20 Feb. 2023).
9. EMA. EMA/189724/2018, 

Reflection Paper on the Use of Extrapolation in the Development of Medicines for Paediatrics—Final

 (7 Oct. 2020).
10. EMA. EMA/56009/2019, 

Preparedness of Medicines Clinical Trials in Paediatrics

When referring to this article, please cite it as Barton, C. EMA Guidance on Paediatric Investigation Plans. 

Stepwise paediatric investigation plans aim to boost the development of medicines for children.

EMA Guidance on Paediatric Investigation Plans 

For more than a decade, manufacturers have been exploring new ways to improve the efficiency of cell therapy production to make it more cost-effective and accessible to those in need. Many companies have been working in this field, including US-based CAMP4 Therapeutics and Stealth Biotherapeutics’ and France-based TreeFrog Therapeutics SAS, and innovative approaches have now been developed to provide viable stem cells, at scale. 

In 2018, Erwan Bezard, Jean-Luc Treillou, Kevin Alessandri, Laurent Cognet, Maxime Feyeux, and Pierre Nassoy co-founded Bordeaux-based TreeFrog Therapeutics with the sole mission to establish a secure cell production process based on their proprietary 3D C-Stem scalable technology to improve the accessibility and affordability of induced pluripotent stem cell (iPSC)-based therapeutics (1).

In July 2022, Peter Nell, PhD, joined TreeFrog as an independent board member. He previously worked at Bayer Healthcare and has extensive knowledge about business development and licensing and clustered regulatory interspaced short palindromic repeats (CRISPR) technology (2).

In January 2022, the company was recognized as one of the top 25 BioTech start-ups (1). Since its conception, it has attracted US$86.9 million (€80.8 million) in series A and B funding from private equity investors, including Leonard Green and Partners, XAnge, AQUITI Gestion, BNP Paribas Développement, and Bpifrance, as well as Bristol Myers Squibb, Aquitaine Science Transfer, and the European Commission (1).

The company has utilized this funding to leverage its C-Stem technology to generate a pipeline of innovative products which include iPSC dopaminergic neurons to treat Parkinson’s diseases (enter Phase I in 2024); and preclinical programmes using hematopoietic stems cells for bone marrow transplant, cardiomyocytes for myocardial infarction, iPSCs platform and NK and T cells for immune‑oncology (3).

TreeFrog’s lead programme targets Parkinson’s disease via the generation of three-dimensional (3D) neurospheres which contain mature dopaminergic neurons. Following promising pre-clinical studies, the company is expecting to enter first-in-human (FIH) trials in 2024 (3).

On 11 Oct. 2022, TreeFrog’s collaboration with the contract development and manufacturing organization (CDMO) Invetech, came to fruition, and the first good manufacturing practice (GMP)-grade cell encapsulation device was installed and will be used to produce TreeFrog’s PD cell therapy candidate.

The device combines microfluidics and C-Stem cell biology to generate biomimetic alginate capsules seeded with iPSCs. The encapsules iPSCs rapidly expand and differentiate in 3D culture to produce ready-to-transplant microtissues. The capsule helps to reduce the impact impeller shear stresses exerted on iPSCs cells in large-scale bioreactors which can generate more than 1000 capsules per second, and are suited to seed reactors from 200 mL to 10 L (4).

In 2023, the GMP-grade cell encapsulation device will be transferred from TreeFrog to the CDMO to manufacturer clinical grade batches for Treefrog Parkinson’s Disease programme, and three additional GMP encapsulation devices will be delivered to Invetech to support TreeFrog’s pipeline programme.

TreeFrog taps into new technologies through strategic partnerships

TreeFrog has forged several partnerships to tap into new gene editing technologies by leveraging its C-Stem technology.

In June 2022, Treefrog teamed up with iPSC engineering Umoja Biopharma, USA, to use it synthetic rapamycin-activated cytokine receptor (RACR) technology in combination with TreeFrogs C-Stem platform to generate off-the-shelf iPSC-derived allogenic products that target immune cells in solid and haematological malignancies (5).

Geographical expansion to drive C-Stem adoption

TreeFrog has ambitious plans to drive adoption of its C-Stem technology across the globe. The company has started expanding its workforce and facilities; in 2022, the company aimed to double its laboratory capacity for the development and production of iPSC therapies.

During 2022, it opened technological hubs in Boston in the United States and Kobe, Japan, and aimed to establish strategic alliances with leading academic and biopharma players.

In 2022, TreeFrog awarded several Stem Cell SpaceShot grants to leading academic institutions including the University of Sheffield, UK; MCR Laboratory of Molecular Biology, Cambridge, UK; Harvard University, USA; University of California, USA; R&D Center for Cell Therapy, Kobe, Japan; and CNRS, France, which brought together experts in stem cell, gene editing and biophysics to drive further innovations in this field (6).

Investors will be watching this unicorn stock closely to see if the company delivers on its business goals, providing three additional GMP-grade devices to Invetech in 2023 and initiating a FIH trial for iPSC targeting Parkinson’s Diseasein 2024.

Additionally, it is anticipated to bring more news during 2023/2024 regarding further partnerships/licensing deals across the globe, as the company leverage its C-Stem technology with leading academic institutes and biopharma companies.

Competition in this field will increase as new technologies come to the forefront and investment in competitor companies such as CAMP4 Therapeutics (7) and Stealth Biotherapeutics’ (8) have products nearing the market.

Crunchbase. TreeFrog Therapeutics, Company Profile & Funding. TreeFrog.fr (accessed 13 Dec. 2022).

TreeFrog Therapeutics. Peter Nell joins TreeFrog Therapeutics as Independent Board Member. Press Release, 25 July 2022 (accessed 13 Dec. 2022).

TreeFrog Therapeutics. Cell therapy pipeline. TreeFrog.fr (accessed 13 Dec 2022).

TreeFrog Therapeutics. Treefrog Therapeutics Moves to GMP Manufacturing with Cell Encapsulation Device Delivered by Invetech. Press Release. 11 Oct. 2022.

Umoja Biopharma. Umoja Biopharma and TreeFrog Therapeutics Announce Collaboration to Address Current Challenges Facing Ex Vivo Allogeneic Therapies in Immuno-Oncology. Press Release. 10 June 2022.

TreeFrog Therapeutics. 3 PhD Students from King’s College London Win the $100,000 Stem Cell SpaceShot Grant. Press Release. 20 Oct. 2022.

CAMP4. CAMP4 Secures $100 Million Series B Financing to Accelerate Expansion of its Novel Regulatory RNA-Targeting Platform and Advance Lead Programs into the Clinic. Press Release. 20 July 2022.

Stealth BioTherapeutics. Programs and Pipeline. Stealthbt.com. (accessed 13 Dec. 2022). 

Pharmaceutical Technology Europe
Volume 47, No.1
January 2023
Pages 17-18

When referring to this article, please cite it as Barton, C. 

Frontrunners in the Latest Stem Cell Technology

. Pharmaceutical Technology Europe 47 (1) 2023.

TreeFrog Therapeutics is leaping ahead in cell therapies through 
resources such as new technologies and investor partnerships.


The current European Union (EU) regulatory system was established in 1995, and the European Medicines Agency (EMA) works with the European Commission (EC) across 27 member states to ensure the efficacy and safety of human and veterinary medicines across Europe and to promote research and innovation in the development of medicines. New medicines are reviewed through either a centralized procedure or by national competent authorities, through a mutual recognition, decentralized, or national procedure, mainly through the Directive 2001/83/EC (1) and Regulation (EC) No. 726/20049 (2). However, over time the EU regulatory framework has become complex and inefficient and is now in need of an overhaul (3).

On 25 Nov. 2020, the EC published the Pharmaceutical Strategy for Europe (4) outlining a new regulatory framework based on a set of four pillars, to promote research and technologies (

). Work is already underway to revise the legislation on rare/orphan disease (5) and paediatrics (6). The Structured Dialogue initiative was launched on 26 Feb. 2021 to address security of medicine supply (7), and further amendments to the Human Medicines Directive and Regulation are anticipated later this year.

On 1 March 2021, the EC published its roadmap to revise the general pharmaceutical legislations building on lessons learnt from the COVID-19 pandemic to ensure that the future regulatory framework is fit-for-purpose and crisis-resistant (3). Since the EC published its strategy roadmap, it has conducted a series of consultations and has proposed a series of amendments to:

foster innovation, including in areas of unmet medical need

adapt to new scientific and technological developments

The Regulatory Scrutiny Board (RSB), an independent body within the EC that undertakes impact assessments and evaluation fitness checks, has reviewed the proposal and drafted a number of negative opinions. These issues will need to be addressed, and the draft report reviewed and resubmitted to the RSB before the proposal can proceed and be accepted by EU policymakers (9). In 2020, the RSB initially rejected the proposal on the legislation on medicines for children and rare disease, but following resubmission, it was accepted (10).

Feedback from the EC regulatory reform was planned for the fourth quarter of 2022 (8), but given the RSB rejection, it is anticipated this feedback will be delayed until 2023 or further, given that European Parliament elections take place in 2024. However, a delay gives the EC more time to review the pharmaceutical landscape and take on board the RSB comments and other organizations such as European Federation of Pharmaceutical Industries and Association (EFPIA), which has been very vocal in this area.

A report by Charles River Associates (CRA) undertaken on behalf of the EFPIA highlights the lack of competitiveness in Europe which has led to a decline in pharmaceutical R&D investment, clinical trials, and manufacturing output in recent years (11). Another report published by the Centre for Innovation in Regulatory Science (CIRS), highlights that EMA’s timeline for regulatory review lags behind other regulatory agencies (12).

According to EFPIA, the overall goal of the new regulations should be to reinforce expertise-driven assessment and enable a more agile centralized authorization framework by facilitating member states and removing unnecessary, burdensome interfaces between committees and the EC (

). To achieve this goal, EFPIA has proposed a number of radical changes which include:

Implementing high-quality assessments by revising the governance framework, to encourage experts from EU member states to contribute, where appropriate

Establishing an agile system and rethinking outdated committees and working parties’ structure to improve agility and efficiency

Identifying and resourcing gaps based on current and future workload and implementing forward‑looking strategies regarding funding and resourcing mechanisms for EMA and the Network.

 Building blocks for a new regulatory framework.

EMA and its member states have been collaborating for more than 27 years and the pharmaceutical regulations have evolved to meet scientific and regulatory demands. Push back from the RSB has given the EC time to reflect on its reform package and make sure the new regulatory framework is fit-for-purpose and meets the goals laid out in the Pharmaceutical Strategy for Europe and roadmap. It also enables the EC to take into account the lessons learnt from the COVID-19 pandemic, environmental challenges, and to reassess new opportunities presented by the digitalization of healthcare data. More haste and less speed may be necessary to ensure that the EU and its member states are in a strong position to compete in the global arena and attract future investment so it can deliver safer, better medicines to patients, faster.

 [Accessed 10 Nov. 2022].
3. EFPIA, “EU Regulatory Network—New Architecture for a New Era,” Guest Blog, 

Structured Dialogue on Security of Medicines Supply

Revision of the EU General Pharmaceuticals Legislation

 [Accessed 10 Nov. 2022].
9. Pinsent Masons, “EU Pharma Law Reforms Face Delay,” Out-Law News, 31 Aug. 2022.
10. RSB, 

Regulatory Scrutiny Board Annual Report 2020

 25 May 2021.
11. CRA on behalf of EFPIA, 

Factors Affecting the Location of Biopharmaceutical Investments and Implications for European Policy Priorities Final Report

New Drug Approvals in Six Major Authorities 2011–2020: Focus on Facilitated Regulatory Pathways and Worksharing


Vol. 34, No. 12
December 2022
Pages: 8–9

When referring to this article, please cite it as C. Barton, “Overhauling the Human Medicines Directive and Regulation,” 

The European Human Medicines Directive and Regulation is due to be updated by the end of 2022, but what changes are on the cards?

Overhauling the Human Medicines Directive and Regulation 

The unitary patent (UP) will build on European Union (EU) patents granted by the European Patent Office (EPO) under the rules of the European Patent Convention (EPC) (1). This system could be very advantageous to owners of EU patent applications and EU patents when it comes into effect, potentially in October 2022. At this point, it will be possible for inventors to gain patent protection in up to 25 EU member states through the submission of a single request to the EPO. The same standards and timelines will apply to patent submissions; however, once a EU patent has been granted, the patent proprietor will be able to request unitary effect, receiving uniform patent protection in up to 25 EU Member States (

The United Kingdom has not been involved the development of the UP policy despite the fact that EU constitutional experts have called for the United Kingdom to be involved, as a non-EU member state, in the Unified Patent Court (UPC) framework (3). It is hoped that the UK, Switzerland, and other EU countries will be incorporated into the UP patent system later. The UP covers 25 member states, whereas the classical European patent system presently covers 38 member states (

Coverage of European patents and those with unitary effect.

Current EU patent process is complex and costly

Currently, an inventor can protect an invention in Europe through an EU or national patent. The EU patent is reviewed centrally by the EPO, and if granted, the EU patent must be validated and maintained individually in each country. This is a complex and costly process resulting in high direct (e.g., translational fees, validation fees, national renewal fess) and indirect (e.g., attorney fees) costs. The UP system aims to reduce the complexity and costs associated with the patent process (

 Unitary patent system reduces the complexity and cost of national validation process.

What does this mean for the pharma industry?

The UP and the new UPC has implications for the pharma industry. On the upside, the UP system provides a simpler, more cost-effective process, and if an EU patent is granted for a pharmaceutical product through the UP system, it would provide patent protection across all 25 member states and enable them to obtain a pan-EU interim injunction should an infringement occur. Challenging or enforcing EU patents on a national scale currently requires separate actions in each individual country of interest. On the flip side, if the UPC system rejects a patent application or a patent is revoked, it may prevent patent protection across all the EU member states.

In the future, the UP is likely to incorporate unitary supplementary protection (SPC) (5). SPCs are an intellectual property (IP) that extends a patent right which apply to specific pharmaceutical and plant protection products that have been authorised by regulatory authorities. SPCs help to offset the loss of patent protection for pharmaceutical (and plant protection products) that can occur due to prolonged clinical trials and compulsory testing, which are required prior to obtaining regulatory marketing approval. An SPC can extend a patent right for a maximum of five years; a six-month extension is for a medicinal product for children for which data has been submitted according to a Paediatric Investigation Plan (PIP) (6).

The first seven years after the UPC comes into effect it will be possible for pharma companies to opt out of from the UPC jurisdiction and this will also extend to SPC based on an EU patent. A sunrise period of up to three months has been proposed to enable companies to consider their options before the system begins (7). Therefore, pharma companies will need to carefully weigh up the merits of opting in or out of this new patent system, and they will need to do this soon as it may come in effect as early as October 2022.

, 17th Edition, November 2020.
2. M. Best, “European Patent System Overhaul—the Unified Patent Court and Unitary Patent,” Client Alert, 5 May 2022.
3. A. Henry, “Unitary Patent System Tipped as Next Biggest IP Development in Europe,” Out-Law News, Pinsent Masons, 11 Feb. 2021.
4. EPO, 

 [Accessed 13 Aug. 2022].
5. C. Drew, “EU Pharma Strategy has Patients and Collaboration at its Heart,” Out-Law News, Pinsent Masons, 25 Nov. 2020.
6. EC, 

Supplementary Protection Certificates for Pharmaceutical and Plant Protection Products

 [Accessed 13 Aug. 2022].
7. V.O., “Be prepared for the Unitary Patent (UP) and the Unified Patent Court (UPC) Sunrise,” News, 2 Feb. 2022.


Vol. 34, No. 9
September 2022
Pages: 7–8

When referring to this article, please cite it as C. Barton, “What Impact Will the New Unitary Patent System Have in Europe,” 

A new unitary patent system is due to come into effect in Europe later on this year.

What Impact Will the New Unitary Patent System Have in Europe

While randomized controlled trials (RCTs) remain the gold standard for evidence-based medicines to achieve regulatory approval, interest in the use of real-world evidence (RWE) to support regulatory decision-making is growing (1). RWE provides additional insights pre- and post-marketing regarding the risk-benefit of a medical product in the real-world setting, and the analysis of real-world data (RWD) contained in electronic health records (EHRs), health claims, patient registries, and from patient-generated data can be leveraged by the pharma industry to drive healthcare decisions and support health technology assessment (HTA) decisions (2).

Over the past decade, pharma has increased their level of activity and planning around the use of RWE and have gradually expanded their collection of RWE (

) (3). To date, most of the RWD in regulatory submissions have been limited to post-marketing safety data or confined to a limited number of orphan or rare disease products, where RCTs are more challenging to conduct (4). However, moving forward it is likely that the regulators will request RWE to support regulatory files for non-specialty and specialty drugs.

European data sources and duration of data collection. 

A retrospective analysis of clinical trials submissions to the EMA during 2018 and 2019 revealed that RWE was included in two-fifths of initial marketing authorizations applications and one-fifth of indication extension applications (5). A more recent analysis by Eskola 

 (2022) revealed that nearly all European Public Assessment Reports (EPARs) include RWE in drug discovery (98%) and life-cycle management (100%) and nearly half included it in the development phase (49%) or to support regulatory decisions at registration (47%) (6).

In 2018, EMA and the US Food and Drug Administration (FDA) reinforced their collaboration on medicines including the use of RWE to support regulatory decisions (7). In November 2021, EMA outlined its vision for the use of RWE in European Union (EU) medicines regulations (8), and this vision is one of the pillars of the European Medicines Regulatory Network (EMRN) strategy to 2025, which aims to establish the use and value of RWE across a spectrum of regulatory use cases (9). During 2022, EU partners will gain access to the Data Analytics and Real-World Interrogation Network (DARWIN EU), allowing them to conduct studies and to access and analyze healthcare data from across the EU (10).

The DARWIN EU will deliver RWE from across Europe on diseases, populations, and the uses and performance of medicines. It will enable EMA and national competent authorities in the EMA network to use these data whenever needed throughout the lifecycle of a medicinal product. DARWIN EU will support regulatory decision-making by:

Establishing and expanding a catalogue of observational data sources for use in medicines regulation

Providing a source of high-quality, validated real-world data on the uses, safety, and efficacy of medicines

Addressing specific questions by conducting high-quality, non-interventional studies, including developing scientific protocols, interrogating relevant data sources, and interpreting and reporting study results (10).

In July 2022, the DARWIN EU advisory board met and is in the process of increasing the number of RWD sources that can be analyzed and to improve the efficiency of performing RWE studies (11). A technical workshop is planned for later this year to identify common “use cases” for real-world evidence that are important to the EMA, HTA bodies, and payers (12).

In December 2021, the United Kingdom’s Medicine and Healthcare products Regulatory Agency (MHRA) published consultation guidance on RCTs generating RWE to support regulatory decisions (13). The guidance covers simple trials and hybrid trials and sets out the factors that need to be considered when collecting RWD as part of a clinical trial. According to MHRA, there is no barrier to using RWE to gain an initial approval or approval of a new indication providing the data quality is “robust” and the trial is “designed in a way which allows it to provide the evidence required to answer the regulatory question” (4). The guidance is part of MHRA’s mission to ensure the UK remains an attractive country in which to conduct clinical research in the post-Brexit era.

Meanwhile, the UK’s HTA appraisal body, the National Institute for Health and Care Excellence (NICE), are reviewing the methods and processes for health technology evaluation programmes and published a framework regarding the use of RWE that will help reduce uncertainties in NICE guidance, fill in evidence gaps, and improve HTA evaluation.

The framework provides in-depth guidance and tools to support the implementation of these core principles across different uses of RWE. It is structured as follows:

It provides a background on RWD and RWE, discusses its strengths and weaknesses, and summarizes current and potential uses within NICE guidance.

It describes NICE’s expectations for planning, conducting, and reporting RWE studies, recognizing that acceptability of evidence will depend on the type of evidence, and other contextual factors.

It assesses data suitability describes the information needed to assess data provenance and its quality and relevance for addressing specific research questions.

It provides more specific recommendations for conducting non-randomized studies. These include traditional observational studies as well as clinical trials that use RWD to form an external control (14).

RWE presents pharma with new opportunities to complement RCTs and inform regulatory and HTA decisions. Given the fluid situation, it is essential for the industry to keep abreast of the regulatory environment and adapt and optimize their RWE strategies in Europe and the UK. Careful attention should be paid to the variations in the definition, scope, and application of RWE across continents to ensure that healthcare data are effectively leveraged to drive product approval and increase patient access to innovative medicines that improve clinical outcomes (15).

., 29, 1514–1517 (2020).
2. P. Arlett et al., 

HMA-EMA Joint Big Data Taskforce Phase II report: ‘Evolving Data-Driven Regulation

 (2019).
4. J. Mulryne and E. Whiu, “UK MHRA Consultation on Real-World Evidence,” 

, Arnold&Porter, 3 Dec. 2020.
5. R. Flynn et al., 

, 111 (1) 90–97 (2022).
6. S.M. Eskola, et al., 

, 111 (1) 310–320 (2022)
7. EMA, “Reinforced EU/US Collaboration on Medicines,” News Release, 

, 22 June 2018.
8. EMA, “A Vision for Use of Real-World Evidence in EU Medicines Regulation,” News Release, 

European Medicines Agencies Network Strategy to 2025

Data Analysis and Real World Interrogation Network (DARWIN EU)

 [Accessed 13 July 2022].
11. I. Scholfield, “EU DARWIN Project To Catalog Real-World Data Sources,” 

 (12 July 2022).
12. V. Sharma, “EMA, HTA Bodies & Payers Explore Common Ground On Use Of RWE,” 

Consultation Document: MHRA Draft Guidance on Randomised Controlled Trials Generating Real-World Evidence to Support Regulatory Decisions

When referring to this article, please cite it as C. Barton, “New Guidance on the Use of Real-World Evidence,” 

Pharma’s leveraging real-world evidence to drive product approval, reimbursement, and market access.