Cheryl Barton is director of PharmaVision, 

Cheryl Barton

On 4 Sep. 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK) issued detailed guidance on the new International Recognition Procedure (IRP) for medicines manufacturers, including how to apply for a medicine licence (1). On 26 May 2023, MHRA announced new recognition routes would replace the current European Commission Decision Reliance Procedure (ECDRP) on 1 Jan. 2024 (2). The new process aims to bring cutting‑edge medicines faster to UK patients by leveraging the expertise and decision-making of trusted regulators in Australia, Canada, the European Union (EU), Japan, Switzerland, Singapore, and the United States (US) and enables MHRA to maintain its position as a sovereign regulator.

EU ‘reliance’ route to cease by the end of 2023

MHRA had previously introduced a temporary route to market for European-approved products in the UK, known as EU ‘reliance’ routes, to ensure that patients could continue to have timely access to new treatments. Currently, Regulation 58(4C) of the Human Medicines Regulations 2012 grants the power to MHRA to rely on the decision of the EC to approve a medicine in the UK for the MHRA to authorize that medicine in the UK without any further consideration, through a procedure known as the ECDRP. The EU ‘reliance’ route will cease on 31 Dec. 2023 and be replaced by the IRP following the completion of the MHRA public consultation, which is due to close on 30 Sep. 2023 (3).

The ECDRP provided market stability following the UK’s exit from the EU, but now the MHRA is in a position to implement a more considered approach to the assessments and accept applications from a wider range of partners. It is important to note that the ECDRP is one of four routes for products that use the EU reliance procedure. The MHRA continues to operate the remaining routes beyond the termination of the ECDRP. These include:

 This consortium is a collaboration of regulatory authorities including Australia, Canada, Singapore, and Switzerland. The UK joined the group in October 2020. The ACCESS consortium is based on a true work-sharing principle, to maximize international co-operation between partners, reduce duplication, and increase each agency’s capacity to ensure patients have timely access to high-quality, safe, and effective therapeutic products.

 This project provides a framework for concurrent reviews of oncology products among international partners. Project Orbis aims to deliver faster patient access to innovative cancer treatments that cater to an unmet medical need and demonstrate notable results (3).

The Mutual Recognition Decentralised Reliance Procedure (MRDCDRP). 

This procedure allows MHRA to take into account marketing authorizations (MAs) approved in EU member states (or Iceland, Liechtenstein, Norway) through decentralized and mutual recognition procedures to grant a MA in the UK (3).

The new IRP framework will be launched on 1 Jan. 2024 meaning all applications with a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), received after 31 Dec. 2023, will be eligible (4). According to David Watson, executive director of Patient Access at the Association of the British Pharmaceutical Industry, “The MHRA’s pragmatic decision regarding GB marketing authorization applications is an important one for our industry. Pharmaceutical companies now have the clarity needed to inform their regulatory decisions for the year” (4).

The new IRP established two recognition timetables for initial MA applications:

Under “Recognition A”—a 60-day timetable will apply to approvals from other regulators granted within the previous two years provided the manufacturing process is the same as that already approved by the other regulator.

Under “Recognition B”—a 110-day timetable will apply to approvals granted within the previous 10 years and will be triggered if any one of a range of criteria is met (5).

MHRA has streamlined clinical trial approval

Earlier in the year, MHRA announced it would be combining regulatory and ethics reviews for trials to speed up approval times and make the UK more attractive for drug research (6). Results from pilot studies indicated that approval times for studies could be halved and the time cut from application to recruiting of the first patient by up to 40 days. MHRA also plans to introduce a 30-day deadline for reviewing clinical trial applications plus a maximum of 10 calendar days for a regulatory decision to be granted once the agency has received any final information (6).

MHRA’s decision to upgrade and streamline the regulatory review framework should help to speed up diagnosis and increase patient access to treatments whilst helping to propel the UK forward as a global leader in the life-science sector. In addition, the UK government’s proposal to set aside £10 million in funding to help accelerate the delivery of cutting-edge treatments, including cancer vaccines, should make it more attractive for scientists and researchers to work in the UK (6). On 11 Sep. 2023, it was announced that UK researchers and small to medium enterprises will be rejoining the Horizon Europe and Copernicus programme highlighting the important role that the UK hopes to play in the advancement of science now and in the future (7).

Guidance Published on the New International Regulatory Recognition Routes for Medicines Approvals

MHRA Announces New Recognition Routes To Facilitate Safe Access To New Medicines With Seven International Partners

Consultation on End to the European Commission Decision Reliance Procedure

, Open Consultation, 30 Aug. 2023.
4. ABPI. 

ABPI Response to MHRA European Commission Decision Reliance Procedure (ECDRP) Announcement

. Press Release, 24 Jan. 2023.
5. Fischer, N. 

MHRA Issues Guidance on New International Recognition Procedure (IRP) for Streamlining Medicine Approvals in the UK

MHRA to Streamline Clinical Trial Approvals in the Biggest Overhaul of Trial Regulation in 20 Years

, Press Release, 21 Mar. 2023.
7. UK Government. 

UK Joins Horizon Europe Under a New Bespoke Deal

Cheryl Barton is director at PharmaVision, Pharmavision.co.uk.


Vol. 35, No. 10
October 2023
Pages: 8–9

When referring to this article, please cite it as Barton, C. MHRA Publishes New Guidance on International Regulatory Recognition Route. 

Articles

The new framework will position the UK as an attractive prospect for new medicine manufacturers.

MHRA Publishes New Guidance on International Regulatory Recognition Route 

TILT Biotherapeutics (TILT) is a Finland-based private biotechnology spin-out from the University of Finland focusing on the development of cancer immunotherapies utilizing oncolytic viruses encoded with a variety of cytokines to treat various cancers. The company was founded in 2013 by Akseli Hemminki, a cancer clinician, and aims to use an oncolytic virus to enhance T-cell therapy, including tumour-infiltrating lymphocytes (TILs), chimeric antigen receptor T cells (CAR-Ts), and checkpoint inhibiting antibody therapy of solid tumours (1).

The therapeutic benefit of various oncolytic viruses has been widely published in the literature, and researchers have improved the efficacy of first-generation products using genetic engineering (2). TILT coordinated a European Union (EU)-funded project, UNLEASHAD, which has developed an adenovirus-based oncolytic product, TILT-123 (igrelimogene litadenorepvec), that specifically targets and lyses cancer cells. It also releases TNF-α and interleukin-2 (IL-2) cytokines into the microenvironment, providing an alert and attracting immune cells to the tumour. This strategy ensures anti-tumour immunity and may be suitable for tumours that are refractory to other types of immunotherapies (3).

TILT-123 is currently in Phase I clinical trials as monotherapy and in combination with TIL therapy in Europe in metastatic melanoma. Preclinical results have been published, and the virus backbone has been demonstrated to be safe and well-tolerated in humans. Trials for other solid tumour indications are planned in combination with TILT-123 and a checkpoint modulator or a CAR-T product (2), and the company has other patent-protected products in the pipeline, including oncolytic viruses coding for bispecific antibodies TILT-321 and TILT-322 (3).

In May 2023, the company announced that the first patient had been dosed in a Phase I solid tumour trial, which will assess TILT-123 in combination with avelumab in squamous cell carcinoma of the head and neck (SCCHN) and melanoma in patients with advanced solid tumours refractory to, or progressing after, anti-programmed cell death ligand 1 (anti-PD-L1) (4). The study is part of TILT’s agreement with Merck KGaA, Darmstadt, Germany, and Pfizer, and the European trial is underway at the Docrates Cancer Center (Helsinki, Finland). The company expects to open its US site in the third quarter of 2023 (5). In November 2022, TILT opened an office in Boston to support its US clinical trial programme.

According to CEO Aseli Hemminki, “The oncolytic virus is designed with T cells in mind, and this design is based on patient observations, not just laboratory data. TILT-123 is armed with the most potent cytokines in the context of adaptive anti-tumour responses; it is genetically modified for improved access to cancer cells and for improved safety. Moreover, adenovirus is the most immunogenic virus type and is possible to upscale in manufacturing for industrial production. Importantly, TILT’s virus backbone has already been demonstrated safe in humans and can access distant tumours by vascular route. Therefore, in addition to intratumoural administration, the product can be administered by systemic route” (1).

TILT has partnered with Germany-based Merck KGaA, Switzerland-based MSD International GmbH, and US-based Pfizer (Merck-Pfizer Alliance). TILT is collaborating with the Cancer Gene Therapy Group at the University of Helsinki and with the University of Pennsylvania, where they are exploring the use of TILT‑123 in combination with CAR-Ts in solid tumours (6).

Since its conception, TILT has attracted more than US$42 million (€39 million) in private investment. On 7 Feb. 2023, it raised €22 million (US$23.8 million) from a financing round led by Finland’s Lifeline Ventures and €5.9 million (US$6 million) equity from the European Innovation Council (EIC) Fund as well as a €2.1 million (US$2.3 million) grant from EIC’s Accelerator programme. In addition, the company has received investments from Stephen Industries Inc Oy and ACME Investments SPF Sàrl. These funds will be used to advance the development of TILT-123 to Phase II clinical trials (7). This follows on from the first funding round of €10 million (US$10.9 million) in June 2022.

There is significant interest in TIL‑based therapeutics, and several companies both in Europe and the United States are exploring this route. In the US, TIL-based therapies are under development from: CTRL Therapeutics (8), Iovance Biotherapeutics (9), Obsidian Therapeutics (10), and Turnstone Biologics (11). Recently, Concerta Bioscience acquired Jounce Therapeutic to gain access to its first-in-class immunotherapy, which is designed to selectively deplete immunosuppressive tumour-infiltrating T regulatory cells in the tumour microenvironment (12).

Over the past few years, R&D efforts in the field of oncolytic viruses have received support from private investors and pharmaceutical companies. TILT’s leading programme, TILT-123, is progressing steadily through Phase I clinical development, and the company has raised sufficient funds to progress into Phase II trials. However, competition within this field is increasing as Concerta Biosciences, CTRL Therapeutics, and Obsidian Therapeutics have pre‑clinical candidates, and Turnstone Biologics has two Phase I trials underway with TILs. Meanwhile, Iovance Biotherapeutics has several Phase II trials nearing completion that are evaluating TILs as monotherapy and in combination with PD-1 or IL-2 analogues. Therefore, investors will be keen to see updates on TILT’s Phase II trial (NCT04217473), which is due for completion in February 2025 (13), and will be closely monitoring other competitor products as they progress through clinical development.

. 2017 13 (5), 970–971.
2. TILT Biotherapeutics. Next-generation Armed Oncolytic Immunotherapies. 

. May 2022.
3. EC. New Immunotherapy Tools to Fight Cancer. UNLEASHAD Project. Results in brief. H2020. CORDIS. 1 July 2018.
4. TILT Biotherapeutics. TILT Biotherapeutics Announces First Patient Dosed in Phase I Solid Tumours. Press Release, 15 May 2023.
5. TILT Biotherapeutics. TILT Biotherapeutics Announces Boston Office Opening as it Expands its Clinical Trials in the US. Press Release, 11 Sep. 2022.
6. TILT Biotherapeutics. Pipeline. 

 (accessed 17 Aug. 2023).
7. TILT Biotherapeutics. TILT Biotherapeutics Announces Final Close of €22 Million Financing. Press Release, 7 Feb. 2023.
8. cTRL Therapeutics. Accessible Cell Therapy (accessed 17 Aug. 2023).
9. Iovance Biotherapeutics, Investigating TIL Therapy & PBL Therapy for Cancer (accessed 17 Aug. 2023).
10. Obsidian Therapeutics. Our Lead Clinical Program (accessed 17 Aug. 2023).
11. Turnstone Biologics. Leading the Fight Against Solid Tumours (accessed 17 Aug. 2023).
12. Jounce Therapeutics. Jounce Therapeutics Enters Into an Agreement to Be Acquired by Concentra Biosciences for $1.85 in Cash per Share Plus Contingent Value Rights. Press Release, 27 Mar. 2023.
13. A Phase 1, Open-Label, Dose-Escalation Clinical Trial of Tumour Necrosis Factor Alpha and Interleukin 2 Coding Oncolytic Adenovirus TILT‑123 in Melanoma Patients Receiving Adoptive Cell Therapy With Tumour Infiltrating Lymphocytes. 

classic.clinicaltrials.gov/ct2/show/NCT04217473

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


Vol. 35, No. 9
September 2023
Pages: 14–15

When referring to this article, please cite it as Barton, C. Harnessing the Power of Oncolytic Viruses. 

Tumour-infiltrating lymphocyte (TIL) therapies offer a new route to target cancer.

Harnessing the Power of Oncolytic Viruses

On 5 May 2023, the World Health Organization (WHO) declared that COVID-19 was no longer a public health emergency following a decrease in COVID-19 deaths, hospitalizations, and intensive care unit admissions across the globe over the past several months (1). On 6 July 2023, the European Medicines Agency (EMA), the European Commission (EC), and the Heads of Medicine Agencies (HMA) announced they would be phasing out the extraordinary COVID-19 regulatory flexibilities introduced in August 2022 in response to the pandemic (2).

Extraordinary regulatory flexibilities introduced during COVID-19

The extraordinary regulation encompassed several different aspects to ensure the continuity of supplies of medicines during the public health emergency. These included greater flexibility for:

good manufacturing practice (GMP) and good distribution practice (GDP) issues

issues related to marketing authorization (MA) and MA procedures

manufacturing and importation of finished products and APIs (3).

EMA’s quick response to the crisis highlighted the need for rapid and coordinated feedback to developers and the importance of continued dialogue with them, to ensure that adaptions to the regulatory environment were workable for the industry (4).

From this point onwards, the regulatory flexibilities that were introduced jointly by the EC, EMA, and HMA during COVID-19 will no longer be granted (3). For products that have already received approved labelling flexibilities, such as COVID-19 vaccines with English-only labelling, the application will be extended until the end of 2023 to prevent any disruptions to supplies; after which time, manufacturers will revert to the original legislations on product labelling (3).

Conversely, on-site GMP and GDP inspections have been reinitiated following their postponement or implementation of remote visits performed during the pandemic (3). GMP and GDP certificates have been extended until the end of 2023, and the GMDP inspectors working group will provide further details over the coming months following a review of information gleaned from remote working of qualified persons during the pandemic (5).

Future regulation, preparedness, and response tools

The COVID-19 pandemic highlighted the importance of deploying a coordinated EU-wide strategy and revealed some vulnerabilities in the current system, including limitations in the regulations, preparedness, and response tools (6). In November 2020, the EC proposed a series of measures, including a revised regulation on serious cross‑border threats to health and proposals to extend the mandates of EMA and the European Centre for Diseases Prevention and Control (ECDC) in public health emergencies, to create a European Health Emergency Preparedness and Response Authority (HERA) (7). In February 2021, the EC also announced that it may consider targeted amendments to the pharmaceutical legislation including developing new regulatory tools to introduce an emergency authorization of vaccines at the EU level with shared liability among member states, during public health threats (6).

On 26 April 2023, EMA published two legislative proposals—a new regulation 2023/0131 and a new directive 2023/0132—to replace the current European Union (EU) regulatory framework for all medicines (8,9). As part of the overhaul, EMA plans to introduce some contingency planning procedures including the compilation of an EU-wide list of critical medicines and recommendations to companies to strengthen the supply chains should the need arise. Under the new proposal, all MA holders will need to put in place a shortage prevention plan for each medicine on the market, any critical shortages would need to be reported to EMA. In addition, the new regulation provides temporary measures such as emergency MA for crisis‑related medicines allowing the EU to take control of drug manufacturing in response to an emergency, this controversial point has raised concerns amongst some pharma industry leaders (10).

The new regulatory framework is currently being reviewed by the European Parliament and the European Council and a decision on the proposed reform is unlikely to take place before the 2024 EU parliamentary elections. In the meantime, data are being gathered by EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products regarding manufacturers’ experience of the COVID-19 regulatory flexibilities (11). EMA will then reflect on how lessons learned during the pandemic can inform best practices for confronting medicine shortages in the presence of new and emerging health challenges in the future (2).

Statement on the Fifteenth Meeting of the IHR (2005) Emergency Committee on the COVID-19 Pandemic

Phasing out of Extraordinary COVID-19 Regulatory Flexibilities

Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use During the COVID-19 Pandemic

, 11 Aug. 2022.
4. Cavaleri, M.; Sweeney, F.; Gonzalez-Quevedo, R.; Carr, M. Shaping EU Medicines Regulation in the Post-COVID-19 Era. 

, 9, 100192.
5. Taylor, N.P. Euro Roundup: EMA Starts Phasing Out Regulatory Flexibilities Provided During the COVID-19 Pandemic. 

, RAPS, 13 July 2023.
6. Beaussier, A.; Cabane, L. Strengthening the EU’s Response Capacity to Health Emergencies: Insights from EU Crisis Management Mechanisms. 

HERA Incubator: Anticipating Together the Threat of COVID-19 Variants

Reform of the EU Pharmaceutical Legislation

Proposal For a Regulation of the European Parliament and of the Council Laying Down Union Procedures for the Authorization and Supervision of Medicinal Products for Human Use And Establishing Rules Governing The European Medicines Agency, Amending Regulat

. Regulation, 26 April 2023.
10. Barton, C. 

EMA Overhauls the Medicine Legislative and Regulatory Framework

Executive Steering Group on Shortages and Safety of Medicinal Products

When referring to this article, please cite it as Barton, C. Phasing Out COVID-19 Regulatory Flexibilities. 

What impact will EMA’s decision to phase out COVID-19 regulatory flexibilities have on the pharma industry?

Phasing Out COVID-19 Regulatory Flexibilities

On 26 April 2023, the European Medicines Agency (EMA) published two legislative proposals—a new Regulation 2023/0131 and a new Directive 2023/0132 to replace the current European Union (EU) regulatory framework for all medicines (1,2). This legislative proposal will amend the current regulations on advanced therapy medicinal products (ATMPs) (3) and clinical trials (4), while also repealing the regulation that sets out the procedures for authorization and supervision of medicinal products (5), and the regulations for rare disease and medicines for children (6). The new regulation aims to make medicine more widely available, accessible, affordable, and sustainable, and to drive innovation and enable the European pharma industry to compete in the wider arena.

The proposal aims to reduce the timeframe of the approval procedure from the current average of 400 days, by cutting regulatory review times from 210 days to 180 days for most medicines and 150 days for medicines that are of major interest to public health. It also reduces the time taken for receiving a decision on marketing authorizations (MA) following recommendations from EMA, from 67 days to 46 days.

EMA will also simplify its structure from five to two main scientific assessment committees for human medicines: the Committee for Human Medicinal Products and the Pharmacovigilance Risk Assessment Committee (PRAC). The current ATMP, orphan, and paediatric committees will be discontinued.

In addition, EMA plans to adopt a “rolling review” system similar to the one that was implemented during the COVID-19 pandemic, which will allow the regulators to examine clinical trial data as they become available, rather than waiting for a single submission once all clinical trials are complete (7).

Potential changes to regulation protection periods

The revised legislation will overhaul the legislative framework and could result in a maximum patent protection of up to 12 years compared to 11 years for non-orphan drugs; however, this will result in market exclusivity being reduced from 10 years (eight years of data exclusivity plus two years of market exclusivity) to eight years (six years of data exclusivity plus two years of market exclusivity). However, new medicines may extend the period of protection by:

addressing an unmet medical need (an additional six months)

conducting comparative clinical trials (an additional six months)

developing a new therapeutic indication (an additional one year)

launching the new medicine in all EU member states (an additional two years).

Similarly, market exclusivity of orphan drugs could result in a maximum patent protection of up to 13 years compared to the current 10-year span for orphan drugs. The standard market exclusivity period will be reduced from 10 years to nine years; however, orphan medicines may benefit from additional periods of protection, increasing the total period up to a maximum of 13 years, with additional increments being available by:

launching the new medicine in all EU member states (an additional year)

addressing a high unmet medical need (an additional one year)

developing a new therapeutic indication (up to an additional two years) (7).

Thus, the new regulation is likely to reduce the period of regulatory protection granted for innovator companies given that it is extremely challenging to gain approval in addition to pricing and reimbursement (P&R) in all member states—P&R is governed by national law and not in the control of the MA holder.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) is concerned that changes in market protection will undermine pharma’s future investment in R&D and the development of innovative medicines (8). Responding to the proposed changes, Nathalie Moll, director general of EFPIA commented, “The approach set out in the pharmaceutical legislation, penalizing innovation if a medicine is not available in all member states within two years, is fundamentally flawed and represents an impossible target for companies. The vast majority of delays in access to new medicines are known to occur after a company has filed for pricing and reimbursement and is awaiting a decision so that the new treatment can be made available to patients” (8).

In terms of contingency planning, EMA will compile an EU-wide list of critical medicines and will provide recommendations to companies to strengthen the supply chains should the need arise. Under the new proposal, all MA holders will need to put in place a shortage prevention plan for each medicine on the market, any critical shortages would need to be reported to EMA.

The new regulation also provides temporary measures such as emergency MA for crisis-related medicines allowing the EU to take control of drug manufacturing in response to an emergency. This point has raised concerns amongst the pharma industry as compulsory licensing could weaken pharma’s ability to protect its intellectual property (IP). In an interview with the Financial Times, Vas Narasimham, the CEO of Novartis, noted that “compulsory licensing will damage the ecosystem for emergency response” (9).

Incentives to tackle microbial resistance

EMA aims to incentivize the industry to develop novel antimicrobial resistance through the introduction of transferable data-exclusivity vouchers, which would grant an additional year of data exclusivity for any medicine and can be sold to other companies (10,11). The vouchers will be provided in limited numbers over a limited period; a maximum of 10 vouchers over 15 years. Strict rules will apply to their transfer and use.

Under the proposed changes, within 30 days of receiving a MA, pharmaceutical companies will be required to publish information regarding all direct financial support for the R&D of medicines received from public authorities or publicly funded bodies.

MA applicants are already required to include an environmental risk assessment (ERA) of the medicine; however, the EC will strengthen the use of the ERAs to reduce the potential adverse impacts of medicines on the environment and public health. Under the new proposals, medicine approvals may be refused if a company does not provide adequate evidence that environmental risks were evaluated, and risk mitigation measures were taken.

Currently, pharmacies are only allowed to prepare and dispense products in response to individual prescriptions. The legal proposal allows hospital pharmacies greater flexibility to prepare a product for dispensing medicines and clarifies rules on hospital exemptions (12).

The Council of the EU is in discussion with its preparatory bodies and will provide the legislative proposal to the European Parliament and the European Council for their consideration. It remains to be seen how the pharma industry will respond to the new proposal given the intense pressure companies are under to lower drug prices whilst recouping a return on investment. In the meantime, EFPIA is committed to working with members of the European Parliament, the Council of the EU, and other stakeholders “to ensure the revised pharmaceutical legislation and patent package meets the needs of patients, our healthcare systems, member states, and Europe’s life science sector” (8).

No timelines on the adoption of this new regulatory framework are forthcoming, but it is unlikely that the proposed reform will take place before the 2024 EU parliamentary elections.

Proposal For a Regulation of the European Parliament and of the Council Laying Down Union Procedures for the Authorization and Supervision of Medicinal Products for Human Use And Establishing Rules Governing The European Medicines Agency, Amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and Repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC and Regulation (EC) No 726/2004 

Consolidated Text: Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 Laying Down Community Procedures for the Authorization and Supervision of Medicinal Products for Human and Veterinary Use and Establishing a European Medicines Agency 

Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 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

 (12 Dec. 2006).
7. Worden, T; Nauth, L. The European Commission Proposes First Major Overhaul of the EU Medicines Regulatory Framework in 20 Years. 

, Alert, 27 April 2023.
8. EFPIA, EU Pharma-Legislation Risks Sabotaging Europe’s Life Science Industry Putting European Patients Further Away from Cutting-Edge Healthcare. 

, 26 April 2023.
9. Mancini, D.P.; Kuchler H., Novartis Chief Criticizes EU Move to Control Pharma Licensing in Emergencies. 

Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions Reform of the Pharmaceutical Legislation and Measures Addressing Antimicrobial Resistance

Proposal for a Council Recommendation on Stepping Up EU Actions to Combat Antimicrobial Resistance in a One Health Approach

 (12 May 2023).
12. Castle, G.; Bogaert, P.; Doyle-Rossi, M. EU Pharma Legislation Review Series: The EU’s Proposals to Amend its Pharmaceutical Laws Released Today. 

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

When referring to this article, please cite it as Barton, C. EMA Overhauls the Medicine Legislative and Regulatory Framework. 

What implications will EMA’s recent regulatory reform have on pharma?

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. 

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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. 


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. 

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.