Cheryl Barton is director of PharmaVision, 

Cheryl Barton

Landkarte *** Europa | Image credit: ©beugdesign - Stock.adobe.com

On 1 Aug. 2024, the European Artificial Intelligence Act (AI Act) came into force (1). The AI Act is designed to ensure that artificial intelligence (AI) developed and used in the European Union (EU) is trustworthy, and that there are safeguards in place to protect people’s fundamental rights. In January 2024, the European Commission (EC) launched a package of measures to support European small and medium enterprises (SMEs) and start-ups in the development of trustworthy AI, and in May, the EC established an AI Office (2,3). In July 2024, the amended European High Performance Computing Joint Undertaking (EuroHPC JU) Regulation came into force to further develop, deploy, extend, and maintain the EU supercomputing and data infrastructure (4). This paved the way for the establishment of AI Factories, dedicated AI supercomputers, that can be used for training General Purpose AI (GPAI) models (5).

This article was published in the September 2024 issue of 

The AI Act aims to harmonize AI across the EU to encourage the uptake of this technology and support innovation and investment. The AI Act also prohibits certain AI practices and sets out regulations on “high-risk” AI systems and those that pose transparency risks (

Figure 1. Definition of artificial intelligence (AI)-based product safety and risk-based approach. (Figure courtesy of the author)

The AI Act also introduces rules to reduce the systemic risk of systemic GPAI models that are capable of performing a wide range of distinct tasks such as the generation of human-like text (6). The new legislation imposes stricter regulation and fines on tech companies operating generative AI models (i.e., DeepMind and OpenAI will fall under the general-use AI category and would be classed as minimal risk). However, developers of high-risk models would be asked to evaluate models, assess and mitigate systemic risks, conduct adversarial testing, report serious incidents to the EC, ensure cybersecurity, and report on their energy efficiency (6).

The European Federation of Pharmaceutical Industries and Associations (EFPIA) welcomes the AI Act and “believes in the potential of applying AI to deliver benefit for patients, life-science companies, and society” (7). However, it stresses that “the regulatory frameworks governing the use of AI in research, development, and manufacture must be fit-for-purpose, risk-based, non-duplicative, globally aligned, and adequately tailored” (7). When AI-enabled tools are used in pharma R&D, they are exempt from the requirements of the EU AI Act; however, developers and deployers of AI-enabled digital health tools (DHTs) and AI-enabled digital medicine would be impacted by the AI Act, but they would not be considered high risk (8).

Enforcement of the AI rules will be phased in

EU Member States have a year to designate national competent authorities to oversee the application of the AI rules. The Commission’s AI Office will oversee the implementation of the AI Act at the EU level, and be responsible for enforcing the rules for GPAI models (1).

The EC will establish the following three advisory bodies to support the implementation of the rules:

European Artificial Intelligence Board—

to ensure the uniform application of the AI Act across EU Member States and to cooperate between the EC and the Member States.

A scientific panel of independent experts—

to offer technical advice and input on enforcement. The panel can issue alerts to the AI Office about risks associated with GPAI models.

a diverse set of stakeholders to offer guidance to the AI Office (1).

The AI Office has the power to enforce these policies. Companies that do not comply with the rules will be fined 1.5–7% of their global annual turnover depending on the violation (e.g., companies can be fined up to 1.5% for supplying incorrect information) (1).

The AI Act’s regulations will take effect in phases. Rules regarding prohibited practices will apply as of 2 Feb. 2025; obligations on GPAI models will apply as of 2 Aug. 2025; and both transparency obligations and obligations on high-risk AI systems will apply as of 2 Aug. 2026 (9).

In the interim, the EC launched the AI Pact to encourage and support organizations before implementing the AI Act (10). The EC has urged the industry to voluntarily commit to the AI Act requirements before the legal deadline. In November 2023, it obtained responses from more than 550 organizations, and the AI Office initiated the development of the AI Pact, based upon two pillars:

establish a gateway to engage the AI Pact network, encourage the exchange of best practices, and provide practical information on the AI Act implementation process

encourage AI system providers and deployers to prepare early and take actions towards compliance with requirements and obligations set out in the legislation.

The AI Pact has enabled the EC to work with stakeholders to support them in understanding the objectives of the AI Act, to adapt and prepare for the implementation of the AI Act, and to share knowledge and build trust in AI technologies (10).

Meanwhile, the Joint Research Centre continues to undertake independent, evidence-based research to support EU policies and determine the societal impact of the AI Act across Europe.

The EU AI Act sends a clear message to the rest of the world that Europe is taking AI very seriously and emphasises the importance of trust, transparency, and accountability. The EC is the first governmental body to create a legal infrastructure on AI and has paved the way for others to emulate and replicate.During the coming months, rules will be phased in and European standards will be refined. Therefore, companies need to work closely with the AI Office and other relevant authorities to ensure the safe deployment of AI solutions that will be beneficial to society and drive future innovation in Europe.

European Artificial Intelligence Act Comes into Force

Commission Launches AI Innovation Package to Support Artificial Intelligence Startups and SMEs

Commission Establishes AI Office to Strengthen EU Leadership in Safe and Trustworthy Artificial Intelligence

Setting Up of AI Factories is Now Possible after EuroHPC Regulation Amendment

The EU Passes the AI Act and its Implications for Digital Medicine Are Unclear

International Bar Association. The Regulation of Foundation Models in the EU AI Act. 

EFPIA Statement on the Use of AI in the Medicinal Product Lifecycle in the Context of the AI Act

Cheryl Barton, PhD,is founder and director of PharmaVision, Pharmavision.co.uk.


Vol. 36, No. 8
September 2024
Pages: 9-10

When referring to this article, please cite it as Barton, C. European Artificial Intelligence Act Comes into Force. 

Articles

What impact will the AI Act have on pharma and digital medicine?

On 3 July 2024, the Health Committee of the Bundestag amended and approved the Federal Government’s Medical Research Act (Medizinforschungsgesetz or MFG) (1). The new legislation will impact national laws to simplify clinical trials and approval processes for drugs and medical devices. MFG will also amend rules on advanced therapy medical products (ATMPs) and drug pricing and reimbursement laws (Arzneimittelmarktneuordnungsgesetz [AMNOG]). In addition, the new legislation will result in a reorganization of the regulatory agencies (The Federal Institute for Drugs and Medical Devices [BfArM] and Paul Ehrlich Institute [PEI]) and ethics committees (2).

Pharma may choose confidential pricing … but at a cost

The MFG allows pharmaceutical companies confidential pricing, providing they have drug research departments in Germany that can demonstrate “relevant own projects and cooperation with public institutions in preclinical or clinical drug research in Germany” (3). For instance, if at least 5% of approved study subjects participate in clinical trials in Germany, then manufacturers could be exempt from the AMNOG guardrails that were introduced with the Statutory Health Insurance Finance Stabilization Act in November 2022 (4).

Once a pharma company has completed price negotiations with the National Association of Statutory Health Insurance Funds (GSK-SV), they will have five days to decide whether to keep the pricing of new patent-protected drugs confidential or transparent. Within seven days of receipt, the GSK-SV will decide whether ‘sufficient’ proof has been provided. If a pharmaceutical company requests confidential pricing, an additional discount of 9% will be imposed on the agreed sales price (not the pharmacy sales price) (3).

Companies that opt for confidentiality will also be obligated to reimburse the health insurance funds and other payors the overpaid difference between the ‘public’ and the ‘real’ price and will also have to reimburse the health insurance funds the overpaid portions of the mandatory surcharges for pharmacies and wholesalers and value-added tax (VAT) (3). Therefore, the final price negotiated by companies to keep drug prices secret could result in more than the 9% discount. The new rules for confidential reimbursement prices shall apply as of 1 Jan. 2025 and will be enforced until 28 June 2028 and reviewed in late 2026 (3).

Confidential pricing has proved a contentious issue among stakeholders in Europe. On one hand, the pharma industry in Europe has been keen to move towards confidential pricing because German reimbursement prices are regularly used as reference prices in other European countries, and an unfavourable price in Germany can have a significant impact on the price achieved in other European countries and abroad. In the past, this has led manufacturers to withdraw drugs from the German market; for instance, Bristol Myers Squibb decided not to launch the cancer drug Opdualag (nivolumab/relatlimab combination) in Germany, due to pricing pressures (5). If a company chooses to keep the reimbursement price confidential, it would not be listed in public sources or disclosed to pharmacies and could lead to differential pricing, the ‘public’ price, and the ‘real’ or agreed (discounted) price (3).

In 2022, the ‘AMNOG guardrails’ regulations were introduced to protect against excessive prices for patent-protected drugs with no or only a small or non-quantifiable benefit (6). These regulations will be deleted and replaced by the economic development goals laid out by the German Government in its new Pharma Strategy (6,7). However, the GSK-SV fears the lack of transparency could lead to increases in pharmaceutical expenditure (8,9). This is a major concern given that more than 73 million German citizens with statutory health insurance have already witnessed a significant increase in health insurance contributions earlier this year, and there is pressure on the Federal Ministry of Health to raise contributions further (6).

The new Pharma Strategy aims to make Germany more attractive to the pharma industry

The MFG is part of the German government’s National Pharma Strategy to strengthen Germany’s position as a business and pharmaceutical location (10). The Strategy Paper 4.0–Improving the General Conditions for the Pharmaceutical Sector in Germany lists several specific reform ideas all of which will have a significant impact on the pharmaceutical industry and aim to improve market access and pricing environment in Germany (Figure 1).

Figure 1: Strategy Paper 4.0 points of reform. Source: modified from (10). Figure courtesy of the author.

Germany is the fourth largest pharmaceutical market in the world and the largest European market generating €56.5 billion in 2022 and growing by 5.4% per annum (11). According to Marcus Schmidt, Germany Trade & Invest Director of Chemicals and Health, “The pharmaceutical strategy underlines the great importance of this sector for the federal government. Together with the laws that have already been introduced, Germany will expand its leading role in Europe in the areas of research and development as well as production” (10). Several pharma companies—Daiichi-Sankyo, Eil Lilly, and Sanofi—have all increased their investment in Germany in the past nine months (12).

The latest reform could have a significant impact on drug pricing and will link it more closely to local investment in clinical trials and R&D in Germany. However, the MFG will not come into force until it has received the seal of approval from the German Federal Council (Bundesrat), and this is unlikely to occur until the fourth quarter of 2024 (3).

 Entwurf eines Medizinforschungsgesetze Drucksache 20/11561. 29 May 2024.

Germany Amends Drug Pricing and Reimbursement Laws with the “Medical Research Act”–Drug Pricing Becomes Intertwined with Local Clinical Research Expectations.

 Blog. Insideeulifesciences.com. 12 July 2024.

Health Committee Approves Medical Research Act.

Simon-Kucher. Germany: How the GKV-FinStG Law is Transforming the Pharma P&R Landscape. Simon-kucher.com. 24 Feb. 2023.

Are German Drug Pricing Regulations Chasing Some Drug Makers Away, Causing Them To Not Launch Products In The Market?

Health Insurance Companies Should Support the Pharmaceutical Industry

German Government Pursues New Pharma Strategy with Significant Reform Ideas

. Blog. Covington. Insideeulifesciences.com. 21 Nov. 2024.

Secret Prices Make Care More Expensive Without Improving It

. GKV. GKV-spitzenverband.de. 6 June 2024.

What are the Implications of Confidential Rebates in Germany?

Big Changes Coming in German Health, Pharma, Pharmaceuticals

. Germany Trade and Invest, GTAI. gtai.de 14 Dec. 2023.

. Germany Trade and Invest, GTAI. gtai.de (accessed 12 July 2024).

Germany’s New Medical Research Act Will Allow Pharma Companies Confidentiality on Price

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

®
Vol. 36, No. 7
July/August 2024
Pages: 9–10

When referring to this article, please cite it as Barton, C. Germany Amends and Approves the New Medical Research Act. 

Germany’s Medical Research Act allows pharmaceutical companies to keep drug prices confidential.

Germany Amends and Approves the New Medical Research Act

European union DNA | Image Credit: ©Kestutis - stock.adobe.com

Over the past two decades, 32 cell and gene therapies (CGTs) have been approved by the regulatory authorities worldwide, and more than 2000 novel products are under clinical investigation (1). However, many patients do not have access to these life-saving therapies, partly due to the complexity and high cost of manufacture (2). But how can CGTs be made more cost-efficient given the high labour and facility costs?

According to Miguel Forte, CEO, of Kiji Therapeutics, France, and president of the International Society for Cell & Gene Therapy, “It is clear that CGTs have the opportunity to deliver enormous value to patients; nonetheless, manufacturing is complex, and it has been challenging to deliver the product. Innovative technologies and services have enabled the industry to move towards an automated, closed-system approach that is easier and safer to operate and is less costly and closer to the patient.”

Cell therapies can be derived ex vivo from autologous cell therapies (patient to patient), allogenic cell therapies (donor to patient), or in vivo cell therapies (cell line to patient). Each approach requires manufacturers to tailor the biomanufacturing process to generate specific cell types (and/or vectors), safely, efficiently, and cost-effectively. Manufacturing tools have tended to lag behind scientific advances in CGTs leading to bottlenecks in cell production. Currently, most CGT manufacturers use disconnected single-step/modular or semi-automated solutions; however, the industry is migrating towards fully automated cell therapy manufacturing processes (3). And this approach could significantly reduce manual intervention, risk of contamination, and human error; improve product quality and speed of delivery; and reduce production costs (4).

According to David Smith, vice president of Development, BioCentriq, “Labour costs, and facility costs are sky high, which have led to high price points, particularly in autologous cell therapies where production is 1:1. Automation is a key part of improving costs, reducing labour both in and outside the clean room, and implementing release by exception can help to reduce bottlenecks. Companies are trying to integrate unit operations whether it’s an ‘all-in-one-box’ approach or a ‘unit-operator’ approach where units can be plugged in or out and are integrated within robotic systems to offer greater flexibility.”

For instance, Lonza’s Cocoon Platform and Miltenyi Biotec CliniMACS Prodigy offer an ‘all-in-one-box’ approach providing a closed, automated system for patient-scale cell therapy manufacturing from cell isolation, activation, transduction/transfection, expansion, and harvest within a validated cell manufacturing system (5,6). CliniMACS Prodigy modular Instruments can also be run in parallel to provide large-scale batch production.

UK-based Ori Biotech launched its IRO platform developed in 2024 in collaboration with CTMC (a joint venture between Resilience and MD Anderson Cancer Center). This platform automates the activation, transduction, expansion, and harvest of a wide range of cell types to rapidly scale up manufacturing from the clinic to the commercial setting (7).

Paris-based Astraveus SAS has developed the Lakhesys Benchtop Cell Factory, an end-to-end solution for the manufacture of adherent, non-adherent, and inducible pluripotent stem cells (iPSCs) (8). The company has raised €16.5 million in seed financing and received a €10.4 million grant from the French government as part of its “Innovation in Biotherapies and Bioproduction” initiative, to advance the development of its technology (9).

Several companies are developing integrated bioreactors, robotic systems, and smart monitoring technologies that can support a ‘unit operator’ approach.

UK-based Cellular Origins, launched Constellation, a closed fully automated, and configurable robotic platform for CGT manufacture in 2023 (10). In May 2023, it forged a partnership with ScaleReddy (a joint venture between Bio-Techne, Fresenius Kabi, and Wilson Wolf) to automate its CGT manufacturing workflow using Cellular Origin’s robotic system (11). According to Jason Jones, Global Business Development lead, Cellular Origins, “Our company integrates existing, proven technologies with mobile robotics to provide fully automated factories that can be scaled up to manufacturers’ requirements, minimize risks, and are GMP [good manufacturing compliance] compliant. We can achieve a 30-fold increase in space efficiency and manufacture and a 16-fold labour reduction, equating to a 51% reduction in cost-of-goods and enabling manufacture 24/7, 365 days a year.”

Swiss-based Limula has taken a different approach and developed a modular solution that combines a bioreactor and centrifuge into one device for on-demand and at-scale manufacturing of cell therapies (12). In May 2024, the company raised CHF 6.2 million (US$6.8 million, €6.24 million) in seed funding to develop its automated CGT manufacturing platform, the funding round was over-subscribed highlighting the interest that venture capitalists have in this field (13).

UK-based MicrofluidX has developed a space-saving stackable multi-bioreactor instrument—the Cyto Engine Stack. Each bioreactor can be controlled and monitored independently, to allow cell therapy manufacturers to expand their manufacturing capacity without increasing the facility footprint. The first Cyto Engine product is scheduled for launch in early 2025 (14).

Other companies have focused on leveraging digital tools and advanced analytics to streamline the manufacturing process. For instance, UK-based Autolomous has launched AutoloMATE Launchpad, a cloud-based CGT platform that allows for the scalability and adaptability of different CGT modalities (15). According to Alexander Seyf, the CEO of Autolomous, “Addressing manufacturing challenges effectively demands a shift towards more integrated and automated systems. By leveraging digital tools and advanced analytics, we can enhance process control, increase reproducibility, and reduce labour-intensive procedures which, in turn, decrease costs significantly. Moreover, digitization can streamline data flow across the manufacturing process, ensuring that critical information is accessible and actionable. This integration leads to improved decision-making, faster turnaround times, and ultimately, more standardized production of therapies.”

In 2024, US-based Cellares, became the first Integrated Development and Manufacturing Organization (IDMO) to offer a high-throughput fully, automated smart manufacturing platform Cell Shuttle. In April 2024, the company signed a US$380 million (€349 million) supply agreement for the manufacture of chimeric antigen receptor-T cell therapies with Bristol-Myers Squibb, and it announced a similar agreement with Kite in June (16,17).

Over the next decade, the demand for CGTs is expected to grow as they move further up the treatment cascade and target more common diseases. It will be essential for companies to address the challenges associated with scaling up the manufacturing process to provide high-quality, consistent autologous and allogenic cell products while adhering to stringent regulatory standards. Fully automated space-saving modular technologies will allow manufacturers to steadily scale up capacity and adapt to demands (18).

Smith notes, “CDMOs [contract development and manufacturing organizations] are looking at the trajectory of pipeline products and questioning where and when they need to invest in new facilities and technologies. Manufacturing is one of the biggest areas of risk in CGT developments, but if we can de-risk the process by deploying robust engineered manufacturing processes and automation, we can reduce the cost of autologous cell manufacture and increase the speed and flexibility to meet individual needs. On the allogenic side, the processes tend to be on a larger scale, and the drug product cost is shared amongst many patients. Although automation can assist in cost reduction, the burden is less steep than for autologous, that said, many of the same automation tools can be used across processes, and the industry is looking to standardize manufacturing.”

In the longer term, the industry could move towards a more decentralized manufacturing model that utilizes automated point-of-care technologies to enable on-sitepreparation of CGTs in or near hospitals, helping to bring therapies closer to the patient.

“The current acute unmet need is on scaling centralized systems, but we’ve had some interesting conversations around decentralization negating operator variability/increasing process comparability and digitalization of information of the product and opening up facilities at the national, regional, and near-hospital levels depending on the therapy and medical need,” observes Jones.

Gene, Cell, and RNA Therapy Landscape Report.

 Q1 2024 Quarterly Data Report. 11 Apr 2024.

Harrison, P.T., Friedmann, T. Correction: Cost of Gene Therapy. Gene Therapy, 2024, 31, 195-196.

Closed, Automated Cell Therapy Manufacturing–Is Your Facility Ready?

Harris, R. Cell Therapy Manufacturing Shifts to Automatic. Genetic Engineering & Biotechnology News. 4 Oct 2021.

The Cocoon® Cell Therapy Manufacturing Platform.

 miltenyibiotec.com (accessed July 2024).

Ori Biotech Unveils IRO Platform at Annual International Society for Cell & Gene Therapy Conference

Lakhesys™ Benchtop Cell Factory - Astraveus - Enable a Healthier Tomorrow

PRNewswire. Astraveus Raises €16.5 Million Series Seed Round to Advance the Development of its Automated, Microfluidic Cell and Gene Therapy Manufacturing Platform. News Release. 27 Jun 2023.

Cellular Origins Launches Constellation™, Its Configurable Robotic Platform to Enable Scalable Manufacture of Advanced Therapies

Cellular Origins Partners with ScaleReady to Simplify, Standardize, and Automate Cell Therapy Manufacturing

The Future of Cell and Gene Therapy is Automated

Limula Raises CHF 6.2 Million in an Oversubscribed Seed Round to Develop an Automated Cell and Gene Therapy Manufacturing Platform

MicrofluidX Secures Innovate UK Award to Advance High Throughput

Autolomous Releases the CGT industry’s First Free eBR Builder, autoloMATE Launchpad, to Empower Digital Planning

Bristol Myers Squibb, and Cellares Announce a $380M Worldwide Capacity Reservation and Supply Agreement for the Manufacture of CAR T Cell Therapies to Bring the Promise of Cell Therapy to More Patients, Faster.

Cellares Announces Agreement with Kite to Evaluate Its Cell Shuttle Automated Manufacturing Platform.

Small Footprint Automated Closed Production Platforms for CAR-T and Other Advanced Therapies

Cheryl Barton, PhD, is director of PharmaVision, 


Vol. 36, No. 7
July/August 2024
Pages: 14–16

When referring to this article, please cite it as Barton, C. Frontrunners in Automated Cell and Gene Therapy Manufacturing. 

Innovative solutions are making personalized cell and gene therapies accessible to all.

Frontrunners in Automated Cell and Gene Therapy Manufacturing

Landkarte *** Europa | Image Credit: © beugdesign - Stock.adobe.com

On 3 May 2024, the European Medicines Agency (EMA) initiated a public consultation to review draft recommendations published in its reflection paper on “the use of real-world data (RWD) in non-interventional studies (NIS) to generate real-world evidence (RWE)” (1). The paper discusses methodological aspects of NIS using RWD, such as claims databases, hospital data, electronic health records (EHR), registries, and medical health data, to generate RWE for regulatory decision-making. The paper is part of the Methodology Working Party Workplan 2022–2024 and the joint Heads of Medicines Agency (HMA)-EMA Big Data Steering Group plan 2023–2025 (2,3).

According to EMA, a clinical trial is defined as a clinical study where:

the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within the normal clinical practice of the member state concerned

the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study

diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects. RWD are data that describe patient characteristics (including treatment utilization and outcomes) in routine clinical practice (1).

A NIS is a clinical study that does not fulfil any of the above conditions, based on Article 48 of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (4).

Key topics discussed in the reflection paper

The reflection paper discusses feasibility assessment, bias, confounding, and data quality and provides guidance on four key areas:

The paper also recognizes the importance of using protocol formats when designing NIS for RWD generation. For example, applying the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Checklist for Study Protocols and The HARmonized Protocol Template to Enhance Reproducibility (HARPER) protocol template (5,6).

In March 2024, the US Food and Drug Administration (FDA) published its draft guidance on 

Real-World Evidence: Considerations Regarding Non-Interventional Studies for Drug and Biological Products

, which is open for consultation until 18 June 2024 (7). EMA’s guidance closely aligns with FDA’s; however, the regulatory agencies’ definition of NIS differs and further clarification and standardization will help drive the utilization of RWD moving forward (8).

EMA promotes the use of RWD in decision-making

EMA’s Regulatory Science Strategy to 2025 promotes using high-quality RWD in decision-making (9). To this end, EMA aims to create a flexible framework to deliver rapid access to and analysis of RWD throughout a product’s lifecycle; to develop computing capacity and skills in the agency to analyze large amounts of healthcare data, and to implement processes to feed data into regulatory assessments.

In March 2024, EMA launched its RWD catalogues to help regulators, pharmaceutical companies, and researchers identify and use RWD to investigate the safety and effectiveness of medicines (10). The catalogue of RWD sources replaces the ENCePP Resources Database. The data are searchable and can be exported by registered entities.

In April 2024, EMA’s Real-World Evidence Team (TDA-RWE) of the Data Analytics and Methods Task Force released new guidance detailing the types of studies that can be performed for RWE generation and how it can be used to support regulatory decision-making (11). The regulators recognize that RWD provides additional benefits compared to traditional randomized control trials. For instance, it can be generated quickly and reduce the risk of data duplication, RWD can be used to fill in knowledge gaps and provide tailored analyses to the committee’s questions (11).

The draft reflection paper highlights the importance that EMA places on RWD and its potential impact on decision-making. It also establishes a framework for scientific and methodological rigour, helps to improve the transparency of data collection and analysis, and ultimately should increase the reliability of RWD generated by the industry.

The reflection paper will be presented at the multi-stakeholder joint HMA-EMA workshop on RWE methods on 14 June 2024 (12). Stakeholders are invited to provide feedback on the draft reflection paper by 31 Aug. 2024.

1. EMA. Reflection Paper on the Use of Real-World Data in Non-Interventional Studies to Generate Real-World Evidence. Draft Reflection Paper. 

. 15 April 2024.
2. EMA. Revised Consolidated 3-Year Work Plan for the Methodology Working Party (MWP). Work Programme. 

. 15 Jan. 2024
3. HMA/EMA Joint Big Data Steering Group. Big Data Workplan 2023–2025. Work Programme. 

Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use

. 16 April 2014.
5. ENCePP. ENCePP Checklist for Study Protocols. 

, 15 Oct. 2018.
6. Wang, S.V.; Pottegård, A.; Crown, P.; et al. HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force. 

. Guidance Document, March 2024.
8. McCully, S. What’s in a Name? Towards Standardizing the Terminology of Real-World Data and Real-World Evidence. 

, 30 Jan. 2024.
9. EMA. Decision-Making. 

. 18 Nov. 2019.
10. EMA. HMA-EMA Catalogues of Real-World Data Sources and Studies. Webinar. 

Real-World Evidence Provided by EMA. Support for Regulatory Decision-Making

. 10 April 2024.
12. EMA. Joint HMA-EMA Big Data Steering Group Workshop on RWE Methods. Event, 14 June 2024.

Cheryl Barton is founder and director of PharmaVision, Pharmavision.co.uk.

When referring to this article, please cite it as Barton, C. Using RWD in Non-Interventional Studies. 

EMA is promoting the use of RWD in decision-making and has started a public consultation to review its draft recommendations.

Using RWD in Non-Interventional Studies

Creative background, the human brain on a blue background, the hemisphere is responsible for logic, and responsible for creativity. different hemispheres of the brain, 3D illustration, 3D render | Image Credit: © Aliaksandr Marko - Stock.adobe.com

The global central nervous system (CNS) therapeutics market is forecast to increase from US$80.25 (€74.7 billion) in 2023 to US$106.19 billion (€98.78 billion) by 2031, growing at a compound annual rate of 4.8%. This market growth can be attributed to a few drivers, including the fact that biopharma companies, such as AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Co, Eisai, Lundbeck, Merck & Co., Novartis, Pfizer, Roche, and Takeda, are all targeting hard-to-treat neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) (1).

Numerous disease-modifying biologics are in late clinical development for treating neurodegenerative diseases (

 [2]), and several brain-penetrant monoclonal antibodies (mAbs) have recently been approved for treating AD. In 2021, the US Food and Drug Administration (FDA) approved Biogen and Eisai’s aducanumab (Aduhelm), the first amyloid beta-directed antibody to reach the market for the treatment of AD (3). However, the clinical results were mixed, and the developers withdrew the European Medicine Agency (EMA) marketing application in April 2022. Aducanumab has also been withdrawn from the US market as a result of low uptake and payor challenges. Aducanumab appears to disrupt the blood–brain barrier (BBB) to have a marginal impact on amyloid plaque formation (4).

Disease modifying biologics under clinical development for Alzheimer’s disease (AD) and Parkinson’s disease (PD).

In the meantime, Biogen/Eisai received FDA approval for lecanemab (Leqembi), in the US in January 2023, and EMA is expected to review the marketing authorization application shortly (5). Leqembi is making steady inroads within the US Alzheimer’s community, and the partners are now working on a subcutaneous formulation to ease use and drive uptake. Now the race is on to see who can develop the next biologic to treat AD or the elusive PD; to do this they will need to use the latest CNS delivery technology to ensure targeted delivery and durable responses.

CNS drug development remains challenging and is associated with high costs and high failure rates, largely due to the difficulties associated with getting drugs across the BBB (6). A host of biomaterials have been designed to bypass or facilitate the passage of small molecules across the BBB including passive transcytosis, conjugate ligands, membrane coating (e.g., erythrocytes, macrophages, neutrophils), liposomal and polymeric nanoparticles, micelles and nanogels, and stimuli-triggered BBB disruption (e.g., electroacupuncture, light, ultrasound) (

). However, the systemic delivery of biopharmaceuticals such as gene therapies, mAbs, and enzyme replacement therapies has remained off-limits as they cannot cross the BBB, so companies have relied on intrathecal or intracranial injections to deliver these therapeutics to the site of action (7). But things are about to change.

Novel approaches to central nervous system drug delivery.

Biopharma companies have begun to develop novel approaches using neurotropic viruses and receptor-mediated transcytosis or “peptide shuttles” to deliver biologics into the brain (8,9). For example, Spain-based Gate2Brain (G2B) has developed peptide shuttles that co-opt receptor mediated transcytosis pathways to transport therapeutic cargo into the brain (10). Conversely, VectorY Therapeutics has taken a novel approach combining antibodies with adeno-associated virus (AAV) capsids to form vectorized antibodies to selectively target the CNS and treat neurodegenerative diseases (11).

G2B novel peptide shuttles to treat glioblastomas

G2B was established in 2020 by CEO, Meritxell Teixidó to exploit delivery technology that was developed at IRB Barcelona. The biotech company focuses on developing innovative non-antigenic, protease-resistant, peptide shuttle conjugates that can penetrate the BBB to deliver antibodies, DNA/RNA, proteins, and small molecules through receptor-mediated transcytosis. It is currently developing G2B-002, with its lead drugs, and is planning to conduct studies with G2B-002 in the treatment of a rare paediatric cancer, diffuse intrinsic pontine glioma (DIPG) (10).

In 2021, G2B was granted financial support from DTI, the Center for Industrial Technological Development, Ministry of Science and Innovation, within the framework of the Neotec projects (12). In December 2022, G2B received €2.5 million in funding to develop its drug delivery technology to target brain cancers. These funds will enable the company to drive the clinical development of G2B-002 over the next few years (13).

But competition in this field is increasing. US-based Denali Therapeutics has also developed transferrin-mediated peptide shuttles to efficiently transport small molecules and biologics drugs to the brain to restore lysosomal function, glial biology, and cellular homeostasis in a variety of rare diseases (14). Denali will begin a Phase I/II clinical trial testing DNL310 (ETV:IDS) in children with Hunter syndrome and plans to expand this technology beyond enzymes and therapeutic antibodies to transport anti-sense oligonucleotides.

Meanwhile, Roche has developed its own transferrin-mediated peptide shuttle delivery technology which it has deployed in its Aβ-immunotherapy gantenerumab. Unfortunately, this antibody failed to show a decline in AD in Phase II clinical trials despite being brain penetrant (15,16).

VectorY Therapeutics next-generation gene therapies

VectorY Therapeutics was established in October 2020 at the Amsterdam Science Park in The Netherlands. The biotech company focuses on the development of innovative gene therapy approaches for the treatment of muscular and neurodegenerative disorders through vectorized antibodies. These non-immunogenic viral vectors enhance the properties of cell type specificity, to improve the delivery, durability, and accessibility of targeted tissues and cells. The company has developed three proprietary delivery technologies:

—an AAV vector that delivers the VecTab transgene (a pathogenic protein) to the neuron where the therapeutic antibody (VecTab) is subsequently produced. The therapeutic antibody binds to disease-associated lipids and proteins to modify the disease.

—a vectorized antibody fused with a degron sequence that directs the target toward pathway-specific degradation. The AAV delivers the VecTron transgene to the neuron where the therapeutic antibody-degron fusion protein (VecTron) is produced and leads to pathway-specific protein degradation.

—tissue-specific recombinant AAV capsids which are optimized for efficient delivery of antibodies intracellularly in the CNS.

—VecTab vectorized antibody programme targeting TDP-43 for the treatment of amyotrophic lateral sclerosis (ALS)

—VecTab/VecTron vectorized antibody targeting misfolded and aggregated huntingtin (HTT) proteins for the treatment of Huntington’s disease (HD)

—VecTab/VecTron vectorized antibody targeting alpha-synuclein for the treatment of PD (17).

On 15 June 2021, VectorY completed a €31 million seed financing round. The oversubscribed round was co-led by founding investors Forbion, BGV, and Eli Lilly & Company (18). In October 2023, VectorY raised €119 million (US $138 million) in a Series A financing round to advance its vectorized antibody programmes in neurodegenerative diseases. The round was co-led by EQT Life Sciences and the Forbion Growth Opportunities Fund and included existing investors MRL Ventures Fund (a corporate venture arm of Merck & Co.) Insight Partners, ALS Investment Fund, Forbion Ventures, BioGeneration Ventures (BGV), and others (19).

Several other companies are looking to use AVV to vectorize antibodies, including US-based Voyager Therapeutics which teamed up with AbbVie on the development of tau and alpha-synuclein vectorized antibodies to treat AD and PD, respectively. AbbVie later terminated the agreement due to a change in pipeline strategies (20). Voyager recently partnered with Neurocrine Biosciences to develop a candidate for the GBA1 gene programme to treat PD utilizing its intravenously administered, BBB penetrant, novel capsid derived from Voyager’s TRACER capsid discovery platform (21).

Challenges and future opportunities in CNS drug delivery

Introducing disease-modifying biologics into the brain poses a unique set of challenges compared to other body tissues due to the protective mechanisms of the BBB. However, new delivery technologies such as G2B’s peptide shuttles and VectorY’s vectorized antibodies demonstrate that these challenges can be overcome, and now it is down to pharma to identify the most appropriate therapeutic targets to pursue. Whether that’s anti-amyloid or anti-tau mAbs for the treatment of AD or alpha-synuclein-targeting gene therapies for PD, a new era of CNS biopharmaceuticals awaits.

1. Precision Reports. CNS Therapeutics Market Size in 2024: Increasing Technological Advancements by Top Key Players to 2031. 6 March 2024.
2. ALZFORUM, Therapeutics. Accessed 1 April 2024.
3. Glymour, M.M.; Weuve, J.; Dufouil, C.; Mayeda, E.R. Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer. 

, 191 (8), 1347-1351.
4. Haddad, H.W.; Malone, G.W.; Comardelle, N.J.; et al. Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer’s Disease: A comprehensive review. 

, 10 (3), 37023.
5. Biogen. FDA Approves LEQEMBI™ (lecanemab-irmb) Under the Accelerated Approval Pathway for the Treatment of Alzheimer’s Disease. News release, 6 Jan. 2023.
6. Nance, E.; Pun, S.H.; Saigal, R.; et al.Drug Delivery to the Central Nervous System. 

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7. Wu, D.; Chen, Q.; Chen, X.; et al. The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. 

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8. Terstappen, G.C.; Meyer, A.H.; Bell, R.D.; et al. Strategies for Delivering Therapeutics Across the Blood-Brain Barrier. 

, 20, 362–383.
9. Sheridan, C. Drugs Catch a Ride Through the Blood-Brain Barrier. 

, 41, 1182–1184.
10. Gate2Brain. Pipeline & Therapeutic Proof of Concept. Accessed 1 May 2024.
11. VectorY Therapeutics. Efficient Intracellular Therapeutic Antibodies. VectorY Platform. Accessed 1 May 2024.
12. Gate2brain, Gate2Brain has been granted financial support by the CDTI. News release, 22 Dec. 2021.
13. Gate2brain. Gate2brain Receives €2.5m Funding to Develop a Technology that Enhances Drug Delivery to the Brain. News release, 21 Dec. 2022.
14. Denali Therapeutics. Pipeline. Accessed 1 May 2024.
15. ALZFORUM. Molecular Transport Vehicle Shuttles Therapies into Brain. 29 May 2020.
16. Alzheimer Research, UK. Alzheimer’s Drug Gantenerumab Fails to Slow Decline in Phase III Clinical Trials. 14 Nov. 2022.
17. Konstantinova, P. Precision Targeted Therapies for Neurodegenerative Diseases. DHDRN Presentation. 23 Jan. 2023.
18. VectorY Therapeutics. VectorY Raises €31 million in Seed Financing to Develop Next-Generation Gene Therapies Aimed at Muscular and CNS Disorders. News release. 15 June 2021.
19. VectorY. VectorY Raises €129 Million ($138 Million) Series A Financing to Advance Vectorized Antibody Programs in Neurodegenerative Diseases. News release, 13 Nov. 2023.
20. Voyager Therapeutics. Voyager Therapeutics Provides Update on AbbVie Vectorized Antibody Collaborations. News release, 3 Aug. 2020.
21. Voyager Therapeutics. Voyager Therapeutics Announces Selection of Development Candidate for GBA1 Program in Collaboration with Neurocrine Biosciences, Triggering Milestone Payment. News release, 16 April 2024.

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

When referring to this article, please cite it as Barton, C. Frontrunners in CNS Drug Delivery. 

Novel delivery technologies enhance brain penetration to target neurodegenerative diseases and glioblastomas.

Frontrunners in CNS Drug Delivery

In December 2021, the European Parliament (EP) passed new legislation, European Union regulation 2021/2282, which amended directive 2011/24/EU and substituted the parallel evaluations of clinical data conducted by multiple country-specific health technology assessment (HTA) bodies with a single harmonized relative effectiveness assessment to reduce fragmentation and duplication (1).

The joint clinical assessment (JCA) is currently a voluntary collaboration, participation by member states is not mandatory, and non-EU countries can participate as observers or in specific collaborations (2). However, the process will be phased in for eligible health technologies starting with oncology products and advanced therapy medicinal products (ATMPs) in January 2025 (

, [3]). Once it is fully implemented in 2030, all drugs registered by the European Medicines Agency (EMA) via the centralized procedure will be subject to a JCA, and therefore, sponsors will need to prepare their new molecular entities (NMEs) for this process.

European Union joint clinical assessment (JCA) regulation will apply from 2025 onwards. 

The JCA enables EMA to run consultations in parallel with the European Network for Health Technology Assessment (EUnetHTA) 21 consortium. It aims to streamline the clinical assessment and cost-effectiveness of medicines to provide recommendations on pricing and reimbursement (P&R) decisions at the national level and improve patient access (4). Although the results of the JCA are currently non-binding, member states must give “due consideration” to the JCA report and can leverage the data to inform P&R decisions that remain under the jurisdiction of each member state (5).

Importantly, the JCA is designed to take into account the different member states’ requirements, for instance, regarding the standard of care (SoC) and patient preferences regarding clinical outcomes (2).

The main aspects covered by regulation (EU) 2021/2282 include:

cooperation and exchange of information with EMA during JCAs

deadlines and procedures for various stages, such as finalizing the assessment scope, submitting dossiers, preparing draft reports, and considering updates

interaction and timing with the Coordination Group, its subgroups, health technology developers (HTDs), patients, clinical experts, and other relevant experts

procedural rules for selecting and consulting stakeholders, patients, clinical experts, and other relevant experts

provisions for confidentiality requests and processing of personal data

requirements for correspondence and use of the HTA IT platform

rules for handling changes to therapeutic indications, re-initiating assessments, and updating assessments

templates and formats for dossiers, JCA reports, and summary reports (6).

Since the framework has been put in place, 68 JCA committees have occurred, but the use of JCA results remains limited by the member states (2). However, the JCA has established numerous guidance documents on procedures, methodology, the Scoping Process, direct and indirect comparisons, and report and dossier templates to help streamline the process (7).

According to OPEN Health analysis, pilot JCAs have considered a wider scope of clinical trials and product comparators compared with national HTAs. In addition, JCAs used a variety of safety endpoints and there was a good level of agreement in the use of efficacy endpoints by the JCA and national HTAs. The analysts concluded: “The new process will likely guarantee fairness in determining the true value and pricing of new technologies, but reimbursement decisions will ultimately rest at the national level” (8).

The European pharma industry needs to be prepared for the new clinical data requirements.