Implications of New European Union Regulations on Advanced Therapy Medicinal Products
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Introduction
Advanced Therapy Medicinal Products (ATMPs) are innovative drugs based on genes, cells, and tissues, offering potentially curative treatment options for a variety of diseases. ATMPs are associated with high costs and, in some cases, uncertainties regarding their effectiveness or safety, which currently presents a barrier to market access for these medications. In the last decade, a total of 24 ATMPs have been approved in the European Union (EU); specifically, 10 are classified as Gene Therapy Medicinal Products, five are classified as Somatic-Cell Therapy Medicinal Products, six are Chimeric Antigen Receptor T-cell-based gene therapies, and three are Tissue-Engineered Medicinal Products.1
In 2021, the European Parliament (EP) and the Council of the EU approved a new EU Health Technology Assessments Regulation (EU HTAR) (Regulation (EU) 2021/2282)2 to establish common rules and methodologies for HTAs. Then in 2023, the European Commission (EC) published a draft3 of a new EU Pharma Package to revise and replace the existing general pharmaceutical legislation. This sweeping set of proposals will likely affect numerous aspects of pharmaceutical regulation in the EU.
This white paper provides an overview of the key changes impacting access to innovative medicines in the evolving EU market and details of the EU HTAR and EU Pharma Package, with some considerations for manufacturers.
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EU HTAR Overview and Impact
EU HTAR Goal and Scope
An HTA aims to determine the value of a health technology in a specific context, ultimately informing decisions on reimbursement and pricing. In the EU, HTAs are primarily conducted at the national level, and approaches, including assessment frameworks, data requirements, and timelines, vary by country. The specific setup in each country duplicates efforts and costs for manufacturers, leading to delays and/or inequalities in access to treatments between countries.
The EU HTAR establishes the procedure for conducting joint clinical assessments (JCAs) of health technologies at the EU level and providing joint scientific consultations (JSCs) for product development to companies upon request. This procedure aims to harmonize processes and evidence requirements, establish predictability, avoid duplication of dossier development for manufacturers, and accelerate patient access across the EU Member States through a single clinical assessment occurring in parallel with the European Medicines Agency (EMA) arketing authorization (MA) process.
Timings for Implementation
The implementation of JCAs will be carried out progressively: JCAs will be mandatory for ATMPs and oncology products by 2025, for orphan drugs by 2028, and for all other products by 2030.
For its implementation, the EU HTAR assigned the EC the responsibility of adopting Implementing Acts (IA) that detail the procedural rules for the different components of the Regulation. Six IAs are planned in 2024, and the EC will hold public consultations for each. The first of the six Implementing Act drafts4 outlines the process for conducting JCAs of new medicines and how to involve patient experts. On May 23rd, 2024, the EC adopted the first implementing regulation ((EU) 2024/1381)5 pursuant to the HTA Regulation ((EU) 2021/2282). As stipulated in this document, the Regulation will enter into force on the twentieth day following its publication in the Official Journal of the EU and will be applicable from 12 January 2025 in all Member States.
HTAR Key Elements
JCAs will provide an assessment of clinical evidence on four domains, partially replacing national HTAs:
- Health problem and currently used technologies
- Description of the technology under evaluation
- Relative clinical effectiveness
- Relative safety
Member States will be responsible for the evaluation of non-clinical evidence (economic evaluation, ethical aspects, organizational aspects, social aspects, legal aspects) and will make the final decision on pricing and
reimbursement for each health technology, considering the clinical evidence from the JCA. Countries may
request additional studies allowing for country-specific information if deemed necessary to inform their
decisions in clinical areas not evaluated in the JCA.
The timeline for the JCA for medicinal products will be linked to the EMA’s centralized MA assessment procedure, operating as a parallel process to ensure timeliness in supporting Member States’ decision-making at the time of launch.
EMA Standard Process Timeline
Note: *Deadline for HTA Dossier Development decreases from 90 to 60 days where the application for a MA is assessed under the accelerated procedure, or for variations in the MA of approved products corresponding to a new added therapeutic indication.
The JCA process will begin shortly after the regulatory dossier submission is completed. Following the submission of a new regulatory authorization request, the EMA will notify the coordinating group of that HTA and share medication details, regulatory information, and the claimed indications.
The assessment scope of the JCA is defined by the PICO framework: Population, Intervention, Comparators, and Outcomes of interest. The JCA process will begin with a survey sent out to gather PICO information determined by each Member State to establish their PICO. After PICO consolidation, the assesment scope is sent to the authorization applicant, who has three months to complete the evidence submission. This JCA dossier is required 45 days prior to the EMA’s Committee for Medicinal Products for Human Use (CHMP) opinion, and the final JCA report will be issued no later than 30 days after the EC’s regulatory decision based solely on the evidence presented in the dossier prepared by the manufacturer.
In addition, the new regulation allows manufacturers to request a JSC. JSCs involve non-binding scientific advice provided by the HTA Coordination Group, the governing body for JCAs and JSCs, to manufacturers regarding the evidence development plan of the medicinal products. The goal is to enhance the quality and suitability of the data produced by the manufacturers in view of future HTA assessments. These JSCs on medicinal products may occur in parallel with EMA scientific advice and will include patient participation as part of the external experts involved in the consultation.
EU HTAR Impact on ATMP Companies
This new regulation plays a significant role in harmonizing HTA processes in Europe. However, it also brings various challenges, such as:
- shared responsibility for access. All stakeholders bear the collective responsibility to ensure widespread access to innovative therapies. This responsibility extends across the entire EU. Balancing the interests and priorities of various stakeholders, including manufacturers, healthcare providers, regulators, and patients, while navigating differences in healthcare systems and reimbursement policies among EU Member States, presents a significant challenge.
- effectiveness of JCAs. While experts agree that the concept of JCAs is a positive step towards harmonizing processes and evidence requirements, there is a concern that it may not necessarily result in earlier patient access to therapies. A key challenge lies in the difficulties with establishing a cost for therapies that is sustainable for the national health system, and in the prolonged negotiations for
reimbursement. - compressed timelines. The brief three-month timeframe allocated for dossier preparation appears
insufficient, highlighting the critical need for parallel activities to compile comprehensive evidence packages, which may become particularly daunting in the case of ATMPs. Plus, small and medium-sized companies may struggle to absorb the significant additional workload associated with the JCA process. - reimbursement process for ATMPs. Reimbursement is a critical bottleneck affecting timely access to therapies. Delays and difficulties in the reimbursement process can impede patient access to these innovative treatments despite the new JCA procedure.
- patients’ perspectives and experiences. Experts stress the importance of including patients’ perspectives and experiences in the evaluation and reimbursement processes to ensure that the access pathways for therapies align with the needs and expectations of the individuals receiving the treatments.
- flexibility in regulation and reimbursement for ATMPs. The consensus is that there is a pressing need for flexibility within the regulatory and reimbursement frameworks. These frameworks must be specifically tailored for ATMPs to address the unique challenges associated with these innovative therapies and to facilitate more efficient access for patients.
- readiness for JCA implementation. Originally anticipated for release in December 2023, prolonged
discussions and meetings within the EC committee on HTA led to a postponement of publication of the first IA draft until March 5, 2024. The release of the majority of IAs for the EU joint HTA has encountered delays ranging from three to six months, as per the EC’s rolling plan for implementing the HTAR. These delays prompt concerns regarding the readiness for the start of JCAs in 2025.
New EU Pharma Package Overview and Impact
EU Pharma Package Goals and Scope
On April 26, 2023, the EC released a revised package of pharmaceutical legislation aiming to improve access to medicines across all EU Member States. The EU Pharma Package comprises two legislative proposals: a new Directive6 on the Community Code relating to Medicinal Products for Human Use, replacing Directives 2001/83 and 2009/35, and a new Regulation7 to replace Regulations (EC) No. 726/2004 (authorization and supervision of medicinal products) and No. 141/2000 (orphan medicinal products), as well as parts of Regulation (EC) No. 1901/2006 (pediatric medicinal products).
On March 19, 2024 , the EP’s Committee on the Environment, Public Health and Food Safety (ENVI) adopted the two proposals that form the EU Pharma Package and voted on key amendments to the reform. The next step is the Council’s amendments and voting process.
EU Pharma Package Key Elements
The key changes to new regulation and legislation impacting ATMPs aim to reduce the regulatory data
protection (RDP) period for innovative drugs.
For non-orphan drugs, proposed changes include decreasing the current minimum RDP for new drugs from eight to six years, with several conditions for extending exclusivity (data and marketing protection) up to a total of 12 years, allowing generic versions to be launched earlier than originally planned. For repurposed medicinal products, a unique four-year data protection applies.
Exclusivity extensions are possible for launching medicinal products in all EU Member States simultaneously covered by the MA (two additional years), addressing high unmet medical needs (six additional months), conducting comparative clinical trials (six additional months), or adding an additional therapeutic indication (one additional year). RDP is followed by a two-year market protection period, remaining unchanged from existing rules.
For orphan drugs addressing high unmet medical need (UMN), a period of ten years for market exclusivity is granted. Products authorized through bibliographic data and established usage receive five years. For all other orphan drugs, there is a reduction in market exclusivity from ten to nine years, with the possibility of extension if launched in all Member States (one additional year), or adding an additional therapeutic indication (up to two additional years). In addition, the definition of significant benefit has been tightened and the clinically relevant advantage to patient care will only be recognized when advantages benefit a substantial part of the target population.
The data protection amendments proposed by the EP’s Committee on the ENVI, impacting the RDP proposal by the EC, and the EC proposal are summarized below.
Non-Orphan Drugs
Note: RDP can be extended upon conditions, to a maximum of 10 years as per EC, or 8 years and 6 months as per EP; The total maximum protection (RDP and market protection) can be 12 years as per EC, and 11 years and 6 months as per EP| 1Market protection can be extended by 1 year if a new indication with significant clinical benefit is developed, differently from the Commission’s proposal, that instead provided 1 year RDP for fulfilling this condition; 2Marketing authorization application using a relevant and evidence-based comparator in accordance with scientific advice provided by the Agency.
Orphan Drugs
Other changes proposed by the new package include:
- simplification of market entry for generics and biosimilars by defining the scope of the ‘‘Bolar exception,’’ allowing studies necessary for regulatory approval, HTA, or pricing and reimbursement to be conducted during the patent period of the brand-name drug.
- accelerating marketing authorization from 210 days to 180 days through electronic submissions, providing greater regulatory support before evaluations, and reforming committee structures within
the EMA. - mitigating medication shortages by creating an EU list of critical drugs, enhancing the monitoring of supply chains, and providing guidance to MA holders to mitigate medication shortages.
- new advertising rules prohibiting comparative advertising unless superiority is demonstrated through
specified product characteristics. - reduction of the environmental impact of medicinal products by tightening the requirements for environmental impact assessment in the MA process.
- incentivizing antibiotic development by granting companies transferable data exclusivity vouchers of up to one year, which can be used for any authorized medication of their choice, except for products that have already benefited from the maximum RDP period.
- promotion of pediatric drug development by adding more detailed rules on Pediatric Investigation Plans (PIPs), and an additional six months of protection under the Supplementary Protection Certificate.
- transparency in public funding, requiring MA holders to publish reports listing all direct financial support received from publicly funded entities for research and development of medicinal products, successful or not.
You can learn more about the impact of the EU Pharmaceutical Package in our series of articles “A Deep Dive into the EU Pharmaceutical Package Changes”:
The Impact of the EU Pharma Package on ATMP Companies
The revised regulations impact all industry stakeholders for marketing and drug development, with the extent dependent on the type and stage of development. The aspects that will have the biggest impact on ATMP companies specifically are:
- innovation threat perception. The new EU Pharma Package is seen as a potential threat to innovation
within the EU pharmaceutical landscape. - inadequacy of incentives for data protection duration. Criticisms are raised regarding the incentives provided for a longer duration of data protection.
- The six+ month extension for addressing unmet medical needs lacks a clear definition of what constitutes an unmet need.
- The two+ years extension for launching in 27 countries is deemed unfeasible for all companies, introducing inequalities.
- The highly specific requirements of ATMPs mean companies face challenges with these incentives, including performing comparative studies in ATMPs, and the six+ months extension is not perceived as a sufficient incentive.
- The one+ year extension for further indications is not always practical for ATMPs, where drugs are highly specific to select targets, populations, or diseases.
- risk of losing innovation, particularly for rare diseases. The incentives provided may pose a risk of
diminishing innovation, particularly in the development of new drugs for rare diseases. - limited sense of collaboration and consensus. Collaboration is deemed crucial for establishing effective and balanced new regulations that consider the interests and concerns of all parties involved.
Conclusion and Takeaways
The introduction of JCAs as part of the new EU HTAR marks a significant step toward collaborative evaluation. The regulatory changes aim to streamline the process of accessing innovative medicines across EU Member States and to help harmonize procedures, reduce duplication, and accelerate patient access to cutting-edge therapies. However, it does not resolve the problem of the price bottleneck, posing a challenge to achieving
seamless patient access to innovative therapies. The issue of determining fair and sustainable reimbursement of ATMPs remains a crucial aspect that requires further consideration within the broader context of healthcare policy and regulation. Addressing the challenges surrounding the effectiveness of JCAs in accelerating access, the demanding timelines for dossier preparation, and the complexities associated with compiling sufficient evidence to meet assessment scopes are pivotal for successful implementation of the EU HTAR and ensuring timely patient access to ATMPs. And concerns persist regarding the readiness for JCA implementation due to delays in the publication of IAs, raising doubts about meeting the 2025 start date for JCAs.
While the new EU Pharma Package introduces incentives for pharmaceutical innovation, concerns linger about the adequacy of certain provisions. The extension of data protection periods, especially for addressing unmet medical needs, may face challenges due to the lack of a clear definition. Additionally, disparities in the feasibility of incentives for both large and small pharmaceutical companies need careful consideration. Striking a balance between incentivizing pharmaceutical innovation and ensuring timely patient access remains a complex challenge. Despite the fact that the regulation aims to encourage research and development, concerns persist that the measures might inadvertently create barriers for certain types of drugs or companies.
Collaboration and consensus among various stakeholders, including industry experts, patients, regulatory bodies, and healthcare providers, are crucial for the successful implementation of the new regulations. Bridging gaps and ensuring that diverse perspectives are considered will be vital to address potential shortcomings and refine the legislation over time.
References
- Bellino, Stefania, et al. ‘‘Cell-based medicinal products approved in the European Union: current evidence and perspectives.’’ Frontiers in Pharmacology 14 (2023).
- European Parliament. Regulation (EU) 2021/2282 on Health Technology Assessment and and amending Directive 2011/24/EU. [cited 2023Dec] https://health.ec.europa.eu/health-technology-assessment/ regulation-health-technology-assessment_en
- Reform of the EU pharmaceutical legislation. [Internet] 2023. [cited 2023Dec] https://health.ec.europa.eu/ medicinal-products/pharmaceutical-strategy-europe/reform-eu-pharmaceutical-legislation_en
- European Parliament. Draft Report on the proposal for a directive of the European Parliament and of the Council on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC. [Internet] 2023. [cited 2023Dec] https://www.europarl.europa.eu/doceo/document/ENVI-PR-753470_EN.pdf
- Official Journal of the European Union. Commission Implementing Regulation (EU) 2024/1381 of 23 May 2024 laying down, pursuant to Regulation (EU) 2021/2282 on health technology assessment, procedural rules for the interaction during, exchange of information on, and participation in, the preparation and update of joint clinical assessments of medicinal products for human use at Union level, as well as templates for those joint clinical assessments. [Internet] 2024. [cited 2024May] https://eur-lex.europa.eu/eli/reg_impl/2024/1381/oj
- European Commission. Health technology assessment – joint clinical assessments of medicinal products. https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/13708-Health-technologyassessment-joint-clinical-assessments-of-medicinal-products_en
- European Parliament. Draft Report on the 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 [Internet] 2023. [cited 2023Dec] https://www.europarl.europa.eu/doceo/document/ENVI-PR-753550_EN.pdf
Authors:
Irene Asensio,
Consultant
Chus Castillo,
Partner Consulting Iberia
Isabel De La Paz,
Engagement Manager
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