Advances in precision medicine (also known as "personalized medicine") have led to an improved understanding of mechanisms underlying disease and the emergence of new tools and technologies, such as next generation sequencing technologies. Novel diagnostics and individualized therapeutics for diagnosis and treatment tailored to specific characteristics can now target disease based on an individual's genetic makeup. Cell and gene therapies in particular, such as adeno-associated virus vectors and Chimeric Antigen Receptor T-Cell products ("CAR-T cell therapies"), hold great potential in battling rare diseases that present in small patient populations.
The complexity of the manufacturing processes that underpin these therapies, however, presents obstacles to their commercial uptake and success. For example, personalized medicines are generally biologically complex and have a short shelf life, making it challenging to ensure consistent quality and potentially requiring manufacturing in close proximity to where the patient is being treated. Regulatory regimes that accommodate large-scale, centralized manufacturing and global distribution schemes thus do not always offer a hand-in-glove model for more small-scale, individualized precision medicines.
Globally, regulators are grappling with how best to regulate the manufacture of these advanced therapies in a way that supports the development of innovative and life-saving medicines, whilst also ensuring an appropriate level of regulation and safety. This article explores regulatory initiatives and approaches in the EU, UK and the U.S.
European Union
Currently, the only alternative to the standard medicines manufacturing paradigm is the hospital exemption ("HE"). In particular, Article 28(2) of Regulation (EU) 1394/2007 (the "ATMP Regulation"), as implemented via Article 3(7) of Directive 2001/83, permits hospitals to produce and supply advanced therapy medicinal products ("ATMPs") such as gene and cell therapies, and tissue-engineered products, without a marketing authorization or manufacturing license, under exceptional circumstances.
The HE provides that an ATMP can be prepared on a non-routine basis according to specific quality standards and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner in order to comply with an individual medical prescription for a custom-made product for an individual patient. By doing so, the HE facilitates small-scale and localized manufacture of unauthorized ATMPs and provides access to treatments that address an unmet medical need. However, there is significant divergence in the interpretation of this exemption throughout the EU. For example, in order to rely on the HE, developers must obtain authorization from their national competent authority; in some Member States this is achieved via the grant of product-specific HE approvals, whilst other Member States issue HE manufacturing licenses.
Acknowledging the difficulties posed by the existing regime, in April 2023, the European Commission published wide-ranging proposals to revise the EU's general pharmaceutical legislation (the "EU Proposals"). Amongst many objectives, the EU Proposals seek to align the interpretation and implementation of the HE across the EU and facilitate decentralized manufacturing of medicines, such as ATMPs. Key aspects of the EU Proposals include:
- The manufacture of ATMPs under the HE would require an HE approval issued by the national competent authority ("NCA") of the Member State where the administering hospital is located. All HE approvals granted in the EU would need to be reported to the European Medicines Agency ("EMA"). Should an NCA revoke an HE approval on the basis of safety or efficacy concerns, the NCA would be required to inform the EMA and the other NCAs of such revocation.
- The manufacture of ATMPs under the HE would need to comply with requirements that are equivalent to the provisions set out in the ATMP Regulation concerning good manufacturing practices and traceability and with pharmacovigilance requirements equivalent to those provided for in Regulation (EC) No 726/2004.
- NCAs would be required to collect data on the use, safety and efficacy of ATMPs prepared under the HE in their Member States, which would then be relayed to the EMA for inclusion in a central repository.
- Instead of requiring each individual manufacturing site to hold its own manufacturing license, standard manufacturing authorizations would specify a central site to be responsible for overseeing additional sites where decentralized manufacturing or testing activities are carried out. It would be the responsibility of the manufacturing license holder to request the NCA of the Member State where the decentralized site is established to register the decentralized site.
- The NCA of the Member State where the decentralized site is established would be responsible for the supervision of the manufacturing and testing activities carried out in the decentralized site.
Even with the facilitation of decentralized manufacturing, there would still be a need for the HE. The HE offers an important lifeline for patients when there is no authorized treatment and no clinical trials for which they are eligible.
Since the EU Proposals are still making their way through the legislative process, it is not clear exactly how they will evolve and if, or when, they will be finalized. Current estimates suggest that agreement may be reached on the final version of the proposed legislation in 2026.
United Kingdom
Since the ATMP Regulation formed part of EU law prior to the UK's departure from the EU, the HE has been retained in UK law and continues to serve as a mechanism by which unauthorized ATMPs can be manufactured in close proximity to where individual patients are being treated.
In addition, the Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2024 (the "UK Proposal"), which was recently laid before Parliament, seeks to introduce a new regulatory framework which accommodates the manufacture of medicines at the point of care ("POC"), or at modular facilities which can be easily relocated, otherwise known as modular manufacturing ("MM"). If adopted, the UK Proposal would amend the Human Medicines Regulations 2012 and the Medicines for Human Use (Clinical Trials) Regulations 2004, both of which envisage large-scale centralized manufacture. Key aspects of the UK Proposal include:
- The introduction of two new types of manufacturing license; an MM license and a POC manufacturing license, each of which could be used to supply both authorized and investigational medicinal products.
- Instead of standard factory-based manufacture, MM licenses and POC manufacturing licenses would provide for a "hub and spoke model" whereby a control site is responsible for overseeing all aspects of POC/MM manufacturing processes conducted at specific manufacturing sites/modular units.
- The handling, control, storage and distribution of any investigational or authorized medicinal products named on these licenses will only be permitted at the control site and the sites/modular units specified in the license.
- All holders of POC manufacturing/MM licenses will be required to maintain one master file per POC/MM medicinal product specified in their license. Amongst other details, the master file must contain a detailed description of the manufacturing and assembly requirements of medicinal products manufactured via these processes, as well as details of the locations of all sites/modular units at which manufacturing or assembly of the specific medicinal products has commenced, been suspended, or ceased.
- The Medicines and Healthcare products Regulatory Agency ("MHRA") will be responsible for the appropriate supervision and control of manufacturing operations conducted under these licenses, to ensure the medicines produced meet the necessary specifications. MM manufacturing/POC license holders will be required to update the MHRA of any changes made to the master files made in the previous 12-month period.
The UK Proposal would come into force six months after being passed. Pending a successful passage through the legislative process, the UK Proposal could become law in 2025. Ahead of this date, the MHRA and other stakeholders will develop detailed guidance to ensure the uniform interpretation of its provisions.
United States
In the U.S., cell and gene therapies are biological products regulated by the U.S. Food and Drug Administration ("FDA"). FDA generally considers cell therapy products to include certain tissue-engineered medical products and human gene therapy products to include all products that mediate their effects by transcription or translation of transferred genetic material or by altering human host genetic sequences (e.g., genetically modified viruses and ex vivo genetically modified human cells). Drug sponsors looking to investigate cell and gene therapy products must submit an investigational new drug application to FDA prior to initiating clinical studies in the U.S. and obtain approval of a biologics license application from FDA prior to commercial marketing of the product in the U.S.
Within this U.S. regulatory framework, cell and gene therapy approvals are gaining momentum. Since 2017, the FDA has approved 41 cell and gene therapies, including 16 in the past two years alone. Recognizing this acceleration in development and approval, and to enhance resources dedicated to this space, FDA's Center for Biologics Evaluation and Research reorganized its Office of Tissue and Advanced Therapies into the new Office of Therapeutics Products ("OTP") in March 2023. Among the OTP's six new offices are the Office of Gene Therapy Chemistry, Manufacturing and Controls ("CMC") and the Office of Cellular Therapy and Human Tissue CMC.
While U.S. product approval numbers are forecast to continue to grow, there remain several technical limitations that developers must overcome for investigational products to advance through development and achieve approval more readily. FDA recognizes that the development, manufacture, testing and clinical assessment of these complex products is challenging. For example, development programs for rare diseases may entail smaller study populations and thereby require fewer manufacturing runs.
These limitations may make it more difficult to evaluate the product's critical quality attributes and establish critical process parameters to ensure quality. Because cell and gene therapy products are biologically complex and may incorporate several functional elements, and because their manufacture often requires multi-step processes with multiple starting materials, there is often variability among product lots with short shelf life and stability. Manufacturing concerns also include potential risks of protein or host cell DNA-based impurities and, considering the diversity of products, the need to develop bespoke assays to test product potency. Moreover, it is not uncommon for there to be multiple changes to the manufacturing process during development, including, for example, if technology transfer occurs from an academic setting for early-stage development to a contract manufacturer for later-stage development or commercialization.
Cell and gene therapy developers are generating inventive solutions to help address these challenges. For example, developers have begun to employ continuous manufacturing processes that do not depend on the completion of an entire manufacturing process before a new batch can be started. Such processes may help lower manufacturing costs and increase scalability and reproducibility. Additionally, the debut of closed, automated systems capable of end-to-end manufacturing of cell therapies offers new potential to reduce risks of operator error and contamination. The emergence of these modern manufacturing techniques will likely serve as a springboard to faster development timelines and solutions to traditional points of failure.
To help support and invite continued innovation, recent legislation has established new programs for designating specific manufacturing methods as advanced manufacturing technologies (the "AMT Designation Program") and certain well-understood and reproducible technologies as designated platform technologies (the "Platform Technology Designation Program"), each providing benefits of early interactions with FDA and timely advice and guidance in support of drug development, manufacturing, and review processes. Although these programs are not specific to cell and gene therapies, cell and gene therapy developers may find them to be particularly useful.
FDA has also issued numerous cell and gene therapy guidance documents in recent years, including guidance specific to the management of manufacturing changes, considerations for the use of human and animal-derived materials in manufacturing, assuring the potency of cell and gene therapies, the development of CAR-T cell therapies, and gene therapy products incorporating human genome editing. Cell and gene therapy developers working towards implementing innovative manufacturing techniques should closely analyze these guidance documents and consider consulting FDA on novel development or manufacturing plans.
Conclusion
Should the above-mentioned initiatives in the EU and UK become law, EU and UK developers of personalized medicines will enjoy greater accommodations for unique manufacturing pathways. This may lead to improved patient access to potentially life-saving medicines, especially for patients who may be too sick to travel or whose reduced immunity makes travel too dangerous. This may also reduce the burden on hospitals by enabling the administration of personalized medicine in, for example, community-based medical practices or at the patient's own home. Whether they pass in their current form or in a slightly revised form, these initiatives demonstrate a permissive approach by EU and UK regulators, who recognize the potential of personalized medicines.
With an acceleration of approvals of cell and gene therapies in the U.S., FDA's creation of the OTP, introduction of new designation programs, and issuance of cell and gene therapy guidance documents signal the agency's commitment to supporting the advancement of these complex and life-altering therapies. Recognizing that cell and gene therapy products pose unique challenges, FDA must maintain a regulatory readiness to keep pace with future anticipated submissions which will likely increase as the emergence of modern manufacturing techniques become more widely adopted. Innovations in manufacturing processes will likely serve as a springboard to faster development timelines and solutions to traditional points of product development failure.
In general, however, additional complex challenges will need to be addressed before personalized medicines can become more mainstream. For example, despite the potential to provide cost savings in the long-term, healthcare providers are often reluctant to reimburse these products which, due to their bespoke nature, often carry considerable price tags. The uptake of these products may also require a cultural shift within the healthcare setting that supports greater numbers of clinicians with the necessary expertise and understanding of these products.
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