Cell and gene therapies (CGTs) are revolutionizing healthcare, offering potential cures for life-threatening diseases, sometimes with just a single dose. These cutting-edge tools, which include gene therapies involving the transfer of genetic material and cell therapies involving the transfer of cells with relevant functions, are rapidly evolving, allowing the treatment of an increasing range of diseases. However, the innovations challenge existing regulatory and market access frameworks, creating hurdles to timely patient access.
Regulatory Framework and Clinical Trials
CGTs, utilizing living cells and genetic material, introduce unique complexities in their development. In the EU, the donation, procurement, and testing of substances of human origin are governed by the Tissues and Cells Directive and the Blood Directive, soon to be replaced by the SoHO Regulation in 2027. Medicines based on genes, tissues, or cells are classified as advanced therapy medicinal products (ATMPs), with specific rules concerning their authorization, supervision, and pharmacovigilance.
In the UK, the Human Tissue Regulations 2007 govern the use of human tissues or cells as starting materials for medicinal products. Compliance is overseen by the Human Fertilisation and Embryology Authority (HFEA) and the Human Tissue Authority (HTA). These regulations establish a licensing regime requiring that procurement and testing of human tissues or cells for ATMP manufacture can only be done by licensed establishments.
Testing Cell and Gene Therapies
In the EU, the testing and manufacturing of CGTs must meet strict regulatory standards. Non-clinical safety studies must adhere to Good Laboratory Practice (GLP), clinical trials to Good Clinical Practice (GCP), and manufacturing to Good Manufacturing Practice (GMP). Due to the unique nature of CGTs, additional requirements apply, particularly in GCP and GMP, to address specific safety concerns. Starting in January 2025, the HTA Regulation will introduce harmonized methods for evaluating health technologies, including CGTs.
In the UK, clinical trials for ATMPs must follow the Medicines for Human Use (Clinical Trials) Regulations 2004, with applications submitted to the MHRA. ATMP developers must apply to the MHRA for various licenses throughout the product development process, including a manufacturer’s license before starting clinical trials and a Manufacturer Authorization before submitting a Marketing Authorisation application.
Emerging Challenges in the EU and the UK
One of the ongoing challenges of developing CGTs, particularly as they move toward commercialization, is scaling up manufacturing processes while ensuring consistent quality and regulatory compliance. Autologous CGTs, which rely on cells obtained from the individual receiving therapy, are time and resource-intensive. Allogeneic CGTs, in contrast, use donor cells, providing superior scalability, reduced time to treatment, and lower manufacturing costs. However, allogeneic therapies face regulatory challenges, particularly in ensuring strict traceability requirements.
The development of CGTs faces several regulatory challenges, including the need to engage with multiple regulatory authorities. Various initiatives have been introduced to streamline regulatory pathways, such as the combined review process and the Innovation Office in the UK, and EMA's early dialogue and Innovation Task Force in the EU.
Market Access: Authorisation, Pricing & Reimbursement Regulatory Approval Processes
Like all medicinal products, CGTs must obtain a marketing authorization (MA) before being marketed in the EU. CGTs must undergo a centralized procedure at the EU level. The EMA’s Committee for Medicinal Products for Human Use (CHMP) issues a scientific opinion on the product within 210 days. The European Commission (EC) then grants an MA, valid across all EU and EEA member states within 67 days.
In the UK, ATMPs require an MA to be marketed. There are various potential routes for MA applications available to ATMP developers, including 150-day assessment, conditional MAs, and Rolling Review. Applicants based in Northern Ireland must ensure compliance with EMA processes and apply to the CAT on the quality, safety, and efficacy of the ATMP prior to MA submission.
Accelerated and Derogatory Pathways
In the EU, alternative pathways exist for products facing challenges in clinical trial data collection, including the Accelerated Assessment Procedure, Conditional MA, and MA under Exceptional Circumstances. CGTs may also qualify for the PRIME scheme, which streamlines development and provides early scientific advice.
In the UK, developers of ATMPs can leverage several national accelerated or derogatory pathways, including the Innovative Licensing and Access Pathway (ILAP), Early Access to Medicines Scheme (EAMS), and Project Orbis. This regulatory framework is designed to streamline the introduction of innovative therapies while ensuring patient access and safety.
Pricing & Reimbursement
The decentralized pricing and reimbursement process within the EU and the UK presents significant challenges for cross-border access and pricing consistency for CGTs. Reimbursement models for CGTs differ markedly from those for traditional medicines, requiring a re-evaluation of health technology assessments and payment models. Adaptive pricing and reimbursement models, such as outcome-based agreements or annuity payments, could be developed to reflect the long-term value of CGTs.
Post-market obligations: monitoring and product liability
CGTs face specific post-market obligations that are critical for ensuring patient safety and maintaining compliance with regulatory standards. In the EU, the EMA issued a draft revised guideline focused on the safety and efficacy follow-up and risk management of ATMPs. In the UK, MA holders must review any imposed conditions to ensure adherence to post-authorisation obligations and ongoing pharmacovigilance procedures.
Future Directions for Cell and Gene Therapy Regulation
As the regulatory landscape evolves and multiple regulatory authorities in the EU and the UK are involved, it is becoming increasingly complex. Collaboration between regulators, researchers, and industry leaders is crucial to overcoming the regulatory hurdles that currently impede the development and approval of CGTs. Harmonized and streamlined regulatory pathways will be crucial for sustaining the momentum of CGT development across the EU and UK.
