Disclaimer: The aim of this article is to provide an overview of the NextGen Therapies regulatory framework and insights in the Cell and Gene Therapy industry. It has solely been written for informative purposes and it does not provide any regulatory and/or legal advice for the development of cell and gene therapy products.

Cell and gene therapy (CGT) products are complex on several fronts: the cell and gene science is innovative, development and manufacturing are intricate and challenging, and the approval regulatory journey is fraught with complexity and risk. The scenario becomes even more convoluted when the same product has to access multiple markets with different regulatory frameworks. The US and the European Union (EU) are two of the major leaders of the CGT market, but key differences in their respective product regulatory journeys produce divergent approval timelines and distinct documentation requirements.

While CGT’s regulatory journey is centralized in the US under the Food and Drug Administration (FDA), the EU faces the challenge of interacting with European and national authorities at different stages of CGT product development. Both regions, however, share some key issues and could benefit from successful resolutions implemented in these areas.

The following four good practices, based on our research and experience working with leading CGT biopharma companies, can help teams efficiently move their CGT products toward streamlined submission and review in both the US and the EU:

Involve Experienced Regulatory Stakeholders

CGT development requires experience. When internal expertise is not available, engage with a third party to secure efficient navigation of critical regulatory discussions and milestones. The third parties should provide an advanced understanding of regulatory strategy, regulatory intelligence, and regulatory submission processes and requirements. CGT development programs generally face disruptions more compared to monoclonal antibodies (mAbs), and the majority of disruptions during regulatory review of CGT programs are caused by chemistry, manufacturing, and controls (CMC) issues, often delaying product development and launch. It is pivotal to proactively determine and address data and quality concerns.

In the EU, the regulatory experience and market is typically more fragmented, making it more difficult to source the required expertise. The national regulations take into consideration the specific requirements of individual countries. For example, product reimbursement negotiations take place at the individual country (or even regional) level, at times delaying the commercialization of a product. To address these hurdles, the European Medicinal Agency (EMA) encourages product developers and sponsors to engage early with the regulatory authorities through a range of advisory services. 

One of those is the joint scientific consultation between EMA and the EU network for Health Technology Assessment (HTA) 21 consortium. 

The objective of this type of consultation is to discuss product development plans to meet the needs of medicine developers, regulators and HTA bodiesi and it can facilitate patient access to new key medicinal products that can benefit overall public health.

Plan Early and Be Prepared for an Accelerated Product Review

The FDA offers several expedited programs (Figure 1). Many CGT teams have been caught off-guard when the agency assigns a “priority review” and teams must scramble to meet accelerated timelines. Plan early for scale-up, transfer, changes to manufacturing platforms, and any process or timing changes required to move toward and support earlier market entry on an accelerated schedule. Ensure that plans exist to scale-up, transfer, and change manufacturing when needed. It is also important to assess and determine process changes including timing (e.g., development of potency assays), comparability, and generate evidence that, pre- and post-changes, the product quality attributes are highly similar and have no adverse impact on the quality, efficacy, and safety of the product.

Similar to the US, in the EU, the EMA offers programs to expedite the approval of medicinal products, including CGT products (Figure 2). An accelerated procedure for Marketing Authorization (MA) is offered to products that have major public health interest and represent a therapeutic innovation. There are also different types of MA, conditional and exceptional circumstances, which can be granted to allow access to market before comprehensive clinical data is available. Additionally, the PRIME (PRIority MEdicines) scheme was launched for developing medicines that target an unmet medical need; it can enhance exchanges between developers and agencies while enabling access to accelerated assessment.

Engage Regulatory Authorities Early

Reduce risk by engaging the EMA/ FDA early in the development of the regulatory strategy (Figure 3 and 4). Their expertise can be beneficial as they provide guidance and recommend a preferred regulatory pathway. In the US, INTERACT and pre-Investigational New Drug (IND), pre-Biologics License Applications (BLA), and others are used to address questions about (pre) clinical development, manufacturing, and supply chain (Chain of Identity / Chain of Custody).1 When possible, make use of the agency’s Priority Review Voucher (PRV) program. Voucher owners can redeem the voucher to reduce agency review time from ten months to six months. Owners can also sell a voucher to secure additional funds for development, manufacturing, etc. Of the 31 Priority Review Vouchers (PRVs) awarded to date, 17 were sold to another sponsor for prices ranging from about $67 to $350 million.

In the EU, scientific advice can be given by EMA or National Competent Authorities (NCA) at different stages of product development (Figure 4). During early development, EMA offers free briefing meetings through the Innovation Taskforce Group. Further tools to access expedited processes or schemes, such as request orphan drug designation and/or Advanced Therapy Medicinal Products (ATMPs) certification (for Small and Medium Enterprises, SMEs), should also be considered.

Data Quality Checks to Streamline Submissions

Focus on the submission planning, strategy, and required capabilities to efficiently produce and submit a compliant dossier. IND submissions are often delayed because of poor or inadequate data quality. If the submission is not clear and concise, longer review timelines and/or “Clinical Hold” designations can occur. For BLAs, poor submission quality or deviations from FDA guidance result in major amendments and the Prescription Drug User Fee Act (PDUFA) clock resets. In case of marketing application, a lack of technical conformance for the electronic submission of data can result in a technical rejection. For example, study data must be submitted in Clinical Data Interchange Standards Consortium (CDISC), Standard for Exchange of Nonclinical Data (SEND), Study Data Tabulation Model (SDTM), and Analysis Data Model (ADaM) formats, and the whole submission must comply with electronic common technical document (eCTD) requirements. A way to manage this risk is to implement a standard Study Data Tabulation Model (SDTM) approach across the supply chain (e.g., contract research organizations) for human clinical trial data tabulations.

In the EU, pre-submission advice from EMA is often recommended ahead of CT and MA application (MAA) to ensure that documentation is complete and adequate. CT applications (CTAs) have now been centralized through an electronic submission system that has been operating since January 31, 2022. The centralized submission should simplify and unify the CTA process, while still considering the different national requirements. Additional efforts towards harmonization in the EU will be required to streamline genetically modified organisms (GMO) applications; these are often part of CTAs when it comes to CGT product development and they are dealt with at the national and/or regional level.  Similar to the US, MAAs in the EU require submission of regulatory information in eCTD format. The MA process for CGT products in the EU is centralized, involving several committees from EMA and it is subject to a final decision by the European Commission.

In 2021, EMA and the FDA created a program to provide parallel scientific advice (PSA) to sponsors with the aim to increase dialogue between the agencies from the beginning of the life cycle.3 This service should facilitate the understanding of the bases of regulatory decisions to help optimize product development  and avoid unnecessary testing replication or different methodologies. The PSA is currently voluntary and available upon sponsor request. It should focus on specific questions and issues regarding product development, upon which EMA and the FDA can provide information and perspectives.

Key Takeaways

Regulatory process clarity can reduce complexity. When CGT teams implement the four described foundational practices, they can be better prepared to decrease risk. By planning early and engaging with experienced stakeholders and regulators, they can position themselves to move their products through regulatory review and approval processes in the most expedient manner. In the EU, an increasing effort towards reducing complexity has been made through the establishment of centralized procedures which has led to increased coordination and harmonization, in some stages, across all the EU countries. Furthermore, the pilot on PSA from EMA and the FDA represents a first step towards an even broader convergence and increased alignment between regulatory authorities involved in CGT of product development.

The existence of a variety of ad-hoc schemes and programs, both in the US and the EU, helps to accommodate specific product needs, offering additional opportunities for those to reach the market. In this light, a solid regulatory strategy, combined with expedited assessment and review processes, can help products to swiftly enter the market.