Cell and gene therapies (CAGT) offer the potential to revolutionize healthcare by addressing unmet medical needs. However, the science is racing ahead, and regulatory authorities are often struggling to keep up with the pace of innovation, putting patient access at risk. Former regulator, Lynne Ensor and industry expert Siegfried Schmitt explain how to build a robust quality and compliance strategy to minimize regulatory risk.
Cell and gene therapies (CAGT) offer the potential to revolutionize healthcare by addressing unmet medical needs. However, the science is racing ahead, and regulatory authorities are often struggling to keep up with the pace of innovation, putting patient access at risk. Former regulator, Lynne Ensor and industry expert Siegfried Schmitt explain how to build a robust quality and compliance strategy to minimize regulatory risk.
Ex-FDA commissioner Scott Gottlieb famously stated that “by 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year based on an assessment of the current pipeline and the clinical success rates of these products"¹. While the industry is not experiencing this rate of approvals yet (five CAGTs were approved by the FDA in 2022), the pipeline is still growing, and there are now a total of 27 FDA-approved CAGTs with 2,084 in clinical pipelines².
There is still much to learn on the developer side too; several high-profile Chemistry, Manufacturing & Controls (CMC) failures in recent years have put CMC compliance under increased scrutiny, both from regulators and investors. For instance, Iovance’s Lifileucel (TIL cell therapy for melanoma) was subject to a delay in BLA filing following a Type B meeting with FDA that resulted in the conclusion that “the Company and the FDA have not been able to agree on the required potency assays to fully define its TIL therapy, which is required as part of a BLA submission”³.
More encouragingly, Sarepta’s Duchenne muscular dystrophy (DMD) gene therapy has recently won accelerated approval (albeit with restricted use) from the FDA after several setbacks that have delayed its progression through the clinic and approval. In September 2020, Sarepta was asked to implement an additional potency assay for release after a Type C ‘written response only’ meeting with the FDA’s Office of Tissues and Advanced Therapies (OTAT)⁴.
These setbacks illustrate that proactive planning for CMC compliance is a significant contributor to ultimate product success. Where compliance is an afterthought, there are often regulatory delays, which are exacerbated by the growing pipeline of therapies and under-resourced regulatory agencies. Therefore, going to the back of the queue at later stages because of preventable compliance mistakes is costly and can jeopardize a first-to-market position.
To ensure patient safety and facilitate successful product development, it is crucial for CAGT developers to adopt a robust quality and compliance strategy. The earlier in the product’s development this is established, the greater the chance is for success without extended timelines, while also reducing resources required to achieve regulatory approval.
In this article, we will explore the importance of phase-appropriate compliance and discuss key considerations for navigating the CAGT regulatory landscape toward commercialization.
Proactive planning for CMC compliance is a significant contributor to ultimate product success. Where compliance is an afterthought, there are often regulatory delays.
Proactive development, early engagement
Several compliance challenges face the CAGT community that if not addressed as early as possible, become the source of significant delays for developers.
The lack of approved CAGT products means there is not enough experience across the various product types in both the manufacturing and regulatory processes. The unique characteristics and complex development processes of CAGTs have little precedence in this relatively new field and so require careful consideration of regulatory compliance at each phase of development.
Due to this lack of experience, typically small to medium size companies navigating clinical trials often do not consider the degree of GxP compliance and quality systems requirements needed from Phase 1 to Phase 3, through regulatory approval and commercial manufacturing. This leaves significant quality and compliance gaps in later clinical phases as developers begin engaging with the agencies for pre-approval inspection. In addition, some will consider GMP compliance to be the responsibility of their contract manufacturing organization (CMO) or contract laboratory, which is not the case.
Throughout early clinical development, the focus is on clinical data and outcomes. What is lacking is the appreciation of the resources needed to establish compliance and so the evolution of quality systems from GLP/GCP to GMP can be neglected. This results in developers being unprepared for and unsuccessful in regulatory approval, and significant delays to commercialization.
In addition, there is a lack of understanding of the regulatory expectations during each phase from R&D to commercial manufacturing. A solid understanding of how regulatory meetings function will enable developers to meet expectations and maximize these opportunities for regulatory feedback and input.
The lack of approved CAGT products means there is not enough experience across the various product types in both the manufacturing and regulatory processes. The unique characteristics and complex development processes of CAGTs have little precedence in this relatively new field and so require careful consideration of regulatory compliance at each phase of development.
Proactive development, early engagement
We believe that the best, and likely most successful, approach to compliance is a proactive one.
Early adherence to GMP is essential for a robust compliance strategy. The overarching aim is to provide assurance that the characteristics and performance of clinical batches are consistent with those at commercial scale, all supported by appropriate quality systems and controls.
The optimal time to establish quality systems and associated compliance expectations is at the start of Phase 1 of development. When compliance is an afterthought, it becomes reactive and a problem-fixer, rather than a way to ensure product quality, prevent regulatory setbacks and create commercial advantage.
Understanding which raw and starting materials, and intermediates must be manufactured and analyzed for GMP, knowing which documentation must be fully compliant with GMPs at which point during development, and applying the appropriate controls for data integrity and compliance is essential. This is not only for developing the CAGT, but manufacturing and testing it in compliance with the applicable regulations and (often unwritten) regulatory expectations.
As an industry, we have a responsibility to advance these life-changing therapies to patients as quickly as possible. Phase-appropriate compliance is critical in achieving this mission. Our guidance for a forward-looking, ideal state of compliance planning includes:
- Build a production environment as close to GMP as possible from the outset
- Engage with regulatory authorities early on
- Do not forfeit quality and compliance for the sake of making a product that could cure a patient, but cannot be approved
- Obtain as much control over your materials as possible
- Develop a clear roadmap to define your supplier relationships and establish shared compliance responsibilities, including developing and implementing strong quality vendor agreements
- Regulatory and reimbursement strategies should go hand in hand
- Establish open communication and transparency between scientists, regulatory experts, payers, and patients
Regulatory agencies are continuously refining their guidelines in line with the evolution of the CAGT field. As such it is also critical to keep up with these emerging regulatory considerations to be able to adapt compliance strategies accordingly. Key considerations include the evolving framework for advanced therapy medicinal products (ATMPs), novel regulatory pathways like accelerated approvals or breakthrough designations, and updates to guidelines related to potency, manufacturing, and quality control.
The final piece of the puzzle is collective expertise. Successfully navigating the complex regulatory landscape for cell and gene therapies requires collaboration between many stakeholders, each with a unique perspective and expertise. Engaging with regulatory authorities as soon as possible in the development process can help align compliance strategies and facilitate smoother interactions during the regulatory review. Seeking expertise from consultants, compliance experts, or regulatory affairs professionals can also provide the knowledge and experience to ensure compliance and regulatory approval.
Understanding which raw and starting materials, and intermediates must be manufactured and analyzed for GMP, knowing which documentation must be fully compliant with GMPs at which point during development, and applying the appropriate controls for data integrity and compliance is essential.
Conclusion
Phase-appropriate compliance is vital for the successful development and commercialization of cell and gene therapy products. By adopting a proactive compliance strategy, developers can navigate the regulatory landscape effectively, ensuring patient safety, and meeting regulatory requirements at each phase of development. An early GMP approach, harnessing collective knowledge and engaging with experts and regulatory agencies can significantly contribute to the smooth progression of therapies from pre-clinical development to regulatory approval, advancing the field of CAGTs and getting life-changing therapies to patients who need them.
