From the President's Desk: Star Wars and Cell and Gene Therapy Access

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Miguel Forte, MD, PhD
President, ISCT
MC4TX
Belgium

The film series Star Wars defined a generation. It combines a forward-looking perspective, anchored in tradition and past history and is welded with emotion, bravery and care. That is the story of development of innovative, patient focused, cell and gene therapy products.

The series character R2-D2 (Artoo - Detoo) is an iconic fictional character in the Star Wars films, known as a small, resourceful droid with a distinctly spunky personality, displaying notable bravery, and remarkable independency. Notably, he never receives a full memory wipe in the films, which allows him to retain knowledge of all events he witnesses, a key reason he is sometimes described as a "keeper of the saga's secrets" (1, 2).

Cell and gene therapy products increasingly deliver transformative, potentially curative, value to patients with progressively more and more solid risk-benefit balanced decisions. The innovative and complex nature of these products combined with the mechanisms of action and delivery represent significant challenges for the risk profile of these products. On the other hand, the building of evidence, the retaining of information and interpretation of data from limited and early patient exposure, clinical trials and real-world evidence growingly enable regulatory risk-benefit decisions that allow for patient access from early provisional to full regulatory approval. The key underlying assumption is the regulatory professional assessment of the risk benefit making the right decision to ensure quality, and a benefit aligned with the need. For challenging risk context, one would say that risk square (R2) requires strong decisions, one would say decision square (D2). R2-D2 represents thus, the need for adequate decision taking at the forefront of innovation to balance the risk of an advancing technology and the benefit that, anchored in evidence and need, it brings!

Several countries, states or regions have addressed the unmet medical need and patient access in different ways trying to expedite patient access (3). It is important to enable fast access to patients in need to therapeutic opportunities as they emerge. Nevertheless, it should always be based on a regulatory rigorous and professional decision considering the risk-benefit and the patient’s need.

In Europe a couple of approaches could be mentioned, the Conditional Marketing Authorization and the Hospital Exemption. In particular, the Hospital Exemption use is limited to a single Member State, but it constitutes a provisional approval granted, upon assessment, by the Member State Regulatory Agency! EMA also offers the Priority Medicines (PRIME) Scheme, which supports therapies showing potential major rewards over existing treatments and can accelerate their assessment (4).

The FDA also provides Accelerated Approval and other expedited pathways including Fast Track, Breakthrough Therapy, and Regenerative Medicine Advanced Therapy (RMAT) designations, all designed to speed up access to promising therapies (5, 6). It is somewhat concerning to see single State use of non-FDA approved or regulated cell and gene therapy products, as the recently published case of Montana enacted la – Senate Bill 535 - as well as some others, unless a proper professional regulatory risk/benefit assessment is made. It should be noted that this expands the use beyond terminally ill patients already considered in the federal Right to Try Act from 2018 (7).

In Asia we have seen a proliferation of accelerated access approaches aiming at patient earlier access but still under regulatory assessment and provisional approval. In Japan, the Sakigake Designation (8) is an expedited pathway for innovative therapies, including gene and cell therapies, allowing conditional marketing approval based on promising early clinical data with post-marketing confirmation required. Another couple of examples are recent developments in Taiwan with the “Regenerative Medicine Act” and “Regenerative Medicine Product Regulations” in issued in June 2024 (9), establishing a dual-track system for managing both medical techniques and drug products containing genes or cells and Thailand with a conditional approval scheme with an associated risk management plan.

Overall, we are increasing the maturity of our decisions on the use of cell and gene therapy products with expanding information on the risks and benefits. A recent positive development has been the removal of the Risk Evaluation and Mitigation Strategies (REMS) for autologous chimeric antigen receptor CAR T cells immunotherapies in oncology (10). This will accelerate and broaden patient’s access to these therapies. While continuing to require experienced teams to deliver these treatments the measure will remove some requirements from hospitals and their associated clinics when dispensing these products. The products will continue to be subject to safety monitoring according to regulations as well as the post marketing observational safety studies with follow-up of patients for 15 years after product administration.

Another recent discussion concerns Elevidys^TM, a gene therapy for Duchenne Muscular Dystrophy (DMD) with the potentially associated deaths all apparently due to liver failure (11, 12). Elevedys, approved in June 2023 and granted accelerated approval on transgene expression, delivers value while carrying some potential risk for liver aggression in view of the high level of viral vector (AAV) needed for delivery. The use of the product is maintained with the FDA together with monitoring, while the EMA recommended, at this stage, against a conditional marketing authorization (13). It is important to view these events as growing maturity of the field combining the value brought to unmet medical needs together with a risk profile that will continue to be improved, namely in gene therapy with better delivery approaches with targeted AAVs or LNPs.

These tragic events may be seen as casting a shadow in the sector and gene therapy. That conclusion is not warranted (14) Cell and gene therapy product developers, regulators and users must take the right approach to bravely progress the delivery of these products to benefit patients while understanding and aiming at improving the risk profile. This is indeed the time to address the evidence and the vision for the cell and gene therapy field with the R2D2 perspective. The benefit of patients today and tomorrow is at stake!

Increasing patient access to cell and gene therapy products is a must both to address the unmet medical needs but also to ensure the sustainability of the field. It is good to see approaches that can lead to the expansion of opportunities for patients to be treated. It is crucial though that access, even if early and based on limited evidence, continuous to rely on adequate, regulatory led, risk-benefit decisions to ensure quality, patient protection and benefit, avoiding the use of unproven cell therapies or inadequate risk exposure for patients, but always view the evidence based benefit that cell and gene therapy products can bring to patients.