A successful cell and gene therapy (CGT) is one that accomplishes the“3 A’s”: approvability, affordability, and accessibility. As a field, we’ve made significant progress navigating complex regulatory landscapes for this unique and relatively new therapeutic modality. Yet our absolute focus on approvability has come with challenges in affordability and accessibility.
The obstacles to affordability and accessibility are complex and multifactorial; they include the complex, high-cost manufacturing processes for personalized living therapies, long vein-to-vein times, complicated logistics, their often-curative nature, and high prices.1-4 Addressing these challenges effectively requires therapy developers to consider affordability and accessibility from early development alongside the traditional focus on safety and efficacy, which drive approvability. Demonstrating approvability can no longer be the sole consideration behind process development and clinical trial design—the lifesaving impact of an approved therapy will never be realized if patients can’t access or afford it.
Planning for patient access from the outset of a new development program will necessarily include planning to treat more patients and do so much earlier on during their disease progression. Early, widespread patient access has largely been out of reach for CGTs, with only 1 in 20 (5%) of patients gaining access to CGTs globally5 and only 1 in 5 (20%) in the US market.6 Recently, axicabtagene ciloleucel (Yescarta; Kite) and lisocabtagene maraleucel (Breyanzi; Bristol Myers Squibb) have achieved second-line approval,7 demonstrating that the clinical evidence supports regulatory approval for earlier-line therapy. Nevertheless, patient access remains challenging due to manufacturability. Manufacturers can play a critical role in continuing this momentum by developing target product profiles early in research and development that balance clinical end points (safety and efficacy) with commercial factors, such as the percentage of patients receiving treatment, target manufacturing throughput, and, especially, target cost of goods (COGs).
Manufacturing processes that are high throughput, low cost, and high quality are required to enable widespread patient access to these potentially lifesaving therapies—not only in the Western world but also globally. Early adoption of manufacturing automation, shorter and more cost-efficient processes, and decentralized manufacturing of cell therapies, alone or in combination, demonstrate the potential to help achieve these goals.3 These improvements can go a long way toward bringing COGs to levels that can make various reimbursement models less risky8 and, therefore, more attractive to payers—ultimately getting CGTs into the hands of more clinicians to treat more patients.
Platforms that can automate and parallelize significant portions of the manufacturing process, such as Oribiotech’s IRO platform9 and Lonza’s Cocoon platform,10 have released data demonstrating that they can increase throughput while simultaneously reducing costs and out-of-spec (OOS) rates with partners like CTMC,11 Charles River Laboratories (IRO),12 and Galapagos (Cocoon).13 The reduced footprint, digital control, and closed nature of new automation platforms like IRO can facilitate parallel processing—with each unit manufacturing an individual therapy for a single patient simultaneously—to increase throughput per square foot and reduce labor requirements without increasing regulatory or quality risk. Automation platforms can also mitigate cross-site variability that can compromise quality and increase OOS rates.
To change their manufacturing process, manufacturers will need to engage with the regulatory agencies once they are in the clinic, where the currently perceived barrier to change is high and the risk tolerance is low among therapy developers and their investors. However, the riskier path would be to continue to pursue clinical development with a process that cannot achieve affordability and accessibility, dooming the product to commercial failure even before launch. A recent example of this is the discontinuation of 2 tumor-infiltrating lymphocyte programs in clinical trials by manufacturer Achilles Therapeutics, not due to safety or efficacy concerns but to commercial viability concerns, even while retaining more than $95 million in the bank.14 Understandably difficult, this path was deemed a means to maximize value rather than burning cash to develop a product that was likely to gain approval but wasn’t going to be affordable or accessible for patients.
Manufacturing automation platforms can also enable distributed manufacturing models15 that can bring manufacturing closer to the patient, shortening vein-to-vein times while simultaneously reducing complexity and costs. By integrating digital tools and automation, we can implement a standardized Design for Manufacturing16 framework that supports reproducible, robust, and Good Manufacturing Practices–compliant manufacturing processes across distributed manufacturing sites that are easily monitored by centrally located personnel. Digital twins (ie, detailed simulation models that replicate processes) are also being explored as powerful tools for supporting supply chain– and manufacturing facility–associated decision-making and have even been used to demonstrate superior turnaround times and resource utilization of distributed manufacturing approaches.7 These approaches can further support community-based care models such as that pioneered by Legend Biotech through their CARTITUDE-4 phase 3 clinical trial (NCT04181827),17 where they dosed 30% to 40% of patients in the community. With more than 20% of patients dying while waiting for therapies,4 methods to shorten vein-to-vein times are crucial for these therapies to achieve their full clinical potential.
Key Takeaways
- Manufacturing Innovation is Critical for Scalability – High costs, lengthy vein-to-vein times, and logistical complexity remain major barriers to widespread CGT adoption. Automation, decentralized manufacturing, and process optimization have the potential to drive affordability and accessibility without compromising regulatory compliance or product quality.
- Early Commercial Planning is Essential – A singular focus on safety and efficacy in early development can doom a therapy to commercial failure, making the integration of cost-of-goods (COGs), manufacturability, and payer-relevant outcomes data into R&D strategy imperative for long-term success.
- Regulatory Engagement Must Evolve – The perceived risk of manufacturing changes post-approval discourages innovation. Early collaboration with regulatory agencies on automation, analytics, and distributed models is needed to align clinical and commercial feasibility.
Beyond manufacturing efficiency and cost benefits, digital infrastructure satisfies another critical need for CGTs: patient outcome tracking. Typically, manufacturers and payers cannot effectively track outcomes prospectively once a therapy reaches the hospital where the patient is located. Payers’ reluctance to reimburse expensive treatments is often due to a lack of robust outcomes data. With current costs for CGTs in the range of $400,000 to $4 million, payers struggle to justify reimbursement when they lack visibility of concrete data demonstrating positive patient improvement or survival outcomes.
Although manufacturing inefficiencies are the single biggest factor reducing the accessibility and affordability of CGTs today, there are others. Implementing new technologies (ie, next-generation sequencing and biosensors7) for continuous, in-line, automated process monitoring can enable faster, more precise analyses of potency, sterility, and other factors required for faster, more efficient product releases. This will expedite the release of high-quality, safe, and effective products. Accelerating product releases could significantly increase the number of patients treated. This, in turn, will increase patient outcomes data, which can make additional inroads toward solving the affordability problem, given that patient outcome data heavily influence payer reimbursement decisions.18,19
A successful CGT launch begins long before a product ever receives marketing authorization. Early planning to achieve commercial viability with a significant focus on product affordability and future patient access must begin during preclinical development and continue through clinical trials, approval, and product launch. A singular focus on achieving safety and efficacy end points is no longer sufficient and has led to high-profile commercial failures (and removals) in recently launched CGT products. New technology platforms can increase throughput, reduce costs of goods, lower OOS rates, reduce required facility investment, shorten development timelines, support faster product release, and enable distributed models—ultimately making CGTs approvable, accessible, and affordable. Many of these technology platforms exist today; now it’s time to use them.
REFERENCES
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