Lev Gerlovin

Now that the first cell and gene therapies have become commercial realities and more companies are involved in precision medicine research, different manufacturing platforms are being developed. However, as the authors write, developers need to consider the fundamental differences between these therapies and more traditional biopharmaceuticals to develop the right commercialization strategies.

Biologics and Sterile Drug Manufacturing 2019

	When referring to this article, please cite it as W. Colasante, P. Diesel, and L. Gerlovin, “The Link Between Manufacturing and Commercialization in Gene and Cell Therapies," 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing 

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The highly customized nature of cell and gene therapy production means that manufacturing innovations for one therapy may not be easily transferable to others.

The Link Between Manufacturing and Commercialization in Gene and Cell Therapies

	While gene and cell therapies have been touted as the future of medicine for decades, there is evidence to indicate that they are finally poised to deliver results. Several products are already on the market, including Kymriah, Yescarta, Luxturna, and many others are advancing to late-stage clinical development and commercialization. In the US alone, there are 34 gene therapies in pivotal trials and another 470 in earlier stages of clinical testing (1).

	Although the long-term transformative promise of gene and cell therapies is becoming increasingly clear and is good news for many patients, these treatments also present unique challenges for a number of stakeholders. Factors that drug developers, regulators, investors, and others must consider include the fact that these therapies often target very small patient populations, have shorter treatment windows, offer potentially curative efficacy, have high up-front costs, lack long-term efficacy and safety data, and involve complex, expensive, and high-risk manufacturing processes. Each of these factors can have a significant impact on the clinical development and regulatory review process and on the chance of successful commercialization. For teams involved in investment and planning related to technology and manufacturing, it is essential to consider commercialization issues, as strategies are planned and implemented from the earliest stages of development.

	Manufacturing and supply chain complexity

	While more traditional therapies, including small molecules and even monoclonal antibodies, generally involve a simpler and more straightforward production process with the potential for scalability and opportunities for cost efficiencies through economies of scale, the production methods for most gene and cell therapies are lengthy, complex, and difficult to expand as production needs rise. For example, the manufacture of autologous therapies such as chimeric antigen receptor T (CAR-T) cells or stem cell therapies requires a process that must be replicated in individualized batches to meet demand at every stage. With allogeneic therapies, the patient-specific nature of production makes it extremely challenging to scale up production.

	The administration of these therapies also creates challenges that can be affected by decisions in technology and engineering. For autologous treatments, a sample is taken from the patient, sent away for processing and modification (often to a single location regardless of geographic origin), and then dispatched back to a designated treatment center for re-administration to the patient. This process requires strict traceability and a robust and reliable chain of temperature control. Planning for this process can face considerable regulatory hurdles related to licensing, monitoring, and troubleshooting.

	Production of gene and cell therapies can also require customized technologies and innovations in production that require the active review and contributions of regulators and experienced outside consultants to achieve target goals in compliance with both regulatory standards and costs. In early clinical stages, the feedback from regulators and others on production procedures will typically focus more on safety and issues such as viral banks, raw materials, and serums. At later stages, feedback tends to focus on the impact of manufacturing decisions on a therapy’s potency, consistency, and variability.

	The rapid growth in development of gene and cell therapies in recent years means that there are now several examples of pharmaceutical companies developing much more efficient production capabilities for these drugs. For example, Novartis and Kite created systems that can produce individualized CAR-T cell therapies in 22 and 17 days, respectively (2). ZIOPHARM Oncology is advancing a non-viral platform called the Sleeping Beauty system that rapidly produces genetically modified T cells within two days with potential for rapid scalability. The highly customized nature of production, however, can often mean that innovations in manufacturing of one therapy may not be easily transferable to others.  

	Considerations in production can also differ within the broad category of gene and cell therapies. For example, production of allogeneic therapies, while they can present challenges related to distribution and shelf life, might be less challenging compared to CAR-T cells and other autologous therapies, given their similarity to cell-based proteins that can be produced in batches and distributed for use off the shelf. The class of drugs known as radiopharmaceuticals, which have extremely short shelf lives, have shown that this challenge can be well managed. Cellectis is exploring new production strategies for off-the-shelf allogeneic therapies. Rather than developing CAR-T cell therapies from patient samples, the company is using healthy donor T cells, which could allow for earlier supply chain preparation, better control over production volume, and, potentially, reduced costs.

	Accessing new technologies and resources 

	As the range of new options in technology expands, companies will continually need to access new levels of skill and insight to identify and acquire the innovations necessary to support production goals at every stage through commercialization. Generally, by Phase 2, manufacturers should at least be aware of the technologies they will need to achieve target goals in scalability and be prepared to make these investments at the appropriate time. By Phase 3, the full range of technologies that companies will need to support commercial production should be in place. Many industry insiders expect that there will be greater demand for advanced technologies including, among others, cryopreservation tools and services, and that development of biomarkers and related diagnostics will become more common and even essential tools in the successful commercialization of gene and cell therapies (3).

	To identify the optimal options in technology, many manufacturers are now considering engaging contract research organizations (CROs) that have specialized expertise in gene and cell therapies, especially for those targeting rare diseases. Some CROs are now well positioned to provide guidance related to regulatory compliance, production scale, and product portability for gene and cell therapy developers. Their teams can provide guidance on how to refine manufacturing processes while maximizing purity and safety with a focus on continuity of care. One example of this type of collaboration is seen in the alliance between the Center for Commercialization of Regenerative Medicine, GE Healthcare, and the Federal Economic Development Agency for Southern Ontario, which joined forces to form the Center for Advanced Therapeutic Cell Technologies in Toronto. The Center was established to help industry partners incorporate new technologies and provide expertise to solve manufacturing challenges, especially for the emerging generation of gene and cell therapies (4).

	When planning for manufacturing needs, drug developers should also consider using a production process that can be adapted for use in different therapeutic areas. While production decisions often focus on basic factors including geographic location, some gene and cell therapies present opportunities for a diversified development platform with a unifying focus. The Human Genome Project and the International HapMap Project are examples of initiatives aimed to better understand genetic factors associated with many diseases. Research can lead to more gene and cell therapies with the potential to expand treatment to additional indications, potentially including disease states with large patient populations. It can be advantageous for manufacturers to expand their focus on production beyond efficiency and to include methods and technologies that may be adaptable and expandable for use in additional indications. 

	Addressing long term concerns about safety and efficacy

	Limitations on data and the potential for curative efficacy requires manufacturers to put systems into place for long-term safety and efficacy monitoring. These current limitations can have a profound impact on costs and commercial viability. When an FDA Advisory Committee unanimously recommended approval of Spark Therapeutics’ Luxturna for treatment of inherited retinal disease in October 2017 (5), they cautioned that a lack of long-term follow-up data makes it unclear whether efficacy could diminish over time. They also raised questions about the potential for future adverse events not demonstrated in clinical research (6). Limitations on data can also fuel the perception that some gene and cell therapies do not provide incremental clinical value over existing therapies, making it difficult to justify their high prices. Here again, companies must plan for technologies and procedures that can meet target goals in long-term patient monitoring to avoid costs and cumbersome record keeping and other requirements that can affect commercial potential of new drugs. 

	In part to support the collection of real-world data, manufacturers should also consider new levels of engagement with key stakeholders, potentially including healthcare providers (HCPs), payers, and clinicians. Alliance with a wide network of stakeholders spanning different geographies could provide valuable resources and facilitate long-term post-marketing surveillance efforts as well as support broader understanding of the benefits and risks of gene and cell therapies.

	Matching production decisions to patient needs

	Collaboration with stakeholder groups, especially patient communities, can also help make sure that manufacturing decisions are in line with both commercialization goals and factors that can affect patient access and management of care. GlaxoSmithKline (GSK) made the decision to offer Strimvelis, a treatment for severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID), at only a single treatment center in Milan, assuming the need for a “specialized [treatment] environment.” The limited options for treatment meant higher costs and challenges related to travel and cross-border European reimbursement for many patients. As a result, only four patients have been treated with Strimvelis at the site since approval in 2016. GSK has since announced its interest in divesting its rare disease division, including Strimvelis (7,8). To support commercialization goals, manufacturers might consider using predictive analytics to inform strategic decisions on the appropriate number of treatment sites, where they should be located, or whether and how they might bring gene and cell therapies directly to patients. 

	While factors including patient population, product value and efficacy benefit, and pricing play the major roles in successful commercialization of gene and cell therapies, it is essential for drug developers to recognize when and where decisions related to production can also have an impact. The application of technology is a critical consideration in planning related to production time, scalability, and product purity and safety, as well as in expansion of target indications. Without access to skilled expertise, many drug developers risk making decisions related to production that can limit or even jeopardize commercial potential. Conversely, companies that can access the talent and insight necessary to make the right technology decisions at the right time at every stage in a development program can build a considerable competitive advantage.

	1.  G. Kolata, “New Gene-Therapy Treatments Will Carry Whopping Price Tags,” 

www.nytimes.com/2017/09/11/health/cost-gene-therapy-drugs.html

	2.    Gilead, “Kite’s Yescarta (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy,” Press Release, October 18, 2017. 

	4.    Business Wire, “E Healthcare, FedDev Ontario Commit CAD $40M for New CCRM-Led Centre to Solve Cell Therapy Manufacturing Challenges,” Press Release, January 13, 2016.

	5.    E. Mullin, “FDA Vote Sets Stage for Gene Therapy’s Future,” 

www.technologyreview.com/s/609075/fda-vote-sets-stage-for-gene-therapys-future/?set=609105

	6.    FDA, “FDA Advisory Committee Briefing Document, Spark Therapeutics Briefing Document,” October 12, 2017, 

www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics/cellulartissueandgenetherapiesadvisorycommittee/ucm579300.pdf

	7.    E.Mullin, “A Year After Approval, Gene-Therapy Cure Gets Its First Customer,” 

www.technologyreview.com/s/604295/a-year-after-approval-gene-therapy-cure-gets-its-first-customer/

	8. A. Regalado, “A First-of-a-Kind Gene Therapy Cure Has Struggled to Find a Market,” 

www.technologyreview.com/s/608349/a-first-of-a-kind-gene-therapy-cure-has-struggled-to-find-a-market/

	Walter Colasante, Pascale Diesel, and Lev Gerlovin are vice-presidents in Charles River Associates’ (CRA’s) Life Sciences Practice. The authors wish to acknowledge the contributions of Stephanie Donahue and Michael Krepps to this article. The views expressed herein are the authors’ and not those of Charles River Associates (CRA) or any of the organizations with which the authors are affiliated.

Think ahead to production requirements when planning strategies in early development of gene and cell therapies.