Immunoassays As An Imperative For Successful Gene Therapy Commercialization: Launch Challenges With Immunoassays And A Framework For Success

By Mathias Cousin, Ashraf Husain, and Shweta Arya, NextGen (Cell & Gene) Therapies Practice at Deloitte

The pathbreaking gene therapy approvals in the last few years have also introduced the industry to commercialization challenges with the diagnostic immunoassays, often required for in-vivo viral vector-based gene therapies. An immunoassay helps screen out patients at risk of immunogenicity to the therapy¹, ensuring both safety and efficacy. Immunoassay development and commercialization are complex and can span across multiple years requiring significant investments from gene therapy manufacturers.

Through practical experience, we are beginning to understand the long assay development time and the need to factor it into planning. Getting immunoassay launch right is imperative for successful gene therapy commercialization as immunoassay delays can delay the gene therapy uptake or even delay the launch. Our experience suggests that immunoassays should be internally regarded as critical for the wider therapy commercialization success. Organizations should recognize the need to allocate appropriately skilled and experienced resources toward the complex effort. This includes an accountable program owner supported by a cross-functional team and a strong governance structure. Given the uncertainties in the space, manufacturers looking to work with vendors for the immunoassay should use a formal vendor assessment framework. This ensures the selected vendor has relevant experience and requisite skills to mitigate potential risks to the program. Finally, the immunoassay team must engage with regulators early and often in the program to ensure agreement on strategy, approach, and timeline.

Viral Vectors and Pre-Existing Immunity

The delivery mechanism of a gene therapy is a key component and a strong determinant of a safe and efficacious therapy. Viral vectors are potent and proven delivery mechanisms that use recombinant viruses to “infect” the cell with the functional gene².

Many potential patients for a viral vector-based gene therapy harbor pre-existing antibodies against the capsid or transgene, potentially rendering the therapy ineffective in those patients. Because of the serious implications on patient safety and therapy efficacy, testing each patient’s pre-existing antibody levels prior to administration is critical³.

Immunoassays – Critical and Complex

To determine patient eligibility for a gene therapy, immunoassays are commonly used to assess and measure any pre-existing immunity against the viral vector. The US FDA also requires immunoassays to assess systemic immune reactions risk and manufacturers are required to submit the immunoassay details as a part of the Biologics License Application (BLA) for any gene therapy¹.

Commercial immunoassay development for a clinical gene therapy requires significant time, effort, and investment from the manufacturer. The process can take 18-24 months and any delays could lead to increased costs and therapy launch delays. Thus, immunoassays are a critical component for the therapy approval.

In our experience, immunoassay development and commercialization challenges are driven by the following factors:

• Assay commercialization is like launching a parallel product for each therapy, requiring extensive patient / HCP education, messaging, and commercial model planning·      
• Immunoassays are developed by an external diagnostic partner requiring rapid decisions and proactive management by the manufacturer
• Constantly evolving regulatory requirements result in continuous adjustments to development, manufacturing, and regulatory strategies, while continuing to manage risks in a highly volatile environment
• The assays require differentiated and assay specific manufacturer capabilities requiring collaboration among multiple cross-functional stakeholders

Typical Challenges with Immunoassay Commercial Launch

Most organizations struggle with the immunoassay commercial launch as they don’t prioritize assay development manufacturing in the initial years. Accelerated approval timelines for gene therapies may catch them off guard, creating bandwidth issues for assay commercialization. In most cases, manufacturers will need to develop a separate lab test for commercial launch because initial assays developed for clinical trials may not be GMP compliant or the originating lab cannot scale up to the levels required for commercial launch. Additionally, with only a few approved products, understanding of immunoassay considerations is still evolving. The lack of a playbook to follow, driven by limited commercial experience in the space, results in low awareness about the extensive assay development and approval process across the organization.

A Proposed Approach to Immunoassay Development and Commercialization

Based on our experience, we view assay development and commercialization as a three-phase process starting at least 18 months ahead of the planned therapy launch. In Phase 1, the organization lays down the groundwork for regulatory and development needs for the commercial assay. In Phase 2, the operational requirements are aligned, and a vendor is selected to develop the assay. In Phase 3, it becomes critical to design the detailed processes, infrastructure, and tactics to successfully commercialize the assay and drive competitive advantage in the market.

Figure 1: Framework for Successful Assay Development and Commercialization

Phase 1: Development and Regulatory

In Phase 1 the organization lays the groundwork for regulatory and development needs for the commercial assay. This includes determining the type of assay, choosing a regulatory pathway, and addressing timelines related to the BLA submission.

1. Manufacturers may choose a neutralizing antibody assay (NAb) or a total antibody assay (TAb)4 depending on the type of antibodies the assay should be able to screen out. The other key considerations for choosing the assay may include the type of existing early-stage assay and any strategic plans for future clinical trials.
2. The regulatory pathway for an assay may depend on the timelines to ensure minimal launch risk to the therapy, risk qualification of the assay, and country-specific regulatory guidance [examples pathways include a lab-developed test (LDT) or a companion diagnostic (CDx) in the US, IVDR in the EU, or a CDx or Independent test in Japan].  Regulators may ask for evidence that an assay is robust, and some pathways may not be meet the threshold of evidence needed (e.g., LDTs while the fastest may have limited clinical data). 
3. The BLA submission requirements for gene therapies require necessary immunoassay data to be available ahead of any planned submission date. Hence, it is critical for the manufacturer to assess feasibility of timelines and align cross-functional teams on key immunoassay milestones.

Phase 2: Where to Play

In this phase, key operational decisions for successful execution of the assay, should be addressed.

1. Test launch timing is a critical consideration for manufacturers. While early launch is better for early treatment eligibility decisions, there may be legal and regulatory risks if a companion diagnostic is launched prior to the associated therapy. The sample collection location (e.g., lab networks, hospital or on-site phlebotomist, gene therapy centers, etc.) should also be identified in this phase to ensure an enhanced and seamless patient experience.
2. Manufacturers should be aware of budgetary, regulatory, and legal considerations when looking at test reimbursement and sponsorship. For instance, while a manufacturer could sponsor a test in the US, they may not be able to sponsor one in Japan because of insurance guidelines. Similarly, when deciding between a global central lab or multiple regional labs, manufacturers must consider budgetary constraints, type of test, regulatory considerations, and turn-around time.

Example of Potential Planning Issues
A pharma company was planning to commercialize its gene therapy in multiple global markets. Their immunoassay was a LDT (laboratory developed test) based in a US lab. Close to therapy launch, one of the targeted Asian countries regulatory authority would not accept LDT results and insisted that the test be localized (testing kit form) and requested additional validation data. This led to significant unplanned efforts to localize the test and adversely impacted the therapy launch in the market.⁵

3. The right vendor selection is critical to ensure operational efficiency and robust execution with requisite requirements such as GMP, QMS compliance. The selected vendor must have substantial assay development experience in the target markets of interest. They must also have experience negotiating with regulatory authorities to get the assay approved in time. Experience running and commercializing the assay in a real-world setting with the manufacturer preferred model (single lab, multiple labs, etc.), and leveraging requisite partnerships with third-party logistics providers (3PL) and data vendors is also pivotal. Phase 3: How to Win

Phase 3: How to Win

The final phase focuses on preparing for launch and aligning the strategy and tactics for maximum assay adoption and uptake.

1. Multiple adoption considerations such as treatment guidelines, treatment labels, KOL influence, and patient advocacy are critical to ensure smooth execution, enhanced uptake, drive awareness for the assay and create competitive advantage in the market.
2. Alignment of needed cross-functional enterprise capabilities enables seamless assay execution and ‘winning’ in the market. Every major function of the organization likely needs specific capabilities to support the assay. CMC & Manufacturing teams need to assess the supply chain regarding assay raw materials supplies to the vendor. Marketing will need to assess their payer/HCP/patient engagement strategy because education and training for the assay is vastly different from the therapy. 
3. Successful commercialization demands an understanding of the range of choices and decisions required. It is pivotal that organizations prioritize the assay and view it as critical as the therapy.

Conclusion
Rather than being seen as a secondary activity, immunoassays should be viewed as business-critical efforts with potential to create competitive advantage for gene therapy manufacturers. It is important to recognize the time, effort, and specialized resources required to support immunoassays. A thoughtful approach that acknowledges the complexity and the importance of the assay and integrates it more closely into the broader commercialization plan, will position the manufacturer for success.

Acknowledgements
The authors would like to acknowledge the work done by Amit Agarwal, Managing Director, Deloitte that helped shape the article. 

About The Authors

Mathias Cousin is a Managing Director at the Boston office of Deloitte. He joined Monitor in Spain in 2007 and has since led engagements in the USA, Europe, Africa, and the Americas. Mathias co-leads the midcap as well as the cell and gene (NextGen) therapy practices in New England and has deep experience in helping pre-commercial and commercial biotech clients explore and define growth options, scale their organizations, and leverage technology to transform their business. He serves clients both on the commercial and R&D side of the business. He also serves as a mentor to Series A / seed-round companies through the MassConnect program from MassBio. He can be contacted at mcousin@deloitte.com.

​Ashraf Husain is a Manager in Deloitte’s NextGen therapies (cell and gene therapies) practice focused on helping biopharma and biotech companies define and implement capabilities to develop, produce, and commercialize cell and gene therapies. Ashraf has led a spectrum of NextGen projects: designing global therapy delivery operations, identifying considerations and roadmap for a pre-clinical therapy, building supply chain and manufacturing processes, commercial launch readiness planning, technology roadmap creation, etc. He can be contacted at ahusain@deloitte.com.

​Shweta Arya is a Senior Consultant is Deloitte’s life sciences practice focusing primarily on cell and gene therapies clients. Shweta has deep experience in commercialization and capability building for cell and gene therapies and their associated companion diagnostics. Her other focus areas include product strategy, launch planning and go-to-market strategy. She can be contacted at shwarya@deloitte.com.

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Sources

1. https://www.fda.gov/vaccines-blood-biologics/biologics-research-projects/immunogenicity-gene-therapy-products\
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507026/
3. https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(22)00027-4
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746592/
5. Based on secondary market research