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22 BioPharm International ® Emerging Therapies eBook September 2023 www.biopharminternational.com Vaccines and blood cancer patients with failed prior treat- ments. A larger population of potential patients in- troduces new challenges and considerations for pa- tient recruitment. Sponsors must understand where patients are and how eligible subpopulations can be identified and targeted. Identif ying eligible subpopulations is especially d i f f icu lt for ca ncer vacci nes t hat ta rget speci f ic tumor antigens, where subpopulations of patients expressing t hese a nt igens need to be ident if ied. Depending on the prevalence of the antigen in the population, this can dramatically limit patient eli- gibility. This issue may be somewhat ameliorated by personalized vaccines, or vaccines targeting multiple antigens, where the eligible population is larger (4). For example, more than 90% of melanoma patients express at least one of the antigens targeted by the BNT111 vaccine mentioned previously. Rega rd less of a nt igen-expression const ra i nts, many cancer patients may be ineligible because of the stage of their cancer, or the treatments they have already undergone. In addition, eligible patients will be distributed across broad geographic locations, and many may not live within the travel distance of sites with appropriate resources and expertise to conduct a trial. New analytics capabilities that can sift out potential study participants from electronic patient records and other digital sources are a considerable step forward, as are the technologies and strategies behind the shif t f rom traditional site-based trial models to decentralized or hybrid clinical trials. Once eligible patients are identified, they must evaluate and choose a potentially transformative, yet essentially hypothetical, approach with the pos- sibility of unknown risk where there may be several other therapeutic options. Therefore, successful pa- tient recruitment requires early engagement, data presentation, and partnering with physicians and patient advocates. Manufacturing and supply chain As with other personalized CGT products, the man- ufacturing platform and supply chain for cancer mRNA vaccines must be designed for the speedy pro- duction and delivery of unique products. However, learnings from supply chains and the manufacturing of other CGTs may need to adjust to larger scales to target a broader range of patients, such as those with solid tumors. At this larger scale, manufacturing approaches for personalized mRNA cancer vaccines must be able to consistently and quick ly produce products of the right quality, independent of the vaccine "sequence," and have the right technology and internal systems in place to establish a regulator y-compliant chain of custody. Speed is imperative because, for person- alized treatments, manufacturing and delivery is a race against an individual's disease progression. Ad- ditionally, there is no room for manufacturing or sup- ply chain error, and the manufacturing process must ensure there is no cross contamination of products. Achieving speed and scale in manufacturing with- out introducing error requires streamlining produc- tion, including generating cell banks that can pro- duce plasmid vaccines and other drug substances when possible. Vaccine developers, such as BioNTech, have successfully implemented strategies to stream- line manufacturing, reducing the manufacturing and deliver y time of their mRNA cancer vaccines from three to four months to three to six weeks (7). Additional considerations must be made during de- livery as well. Cancer mRNA vaccines will require spe- cialized storage to ensure stability and may also need to adhere to country-specific guidelines on import and export of CGTs. Given that many cancer vaccines will be personalized, the supply chain process must also imple- ment product tracing to ensure products are segregated. Streamlined product release can benefit from the adop- tion of paperless approaches. Finally, growing consid- erations may need to be made for the coordination of manufacturing and the delivery of multiple different therapies at once, as the combination of CGTs for cancer become more commonplace (such as the combination mRNA vaccines and CAR T-cell therapies). Regulatory compliance Conducting clinical trials for cancer vaccines involves complying with a range of local regulatory require- ments. Regulatory review will include many facets of production and distribution, including the receipt of the initial plasmid, the dispatch of material to the clinic, supply chains for the equipment and materials used in the production processes, batch manufacturing record review, and analytical testing. The regulatory challenges for CGTs are eased, to some extent, by the existence of only partial or constantly evolving guidelines. This enables companies to work more closely with regulators in plotting approval path- ways collaboratively. However, it requires early and pro- active engagement. Ensuring that platforms are safe and will achieve clinical thresholds requires close relationships between drug developers, manufacturers, and regulatory author- ities. Interdisciplinary collaboration during the initial planning and development stages can help ensure man- ufacturing platforms have a well-defined and validated manufacturing process that remains the same regard- less of the specific mRNA sequence. Funding CGT manufacturing, for clinical trials and beyond, is often a high cost in terms of capital investment, the