Managing Biospecimens in Cell and Gene Therapy Trials

One of the most powerful and significant developments in medical therapies in the past decade has been the maturing of cell and gene therapy (CGT) treatments. Cell therapies such as CAR-T and TCR-T offer transformative outcomes for challenging diseases. Recent cell therapy approvals and the growing number of clinical trials are accelerating the process from discovery through clinical trials to commercial manufacturing and delivery.¹

Gene therapies can provide significant—and possibly curative—benefits to patients who have genetic or acquired diseases. Through the direct expression of a therapeutic protein or by restoring the expression of an under expressed protein, gene therapy uses vectors to deliver gene-based drugs and therapeutic loads to patients.

While the approvals for treatments for rare diseases are certainly early wins, the impact of gene therapies will significantly expand as approved treatments are administered to larger patient groups and studies expand to address diseases that are broader reaching—for example, with treatments for multiple myeloma, leukemia, and other forms of cancer.²

Biospecimen management challenges

Compared to more standard biopharmaceutical clinical trials, there are unique challenges associated with managing biospecimen samples during trials of CGTs. One of the most critical challenges is properly and safely managing the specimens taken from each patient, since those specimens can actually be used to create the therapy and must be returned with absolute safety to the patient for treatment.

CGT trials, while following their own specific workflows, are generally carried out in similar stages. Cell therapy can be allogenic when produced from cells that are collected from a healthy donor and shipped to a clinical site to treat a patient. Alternatively, there can be autologous therapy, where the biological material is from the patient and is transferred to a biomanufacturing site for genetic modification, and then returned and administered to the patient the sample was taken from.

Although each trial is unique, the major workflow steps are relatively similar. First, genetic or cell-based disease states and potential therapeutic pathways are identified by researchers and the trial design begins to be developed.

Once a trial is designed, trial participants need to be identified. Unlike other biopharmaceutical trials, CGT trials tend to have much smaller patient populations. Biospecimen cells are collected from these patients and need to be transported under the most stringent safety and cryopreservation conditions in coordination with regulatory requirements.³ This includes having well-established cold chain logistics that manage and document each specimen’s condition to ensure that no temperature-related degradation occurs.

Each specimen is then used to biomanufacture the therapeutic cells—either through modification of the cell genome (for cell therapy) or through creation of the viral vectors to deliver gene-based drugs and therapeutic loads to the patients. These temperature-sensitive therapies must then be carefully thawed, with minimum impact on viability and functionality, to be delivered to the patient by the clinical trial team at the investigative sites.

In addition, as part of the clinical trial, portions of the specimens need to be set aside, before and after biomanufacturing, for various testing requirements. Tests like qPCR, ELISA, flow cytometry, and others are critical to conducting the analysis of the therapeutic steps being studied, so proper storage (short-term and long-term) needs to be fully managed.^4-5

Proper management of aliquoting biological samples is also a critical element in biospecimen management for these trials in order to mitigate risk of cell deterioration from freeze-thaw cycles. Many research centers require aliquoting to generate sub-samples for distribution to third-party laboratories and clinical partners. Since the source biospecimens from each patient are so much smaller in actual quantity, extraordinary care is needed at every step of biospecimen management not to lose any biological material.

Finally, biospecimen management for CGT trials must include support for stable, multiyear storage. With the administration of gene therapy products into a patient, there is a possibility of delayed biological events that demand the collection of data for a longer period. The therapeutic changes that patients experience due to genomic modification often need to be tracked for 10 to 15 years, so long-term cryogenic storage of the modified cells is a critical element for supporting the trial.⁶

As CGT trials expand, it is important for the industry to investigate and fully understand the best practices researchers should follow for managing living/active samples during CGT clinical trials, especially given some of the unique processes described earlier.

Along with management during the active trial, it is also crucial to long-term biorepository and sample management to ensure your biospecimens are secure and safely stored. These best practices include having a thorough appreciation of the regulatory factors to consider when managing the type of data generated by these trials.

Due to the sensitive nature of this personalized kind of medicine, researchers need to work very closely with regulatory agencies to fully understand and plan the trials according to established protocols. Gene therapy developers have access to expedited approval pathways such as Regenerative Medicine Advanced Therapy (RMAT) designation in the US, PRIority MEdicines (PRIME) designation in the EU, and SAKIGAKE designation in Japan.

Biorepositories address management obstacles

Leading biorepository providers across the globe are responding to the heightened complexities and risks of biospecimen management in CGT trials. They are building on established sample logistics, storage, and management tools to address these unique challenges more fully. Concerns include:

Preserving the specimens from collecting the cells from patients through cell therapy manufacturing and delivery to them. Unlike other treatment regimens, the specimen is also the therapeutic pathway—its safe preservation, management and storage is critical to the progress of the clinical trial and ultimate demonstration that the therapy can be successfully applied.

Rigorous cold chain transport logistics to ensure cryopreservation at multiple stages. This requires detailed, multifactor tracking of each sample so that it is clearly and permanently associated with a specific patient at every point of exchange and every process step, including ancillary steps associated with clinical testing and long-term storage.

Detailed familiarity with requirements and compliance: All clinical practitioners and personnel from biorepository logistics and storage organizations need to be thoroughly grounded in the strict protocols established for each trial and demonstrate how their procedures comply; since CGT therapies are so new, and patient risk is elevated, biorepository operations have a special duty to manage any biospecimen management safety concerns.

The relative newness of CGT programs at major life sciences research institutions has led, in some instances, to a preference for keeping all aspects of clinical trials within a single research organization or network of researchers.^7,8

Because the relatively small size of the target patient in a given geographical region is as small as one-tenth the number of patients participating in traditional clinical trials, it has created the need for multiple locations worldwide for conducting clinical trials or having the patients travel for getting the clinical treatment. As a result, researchers tend to set up their own biorepositories, biospecimen management systems, and model industry best practices to maintain sample integrity and traceability across the sample management ecosystem.

While the desire for comprehensive control would seem to make sense, there are distinct advantages to working with expert biorepository operations to manage all key aspects of biospecimen capture, transport and storage. GxP or “good practice” quality guidelines and regulations with leading service providers assures proper storage for the viral vectors and cells so they have the traceability and consistency.

These include creating rigorous chain-of-custody procedures with advanced biospecimen digital documentation and tracking tools that tightly associate each specimen with its source patient throughout every exchange. They have established meticulous biospecimen collection and registration procedures that are flexible enough to adapt to specific clinical trial procedures, patient populations, manufacturing locations and regulatory protocols.

Biorepositories are also customizing their cold-storage logistics and transport procedures to support CGT biospecimens. This includes tracking shipments in real time using automated tracing software and GPS-based tools, as well as working with clinical researchers to minimize transport times from the site of specimen collection to therapeutic manufacturing and specimen storage locations.

Leading biorepositories have also made extensive investments in large-scale, custom-built cryogenic storage facilities. These plants offer storage temperatures ranging from cryogenic -196 °C and ultralow -80 °C to refrigerated and controlled room temperature storage, offering researchers much greater flexibility. These specialized systems are continuously monitored and typically include multiple backup systems to prevent accidental specimen loss due to outside events or local power failures. Some of the leading biorepository providers have sited these state-of-the-art facilities in multiple locations worldwide to enable CGT trials with global footprints and patient populations to work with a single biospecimen management provider.

There are biorepository and biospecimen logistics providers who are actively investing in more robust, expert biospecimen data management systems. Just like their operational procedures, these tools have been developed and continually improved through hands-on experience managing millions of samples for a wide range of research applications.

These material management systems give instant digital access to comprehensive data of biospecimens that have been transported and stored, allowing researchers to efficiently manage biospecimen inventory, submit work requests, and generate standard or custom reports.

In addition, they are further developing these systems to satisfy evolving regulatory requirements for CGT clinical trial data management, since the conditions of the biospecimens at all stages of transport, biomanufacture, and storage need to be exhaustively documented.

Working with expert biorepository organizations and outsourcing biospecimen collection, cold transport logistics and both short- and long-term storage provide CGT researchers with a proven resource that can help prevent error, protect patient safety, and help make CGT trials more efficient.

An effective path forward would include increased collaboration between professional biorepository operations and clinical trial researchers. By fostering true working partnerships, these experts can educate researchers on the risks associated with imperfect or poorly planned biospecimen logistics; especially with multisite trials, they can work to refine standardized procedures and tools used to collect, secure, document, and transport specimens to reduce the risk of error or inefficiencies.

Streamlining and standardizing biospecimen management can ultimately help reduce costs, minimize rework and simplify many clinical trial management tasks often carried out by researchers. The advanced data management capabilities also provide a powerful foundation for conducting advanced data mining and analysis of trial and biospecimen data to augment other research results.

Most importantly, working with biorepository experts to handle these critical tasks will free researchers to focus their valuable time and efforts on advancing the science CGTs.

Navjot Kaur, PhD, Business Segment Manager, and Radha Krishnan, Global Director, Biorepository Operations and Strategy; both with Avantor

References

1. A-GENE. (2021). Alliance for Regenerative Medicine. Accessed Dec. 8, 2021. https://alliancerm.org/manufacturing/a-gene-2021
2. Bulaklak, K., & Gersbach, C. A. (2020). The once and future gene therapy. Nature Communications, (11). https://doi.org/10.1038/s41467-020-19505-2
3. Meneghel J, Kilbride P, Morris GJ (2020). Cryopreservation as a Key Element in the Successful Delivery of Cell-Based Therapies-A Review. Frontiers in Medicine, (7)592242. https://doi.org/10.3389/fmed.2020.592242.
4. Guidance for Industry: Long Term Follow-Up After Administration of Human Gene Therapy Products, January 2020. https://www.fda.gov/media/113768/download
5. King, D., Schwartz, C., Pincus, S., & Forsberg, N. (2018). Viral Vector Characterization: A Look at Analytical Tools. Cell Culture Dish. Accessed Dec. 8, 2021. https://www.vironova.com/hubfs/minitem/pdfs/minitem-publication-key-considerations-gen-therapy-manufacturing-commercialization.pdf
6. Gene therapy needs a long-term approach. (2021). Nature Medicine, 27(4), 563. https://doi.org/10.1038/s41591-021-01333-6
7. Lindgren, C., et al. (2021). Processing laboratory considerations for multi-center cellular therapy clinical trials: a report from the Consortium for Pediatric Cellular Immunotherapy. Cytotherapy, 23(2), 157–164. https://doi.org/10.1016/j.jcyt.2020.09.013
8. Harrison, R. P., Rafiq, Q. A., & Medcalf, N. (2018). Centralized versus decentralised manufacturing and the delivery of healthcare products: A United Kingdom exemplar. Cytotherapy, 20(6), 873–890. https://doi.org/10.1016/j.jcyt.2018.05.003