The Need for Standards in Cell and Gene Therapy

The regenerative medicine industry is developing life changing therapies for many diseases and conditions, which to date, have not had any viable treatments. In addition, novel approaches for using cells for tissue engineering, along with in vitro cell and organ models are allowing researchers and clinicians to approach diseases and disease modeling in very different ways. As the technologies for developing these cell-based therapies and models are new as well, the Standards Coordinating Body for Regenerative Medicine (SCB) seeks to identify and understand the areas with the greatest need for standardization to help the industry progress as quickly—and safely—as possible. In this article, I outline our recently published document entitled: “Community Perspectives: Needed Standards in Regenerative Medicine.” 

Accelerating Standards Development
The primary goal of SCB is to accelerate standards development. Patients are counting on the industry to bring these new, novel and innovative therapies and products as quickly as they can.

In the past, standards development has been seen to take years. This can be attributed to the passive process of standards work which is primarily based on volunteer contributors from the industry. SCB makes accelerated standards advancements possible by focusing on the high priority/high impact standards and actively facilitating the process. Without a coordinating body like SCB, these pre-development steps can take up to six years; with SCB’s support, these steps take as little as six months to one year.

The data in support of the need for regenerative medicine and cell and gene therapies is clear. The Alliance for Regenerative Medicine identified in their State of the Industry (SOTI, January 2021) report, there are more than 1220 clinical trials underway, 152 in Phase III, and nearly $20 billion dollars was raised in 2020. Along with this intense interest and activity, major questions and themes for the industry remain including: 

• How do we address commercialization/industrialization (scale-up or out) of cell and gene therapies?
• How do we address costs?
• How do we accelerate innovation to help support these goals?
• How do developers of therapeutics most efficiently address tech transfer as many products are being manufactured in CDMOs?

The 21st Century Cures Act—signed into law on December 2016—directed the U.S. Food and Drug Administration (FDA) to accelerate medical product development through the advancement of standards. SCB has been supporting this need by identifying existing and in-development standards relevant to regenerative medicine.

Regenerative medicine has relatively few existing standards compared with more mature medical fields, leaving researchers and manufacturers to solve complex challenges of clinical translation and scaling of commercial products independently. Furthermore, regenerative medicine products are highly personalized and are often made of dynamic, living cells, which creates unique difficulties with establishing common practices for comparing test results and ensuring consistent product quality and safety.

Beginning in 2018, SCB gathered feedback and input from more than 250 regenerative medicine stakeholders (Figure 1) for the “Needed Standards Report” through expert interviews, a community-wide survey, and community prioritization exercises at several workshops.  

This report compiled the information provided by the industry and stakeholders and segmented data into the sectors of regenerative medicine that each area was most relevant to:

• Cell therapy: Products made from living, whole cells that are injected into a patient in order to treat a disease.
• Gene therapy: Products that aim to correct or compensate for defective versions of genes by delivering a healthy copy into patients’ cells.
• Tissue engineering: Products made from scaffolds, cells, and/or biologically active molecules to create new, functional tissue or whole organs.

In addition, detailed standards were assigned to appropriate functional areas where they would be most applicable.

• Bioprocessing and Production: The design and development of processes, materials, and equipment for manufacturing products from raw/ancillary biological materials (e.g., the characterization of starting materials such as cells, gene therapy vectors, and biomaterials).
• Analytics and Testing Methods: The tools and methods used to detect, measure, and/or monitor the properties and state of regenerative medicine product components.
• Product Quality and Characterization: The measurements and guidelines needed to convey well-defined quality attributes of materials used in regenerative medicine therapies and provide a clear understanding of their intended use.
• Logistics and Compliance: The processes and protocols surrounding the coordinated collection, manufacturing, and administration of cells and other therapy products across the supply chain.
• Preclinical Studies: The testing of a drug, procedure, or other medical treatment in animals before clinical trials in humans can be started.
• Clinical Trials: The research studies that determine whether a regenerative medicine strategy, treatment, or device is safe and effective for human use.

Many of the standards needs listed in the report describe challenges common to multiple regenerative medicine sectors. All of the standards needs in the cell therapy section will relate to common regenerative medicine process or quality concerns and are therefore also applicable to the tissue engineering and/or gene therapy sectors.

The insights gleaned from the research identified 44 areas identified and prioritized by the regenerative medicine community where standards could yield significant benefits to the field (Figure 2).
Additionally, we wanted to understand the relative priority of each of these needs based on their potential impact to the field and the urgency with which a need must be addressed:

• Impact is defined as the difference a needed standard could have on the regenerative medicine community, product development, and ultimately on patient care. This includes the   extent to which addressing this need could improve the safety/quality, and/or accelerate the time to market or development of a product, lower the cost to develop products, and improve patient access and care.
• Urgency refers to the difference that acting now versus later could make to the quality and safety of regenerative medicine products.  (We use a 5-year time horizon as reference)

The top five areas of need, which are revisited annually in light of industry dynamics and trends are defined as follows (“G” refers to gene therapy; “C” cell therapy; “T” tissue engineering):

• G4 Viral Vector Gene Quantification
• G1 Framework for Gene Delivery Methods & Gene Editing Tools
• C12 Test Methods to Measure Sterility, Mycoplasma, and Adventitious Agents
• T1 Characterization of Scaffold Materials
• C22 Transportation Standards for Regenerative Medicine Products

With the progress of gene therapy and gene-modified therapeutic products, it should be no surprise that Viral Vector Gene Quantification and Gene Delivery Methods/Gene Editing tools were identified as most impactful and urgent. The industry has struggled generally with assessment of sterility, mycoplasma and adventitious agents due to the nature of cell-based products. 

Additionally, for autologous therapies where the time between final dose preparation and administration is generally much less than 14 days, standard USP sterility tests cannot be employed. Rapid methods have the potential to have great impact here and the National Institute of Standards and Technology (NIST) has recently established a Rapid Microbial Testing Methods consortium to address these very issues ( https://www.nist.gov/programs-projects/nist-rapid-microbial-testing-methods-consortium). The characterization of scaffold materials in tissue engineered products is not surprising given the complexities of the materials and the structures produced in this area. Transportation standards for Regenerative Medicine products are becoming more and more important especially with patient-specific therapies being approved (Figure 3).

Key Themes from the Segments Cell Therapy

• Many of the needs in this sector are interrelated with gene therapy and tissue engineering.
• A core challenge of cell therapy is cell characterization—defining critical quality attributes (CQAs) and optimal testing methods to ensure that cell therapy products are safe and effective.
• Several other standards needs relate to better understanding individual areas of CQAs: identity, cell counting, and viability.
• Other key challenges include mitigating the potentially harmful effects of foreign agents in cell therapy products (e.g., microbes, particulates) and working around short product shelf lives.
• Criteria for method selection (i.e., which assay to use and when to use it) will help improve efficiency and consistency in cell therapy production.

Gene Therapy

• Delivery of appropriate doses of vectors to patients is a foundational challenge that could be addressed through vector quantification standards.
• The factors that cause adverse reactions in gene therapy patients (e.g., immune response to T-cell therapy products or complications from replication-competent retroviruses [RCRs]) must be better understood.
• The sector also needs robust best practices for gene editing tool selection and use to support overall safety and effectiveness of products

Tissue Engineering

• Researchers and product developers are working to create tissue engineering scaffolds with consistent properties and long-term integrity. Standards can help with this challenge.
• The tissue engineering sector currently lacks specific standards to define optimal testing methods and fit-for-purpose measurements, particularly in the Bioprocessing and Production and Clinical Trials functional areas.

The Way Forward
The top areas of need as identified in the Needed Standards report will be assessed for Feasibility for standards development.  Feasibility is an objective assessment by which Tier 1 (Technical, Economic and Operational aspects are considered) and Tier 2 (Legal, Resource (SDO and SME) and Schedule) parameters are reviewed with stakeholders. This determination helps us understand whether a particular area is ready for proceed into the standards development process. 

The industry faces many challenges in cost, time, and efficiency. Virtually every product can benefit from the development of standards in areas that are common across platforms (e.g. Ancillary Materials, Cell Viability, Cell Counting) and aid in both process development and characterization in addition to easing regulatory review burdens. SCB is an organization focused on continuing to accelerate the standards development process, inform and educate the field by making information as readily available as possible, and is looking to help industry implement standards in the most efficient and appropriate ways.

Development of standards can help address many challenges the industry faces. In order to support the growth of this field and the continued success of emerging therapies, the regenerative medicine community must advance new standards targeted at the field’s most pressing needs. The Needed Standards Report is intended to help identify these areas and focus efforts to support efficient, and scalable practices and reduce the burden on companies seeking regulatory approval for their products. 

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Bob Shaw is the executive director of the Standards Coordinating Body (SCB). Bob’s past experience spans nearly 30 years of technical, operational, strategic, and commercial development in the regenerative medicine and biotechnology fields. Prior to joining SCB, he served as Vice President of Thermo Fisher Scientific, where he implemented a number of innovations to drive growth and expansion, including strategic processes to improve the structure and function of their Field Scientist and Program Management functions.