Applying Systems Thinking to Regenerative Medicine Proceedings of a Workshop (2021) / Chapter Skim
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3 Exploring the Challenges of Critical Quality Attributes: The Role of Systems Thinking
3 Exploring the Challenges of Critical Quality Attributes: The Role of Systems Thinking
Pages 29-46
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From page 29... ...
• Systems thinking can be applied to therapeutic cell product development through an iterative process of integrating information about complex cell product characteristics with patient response data to identify the critical quality attributes of the cell product that should be monitored during good manufacturing practices. (Temple)
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; and Sally Temple, the scientific director, the principal investigator, and the co-founder of the Neural Stem Cell Institute. This session's objective was to understand the challenges associated with identifying critical quality attributes in the discovery, regulation, and manufacturing of regenerative medicine products and how systems thinking approaches may be applied.
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on the discovery side together with clinical data can support clinical evaluation. For example, Abernethy said, next-generation genomic sequencing data have been combined with electronic health record data to create appended datasets that marry those two types of information.
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For example, FDA is conducting a Model-Informed Drug Development pilot program1 in which clinical pharmacologists, statisticians, and other FDA professionals are working with industry and drug developers to use preclinical and early clinical data to improve the planning of clinical trials, identify dosing more carefully, and predict the most consequential trial outcomes more accurately. Using information gathered from sources that historically were excluded from the trial design process, this process is increasing the knowledge used in the clinical trials context.
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Abernethy remarked that when she joined FDA in 2019, she discovered that the elements of the tightly controlled, professionalized manufacturing process were not specifically appended to an understanding of how patients perform. At that time, cross-linking manufacturing details and optimization details with electronic health records data went against common practice, she said.
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Facilitating Systems Thinking Among FDA Sponsors Is FDA planning, Plant asked, on taking any actions to facilitate systems thinking on the part of FDA sponsors? The Model-Informed Drug Development pilot is a good example of encouraging this shift, Abernethy replied.
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Examples of reference datasets can be found in the laboratory and microbiology space, she said. Abernethy did not comment on the specific direction FDA plans to take in this area, but she suggested that the organization's Orphan Products Grants Program may pertain to this topic.4 Does FDA, Plant asked, offer incentives to stimulate data sharing among companies that may have proprietary information concerns?
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Systems thinking in health care delivery, especially for therapies such as chimeric antigen receptor (CAR) T cell therapy, can increase optimization across the service chain and have resulting value.
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Iterative Process of Defining Critical Quality Attributes Temple discussed the value of systems thinking to therapeutic cell product development. Cell products are a relatively new and growing area of therapy development.
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Although the challenges involved are considerable, she said, this process of defining critical quality attributes is essential to ensure reliable manufacturing of products that are safe and effective for patients. Process of Cell Therapy Development as a System Manian discussed the process of cell therapy development as a system (see Figure 3-1)
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FIGURE 3-1 Process of cell therapy development as a system. SOURCE: Bala Manian workshop presentation, October 22, 2020.
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He provided an overview of CAR T cell technology and the modern approaches based on machine learning that are used to understand the separate components of the system and bring them together in an integrative model. The current version of CAR T cell therapy involves genetically engineering lymphocytes harvested through apheresis from each individual patient.
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He presented a model of CAR T cell therapy that depicts how CAR T cells work, why they sometimes fail, and how they are identified. The critical product attributes of CAR T cells include intrinsic T cell fitness or expansion capability, T cell polyfunctionality, CAR functional avidity, and receptor density.
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it can be difficult to determine what to measure and for how long to measure it. However, critical quality attributes cannot be identified until patient data, including data about response, are incorporated into these analyses, Temple said.
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Improving Patient Data Collection Given the variability driven by different starting materials and diverse patient characteristics, Lebkowski asked, are clinical trials collecting sufficient data about patients and products to integrate aspects of manufacturing or patient variability into systems-based thinking? If it is not sufficient, she continued, which types of data should be collected and how can data collection, particularly from patients, be improved?
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Typically, cell therapy is approached in terms of making measurements with existing instrumentation; instead, he said, the process should start with defining the parameters critical to quality in order to determine the type of measurements needed. New methods developed to generate information about phenomena -- such as cytokine profiling and phenotyping -- across multiple patients and multiple types of drugs for the same disease state will likely further reveal how systems biology can affect manufacturing.
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Costs of Not Implementing Systems Thinking What are the costs to the field of regenerative medicine, Lebkowski asked, if systems thinking approaches are not implemented? Temple described a real-world example of a company that was generating a cell therapy for spinal cord injury and discovered that some element of the manufacturing process led to failure of that product.
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If systems thinking is not applied, then individualized patient-by-patient processes will remain unaffordable for a large segment of the population. Bot added that the costs of not implementing systems thinking are the missed opportunities to expand the footprint of potentially curative interventions in early disease stages and to benefit as many patients as possible.
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