Potential Next Steps for Supporting the Development, Manufacture, and Regulation of Regenerative Medicine Therapies
The workshop’s final session included a keynote address by Dean Kamen, founder and president of DEKA Research and Development Corporation and founder of the Advanced Regenerative Manufacturing Institute (ARMI) and For Inspiration and Recognition of Science and Technology (FIRST). The keynote address was followed by reflections from Robert Preti, Anne Plant, Phil Vanek, and Robert McBurney. There were several areas of discussion that arose as the panel reflected on the workshop and the important ideas that had emerged throughout the day (see Box 6-1). These areas included emerging technologies and scientific challenges, developing standards and a regulatory framework, interdisciplinary collaboration, workforce training and management, the role of the patient in the discovery and development process, and planning for the future in the regenerative medicine industry.
In preparing to respond to a funding opportunity announcement from the U.S. Department of Defense that sought to establish a facility to develop advanced manufacturing technologies for regenerative medicine, Kamen said, he led a team that visited cutting-edge academic laboratories, where they were impressed by “22nd-century science fiction” being accomplished using equipment and techniques that would have been familiar to Louis Pasteur. “It was astonishing what [researchers and graduate students] could do with virtually no modern process control, no tools of robotics, sensors,
high-precision feedback systems, or documentation systems,” he said. From these visits, he said that he realized that the research and discovery being carried out in these labs could be accelerated and supported through the application of engineering, mathematics, and robotics. The idea for such a collaboration between scientists and engineers resulted in the formation of the nonprofit BioFabUSA in conjunction with ARMI.1 ARMI’s mission
is to make practical the large-scale manufacturing of engineered tissues and tissue-related technologies, Kamen said. In support of that mission, BioFabUSA was created as a ManufacturingUSA Innovation Institute to drive technological innovation in five areas: cell selection, culture, and scale-up; biomaterial selection and scale-up; tissue process automation and monitoring; tissue maturing technologies; and tissue preservation and transport. “As part of the BioFabUSA coalition, we have some of the most creative and brilliant engineers and we think out of the box, but we don’t think inside the cell,” Kamen said. Though his group has little experience in regenerative medicine, he believes that the engineers at BioFabUSA can help in achieving progress in these five areas of innovation, he said.
The collaborative model used for BioFabUSA is based on the model used to establish the nonprofit FIRST, Kamen said. The mission of FIRST is to inspire the next generation of young people to become interested in science and technology by engaging them in programs that focus on innovation and building self-confidence (see Chapter 2 for further discussion on manufacturing workforce issues). Founded 25 years ago with the goal of increasing the number of children with backgrounds in science, technology, engineering, and mathematics (STEM), FIRST was created to bring industry, universities, parents, teachers, and governments together to create a fun environment in which children, particularly women and groups underrepresented in the STEM fields, would see science and engineering as attractive fields to pursue, said Kamen. The intent is that BioFabUSA will follow a similar growth trajectory as FIRST, resulting in a thriving collaborative effort that will advance innovation in the field of regenerative medicine, he said.
FIRST started with a competition in which 23 teams participated, about the same number of teams that have now joined BioFabUSA, Kamen said. Initially, he said, he encountered skepticism from people who claimed the program would not grow in scale and that he would not be able to convince engineers and scientists to take time to be mentors for these children. Twenty-five years later, he said, FIRST now has 55,000 teams from 83 countries participating in 140 events. The program collaborates with approximately 200 universities, which provided $50 million in scholarships, and 3,700 corporate sponsors who are active members. Most of the major aerospace and technology companies sponsor FIRST teams, Kamen said, and the top two sponsors are the U.S. Department of Defense, with 651 teams, and the National Aeronautics and Space Administration, with 230 teams.
Though BioFabUSA was only a few months old at the time of the workshop, Kamen said that the parallels with the origins of FIRST offer hope that it will experience similar growth in participation and enthusiasm across its stakeholder groups. The constituents of the two groups are very similar, Kamen said, with government, industry, universities, and citizens
collaborating through BioFabUSA much as they do through the FIRST program. As much as the world needs more scientists and engineers like those that FIRST is creating, Kamen said, there also needs to be a massive coalition of technical experts who will contribute their expertise and help move today’s exciting therapeutic breakthroughs to a practical industrial scale. ARMI and its partners are now evaluating 21 quick-start proposals with the intent to foster technical and scientific innovation through collaboration. The more radical an idea is, he said, the harder it is to set a regulatory precedent. To that end, the organization has emphasized including FDA throughout the discovery and development process as it begins to integrate science and engineering to create new technologies. There is a lot that the engineering community has sitting on the shelf that could be modified to help bring scientific discovery out of the “roller bottle” (where cell cultures are grown and stored) and into scale, Kamen said.
The goal of BioFabUSA, Kamen said, is to help the field navigate the existing gap between basic research and commercialization. In this gap, the advancement of new therapies and discoveries can become overwhelmed by the technical and financial challenges of scaling up and thus fail to reach commercial production. By applying engineering principles to the scaling-up process and modifying existing technologies, those at BioFabUSA plan to develop a new vision for regenerative medicine therapies. For example, a proposal currently under consideration uses the model for a home dialysis machine as a basis for the development of a self-contained biosystem capable of processing cells and other biomaterials in a small, sterile system that does not require clean room facilities. “We are going to change the world,” Kamen said. “Along the way, we are going to build a coalition that will be the next big advance in health care.”
Scientific Challenges and Emerging Technologies
The biggest opportunity to move the field of regenerative medicine manufacturing forward lies in robotics and automation, Anne Plant said. Successful automation would not only help control the manufacturing process and improve the quality of measurements, but would also provide clarity about what parameters affect the clinical potency of a product, she said. The number of potential parameters is very large, and today the field relies on individuals and the execution of manufacturing processes by hand to determine which parameters are relevant to a product’s potency. Automation can reduce variability and make it easier to minimize the “parameter space” because while it is dependent on knowing what to measure and how
to control a manufacturing process, the desire to automate will help to clarify what to measure, what characteristics are critical to a product, and how to control the various parts of the manufacturing process that affect those characteristics. “Right now, there is so much variability in a process, a product, or how a patient responds that [it is difficult to know] where to start with respect to understanding how to minimize that variability,” Plant said. Automation is the way to reduce that variability, she concluded, but it must be designed with both statistical and engineering principles.
There is a need to constrain the “parameter space” appropriately and to develop a greater understanding of fundamental scientific principles as a more practical approach to derive realistic solutions, a workshop participant said. “This is a critical idea, and even though those of us who are physical scientists and engineers understand this, it does not get explicitly expressed enough,” he said. “Understanding the laws of nature, the ‘rules of life,’ so to speak, is a practical approach to problem solving.”
One technical challenge facing the field is that the current understanding of CMC issues is lagging behind clinical development, Preti said. There remain many unknowns and variables when producing regenerative medicine therapies, and research and process analysis must be ongoing in order to better understand what chemical, biological, and process parameters affect the effectiveness of a new therapy. To move the field forward, researchers and manufacturers must understand that product identity is not potency and that the process is not the product, he said, emphasizing that a list of a product’s characteristics does not necessarily indicate its potency and that following a manufacturing protocol does not necessarily yield an effective product. Vanek agreed, adding that it will be vital to improve techniques for characterization, process development, and assay development for measuring comparability. As a tool-providing company, GE is greatly concerned with comparability and scalability, he said, and it will be a challenge to introduce new tools that can provide both in an effective and innovative way.
Developing Standards and a Regulatory Framework
A common theme throughout the day was the importance of communication and collaboration among academia, industry, government, patients, and advocacy groups. A workshop participant said that the field is on a good track with regard to developing guidance documents and standards, which take a tremendous amount of effort to develop, and he asked how the panelists would suggest that FDA communicate and engage with stakeholders in the field to support these efforts. There are a number of venues where these conversations do occur, Vanek said, such as through the Alliance for Regenerative Medicine, the International Society for Cellular
Therapy, and the National Academies’ Forum on Regenerative Medicine. Regulators do understand the challenges facing the development of these therapies, Preti added, noting that he has had many interactions with FDA over the years and found them to be very useful. “I do not know what else FDA could do,” he said. “The fact that FDA listens and responds the way it does has been really helpful.” Increasing transparency about the ongoing activity at FDA that might affect some of the challenges that industry faces when it runs into roadblocks could be beneficial, he suggested. It would also be helpful, he said, if FDA would continue to educate industry stakeholders about how they can improve the materials they submit for FDA review and about where they could improve on their implementation of FDA advice and guidance.
FDA and industry should both be working to get better clinical solutions to people that will improve health and reduce costs as quickly as possible, Kamen said, adding that he would like to see FDA become more of a partner without giving up its role as a regulator. If something causes delays or prevents patient access to new therapies, he said, it violates both of those objectives. Kamen suggested that FDA should act more like a government building department, which approves plans before a building is built and provides advice and review throughout the building process, so that the final approval is almost a formality. Partnering with FDA throughout the development process may depend on how a company approaches them, Preti said. FDA has been a good partner through programs such as special protocol assessments, he said, and in his experience the problem has been that industry has not developed transformative therapies.
FDA has provided tremendous assistance to the biotechnology industry as biological therapies such as monoclonal antibodies were developed, even before the science of these therapies was well understood, Siegel said, citing FDA’s mission statement that includes the responsibility to “advance public health by helping to speed innovations that make medical products more effective, safer, and more affordable by helping the public get the accurate, science-based information they need to use medical products and foods to maintain and improve their health.”2 Cell therapy is following a similar pathway to that of monoclonal antibodies, Siegel said, adding that his hope is that it will lead to improved manufacturing processes, more automation and standardization, and a detailed understanding of the CQAs that will accelerate the process of bringing products to market. In addition, he said, the ongoing efforts to create standards and invest in the science and automation will get the field to where it can generate therapies much faster.
All stakeholders, including scientists, patient advocates, standards organizations, companies, clinicians, and regulators, should participate in the effort to automate the production of regenerative medicine products, Kamen said. That is the intent of the U.S. Department of Defense’s investment in ARMI, he added. While acknowledging the importance of competition and intellectual property, Kamen said that there is a pre-competitive space in which all stakeholders can work together. Biologists and clinicians should start working with mathematicians and engineers to identify fundamental ideas that can dramatically increase the rate at which the field progresses, he said.
Transformative solutions to the challenges facing the field of regenerative medicine will likely come from mathematicians, a workshop participant said. In his view, he continued, the “design space” of the living cell—i.e., the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that provide assurance of quality—is too large for the human brain to fully visualize. Improving the development process will require software that can accommodate the complexity of the living cell’s design space and generate the particular conditions that an engineer needs to scale a manufacturing process, he said. In the future, he predicted, researchers will use this type of approach to design cells with the characteristics desired for a specific application.
Training the Workforce of the Future
Addressing the lack of trained workers will be a major challenge, McBurney said. Vanek agreed, saying that training and motivating the workforce that the regenerative medicine industry needs to be successful will be a significant hurdle. It will be important to engage the STEM community and instill a sense of ownership and passion for this work, Vanek continued, and it will require companies to think creatively about the range of skill sets and expertise levels needed to support the manufacturing process. The manufacturing environment is challenging, Preti added, and advancing the potential for companies to develop innovative products will be dependent on bringing together individuals with the right expertise rather than on relying on generalists to carry out the full development process. Zylberberg added that the workforce should be trained to meet the industry’s future needs. Although automation may replace some jobs, she said, there will be many others that require humans, and she suggested that the existing consortia can play an important role in training that workforce.
The Role of the Patient in the Discovery and Development Process
Patient advocates have a rational approach to therapy development, Preti said. They want more than simply getting treatments as soon as possible; they would prefer to participate in the development process themselves and to support the advancement of efficient, evidence-based therapies. Levine said that there should be continued and enhanced participation of patients through the National Academies’ Forum on Regenerative Medicine, through BioFabUSA, and through the National Institute for Innovation in Manufacturing Biopharmaceuticals because that is how the field will communicate with the rest of the world. “The rest of the world will not see the data,” Levine said. “They are going to see patient stories.”
Transforming the Industry
Five years ago, manufacturers in the regenerative medicine industry were not aware of what they did not understand about the development of regenerative medicine therapies, Vanek said, but that has started to change. Big data, artificial intelligence, and machine learning have the potential to improve this understanding and transform the industry, he predicted. “How can the industry prioritize moving forward more rapidly in a way that incorporates all that has been learned about quality and regulatory oversight?” he asked. The first step, he said, will be to truly understand the science in order to improve analytical and production processes, followed by addressing the issues of scalability and comparability. “Attend to the biology and the science first,” he said, “and the cost reduction will follow.”
From a big picture point of view, Preti said, there are three important points regarding the future of regenerative medicine manufacturing that emerged from the workshop presentations and discussion: There is organic growth happening in the industry. There is funding coming into the field to support the development of these products. And this is a community of people who continue to collaborate with each other in order that patients worldwide will have these therapies accessible to them in the very near future.
The regenerative medicine community must move forward with an inclusive approach to the discovery and development of new therapies, McBurney said. Training should not be regarded in terms of science versus engineering, product development should not be approached in terms of complexity versus consistency, and the regulatory environment should not pit patient demand against regulation. Once the field starts prioritizing collaboration and applying a design framework to the development and manufacturing processes, he predicted, progress will accelerate to a degree that it will take a mere 20 years for regenerative medicine to become a dominant part of therapeutics.
In offering some final thoughts on the day, workshop co-chair Steven Oh said that it was clear from the day’s presentations that there are numerous challenges facing the field, many of them related to science and technology, others related to successfully navigating the manufacturing process and ensuring the quality of regenerative medicine products. Other challenges, he said, are related to information technology issues, such as how to manage and share data, while still others have to do with workforce training.
The day’s discussions highlighted the fact that fostering an environment that can maintain a good balance among technology innovation, safety and quality, and patient benefit will be crucial to the success of navigating the manufacturing process and assuring the quality of the regenerative medicine products, Oh said. Another important lesson, he said, was that when issues such as demonstrating product comparability or validating new manufacturing methods arise, taking a science-based approach will offer the best chance of addressing those issues. “From the regulatory perspective,” he said, “we whole-heartedly agree that [science-based approaches] should guide us as we move forward with any of the manufacturing problems we want to deal with in this regenerative medicine therapy product space.”
There are differences in the ways that regulatory agencies around the world think about manufacturing processes and quality assurance, and in turn, how manufacturers approach their processes as a result of these differences, Oh said, agreeing that the field needs to consider how to narrow those existing gaps between regulators and manufacturers. The industry’s desire to develop point-of-care manufacturing will be a complex challenge to address from the regulatory, manufacturing, and quality assurance perspectives, he said, and he challenged workshop participants to start thinking about how to address the issues that will arise in moving to point-of-care manufacturing of regenerative medicine therapies.
Continued dialog among all of the stakeholders in the regenerative medicine field will important moving forward, Oh said. “I think it is essential that we have a good dialog early on,” he said, adding that stakeholders are still figuring out the best way to initiate or continue that dialog.
Workshop co-chair Claudia Zylberberg said that organizations such as the Standards Coordinating Body can help move the field forward and that they should do so in coordination with FDA. In the quest to understand what cells are doing and to move the field forward, she said, progress is sometimes limited by the available technologies. There is an opportunity, she said, for biologists, engineers, and physical scientists to innovate together to come up with ways that existing technologies or ones yet to be developed can measure the important attributes of cells and provide the insights that will drive progress.
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