United States Government Accountability Office Report to Congressional Committees July 2023 TECHNOLOGY ASSESSMENT Regenerative Medicine Therapeutic Applications, Challenges, and Policy Options GAO-23-105430 The cover image displays a stylized representation of a human body, circled by icons representing key regenerative medicine technologies. Cover source: GAO; Anttoniart/derariad/greenvector/mariia/microone/texvector/stock.adobe.com (images). | GAO- 23-105430 TECHNOLOGY ASSESSMENT Highlights of GAO-23-105430, a report to Regenerative Medicine congressional committees Therapeutic Applications, Challenges, and July 2023 Policy Options Why GAO did this study What GAO found Regenerative medicine represents a Regenerative medicine offers the hope of being able to restore or replace cell, paradigm shift in the medical field tissue, and organ functions affected by disease, injury, or aging. This may eventually because it aims to restore or help manage or cure many conditions that are currently considered chronic, supplement function, rather than just untreatable, or terminal. treating symptoms, and opens the Examples of Diseases and Regenerative Medicine Therapies That Might Address Them door for personalized therapies. GAO conducted an assessment of current and emerging regenerative medicine technologies and therapeutic applications. This report examines (1) current and emerging regenerative medicine technologies and therapies and their potential benefits, (2) challenges that hinder their development and use, and (3) policy options that could help enhance benefits and mitigate challenges associated with these technologies and therapies. GAO reviewed scientific and policy literature and other key reports; GAO identified many challenges that may affect the development and use of convened a 3-day expert meeting; regenerative medicine technologies and therapies including: and interviewed subject matter experts and stakeholder groups Challenges related to standardization. Standards are rules, conditions, guidelines, including government agencies, such or agreed-upon practices that are adopted within an industry to provide developers as the Department of Health and with a common framework and promote consistency. Developing regenerative Human Services, non-government medicine standards is challenging because these technologies and therapies are organizations, industry, academia, complex and rapidly evolving. In addition, standards require consensus from end user groups such as patient stakeholders, which may be difficult to obtain. groups. GAO is identifying policy Challenges related to regulation. The Food and Drug Administration (FDA) ensures options in this report. the safety, efficacy, and security of human medical products in the U.S. through regulation. Regenerative medicine faces challenges related to regulation, including difficulty navigating a complex regulatory framework, uncertainty over which regulatory pathway is most appropriate for certain emerging technologies and therapies, and staffing shortages at FDA and collaborating agencies. Challenges related to manufacturing. Manufacturing is the creation of products from starting materials, in a way that is generally consistent and reproducible. It is a key step for many emerging technologies and therapies, but the cells, tissues, and organs used for regenerative medicine are complex and difficult to manufacture at scale. Other challenges related to manufacturing include a lack of infrastructure and View GAO-23-105430. For more information, contact Karen L. Howard at (202) 512-6888 difficulty ensuring quality and consistency. or HowardK@gao.gov. United States Government Accountability Office GAO developed 11 policy options that could help address the challenges or enhance the benefits of regenerative medicine. These policy options are provided to inform policymakers of potential actions to address the policy challenges identified in this technology assessment. They identify possible actions by policymakers, which include Congress, federal agencies, state and local governments, academic and research institutions, and industry. Policymakers would need to consider the impacts these new technologies will have on existing federal programs that are already strained. We suggested possible federal components for the policy options. See tables 1-3 for a full list of the policy options, potential implementation approaches, and opportunities and considerations. Selected Policy Options to Mitigate Challenges Associated with Regenerative Medicine Technologies and Therapies Selected policy option Opportunities Considerations Invest in standards development.  Could streamline standards development,  Existing organizations may not include all (report p. 25) which may, in turn, accelerate innovation, stakeholders, and stakeholders may increase product safety and reliability, hesitate to accept standards created This policy option could help address the accelerate regulatory review, and decrease without their input. challenge that standards require consensus. costs of regenerative medicine therapies.  Industry stakeholders may hesitate to adopt standards if they perceive it will cost them a controlling position in the market.  Standards should be appropriately flexible to allow for innovation, while still being detailed and specific enough to support manufacturing of consistent, quality products. Provide opportunities for increased  May provide more timely advice and avoid  May require additional resources to interactions between regulatory unnecessary delays or uncertainty by pursuing bolster the workforce of regulatory the wrong regulatory pathways or submitting scientists at FDA or public-private experts (at FDA or in industry) and data that do not meet regulatory partnerships. smaller companies, especially early in requirements.  FDA may be limited in its ability to advise the development process (report p. 31) companies early in the process so as not to create a conflict of interest. This policy option could help address the lack of access to regulatory expertise. Consider whether changes to the  May encourage innovators, researchers, and  Coordinating among stakeholders to framework for evaluating combination developers of new products to provide consider changes to regulatory pathways valuable feedback to regulators. may be time- and resource-intensive. products and medical devices to  If such consideration leads to accommodate emerging technologies recommended changes to the and therapies may be necessary. framework, statutory and regulatory (report p. 32) changes may be necessary. This policy option could help address whether current regulatory pathways are sufficient for emerging technologies and therapies. Provide more oversight and feedback  May accelerate manufacturing by reducing  Starting material suppliers may lack to suppliers to increase consistency in variation in input materials. incentives to follow standards if they  May reduce the risk of failure during product lead to higher costs. starting materials (report p. 39) development. This policy option could help address inconsistency in starting materials for manufacturing. Source: GAO. | GAO-23-105430 This is a work of the U.S. government and is not subject to copyright protection in the United States. The published product may be reproduced and distributed in its entirety without further permission from GAO. However, because this work may contain copyrighted images or other material, permission from the copyright holder may be necessary if you wish to reproduce this material separately. Table of Contents Introduction ........................................................................................................................ 1 1 Background ...................................................................................................................... 3 1.1 Definition ........................................................................................................................ 3 1.2 How regenerative medicine works .................................................................................. 3 1.3 The development and licensure process for biologics ..................................................... 3 1.4 Advancements in regenerative medicine ........................................................................ 6 2 Current and Emerging Technologies in Regenerative Medicine ..................................... 7 2.1 Cell technologies ............................................................................................................. 8 2.2 Tissue technologies ....................................................................................................... 13 2.3 Organ technologies ....................................................................................................... 15 3 Challenges and Policy Options for Regenerative Medicine Technologies and Therapies........................................................................................................................... 21 3.1 Challenges related to standardization ........................................................................... 21 3.2 Challenges related to regulation ................................................................................... 26 3.3 Challenges related to manufacturing ............................................................................ 34 4 Agency and Expert Comments ....................................................................................... 41 Appendix I: Objectives, Scope, and Methodology ............................................................ 42 Objectives ........................................................................................................................... 42 Appendix II: Expert Participation ...................................................................................... 45 Appendix III: GAO Contact and Staff Acknowledgments .................................................. 46 Regenerative Medicine GAO-23-105430 i Tables Table 1: Policy options for regenerative medicine standardization ................................. 25 Table 2: Policy options for regenerative medicine regulation ......................................... 31 Table 3: Policy options for regenerative medicine manufacturing .................................. 39 Figures Figure 1: Conventional development and licensure process for regenerative medicine products .............................................................................................................................. 5 Figure 2: Levels of complexity in cells, tissues, and organs ................................................ 8 Figure 3: Scaffold de- and recellularization of a liver ....................................................... 15 Figure 4: An engineered bladder using a patient's cells and a biodegradable scaffold ... 20 Figure 5: Comparison of potential centralized and distributed manufacturing models .. 36 Regenerative Medicine GAO-23-105430 ii Abbreviations AMD age-related macular degeneration CAR T Cell chimeric antigen receptor T cell CQA critical quality attribute CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health FDA Food and Drug Administration NIST National Institute of Standards and Technology RMAT regenerative medicine advanced therapy SCB Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery Regenerative Medicine GAO-23-105430 iii 441 G St. N.W. Washington, DC 20548 Introduction July 13, 2023 The Honorable Bernard Sanders Chair The Honorable Bill Cassidy, M.D. Ranking Member Committee on Health, Education, Labor, and Pensions United States Senate The Honorable Frank D. Lucas Chair The Honorable Zoe Lofgren Ranking Member Committee on Science, Space, and Technology House of Representatives Regenerative medicine technologies offer the hope of creating therapeutic products that restore cell, tissue, and organ functions affected by disease, injury, or aging. These technologies represent a paradigm shift in the medical field, away from developing therapies that treat symptoms and toward creating products that cure the underlying disease or restore function. They also open the door to personalized therapies that use an individual's own genes or cells, sometimes engineered to replace or augment their functions. Currently, these technologies are being used to create life-saving therapies for broad categories of diseases, which may help Americans with diabetes (accounting for one-quarter of all U.S. health care costs), cancer (about 1.7 million new cases annually), non-fatal fall injuries (about 8 million cases in 2018), or age- related macular degeneration (AMD) (about 20 million cases overall as of 2019).1 In addition, regenerative medicine may one day offer relief to the approximately 104,000 individuals in need of an organ transplant who are on a waiting list that far exceeds availability.2 1 Centers for Disease Control and Prevention, Cancer Data and Statistics, https://www.cdc.gov/cancer/dcpc/data/, accessed Mar. 17, 2023. Briana Moreland et al. Trends in Nonfatal Falls and Fall-Related Injuries Among Adults Aged ≥65 Years - United States, 2012– 2018. MMWR Morb Mortal Wkly Rep 2020;69:875–881. http://doi.org/10.15585/mmwr.mm6927a5. Centers for Disease Control and Prevention, Prevalence of Age-Related Macular Degeneration (AMD), https://www.cdc.gov/visionhealth/vehss/estimates/amd- prevalence.html, accessed Mar. 17, 2023. 2The Health Resources and Services Administration website shows 104,200 individuals were on the organ transplant waiting list as of March 2023. https://www.organdonor.gov/learn/organ-donation-statistics, accessed Mar. 28, 2023. Regenerative Medicine GAO-23-105430 1 GAO has done prior work on funding streams, workforce, and education for regenerative medicine and the known problems within the organ transplant system.3 We prepared this report under the authority of the Comptroller General in light of congressional interest in the potential of this field. This report examines: (1) current and emerging regenerative medicine technologies and therapies and their potential benefits, (2) challenges that hinder the development and use of regenerative medicine technologies and therapies, and (3) policy options that could help enhance benefits and mitigate challenges associated with these technologies and therapies. To address these objectives, we conducted a literature search; interviewed officials and representatives from government, industry, academia, and end user groups such as patient groups; and convened a 3-day expert meeting. See appendix I for the full objectives, scope, and methodology used in this report and appendix II for the list of participants in our expert meeting. We conducted our work from September 2021 through July 2023 in accordance with all sections of GAO's Quality Assurance Framework that are relevant to technology assessments. The framework requires that we plan and perform the engagement to obtain sufficient and appropriate evidence to meet our stated objectives and to discuss any limitations to our work. We believe that the information and data obtained, and the analysis conducted, provide a reasonable basis for the findings and conclusions in this product. 3GAO, Regenerative Medicine and Advanced Therapies: Information on Workforce and Education, GAO-23-106030 (Washington, D.C.: Mar. 23, 2023); Organ Transplants: Changes in Allocation Policies for Donated Livers and Lungs, GAO-21-70 (Washington, D.C.: Oct. 16, 2020); Regenerative Medicine: Federal Investment, Information Sharing, and Challenges in an Evolving Field, GAO-15-553 (Washington, D.C.: June 23, 2015). Regenerative Medicine GAO-23-105430 2 1 Background 1.1 Definition that was absent at birth, or to augment natural function to fight a disease. There is Regenerative medicine refers to a general a wide range of technologies available in approach to restore, replace, or recreate the field. For example, some researchers cells, tissues, or organs to treat or mitigate are using gene editing technology to correct disease.4 Under the Federal Food, Drug, and genetic defects or introduce new healing Cosmetic Act, the Food and Drug capabilities for diseases such as sickle cell Administration (FDA) regulates regenerative disease. Another tool is the use of medicine products, which include cell implanted materials that, unlike existing therapies, therapeutic tissue engineering medical implants, interact with the body to products, combination products using such encourage healing. Yet another is tissue therapies or products, some gene therapy engineering, the practice of combining products, and certain human cell and tissue materials, cells, and biologically active products.5 molecules into functional tissues. These tools can often be used on or in combination with patients' own cells, which 1.2 How regenerative medicine could bring additional benefits. For works example, the use of a patient's own cells to create a personalized organ could Regenerative medicine aims to develop new transform organ transplantation by therapies that offer benefits beyond those alleviating donor organ shortages and offered by existing medical treatments. eliminating organ rejection-a reaction to These therapies can be highly personalized foreign biological material that requires and may eventually help manage or cure transplant patients to take many conditions that are currently immunosuppressive drugs for the rest of considered chronic, untreatable, or their lives. terminal. These include heart disease, diabetes, cancer, and sickle cell disease, as 1.3 The development and licensure well as severe burns and certain types of bone fractures. process for biologics Regenerative medicine works by harnessing Biologics, a category that includes the body's own healing ability to restore regenerative medicine products, are a lost function, to establish normal function diverse group of products regulated by 4See 21 U.S.C. § 356(g)(8). designation, which provides drug sponsors with certain benefits, such as expedited review. See 21 U.S.C. § 356(g). 5Certain regenerative medicine products may be eligible for regenerative medicine advanced therapy (RMAT) Regenerative Medicine GAO-23-105430 3 FDA.6 FDA is responsible for the safety, Center for Biologics Evaluation and efficacy, and security of human medical Research (CBER) (which regulates most products marketed in the U.S., which for biologics), and the Center for Devices and biologics, includes premarket review and Radiological Health (CDRH) (which regulates approval of a biologics license application. devices). Agency officials told us that Figure 1 shows the conventional process for regenerative medicine products are developing and licensing regenerative generally under the purview of CBER. For medicine products. combination products-such as those that combine two or more regulated products Depending on the medical product type, (e.g., a biologic and a device)-the center different FDA centers may handle the with primary jurisdiction over the product's review process: the Center for Drug primary mode of action will review and Evaluation and Research (CDER) (which regulate the product.7 regulates drugs and certain biologics), the 6Biological products-which may also be called biologics- therapeutic action of the combination product. The most include vaccines and allergenic products, blood and blood important therapeutic action is the mode of action expected components, and proteins applicable to the prevention, to make the greatest contribution to the overall intended treatment, or cure of a disease or condition. 42 U.S.C. § therapeutic effect of the combination product. 21 C.F.R. § 262(i)(1). Biologics are derived from living sources, such as 3.2(m) (2022). The Office of Combination Products assigns humans, animals, and microorganisms. FDA licenses combination products to FDA's medical product centers for biologics that are safe, pure, and potent (i.e., safe and review, and coordinates reviews involving more than one effective). FDA center. 7The primary mode of action is the single mode of action of a combination product that provides the most important Regenerative Medicine GAO-23-105430 4 Regenerative Medicine GAO-23-105430 5 1.4 Advancements in regenerative from person to person. This fact underpins medicine many of the challenges in the field, which we describe in chapter 3. FDA first licensed a tissue-engineered product in 1998-a skin graft for the Recent laws may help accelerate medical treatment of a form of skin ulcers.8 Since product development, bringing new then, technological advances have innovations and advances to patients more increased steadily, and the number of quickly and efficiently. For example, the investigational new drug applications for 21st Century Cures Act created an regenerative medicine products, as well as expedited process for FDA evaluation of the number of products in clinical trials certain regenerative medicine therapies, continues to grow.9 These applications known as the regenerative medicine include cell therapy to cure blood cancers advanced therapeutic (RMAT) and gene therapy to cure sickle cell disease. designation.10 Further, researchers have successfully grown whole organs such as livers Chapter 2 of this report discusses the and bladders. current and emerging technologies in regenerative medicine, including cell, tissue, Despite these advances, the number of and organ technologies that may be used to regenerative medicine products licensed for develop therapeutic products. Chapter 3 use in humans remains small. Many discusses the challenges that researchers regenerative medicine products are and developers face in developing and considered more complex than certain bringing regenerative medicine products to other biologics, such as monoclonal market. In chapter 3, we also present policy antibodies. Unlike drugs, cells and tissues options that may help address are living, constantly changing, and variable these challenges. 8FDA CDRH, Summary of Safety and Effectiveness Data, 10Pub. L. No. 114-255, § 3036, 130 Stat. 1033, 1104 (2016) https://www.accessdata.fda.gov/cdrh_docs/pdf/P950032S0 (codified at 21 U.S.C. § 356(g)). FDA is required to designate 16b.pdf, 7, accessed Mar. 27, 2023. a drug as a regenerative medicine advanced therapy if (1) 9A drug sponsor may not conduct human clinical trials until the drug is a cell therapy, therapeutic tissue engineering product, human cell or tissue product, or combination it has submitted an investigational new drug application to product (with certain exceptions); (2) the drug is intended to FDA. Once submitted, the sponsor may begin clinical trials treat, modify, reverse, or cure a serious or life-threatening after 30 days unless FDA issues a clinical hold. See 21 C.F.R. § disease or condition; and (3) preliminary clinical evidence 312.40 (2022). indicates that the drug has the potential to address unmet medical needs for such disease or condition. Once an RMAT designation has been made, FDA is required to facilitate an efficient development program for and expedite review of the drug. RMAT designation includes the benefits of certain other expedited programs, and early interactions with FDA may be used to discuss potential surrogate or intermediate endpoints to support accelerated approval. See 21 U.S.C. § 356(g). Regenerative Medicine GAO-23-105430 6 2 Current and Emerging Technologies in Regenerative Medicine Regenerative medicine technologies can be makes up the skin. Organs are collections of grouped in various ways including broad several different tissues arranged to categories such as cells, tissues, and organs, perform a special function in the body. The which can be used to develop therapeutic human heart, for example, contains cardiac products. These vary in complexity muscle tissue, connective tissue (which according to their level of structural holds the muscle tissue together), epithelial organization.11 A cell is a self-sustainable tissue (which creates the lining of the unit that can replicate itself and carry on all heart), nerve tissues, and specialized the metabolic processes essential for life. pacemaker cells, which coordinate the Tissues are groups of cells that function heartbeat. The level of structural together as a unit. For example, epithelial organization increases moving from cells to tissue lines the various passages inside the tissues to organs, leading to technologies body such as the intestinal lining, and also with increasing engineering complexity (see fig. 2). 11For the purposes of this report, technologies are grouped Gene therapy products are biologics, as the term is defined into broad categories that aim to regenerate or restore cells, under 42 U.S.C. § 262(i)(1). While human gene therapy tissues, and organs. FDA uses the term "cell and gene products may include ex vivo modified cells, FDA therapy products" to describe a wide range of products. distinguishes between cellular and gene therapies. Regenerative Medicine GAO-23-105430 7 2.1 Cell technologies cells from a patient's own body or cells from a donor as the starting material for Cells are the smallest units of life and make therapy. Regenerative medicine up all living organisms. Each cell has a full technologies may use specialized or set of genetic material (i.e., a genome) that unspecialized cells. Specialized cells are provides the instructions needed to those that have undergone genetic changes perform essential processes and reproduce. to become a specific type of cell, such as a Cell-based regenerative medicine red or white blood cell.12 Unspecialized technologies may be used to develop cures cells, which are known as stem cells and for a variety of diseases and can use either found in both embryos and adults, have not yet undergone these changes and have the 12The process by which a cell becomes specialized in order to perform a specific function is called 'differentiation.' When cells differentiate, certain genes are turned on or off and this determines what type of cell will result. Regenerative Medicine GAO-23-105430 8 ability to become different types of cells. research in the 1950s and 1960s used Finally, regenerative medicine technologies embryonic stem cells from mice, as they are may incorporate gene-editing techniques to more flexible and have the natural ability to produce gene-edited cells. turn into any type of cell. However, controversies around the use of human The following describes current and embryonic stem cells turned researchers' potential cell-based therapies. We group focus toward applying gene-editing them into therapies based on stem cells and techniques to specialized cells and adult those based on gene-edited cells, although stem cells (see text box). some therapies use stem cells that have also been gene-edited. Embryonic stem cell concerns and the discovery of induced pluripotent stem cells Stem cell therapies. Stem cells have been Embryonic stem cells come from a human embryo and used to replace damaged cells and restore their use has raised ethical concerns. In January 1996, federal law prohibited the use of federal funds on or improve bodily functions since the first research that created or destroyed human embryos.a This bone marrow transplant more than 60 policy limited some research on embryonic stem cells, and led scientists to search for alternative stem cell sources. years ago (bone marrow makes stem cells). Today, there are several types of stem cell In 2006, researchers identified conditions that allowed adult human cells to revert to a state similar to an transplants. For example, hematopoietic embryonic stem cell. In 2007, researchers developed the stem cell transplants provide a person with first human cells of this kind, known as induced pluripotent stem cells.b Similar to embryonic stem cells, a blood disorder, such as anemia or cancer, induced pluripotent stem cells can change into all types of with an infusion of stem cells that restores cells in the body. These cells can provide a replacement for embryonic stem cells. They may be derived from a their ability to produce blood cells.13 patient's own cells, offering the benefit of avoiding Depending on the circumstances, the stem rejection by the host immune system. cells may be obtained from the patient or a Source: GAO. | GAO-23-105430 donor and may be derived from bone aBalanced Budget Downpayment Act, I, Pub. L. No. 104-99, § 128, 110 Stat. 26, 34 (1996). The parameters on fetal research, transplantation of fetal marrow, peripheral blood, umbilical cord tissue, and prohibitions regarding fetal tissue are governed by the provisions of 42 U.S.C. §§ 289g-289g-2. blood, or other sources. Stem cells have bSee Kazutoshi Takahashi et al. "Induction of pluripotent stem cells from adult also been used in certain types of tissue human fibroblasts by defined factors." Cell, vol. 131, 5 (2007): 861-72. https://doi.org/10.1016/j.cell.2007.11.019. grafts for patients with corneal eye diseases and skin grafts for burn victims.14 Gene-edited cell therapies. Gene-edited Stem cell therapies have the potential to cells have been manipulated using a gene cure numerous diseases and injuries. Initial 13Hematopoiesis is the term for blood cell production. The Araujo, Aline Lütz, and José Álvaro Pereira Gomes. "Corneal body continually makes new blood cells to replace old ones stem cells and tissue engineering: Current advances and to supply oxygen to the tissues (red blood cells), fight future perspectives." World journal of stem cells, vol. 7, 5 infection (white blood cells), and clot the blood after injury (2015): 806-14. https://doi.org/10.4252/wjsc.v7.i5.806. And (platelets). Stem cell transplant for cancer may help to Chen, Ming et al. "Stem cells for skin tissue engineering and restore normal stem cells after chemotherapy or radiation, wound healing." Critical reviews in biomedical engineering, or it may act against cancers like leukemia or myeloma. vol. 37, 4-5 (2009): 399-421. https://doi.org/10.1615/critrevbiomedeng.v37.i4-5.50. 14For a more detailed explanation of how stem cells are used in tissue grafts for eye and skin regeneration, see de Regenerative Medicine GAO-23-105430 9 editing technology, such as CRISPR, to alter 2). The combination of gene editing and a gene that codes for a particular protein. 15 stem cells could help researchers achieve therapy breakthroughs for a variety of These changes can restore cellular functions diseases. This includes severe combined or give cells new functions, such as the immunodeficiency, a group of hereditary potential to fight disease. Gene editing can diseases that severely compromises or be used on specialized cells or stem cells. destroys the immune system; For example, chimeric antigen receptor leukodystrophies, which are rare, (CAR) T cells are gene-edited versions of a degenerative diseases of the nervous patient's own immune cells that target and system; and junctional epidermolysis kill certain types of cancer cells in their bullosa, a group of genetic conditions that body (see vignette 1).16 cause the skin to be very fragile and to blister easily. Similarly, gene-edited stem cell therapies are being used to treat sickle cell disease, an inherited blood disorder that causes sickle-shaped red blood cells (see vignette 15CRISPR and other gene editing technologies can delete, 16T cells, also known as T lymphocytes or thymocytes, are insert, replace, or modify parts of a cell's DNA. DNA is a part of the immune system and develop from stem cells in molecule that stores hereditary information in humans and the bone marrow. They help protect the body from infection other organisms. For more information on gene editing and may help fight cancer. CAR T cells are modified versions technologies and CRISPR, see GAO, Science & Tech Spotlight: of T cells. CRISPR Gene Editing. GAO-20-478SP (Washington, D.C.: Apr. 7, 2020). Regenerative Medicine GAO-23-105430 10 VIGNET TE 1 CHIMERIC ANTIGEN RECEPTOR T CELLS AS A THERAPY FOR CANCER Source: Design cells/solvod/stock.adobe.com (images). | GAO-23-105430 WHAT IS IT? Cancer occurs when cells grow uncontrolla- A possible process for making CAR T cells. bly. It is among the leading causes of death worldwide, and an estimated 1.7 million Americans are diagnosed with cancer every year-about 186,000 of them with leukemia, lymphoma, or myeloma. These blood cancers are caused by excessive production of white blood cells in the bone marrow. Patients un- dergoing treatment for cancer often receive chemotherapy or radiation, but recurrence is common. Chimeric antigen receptor (CAR) T cells are a therapy alternative for patients for whom standard treatment is not effective, or whose cancer returns after initial treatment. WHAT'S NEXT? CAR T cell therapies have emerged as one of the major breakthroughs in cancer therapies over the last decade. The first CAR T cell therapy received FDA licensure in 2017. As of March 2022, there are at least six licensed therapies for various types of blood cancers. Researchers are developing new CAR T therapies for other types of cancers. For example, some early studies have shown that CAR T cells may be able to treat solid tumors, such as glioblastoma, which is an aggressive type of cancer that can occur in the brain or spinal cord. Researchers are also exploring the use of donor cells for CAR T therapies, which may enable larger-scale manufacturing. Source: GAO (analysis); Designua/greenvector/microone/topvectors/ stock.adobe.com (images). | GAO-23-105430 Regenerative Medicine GAO-23-105430 11 VIGNET TE 2 GENE-EDITED STEM CELLS AS A THERAPY FOR SICKLE CELL DISEASE Source: tussika/solvod/stock.adobe.com (images). | GAO-23-105430 WHAT IS IT? Sickle cell disease is a group of inherited disorder called beta-thalassemia. Other applications of this genetic disorders caused by an abnormal he- technology-for sickle cell disease and other diseases, such moglobin gene. This gene causes red blood as diabetes-are being studied in phase 1 and 2 clinical trials. cells to stick together and take on a rigid sickle A possible process for genetically editing stem cells. shape rather than the flexible round shape found in healthy cells. Approximately 100,000 Americans are affected by sickle cell disease, including approximately one in 365 African Americans. Sickled cells can cause a broad range of symptoms, including pain, stroke, and organ damage. Current patient care is primarily limited to relieving symptoms rather than treating the disease. Some patients with sickle cell disease may receive blood transfu- sions or bone marrow transplants, but these therapies have risks. Red blood cells come from bone marrow stem cells, so genetically editing stem cells can correct a patient's he- moglobin gene and lead to the production of healthy red blood cells. WHAT'S NEXT? Genetically edited stem cells have significant potential for treating hereditary and rare diseases, according to experts. In August 2022, FDA licensed the first gene-edit- Source: GAO (analysis); Mariia/microone/stock.adobe.com (images). | ed stem cell treatment for a related blood GAO-23-105430 Regenerative Medicine GAO-23-105430 12 2.2 Tissue technologies for cells to attach or interact with them to actively facilitate healing responses. While Tissue technologies for regenerative medicine these materials have the potential to combine cells and biocompatible materials significantly advance regenerative medicine, into a single product. By combining these there are limitations. For example, new materials with cells, tissue technologies help applications of biologically active or cells stay at a specific location in the body, regenerative materials will require much provide structural support, and enable more closer monitoring and testing to ensure targeted therapeutic approaches. patient safety because they do not have the well-established performance records of inert The following describes two categories of materials. tissue technologies that may have therapeutic applications: Combination products. Combination products are products made up of two or more Biocompatible materials. Biocompatible components regulated by FDA. For example, a materials come from natural or artificial tissue-engineered product containing both sources and serve as structural scaffolds. living cells and biocompatible materials is When implanted into a patient, they can be classified as a combination product because it used to support or replace damaged tissues. has elements of both a biologic and device. Certain materials, such as metals, ceramics, Combination products may address certain plastic, or glass, have been used extensively age-related conditions that can cause as surgical implants and scaffolds because structural and functional changes in the cells they replace the function of tissue and are and tissues. For example, a retinal implant not biologically active-meaning they that combines a patient's cells with a typically do not actively interact with a biodegradable scaffold to create a patient's body. Biomaterials under combination product may cure advanced dry development for regenerative medicine age-related macular degeneration (AMD), an technologies-such as hydrogels-differ from eye disease that can blur the central part of a those currently used in surgical implants person's vision (see vignette 3). because they are not inert and are designed Regenerative Medicine GAO-23-105430 13 VIGNET TE 3 RETINAL IMPLANTS AS A THERAPY FOR DRY AGE- RELATED MACULAR DEGENERATION Source: Firefighter Montreal/solvod/stock.adobe.com (images). | GAO-23-105430 WHAT IS IT? Dry age-related macular degeneration (AMD) A possible process for making retinal implants. is an eye disease caused by damage to a person's retina as they age. Approximately 20 million Americans have AMD, more than 1.7 million of whom have an advanced form of the disease that results in vision loss. Such vision loss makes it hard to do everyday tasks, including seeing faces, reading, driving, or working around the house. There are currently no effective therapies. Retinal implants-a patch made from a patient's cells and a synthetic scaffold-are being developed with the hope of providing the first therapy for this type of vision loss. WHAT'S NEXT? At least three different stem-cell-based therapies for AMD are in phase 1 and 2 clinical trials. Further developments in tissue engi- neering may pave the way for other combina- tion products made from a patient's own cells. Researchers are exploring tissue engineering for other conditions, but it is difficult to predict the future direction of this technology given its Source: GAO (analysis); Greenvector/pattarawit/stock.adobe.com (images). | early development stage. GAO-23-105430 Regenerative Medicine GAO-23-105430 14 2.3 Organ technologies Scaffold de- and recellularization. Scaffold decellularization removes cells from tissues or Organ technologies, such as artificial hearts organs and leaves behind the non-cellular and kidneys, can have more complex portion of a tissue (i.e., scaffold) which mainly structures and functions than cell or tissue provides physical support. Recellularization technologies. They combine multiple cell and adds new cells from a patient or other tissue types to create complex 3D structures. external source to the scaffold, where those New strategies will be required to support cells will attach and grow. Patients needing these technologies. organ transplants may benefit from the use of this technology once it is more developed. For Some technologies under development for example, a pig liver can be decellularized and potential therapeutic application include the the resulting scaffold may be repopulated following: with patient-derived cells, which makes it less likely that the new liver would be rejected (see fig. 3). 3D bioprinting. 3D bioprinting uses 3D These advances highlight the potential printing techniques to create implantable application of 3D bioprinted technologies, but structures. The material used as ink for the 3D applications that allow for the treatment of printer can contain cells, or cells can be added human disease are still under development. after printing is complete. Researchers have For example, researchers are pursuing 3D successfully implanted 3D printed bone and printed tissues to cure bone defects or muscle structures into animals. Additionally, injuries (see vignette 4). in June 2022, a human patient received a 3D printed ear implant as part of a clinical trial.17 17See ClinicalTrials.gov, AuriNovo for Auricular Reconstruction, https://clinicaltrials.gov/ct2/show/NCT04399239, accessed Mar. 28, 2023. Regenerative Medicine GAO-23-105430 15 VIGNET TE 4 BIOPRINTED BONE REPLACEMENTS AS A THERAPY FOR ACUTE BONE INJURIES Source: Sutthab/solvod/stock.adobe.com (images). | GAO-23-105430 WHAT IS IT? Injuries and accidents can cause bone A possible process for bioprinting bone material. fractures. Between 11 million and 15 million bone fractures occur in the U.S. every year, of which more than 1 million fail to heal properly. Current therapies may use transplanted tissues or inorganic materials, but neither of these fully restores functionality. Bioprinted bones could combine a 3D printed biocom- patible material with a patient's own bone cells to create customized replacements for damaged bone. WHAT'S NEXT? 3D bioprinted bone replacements are still in research and development. No bone construct has been made by combining tissue engineering and 3D bioprinting, but studies have been done in animals. Further progress requires research into creating blood vessels in implanted materials and developing stronger, more flexible materials, among other areas. Additionally, a report from the Pew Charitable Trusts published in July 2022 noted that current FDA guidance does not clearly explain how bioprinted products will be regulated, which may cause some companies to be hesitant about using new manufacturing technologies like 3D printing. Source: GAO (Analysis). Derariad /rumruay/ stock.adobe.com (images). | GAO-23-105430 Regenerative Medicine GAO-23-105430 16 Organoids. Organoids are small, artificially primarily for research and testing during grown groups of cells or tissues that resemble multiple stages of the drug development an organ and mimic the original tissue process. However, researchers are also architecture. Organoids can be grown from evaluating a variety of organoid technologies patient tissues, and have been successfully to determine whether they may be used to generated from several kinds of human cure diseases such as diabetes-which affects tissues including heart, liver, brain, and how the body uses sugar (see vignette 5). kidney. Currently, organoids are being used Regenerative Medicine GAO-23-105430 17 VIGNET TE 5 PANCREATIC ISLET CELL ORGANOIDS AS A THERAPY FOR T YPE 1 DIABETES Source: Rfbsip/solvod/stock.adobe.com (images). | GAO-23-105430 WHAT IS IT? Type 1 diabetes occurs when a person's A possible process for generating pancreatic organoids. immune cells attack pancreatic islet cells. This destroys the person's ability to produce insulin, an essential hormone needed to properly convert sugars to energy and control blood sugar levels in the human body. About 1.6 million Americans have type 1 diabetes and need daily insulin injections throughout their lives, a significant economic burden to the individual and the U.S. health care system. Pancreatic islet organoids offer the possibility of curing the disease by restoring a patient's ability to produce insulin. WHAT'S NEXT? Pancreatic islet organoids are in phase 1 and 2 clinical trials in humans. Organoid technol- ogies have significant potential to transform research and therapeutics. As a research technology, organoids may model human disease more accurately than animals and help drugs move from the laboratory to the clinic more quickly. As therapeutics, they may be capable of more complex functions than simple biological products. However, it is difficult to predict the future direction of this technology given its early develop- ment stage. Source: GAO (analysis); Microone/christosgeorghiou/stock.adobe.com (images). | GAO-23-105430 Regenerative Medicine GAO-23-105430 18 Full-size organs. Whole organs can be and used them to cure spina bifida-induced engineered using the methods described bladder damage.18 Lab-grown bladders, above. However, full-size engineered organs developed from a small piece of a patient's for clinical use are still in the early research bladder, have smooth muscle cells on the and development phase and face several outside and specialized bladder-lining cells on technical limitations. In order to restore the the inside. Researchers grew both types of function of an organ, all the relevant cells separately at first and layered them components need to be engineered. The together onto a bladder-shaped, vessels that carry blood and other cells biodegradable scaffold. After further growth, throughout the body are important, as they the bladders were implanted into children allow oxygen, nutrients, and immune cells to whose spina bifida had damaged the neural reach every part of the body. These vessels connections that allow nerve cells to help are a fundamental feature of most complex signal a full bladder (see fig. 4). However, the organs, and researchers are studying how to use of engineered bladders to treat patients is engineer organs with vascular systems. currently advancing through clinical trials. Researchers have successfully developed organs that have less engineering complexity 18Anthony Atala et al. "Tissue-engineered autologous bladders vol. 367, 9518 (2006): 1241-6. https://doi.org/10.1016/S0140- for patients needing cystoplasty." Lancet (London, England), 6736(06)68438-9. Regenerative Medicine GAO-23-105430 19 Regenerative Medicine GAO-23-105430 20 3 Challenges and Policy Options for Regenerative Medicine Technologies and Therapies Regenerative medicine technologies and and Standards Coordinating Body for Gene, therapies have potential benefits, but Cell, and Regenerative Medicines and Cell- challenges may affect their development Based Drug Discovery (SCB) identified a strong and use. We identified challenges including need for more standards and outlined more but not limited to: standardization, than 250 needed standards relevant to regulations, and manufacturing.19 regenerative medicine.20 However, developing standards is challenging because GAO developed 11 policy options that could these technologies are complex and rapidly help address these challenges or enhance the evolving. Developing standards is also benefits of regenerative medicine. These challenging because of the need to reach policy options are provided to inform consensus across a range of stakeholders and policymakers of potential actions to address the need for accurate, well-developed the policy challenges identified in this measurement science in the field. technology assessment. They identify possible actions by policymakers, which include Standards are rules, conditions, guidelines, or Congress, federal agencies, state and local agreed-upon practices that are adopted governments, academic and research within an industry.21 They are created to institutions, and industry. provide researchers and developers with a common framework, which promotes consistency across product development, 3.1 Challenges related to manufacturing, and other processes. standardization Standards are generally developed outside of the federal government by independent Standardization can help promote more rapid organizations and are therefore distinct from and effective technology development, but federal statutory or regulatory requirements, relatively few standards exist for regenerative unless the regulations are specifically tied to medicine technology. A 2020 FDA- commissioned report from the Nexight Group 19We identified other challenges that may affect the 64528/t/5fc51dfc173fb5383b470452/1606753809117/Landsca development and use of regenerative medicine technologies peReportFall2020.pdf, accessed Mar. 3, 2023. including: Gaps in funding for translational research, market 21Standards include documentary standards, reference access and reimbursement, and potential difficulty in materials, and reference data. Documentary standards are understanding safety of some therapies in the short-term. written documents containing protocols, experimental 20SCB is a nonprofit organization first established as an methods, technical specifications, or terminologies. Reference initiative by the Alliance for Regenerative Medicine, but is now materials are highly characterized substances with known an independent organization that engages industry, academic, properties, used to ensure consistency and quality of a and government stakeholders to accelerate the standards product, calibrate equipment, serve as experimental controls, development process. SCB is also referred to as the Standards or aid in describing and evaluating qualitative and quantitative Coordinating Body. See SCB, The Regenerative Medicine data. Reference data are critically evaluated quantitative data Standards Landscape (Fall 2020), related to a measurable physical or chemical property of a https://static1.squarespace.com/static/58a331b0db29d63c7fb substance. Regenerative Medicine GAO-23-105430 21 such standards.22 For example, the U.S. are sterile, even though such guidance could Pharmacopeial Convention, a nonprofit significantly reduce the potential for organization, publishes the U.S. contamination.24 Pharmacopeia: a continuously revised document that sets quality, purity, and SCB also agreed that advancing the strength standards for medicines, food development and use of voluntary consensus ingredients, and dietary supplements. Small- standards in regenerative medicine may molecule drug manufacturers test their accelerate innovation, increase product safety products, which include over-the-counter and reliability, accelerate regulatory review, drugs like aspirin, against the U.S. and decrease costs. The 21st Century Cures Pharmacopeia's published standards to help Act, enacted in 2016, required the Secretary ensure safety and consistency. of Health and Human Services, in consultation with the National Institute of Standards and However, regenerative medicine technologies Technology (NIST) to facilitate an effort to and therapies are significantly more complex coordinate and prioritize the development of than small-molecule drugs, in part because standards for regenerative medicine.25 SCB's they can be highly personalized and made of 2020 report stated that a lack of standards living cells. Currently, regenerative medicine leaves researchers and manufacturers to has relatively few standards, which raised independently solve the complex challenges concerns with some experts we spoke with.23 of clinical translation and scaling of For example, a report from a leading commercial products. The report also noted advocacy organization said there is unclear that a lack of standards may raise safety guidance on how to ensure certain products concerns (see text box) and prevent novel 22The National Technology Transfer and Advancement Act of 23We interviewed experts from government, academia, 1995, codified the existing policies in Office of Management industry, and the nonprofit sector, and convened an expert and Budget Circular A-119, "Federal Participation in the meeting to discuss the objective topics. See Objectives, Scope, Development and Use of Voluntary Consensus Standards and in and Methodology section for more details. The U.S. Conformity Assessment Activities." The act states that the Pharmacopeia does not have the authority to create standards National Institute of Standards and Technology (NIST) should for regenerative medicine. According to the National facilitate standards-related information sharing and Technology Transfer and Advancement Act of 1995 and the cooperation between federal agencies and to coordinate the Office of Management and Budget Circular No. A-119, the use by federal agencies of private sector standards federal government prefers the use of standards developed emphasizing where possible, the use of standards developed through a consensus-based process. Standards development by private, consensus organizations. Pub. L. No. 104-113, § 12, organizations that follow a consensus-based process can be 110 Stat. 775, 782 (1996) (codified at 15 U.S.C. § 272(b)(3)). accredited by the American National Standards Institute and Similarly, the Office of Management and Budget guidance include organizations like the International Society of states that its policies are intended to encourage federal Automation and the International Organization for agencies to benefit from the expertise of the private sector, Standardization. The U.S. Pharmacopeia does not meet these promote federal agency participation in standards bodies to requirements and is therefore not recognized as a consensus support the creation of standards that are useable by federal standards developing body. agencies, and minimize reliance on government-unique 24Alliance for Regenerative Medicine, A-CELL: A case study- standards where an existing standard would meet the federal government's objective. Office of Management and Budget, based approach to integrating QbD principles in Cell-based OMB Circular No. A-119, Federal Participation in the Therapy CMC programs, https://alliancerm.org/wp- Development and Use of Voluntary Consensus Standards and in content/uploads/2022/09/PROJECT-A-CELL-V2.pdf, accessed Conformity Assessment Activities, (originally issued Oct. 20, Feb. 22, 2023. 1993, it was subsequently revised and replaced in 1998, and 25Pub. L. No. 114-255, § 3036, 130 Stat. at 1104 (codified at 21 later revised Jan. 27, 2016). U.S.C. § 356g). Regenerative Medicine GAO-23-105430 22 regenerative medicine therapies from make it difficult to develop and establish becoming commercially viable. standards in the field. Standards can help address safety concerns Standards require consensus. Standards are Viral vectors are commonly used as delivery vehicles for developed through a consensus-building gene therapy products. The viral vectors insert a modified process that requires participation from a DNA sequence into patient's cells, which can help cure a wide range of diseases and genetic disorders. However, range of stakeholders. Unlike regulations, according to the Standards Coordinating Body for Gene, standards can be voluntary and are not Cell, and Regenerative Medicines and Cell-Based Drug Discovery (SCB), therapies using viral vectors can produce typically developed by government agencies, adverse and even life-threatening reactions in patients if so broad buy-in is important for them to be administered at the wrong dose.a In 1999, a patient died due to a severe immune response during a gene therapy accepted and used. However, even if trial that used a viral vector. The field lacked a reference stakeholders agree that a particular standard material that could help regulators to adequately evaluate the safety of such therapies. should exist, it can be difficult to reach agreement on the details. This is especially In response to this incident, a working group of experts from industry, academia, and FDA created a standard true if one or more companies have existing reference material for that viral vector: a highly products or infrastructure that do not align characterized sample containing a known concentration of viral vectors. This material, first released in 2002 and used with the proposed standard. For example, until 2022, helped developers accurately determine viral experts noted that companies that have vector concentrations in their products. While developers are not required to use a reference material, and FDA has already built unique data infrastructures are additional processes to establish a product's safety and unlikely to adopt new data standards if effectiveness, SCB stated that this viral vector reference switching would require significant time and material helped address safety concerns and restore public confidence in gene therapies. money. Source: GAO. | GAO-23-105340 a SCB, Standards Development in Action: Reference Material for Human To overcome this barrier and accelerate the Adenovirus 5, https://www.standardscoordinatingbody.org/adenovirus, accessed Mar. 14, 2023. standards development process, SCB engages with various regenerative medicine stakeholders in industry, academia, and However, overly rigid standards may also government. This engagement has helped cause problems. FDA officials cautioned that, identify, prioritize, and develop voluntary at this time, standards for regenerative standards, including standards related to medicine should be optional and take a sterility testing and cell counting. However, flexible approach that can account for the SCB's impact is limited by its current size and complexity of biological products. They said funding. According to an SCB representative, that imposing stringent, mandatory SCB receives the majority of its operating standards, such as those used for small- budget through FDA and NIST contracts, molecule drugs, may impede the which facilitates federal participation in development of innovative biologics and standards development but is not sufficient to place unnecessary burdens on industry and address the current need for regenerative on FDA reviewers. medicine standards. This representative stated that SCB is hesitant to collect In addition to the complexity of regenerative membership fees because it could limit medicine technologies and therapies, we stakeholder participation in the standards identified the following two challenges that development process and would be counter Regenerative Medicine GAO-23-105430 23 to the consensus-based process supported by FDA, several organizations stated that the federal stakeholders. agency's process for recognizing voluntary standards has not been clear for regenerative Two federal agencies-NIST and FDA-have medicine, and stakeholders may therefore important roles in standards development. hesitate to commit resources to developing NIST engages with key stakeholders to standards. FDA published draft guidance on develop consensus and helps ensure that the Voluntary Consensus Standards standards do not conflict with or duplicate Recognition Program for Regenerative each other.26 It currently runs laboratory Medicine Therapies in June 2022, which the programs to advance measurements needed agency said can facilitate the development of for the characterization and testing of safe and effective regenerative medicine regenerative medicine manufacturing and products.29 Agency officials told us that leads multiple consortia to develop or support finalized guidance is anticipated to be the development of documentary standards published in calendar year 2023. and reference materials for regenerative medicine.27 Federal law and policy encourage Additional measurement science is needed. agencies to use industry-developed standards Measurement science ensures that whenever possible. NIST therefore works with measurements are reliable, comparable, and appropriate standards development accurate. Reliable measurements are a key organizations to advance documentary driver for emerging technologies, but often standards for regenerative medicine. NIST require dedicated research that is separate also supports the development of reference from technology development. For example, materials made available through NIST or it took decades of measurement science another entity. research to directly connect the measurement of time to a fundamental FDA also has a role, as FDA officials review physical constant-the vibration of a cesium and recognize the voluntary standards that atom. Once time could be measured the agency can apply during its review of consistently around the globe, new products for regulatory approval. Product technologies that rely on highly accurate time sponsors can choose to follow a voluntary measurements could start to emerge, like standard recognized by FDA, which may global positioning systems (GPS). Similarly, reduce the amount of supporting data and advancing measurement science in different information they need to submit to FDA.28 areas of regenerative medicine can support However, in response to draft guidance from 26According to NIST officials, the agency's role is to support 28A product sponsor or applicant means any person who research and development, translation, and manufacturing, submits or plans to submit an application to FDA for premarket including characterization and testing, as well as promoting the review. 21 C.F.R. § 3.2(c) (2022). broader ecosystem. 29Food and Drug Administration, Voluntary Consensus 27NIST leads multiple laboratory programs for regenerative Standards Recognition Program for Regenerative Medicine medicine and has a contract with SCB to support standards Therapies (June 16, 2022). Available from: development. NIST, RMAT Laboratory Programs, https://www.fda.gov/media/159237/download, accessed June https://www.nist.gov/regenerative-medicine, accessed Apr. 5, 16, 2022. 2023. Regenerative Medicine GAO-23-105430 24 Measurement science in regenerative medicine standardization and technology development (see text box). Sickle cell disease is a genetic condition caused by a one- letter mutation in the gene for hemoglobin, a protein in red blood cells. As a result of this genetic mutation, red NIST officials told us that budgetary resources blood cells change to a crescent (or sickle) shape and can cause significant pain. Gene therapies aim to cure sickle for regenerative medicine standards, which cell disease by changing the incorrect letter without includes work on measurement science, have altering any of the other 3 billion letters in the patient's genome. However, it is difficult to measure whether a been limited and inconsistent. Agency officials gene therapy has created any unintended changes. also said that fluctuating resources may DNA sequencing, a measurement technology used to hinder efforts to support industry and observe the effects of gene therapies (among other uses), advance regenerative medicine standards. is imperfect and accuracy can vary depending on the technique being used. Even the most accurate existing methods will still take many inaccurate measurements We identified three policy options to help across a person's full genome, due to inherent errors in the process. This creates a critical measurement address challenges in regenerative medicine challenge, because it will not be clear whether an altered standardization. Table 1 presents these letter in the data was caused by the gene therapy or the sequencing method. Improved DNA sequencing options, along with potential opportunities technologies, standards, and reference materials could and considerations. therefore increase confidence in gene therapies. Such improvements will require specific research on the methods used for sequencing and on new chemistry or data analysis techniques that could reduce error. Source: GAO. | GAO-23-105340 Table 1: Policy options for regenerative medicine standardization Policy options Opportunities Considerations  Invest in standards development  Could streamline standards  Existing organizations may not development, which may, in turn, include all stakeholders, and This policy option could help accelerate innovation, increase stakeholders may hesitate to accept address the challenge that product safety and reliability, standards created without their standards require consensus. accelerate regulatory review, and input. Potential implementation decrease costs of regenerative  Industry stakeholders may hesitate approaches: medicine therapies. to adopt standards if they perceive Government agencies could it will cost them a controlling support organizations that position in the market. develop regenerative medicine  Standards should be appropriately consensus standards. flexible to allow for innovation, Government agencies could while still being detailed and specific support consensus-building enough to support manufacturing of activities between stakeholders, consistent, quality products. such as those conducted by the Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery. Regenerative Medicine GAO-23-105430 25  Provide more consistent support  Could enable more or faster  Additional federal spending on for measurement science development of regenerative measurement science for research. medicine technologies, and could regenerative medicine may shift provide additional benefits resources that were supporting This policy option could help outside of regenerative medicine. other emerging technologies. address the need for more measurement science.  Private industry may not invest in measurement science since they Potential implementation may not receive a timely return on approaches: investment. Government agencies (e.g., NIST, FDA) could dedicate specific funding for measurement science research. Industry stakeholders could devote more resources to measurement science research initiatives.  Maintain the status quo.  Standards may be developed  Technologies may be more likely to without further intervention. fail in development or during regulatory review due to a lack of  Potential cost savings for federal standardization. agencies.  Companies may need to spend more  Would avoid establishing to meet safety requirements for standards too early, which can FDA approval or licensure. stifle innovation and competition.  Companies may not be willing to change their existing processes if standards are not established early enough. Source: GAO. | GAO-23-105430 3.2 Challenges related to regulation  Staffing shortages at FDA and collaborating agencies. According to experts we interviewed, the field  Unlicensed stem cell products. of regenerative medicine faces several challenges related to regulation, including: Lack of access to regulatory expertise. Sponsors who develop regenerative medicine  Lack of access to regulatory expertise. products need regulatory expertise  Difficulty navigating a complex regulatory throughout all stages of product framework. development, including the stage where they submit a product for FDA review. Start-ups  Current regulatory pathways may be and other small companies or academic insufficient for emerging technologies and institutes that do not have designated in- therapies. house regulatory departments may be at a disadvantage due to lack of expertise on the Regenerative Medicine GAO-23-105430 26 complex regulatory process. This lack of regenerative medicine products may be expertise could delay the product eligible. Sponsors of regenerative medicine development process. For example, products can ask FDA to review their product companies could spend time and resources under one or more of these programs if they generating data that do not meet FDA meet the criteria. For example, they can requirements. An expert told us that these request RMAT designation, which allows for companies need access to knowledgeable accelerated approval of products with the regulatory experts and adequate potential to address unmet medical needs. In opportunities to interact with FDA addition, regenerative medicine products may reviewers.30 be eligible for other expedited programs, including fast track designation, breakthrough Difficulty navigating a complex regulatory therapy designation, accelerated approval, framework. Clear and predictable regulations and priority review designation. Sponsors may ensure that product developers are able to receive more than one designation for a given understand the data and other requirements product, but they must request each one needed for approval without unnecessary separately.32 delays or uncertainty. Experts told us that it can be challenging for product sponsors to To understand which programs are available navigate the complex regulatory framework before submitting, product sponsors can get for regenerative medicine products, which information in many ways including seeking may span multiple FDA centers and pathways advice from FDA. Experts told us that FDA was to approval. Some regenerative medicine generally inclined to provide advice to products are combination products (see sec. sponsors who ask for it, but the agency does 2.2), and it can be difficult to understand not always have the ability to respond as what classification they fall under.31 While quickly as it would like. We also heard from some regenerative medicine products clearly experts that such advice, when provided to fit in to a particular classification, others may regenerative medicine product sponsors, is be less clear. This can be challenging for not always clear, leading sponsors to spend technologies and therapies for which the extra time seeking information. Experts also primary mode of action may not be known or told us that sponsors could benefit from clear fully understood. guidance documents and additional opportunity for interaction with FDA Another layer of complexity comes from the reviewers at various stages of product multiple FDA programs for which 30In order to address the substantial growth in the products as well as other articles for which the classification as development of novel products, CBER has established a new drug, device, and/or biologic is unclear. Officials told us that Office of Therapeutic Products. This reorganization is intended the Office of Combination Products has various mechanisms for to create flexibility and capacity for future growth in the stakeholders to obtain recommendations or determinations for number of full-time employee positions and enhance the their products. timeliness and consistency of the office's interactions with 32Priority review designation is determined for every product sponsors. application, regardless of whether the product sponsor 31Officials told us that the Office of Combination Products requested it. situated in FDA's Office of the Commissioner evaluates the classification and regulatory review jurisdiction of combination Regenerative Medicine GAO-23-105430 27 development.33 They said clarifying guidance materials that are biologically active and to sponsors as early as possible in the product promote cell regeneration. development process could save time and resources, potentially making therapies Another possible difficulty is that companies available to patients sooner.34 that develop novel products may lack examples of the same types of products Current regulatory pathways may be previously going through the regulatory insufficient for emerging technologies. process. Experts said that this can lead to Emerging regenerative medicine technologies confusion about which regulatory pathway is and therapies may blur the lines between most appropriate for their product.36 We drugs, biologics, and devices which could heard from experts that there is an make their pathways to approval or licensure opportunity for FDA to clarify regulatory more uncertain. Participants in our expert pathways for regenerative medicine products meeting and other experts told us that the and assess the need for alternative pathways. requirements for these types of products can For example, experts said that a new pathway unintentionally hinder the development of or amendments to current pathways could be emerging technologies. To illustrate this, proposed to allow for devices with experts told us about medical devices made regenerative properties. from materials that can promote cell growth or tissue healing. One such device is known as Staffing shortages at FDA and collaborating a tissue fixation implantable device which is agencies. FDA needs knowledgeable used to attach soft tissue grafts to a fractured personnel to handle incoming applications, bone to promote healing. These experts told provide clear advice to product sponsors, and us that products made with such materials achieve the agency's mission of advancing are regulated as devices, and FDA guidance public health. Agencies that collaborate with does not allow sponsors to claim regenerative FDA and fund regenerative medicine properties for products regulated solely as programs, like the National Institutes of devices.35 However, experts said there is a Health, also need to have personnel growing understanding that devices may be more effective if they are made from 33Sponsors can obtain early feedback from FDA through an 36GAO previously reported that FDA is working to clarify and Initial Targeted Engagement for Regulatory Advice on address similar challenges related to the agency's review of CBER/CDER Products (INTERACT), which is a meeting at a drugs made using advanced manufacturing technology. For specific time early in product development. example, FDA has a website that has a list of technologies that 34GAO previously reported similar challenges with existing FDA have been accepted into CDER's Emerging Technology Program, thus informing industry stakeholders about the type guidance related to advanced manufacturing for drugs. See of technologies FDA has experience reviewing. In addition, GAO, Drug Manufacturing: FDA Should Fully Assess Its Efforts CDER is implementing an initiative to examine its regulatory to Encourage Innovation, GAO-23-105650 (Washington, D.C.: framework for advanced manufacturing to determine whether Mar. 10, 2023). changes are needed to its statutory authorities, regulations, 35According to FDA, combination products can be eligible for and guidance in order to facilitate the agency's review of RMAT designation when the biologic constituent part of the applications that use advanced manufacturing technologies. product is a regenerative medicine therapy and that therapy See GAO-23-105650. serves as the product's primary mode of action. Regenerative Medicine GAO-23-105430 28 knowledgeable in regulatory science.37 We derived from cord blood for limited use in heard from experts that even when provided patients with blood disorders. However, some with a potentially sufficient number of U.S. clinics offer stem cell products that are positions, agencies have historically faced not FDA licensed. Experts told us that such challenges meeting their medical product clinics are eroding public trust in regenerative workforce needs, due in part to competition medicine technologies and therapies, and are with the private sector. Experts we spoke a threat to public health and safety. According with said that FDA continues to lack adequate to a study in 2021, more than 2,700 clinics capabilities, including the ability to recruit, were found selling purported stem cell train, and retain regulatory scientists. treatments in the U.S.40 In 2019, FDA issued a Without sufficient interdisciplinary training, warning about stem cell treatments that are FDA reviewers may be less familiar with novel illegal and potentially harmful and asked and complex emerging regenerative medicine patients to ensure any treatments they are technologies.38 Experts told us that this can considering are either FDA licensed or part of lead to inconsistent or contradictory advice an FDA-approved study.41 FDA stated that it over the course of product development. "is increasing its oversight and enforcement Experts conveyed the importance of to protect people from dishonest and bolstering FDA's ability to hire and retain unscrupulous stem cell clinics, while reviewers trained in evaluating emerging continuing to encourage innovation so that technologies and therapies. A recent GAO the medical industry can properly harness the report recommended that FDA develop and potential of stem cell products." implement an agency-wide strategic workforce plan with performance measures Other government agencies and states are to ensure it can evaluate the effectiveness of also taking action against clinics marketing its human capital efforts.39 certain unlicensed stem cell products. For example, in 2021, the Federal Trade Unlicensed stem cell products. Stem cells can Commission (FTC) and the Georgia Attorney be the basis for safe and effective treatments General's Office sued the co-founders of the and FDA has licensed stem-cell products Stem Cell Institute of America for allegedly 37Regulatory science is the science of developing new tools, Future Needs, GAO-22-104791 (Washington, D.C.: Jan. 14, standards, and approaches to assess the safety, efficacy, 2022). quality, and performance of all FDA-regulated products. In response, FDA stated in July 2022 that it was working to https://www.fda.gov/science-research/science-and-research- develop and implement an agency-wide strategic workforce special-topics/advancing-regulatory-science, accessed July 6, plan to document human capital goals, and anticipates having a 2023. baseline version of this plan by the end of fiscal year 2024. GAO 38FDA hosts the Centers of Excellence in Regulatory Science will continue to follow the agency's progress on this activity. 40Turner, Leigh. "The American stem cell sell in 2021: U.S. and Innovation (CERSI) program to foster robust and innovative approaches to advance regulatory science, and the goal is for businesses selling unlicensed and unproven stem cell the CERSIs to advance regulatory science individually and interventions." Cell stem cell vol. 28, 11 (2021): 1891-1895. synergistically through collaborative interactions with FDA https://doi.org/10.1016/j.stem.2021.10.008. scientific experts and funding offices. 41Food and Drug Administration, FDA Warns About Stem Cell 39GAO, FDA Workforce: Agency-Wide Workforce Planning Therapies (Washington, D.C.: Sept. 3, 2019). Needed to Ensure Medical Product Staff Meet Current and https://www.fda.gov/consumers/consumer-updates/fda- warns-about-stem-cell-therapies, accessed Mar. 28, 2023. Regenerative Medicine GAO-23-105430 29 marketing stem cell therapy to seniors obtain information to inform themselves and nationwide using "bogus claims" that it is their patients about unlicensed regenerative effective in treating arthritis, joint pain, and a medicine therapies.45 Experts warned that the range of other orthopedic ailments.42 FTC also public may be vulnerable to confusion and issued a warning about false and misleading the spread of false information online, information about stem cell therapies, as a partially because of the novelty and number of them have not been shown to be complexity of these emerging technologies. safe or effective.43 We identified five policy options to help A recent report suggests that patients address challenges related to the regulation considering stem cell and regenerative of regenerative medicine products. Table 2 medicine interventions do research online or presents these options, along with the option by contacting friends, family, medical of maintaining the status quo, and providers, and consultation services.44 opportunities and considerations. However, a 2021 study concluded that efforts should be directed at helping physicians 42Federal Trade Commission et al v. Peyroux et al, 1:21-vc- Regenerative Medicine Consult Service," npj Regenerative 03329 (N.D. Ga. Filed Aug. 16, 2021). Medicine (2022) 7:20. https://doi.org/10.1038/s41536-022- 00215-w. 43FTC, Think Stem Cell Therapy Can Treat Your Ailments? It 45Smith, Cambray et al, "Academic Physician Specialists' may pay to think twice (Aug. 17, 2021), https://consumer.ftc.gov/consumer-alerts/2021/08/think- Approaches to Counseling Patients Interested in Unproven stem-cell-therapy-can-treat-your-ailments-it-may-pay-think- Stem Cell and Regenerative Therapies - A Qualitative Analysis," twice, accessed on Mar. 26, 2023. Mayo Clinic Proceedings, vol. 96, 12 (2021): 3086-3096. https://doi.org/10.1016/j.mayocp.2021.06.026. 44Arthurs, Jennifer et al, "Patients seeking stem cell therapies-a prospective qualitative analysis from a Regenerative Medicine GAO-23-105430 30 Table 2: Policy options for regenerative medicine regulation Policy options Opportunities Considerations  Provide opportunities for  May provide more timely advice  May require additional resources increased interactions between and avoid unnecessary delays or to bolster the workforce of regulatory experts (at FDA or in uncertainty by pursuing the regulatory scientists at FDA or industry) and smaller companies, wrong regulatory pathways or public-private partnerships. especially early in the submitting data that do not meet  FDA may be limited in its ability to development process. regulatory requirements. advise companies early in the This policy option could help process so as not to create a address the lack of access to conflict of interest. regulatory expertise. Potential implementation approaches: Policymakers could increase funding to existing public-private partnerships that can provide access to regulatory experts. Sponsors could devote more resources to sharing lessons learned from their regulatory submissions to help accelerate technology development across the field.  Identify mechanisms for FDA to  Could encourage new products  The rapidly changing field of clearly communicate advice for and may speed up the review regenerative medicine may regenerative medicine product process. necessitate more frequent classification and update updates to guidance documents.  Examples can further clarify guidance documents product classifications.  Guidance that is too specific can accordingly. be a constraint if there are This policy option could help multiple valid ways of doing address the challenge of things. navigating a complex regulatory framework. Potential implementation approaches: FDA could provide examples in guidance documents to further clarify product classifications. Examples could be provided for technologies and therapies that FDA has experience reviewing. FDA could provide mechanisms to ensure consistent advice across FDA reviewers when Regenerative Medicine GAO-23-105430 31 Policy options Opportunities Considerations responding to product sponsor inquiries.  Consider whether changes to the  May encourage innovators,  Coordinating among stakeholders framework for evaluating researchers, and developers of to consider changes to regulatory combination products and new products to provide pathways may be time- and medical devices to valuable feedback to regulators. resource-intensive. accommodate emerging  If such consideration leads to technologies and therapies may recommended changes to the be necessary. framework, statutory and This policy option could help regulatory changes may be address whether current necessary. regulatory pathways are sufficient for emerging technologies and therapies. Potential implementation approaches: FDA could consult with other stakeholders to determine whether amendments to existing pathways or additional pathways are needed. The framework could allow products regulated solely as medical devices and made from materials that promote cell growth or tissue healing to claim regenerative properties.  Improve FDA's ability to develop  Could result in timely feedback  Could require funding for FDA for and maintain an appropriate to sponsors, enable increased additional positions. interdisciplinary regulatory interaction between reviewers  Salaries may need to be increased workforce. and sponsors, and make for FDA to compete with the therapies available to patients This policy option could help private sector. sooner. address the challenge of staffing shortages at agencies like FDA. Potential implementation approaches: FDA could continue to develop and implement an agency-wide strategic workforce plan. FDA could improve training for current staff on the latest technologies and therapies.  A public education campaign could  Support better and more  Combat false information and require significant resources, and effective information tools that improve public trust. it is unclear how its effectiveness  Help patients to evaluate the would be evaluated. legitimacy of available therapies. Regenerative Medicine GAO-23-105430 32 Policy options Opportunities Considerations are publicly available to  Help increase the diversity of  Even with more accurate clinicians and patients. clinical trial participants, which information, patients ultimately improves understanding of the decide what is best for their This policy option could help safety and effectiveness of health based on their personal address the challenge of medical products for different circumstances. For example, unlicensed stem cell products. populations. studies show that patient Potential implementation decisions on whether to undergo approaches: an unapproved or unlicensed intervention are complex and Key stakeholders-such as depend on the patient's condition, councils or associations of consideration of medical risks, governments or federal or state trust in research or medical agencies-could coordinate institutions, and other factors. strategic campaigns and partnerships between government health agencies and organizations that have broad public appeal (e.g., faith-or community-based organizations, sports, or patient advocacy groups). FDA and state health departments or medical boards could create and publicize a shared database of clinics offering unlicensed stem cell products. Federal agencies and organizations that help consumers gauge the value, quality, or authenticity of goods and services could create informational materials with strategies for consumers to evaluate medical claims and advertising.  Maintain the status quo. • Could allow current regulatory • Product developers may have framework for evaluating difficulties advancing new regenerative products to remain technologies and therapies to the unchanged. market. • Could save government or • Larger companies may continue to private sector resources for maintain advantage such as access other priorities, including to regulatory advisors over smaller promising medical technologies companies. and therapies other than • Consumers may continue to fall regenerative medicine. prey to misleading marketing • Would avoid making changes to about unapproved or unlicensed regulatory framework that may stem cell products. not address the needs of technologies and therapies yet to be developed. Source: GAO. | GAO-23-105430 Regenerative Medicine GAO-23-105430 33 3.3 Challenges related to Biologics are significantly more complex than small- manufacturing molecule drugs Even though small-molecule drugs and biologics are often discussed in similar contexts, their complexity differs Manufacturing is the creation of new substantially. Aspirin is a drug that has 21 atoms. products from starting materials, in a way Monoclonal antibodies, which experts consider to be relatively simple biologics, have around 25,000 atoms. Thus, that is generally consistent and the difference in complexity between small-molecule drugs reproducible.46 It is a key step for many and monoclonal antibodies is similar to the difference between a bicycle and a commercial jet. emerging technologies and therapies, because it can help increase product A human cell is far more complex than a single protein, like an antibody. An average cell is estimated to contain 42 consistency, decrease costs, and facilitate million proteins, and the precise composition of these larger production volumes that make proteins is constantly changing as the cell uses energy and grows.a products more accessible and affordable. Existing manufacturing technologies, even those used to manufacture simpler biologics, require significant Biologics, including cells, tissues, and organs adaptations and advances to manufacture the complex used for regenerative medicine are difficult to biologics needed for regenerative medicine. manufacture at scale because they are far Source: GAO analysis. | GAO-23-105430 aBrandon Ho et al. "Unification of Protein Abundance Datasets Yields more complex than many other medical a Quantitative Saccharomyces cerevisiae Proteome" Cell Systems products, such as small-molecule drugs (see vol. 6, 192–205 (2018). https://doi.org/10.1016/j.cels.2017.12.004. text box). This complexity also contributes to three challenges related to manufacturing in We identified the following three challenges regenerative medicine: lack of infrastructure, to the widespread and efficient manufacture ensuring quality, and workforce shortages. of regenerative medicine products. Currently, some components of certain regenerative medicine products can be Lack of infrastructure. The cell, tissue, and reliably manufactured. For example, the DNA organ products being developed for and viral vectors used to alter a cell's regenerative medicine will require more genome-a key part of gene and cell complex manufacturing facilities than are therapies-can be produced at large scales. currently used to produce small-molecule However, producing complete products, such drugs. For example, many existing as CAR T cell that may cure certain types of pharmaceutical manufacturing lines are not cancer, currently requires technicians to entirely closed off from the external perform many steps manually. Experts stated environment, because small-molecule drugs that regenerative medicine technologies and can be sterilized once manufacturing is therapies will require increased levels of complete, using tools like heat, chemicals, automation if they are to be widely accessible and radiation. Regenerative medicine and affordable. products cannot be sterilized, because sterilization can damage or kill cells and tissues. Therefore, manufacturing facilities will need complex systems to prevent 46Starting or ancillary materials are materials used during the manufacturing of cell and tissue products that are not intended to be a part of the therapy itself. Regenerative Medicine GAO-23-105430 34 contamination and keep products sterile facility where member organizations can test throughout manufacturing. Additionally, and develop manufacturing processes for new manufacturing facilities will need to allow for products.47 Similarly, the Wake Forest some customization to individual patients, Institute for Regenerative Medicine has a while also enabling some level of mass manufacturing facility that helps researchers production to reduce costs. test manufacturing processes as they develop their technologies. Additionally, the California Experts stated that standing up such facilities Institute for Regenerative Medicine is will be risky for private companies. The planning to build a California Cell and Gene necessary complexity will require significant Therapy Manufacturing Network that will investment, regardless of whether the address manufacturing bottlenecks and help facilities are newly built or remodeled. advance regenerative medicine therapies to Further, a company likely will not receive a patients. However, industry experts, including return on this investment until FDA has those at ARMI, stated that more facilities may licensed its product, a process that generally be needed to meet the demands of the takes years and is difficult to predict early in regenerative medicine industry. In particular, product development, according to experts. patients receiving therapies that use their own cells or tissues could benefit from Some initiatives are underway to help distributed manufacturing facilities to help companies develop their manufacturing increase production capacity and allow processes at testbed facilities before building patients to receive therapies more quickly.48 A at larger scales. These facilities, sometimes greater and more widely distributed number operated as public-private partnerships, can of manufacturing facilities may be beneficial, help smaller companies pilot their because there are few existing facilities and manufacturing processes or begin scaling up patient cells must be flown to one of those production, before they engage with larger facilities from hospitals around the country companies or contract manufacturers. For (see fig. 5). example, the Advanced Regenerative Manufacturing Institute (ARMI) has a shared 47The Departments of Commerce, Defense, and Energy have regularly assess the operation of this network. See, for established a network of innovation institutes-known as example, GAO, Advanced Manufacturing: Innovation Institutes Manufacturing USA institutes-to promote research, Report Technology Progress and Members Report Satisfaction development, and commercialization of advanced with Their Involvement, GAO-22-103979 (Washington, D.C.: manufacturing technologies. ARMI is a non-profit organization Dec. 16, 2021). administering BioFabUSA, a Manufacturing USA institute (also 48Distributed manufacturing is a decentralized manufacturing known as a Manufacturing Innovation Institute) founded in strategy in which portable manufacturing units may be 2017 and funded by the Department of Defense. Its goal is to deployed to multiple locations. Point-of-care manufacturing is make practical the scalable, consistent, and cost-effective a type of distributed manufacturing in which manufacturing manufacturing of cells, tissues, and organs. The National units are deployed to places close to where patients may Institute for Innovation in Manufacturing Biopharmaceuticals is receive care, such as a health care facility. Point-of-care another manufacturing innovation institute funded by NIST, manufacturing could thus be used by health care facilities to whose mission is to accelerate biopharmaceutical innovation, meet specific patient needs. including in the area of cell therapies. GAO is mandated to Regenerative Medicine GAO-23-105430 35 Ensuring quality. All medical products have small-molecule drug like aspirin might be the defined properties or characteristics that help active ingredient's concentration or the ensure quality, known as critical quality product's purity. These properties can be attributes (CQA). For example, the CQAs for a measured by, for example, comparing them Regenerative Medicine GAO-23-105430 36 to established standards.49 A batch of a drug update CQAs for each regenerative medicine can be stored as a reference so future batches product and establish processes to measure can be compared against it. them. However, stakeholders often lack consensus Keeping manufacturing consistent may also on how to measure quality for regenerative be difficult because the starting materials medicine products. There are also few used in regenerative medicine are inherently standardized reference materials that can be variable in their composition. For example, in used to evaluate a finished product, making it the area of stem cell therapies, starting difficult to identify CQAs. Furthermore, materials include nutrients for growing cells because regenerative medicine products and growth factors for triggering stem cells to contain living cells, they can change over time grow into the specific type of cell needed for or with environmental conditions. For a therapy. Variation in these materials can example, cells in a laboratory may function reduce product consistency or cause differently than the same cells in a patient. contamination.51 Product quality standards Instead of comparing their products to and oversight may reduce such variation, but reference materials, many regenerative according to experts we spoke with, few medicine manufacturers operate under the quality standards currently exist for these assumption that if their manufacturing materials or even for the starting materials processes are consistent, the final product used to make them.52 will be high quality and consistent. FDA has issued several guidance documents to help Workforce shortages. According to industry product developers identify CQAs.50 However, experts, there is a shortage of skilled technical CQAs are often product-specific and may be personnel who could work on regenerative challenging to identify during early clinical medicine manufacturing lines. As demand for development. Therefore, additional studies regenerative medicine products grows, may be needed later in development to workforce needs will also continue to grow. 49Standards for manufacturing may include reference depending on factors such as source or vendors. They also note materials, or internal standards that a company establishes for that lot-to-lot variability and stability of reagents can be their specific products and processes. problematic. Food and Drug Administration, Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell 50Food and Drug Administration, Human Gene Therapy Products. (Mar. 2022). Products Incorporating Human Genome Editing (Mar. 2022), https://www.fda.gov/media/156896/download, 9, accessed https://www.fda.gov/media/156894/download, accessed Apr. Mar. 13, 2023. Experts told us that, unlike sponsors, starting 11, 2023; Considerations for the Development of Chimeric material suppliers are not required to follow current good Antigen Receptor (CAR) T Cell Products (Mar. 2022), manufacturing practice regulations if a material is not https://www.fda.gov/media/156896/download, accessed Mar. incorporated into a final product. 8, 2023; Chemistry, Manufacturing, and Control (CMC) 52The International Organization for Standardization has Information for Human Gene Therapy Investigational New Drug Applications (INDs) (Jan. 2020), recently published a standard that gives guidance to suppliers https://www.fda.gov/media/113760/download, accessed Mar. and users of ancillary materials to improve the consistency and 8, 2023; and Potency Tests for Cellular and Gene Therapy quality of ancillary materials used in the production of cellular Products (Jan. 2011), therapeutic products and gene therapy products for human use. https://www.fda.gov/media/79856/download, accessed Apr. International Organization for Standardization, "ISO 20399:2022 11, 2023. Biotechnology – Ancillary materials present during the production of cellular therapeutic products and gene therapy products," 51Recent FDA draft guidance acknowledges that the safety and December 2022. https://www.iso.org/standard/79399.html, quality of starting and ancillary materials can vary widely accessed Mar. 13, 2023. Regenerative Medicine GAO-23-105430 37 Additionally, manufacturing may need to be Foundation Advanced Technical Education spread out geographically because some program is supporting some workforce regenerative medicine products would be development programs for biotechnology easier to produce near patient care centers. training, but an expert emphasized the need The industry may therefore need technical to expand to more campuses and increase workers in many locations, not just cities that awareness about regenerative medicine at already have a large biomedical workforce. the pre-college level.54 We previously reported on the regenerative medicine A recent study noted that regenerative workforce and found that, in addition to a medicine manufacturing requires people to shortage of existing skilled laboratory and perform routine, repetitive processes with as manufacturing technicians, vocational and much consistency as possible.53 Experts also technical education is insufficient to meet suggested that workers will need technical both current and future workforce needs.55 skills, such as the ability to accurately handle liquids and keep materials sterile, but they We identified three policy options to help may not need significant theoretical address these manufacturing challenges. background in biology. Experts said Table 3 presents these options, along with the community and technical colleges may be option of maintaining the status quo and best suited to train students for such careers, opportunities and considerations. because they have robust workforce development programs. The National Science 53Gary M. Green et al, "Recommendations for workforce https://beta.nsf.gov/funding/opportunities/advanced- development in regenerative medicine biomanufacturing," technological-education-ate, accessed Feb. 21, 2023. Stem Cells Translational Medicine, (2021) 10; 1365-1371. 55GAO, Regenerative Medicine and Advanced Therapies: https://doi.org/10.1002/sctm.21-0037. FDA ensures the quality Information on Workforce and Education, GAO-23-106030 of drugs and biologics by monitoring manufacturers' (Washington, D.C.: Mar. 23, 2023). We also found that there compliance with its current good manufacturing practice were no nationally recognized regenerative medicine regulations. 21 C.F.R. Parts 210, 211, 212, and 600 (2022). education curricula for various postsecondary degrees. For more information about the National Science Foundation 54 Advanced Technological Education (ATE), see Regenerative Medicine GAO-23-105430 38 Table 3: Policy options for regenerative medicine manufacturing Policy options Opportunities Considerations  Create more shared pilot- and  May accelerate product  It will be costly to build shared mid-scale manufacturing development. manufacturing infrastructure. facilities to help companies  May help companies de-risk their  It is unclear which stakeholders develop their manufacturing products by giving them should be responsible for funding processes. opportunities to develop and and operating shared facilities. This policy option could help confirm the effectiveness of  Not all therapies require the same address the lack of automated and scalable level of scale-up (e.g., therapies for manufacturing infrastructure. manufacturing processes. rare diseases have smaller market Potential implementation  May save time and money by sizes, so fewer doses will be approaches: allowing companies to postpone needed). building infrastructure until after Government agencies could  Not all stakeholders agree that their products and manufacturing support more public-private there should be a federal role and processes are further along the partnerships that can share costs may, instead, prefer to maintain the development pipeline. for manufacturing facilities. current free-market model for developing regenerative medicine Industry stakeholders could products. partner with academic researchers to increase  Issues may arise when sponsors manufacturing readiness of transition from development technologies and prepare them processes in one location to for commercialization. commercial processes in a second location.  Proprietary manufacturing processes may be a component of FDA licensure. If FDA were engaged with private companies in developing such processes, FDA would need to ensure there was no conflict of interest and that other companies had a level playing field.  Provide more oversight and  May accelerate manufacturing by  Starting material suppliers may lack feedback to suppliers to increase reducing variation in input incentives to follow standards if consistency in starting materials. materials. they lead to higher costs. This policy option could help  May reduce the risk of failure address inconsistency in starting during product development. materials for manufacturing. Potential implementation approaches: FDA could work with the Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery and manufacturers to establish quality standards for starting materials. Regenerative Medicine GAO-23-105430 39 Starting material suppliers could commit to following starting material consensus standards, like those published by the International Organization for Standardization.  Create hands-on training  Could expand the regenerative  Educational programs may need to programs at community and medicine workforce and help be integrated with regenerative technical colleges to address students develop technical skills medicine research programs to workforce shortages. to meet existing and future needs. ensure that trainees can stay up to date on techniques and This policy option could help  Could lead to increased domestic technologies. address manufacturing workforce manufacturing, which can shortages. contribute to U.S. global  Community and technical colleges competitiveness. may have limited access to training Potential implementation facilities. approaches:  Could create opportunities for high-paying jobs that do not Academic stakeholders could use require an advanced degree. government-run pilot facilities to train students. Academic stakeholders could create standardized training certifications to expand opportunities for both trainees and employers.  Maintain the status quo.  Could allow manufacturing to  Larger companies may continue to continue its current incremental control manufacturing. development.  Product developers may have  Could save government or private difficulty accessing manufacturing sector resources for other facilities during development, priorities, including promising creating high potential for product medical technologies other than failure once they begin regenerative medicine. manufacturing at scale. Source: GAO. | GAO-23-105430 Regenerative Medicine GAO-23-105430 40 4 Agency and Expert Comments We provided a draft of this product to Department of Health and Human Services' FDA and National Institutes of Health, Department of Defense, and Department of Commerce's NIST for review. Department of Defense concurred without comment. The other agencies and some participants from our expert meeting provided technical comments, which we incorporated as appropriate. We are sending copies of this report to the appropriate congressional committees and other interested parties. In addition, the report is available at no charge on the GAO website at https://www.gao.gov. If you or your staff have any questions about this report, please contact me at (202) 512-6888 or HowardK@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix III. Karen L. Howard, PhD Acting Chief Scientist and Director, Science, Technology Assessment, and Analytics Regenerative Medicine GAO-23-105430 41 Appendix I: Objectives, Scope, (FDA) guidance on the biologics license applications process. and Methodology Limitations to scope Objectives The list of key technologies discussed in this This report examines: report is not intended to be exhaustive. Based on our review of the literature and (1) current and emerging regenerative discussions with federal agency officials and medicine technologies and therapies and other experts, we selected technologies their potential benefits, currently in use or under development by researchers to restore body functions that (2) challenges that hinder the development may be lost to disease or injury. We did not and use of regenerative medicine include technologies used for research technologies and therapies, and purposes, testing, or diagnostics, such as organ-on-a-chip devices. Though regenerative (3) policy options that could help enhance medicine technologies may be developed or benefits and mitigate challenges associated used internationally, the policy options we with these technologies and therapies. identified represent possible actions U.S. policymakers and stakeholders could take. Scope and methodology Literature search To address all three of our objectives, we assessed available and developing In the course of our review, we conducted a regenerative medicine technologies and literature search of key technologies for approaches that may restore cell, tissue, and curing human disease and restoring bodily organ functions lost to disease or injury. For functions using search terms including all of our objectives, we reviewed peer- "regenerative medicine," "bioprinting," and reviewed scientific literature and other "organs," among other keywords relevant to documents describing current and developing technologies for regenerative medicine. We technologies; interviewed federal agency also conducted a broad search of materials officials and experts from government, published within the last 10 years, including academia, industry, the nonprofit sector, and scholarly articles and government reports. end user groups such as patient groups; and From these searches, we identified and convened a 3-day expert meeting with selected relevant articles to include in our assistance from the National Academies of review. We used the results of our literature Sciences, Engineering, and Medicine (National review to inform our findings as well as Academies) to discuss the objective topics. identify experts to interview or invite to We provide more details on these participate in our expert meeting. methodologies below. We also reviewed federal agency guidance on the development and deployment of relevant technologies, such as Food and Drug Administration Regenerative Medicine GAO-23-105430 42 Interviews We selected meeting participants based on their expertise in at least one area related to We interviewed federal agency officials and our objectives. We provided the National researchers as well as nonfederal experts with Academies staff with descriptions of the a diverse set of perspectives on the science expertise needed by expert meeting and application of these technologies. The participants. From this information, the staff federal experts included individuals from FDA, provided an initial list of potential participants the National Institutes of Health, Department for the expert meeting. We reviewed the list of Defense, and National Institute of and provided an additional list of experts Standards and Technology (NIST). We also based on our review of the literature. interviewed experts from technology companies, universities, and research In addition to evaluating experts on the basis institutes that use or develop regenerative of their expertise, we evaluated them for any medicine technologies and representatives conflicts of interest. A conflict of interest was from national advocacy organizations, such as considered to be any current financial or the American Society of Gene and Cell other interest, such as an organizational Therapy and the Alliance for Regenerative position, that might conflict with the service Medicine. of an individual because it could (1) impair objectivity or (2) create an unfair competitive Expert meeting advantage for any person or organization. Of the 18 experts who participated in the expert meeting, some were affiliated with To address all of our objectives, we also held companies, government agencies, a 3-day expert meeting on April 13, 19, and universities, or public-private partnerships. 22, 2022. This meeting was held with We took these affiliations into consideration assistance from the National Academies and as potential conflicts of interest when was divided into six sessions: (1) emerging conducting our analysis and preparing our regenerative medicine technologies; (2) report. We determined that these experts' regulatory challenges for new regenerative affiliations were unlikely to bias our overall medicine technologies; (3) manufacturing and reporting. standardization challenges in regenerative medicine; (4) social, economic, and ethical implications of emerging regenerative Policy options medicine technologies; (5) translational hurdles for emerging regenerative medicine Based on our research, we developed a series technologies; and (6) potential policy options of policy options. These are not listed in any that could help address technology limitations particular order, nor are they inclusive of all and other challenges.56 possible policy options. Policy options are intended to represent possible options policymakers can take to address a policy 56This meeting of experts was planned and convened with However, all final decisions regarding meeting substance and assistance from the National Academies to better ensure that a expert participation were the responsibility of GAO. breadth of expertise was brought to bear in its preparation. Regenerative Medicine GAO-23-105430 43 objective. We consider policymakers to We conducted our work from September include Congress, federal agencies, state and 2021 to July 2023 in accordance with all local governments, academia, and industry. sections of GAO's Quality Assurance For each policy option, we discussed potential Framework that are relevant to technology opportunities and considerations. We limited assessments. The framework requires that we policy options to those that fit the objective plan and perform the engagement to obtain and fell within the report scope. sufficient and appropriate evidence to meet our stated objectives and to discuss any To develop our policy options, we compiled a limitations to our work. Consistent with our list of possible options over the course of our quality assurance framework, we provided work based on review of the literature, the relevant agencies and experts with a draft interviews with experts, and our expert of our report and solicited their feedback, meeting. We further refined and assessed which we incorporated as appropriate. We these options to ensure they were adequately believe that the information and data supported by the evidence we collected, obtained, and the analysis conducted, provide could be feasibly implemented, and fit into a reasonable basis for any findings and the overall scope of our work. We then conclusions in this product. analyzed the information we collected to identify potential benefits and considerations of implementing each policy option. The policy options and analyses were supported by documentary and testimonial evidence. Regenerative Medicine GAO-23-105430 44 Appendix II: Expert Participation We convened a 3-day meeting of 18 experts with assistance from the National Academies of Sciences, Engineering, and Medicine to inform our work on regenerative medicine technologies; the meeting was held virtually on April 13, 19, and 22, 2022. The experts who participated in this meeting are listed below. Some of these experts gave us additional assistance throughout our work, including eight experts who provided additional assistance during our study by sending material for review or participating in interviews and the experts who reviewed our draft report for accuracy and provided technical comments. Guillermo Ameer Mahendra Rao Northwestern University PanCELLa Anthony Axtala Liz Richardson Wake Forest Institute for Regenerative Pew Charitable Trusts Medicine David Ridley Glenn Cohen Duke University Harvard Law School Derek Robertson Kurt Gunter The Maryland Sickle Cell Disease Association Athenex Krishnendu Roy Kelvin Lee Georgia Tech Cell Manufacturing University of Delaware; National Institute for Technologies Innovation in Manufacturing Kris Saha Biopharmaceuticals University of Wisconsin-Madison Tim Miller Kevin Schulman Forge Biologics Stanford University Richard McFarland Sohel Talib Advanced Regenerative Manufacturing Institute; Standards Coordinating Body for California Institute for Regenerative Medicine Gene, Cell, and Regenerative Medicines and Kathy Tsokas Cell-Based Drug Discovery Janssen Inc. Canada Maria Millan James Yoo California Institute for Regenerative Medicine Wake Forest Institute for Regenerative Medicine Regenerative Medicine GAO-23-105430 45 Appendix III: GAO Contact and Staff Acknowledgments GAO contact Karen L. Howard, PhD, Acting Chief Scientist and Director, Science, Technology Assessment, and Analytics (STAA), at (202) 512-6888 or HowardK@gao.gov Staff acknowledgments In addition to the contact named above, the following STAA staff made key contributions to this report: Sarah Harvey, MS, Assistant Director Cindy Korir-Morrison, PhD, Analyst-in-Charge and Senior Biological Scientist Kristin Hook, PhD, Biological Scientist Eric D. Lee, PhD, Senior Biological Scientist These staff also contributed to this work: Nora Adkins, Senior Attorney Virginia Chanley, PhD, Senior Design Methodologist Jehan Chase, Senior Attorney Ailene Edwards, Intern Kaitlin Farquharson, Senior Attorney John Karikari, PhD, Assistant Director, Economist Flora Ngo, Intern Emily Quick-Cole, Intern Joe Rando, Visual Communications Analyst Ben Shouse, MS, Communications Analyst Walter Vance, PhD, Assistant Director Regenerative Medicine GAO-23-105430 46 GAO's Mission The Government Accountability Office, the audit, evaluation, and investigative arm of Congress, exists to support Congress in meeting its constitutional responsibilities and to help improve the performance and accountability of the federal government for the American people. 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Nicole Clowers, Managing Director, ClowersA@gao.gov, (202) 512-4400, U.S. Government Accountability Office, 441 G Street NW, Room 7125, Washington, DC 20548 Public Affairs Chuck Young, Managing Director, YoungC1@gao.gov, (202) 512-4800 U.S. Government Accountability Office, 441 G Street NW, Room 7149, Washington, DC 20548 Strategic Planning and External Liaison Stephen Sanford, Managing Director, spel@gao.gov, (202) 512-9715 U.S. Government Accountability Office, 441 G Street NW, Room 7B37N, Washington, DC 20548 Regenerative Medicine GAO-23-105430 47