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Author: 
Lilia Carolina Leon-Moreno, PhD
Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ) 
México

Editor:
Fernando E. Figueroa, MD, FACP
Universidad de los Andes School of Medicine
Chile

The field of Advanced Therapy Medicinal Products (ATMPs) such as cell and gene therapies, is revolutionizing medicine, offering groundbreaking treatments for previously incurable diseases. These therapies include cellular and genetic approaches addressing a wide array of conditions and products, such as mesenchymal stem cell (MSC) therapies, gene therapies for rare diseases, and tissue-engineered products with the potential to widely impact the healthcare landscape.

There are many challenges for the deployment of these therapies globally, some of which remain concentrated in high-income countries. Despite this, in South and Central America the landscape is evolving, slowly but steadily, and the region is becoming an increasingly important player in the global ATMP market, driven by regulatory reforms, clinical advancements, and a growing interest in biotechnology. However, there are diverse challenges that need to be addressed such as deficits in infrastructure, regulatory frameworks, and public awareness in order to fully unlock the potential of ATMPs in this region.

While much of the spotlight has been on CAR-T (Chimeric Antigen Receptor T-cell) therapies due to different commercial approvals in the last few years, several non-CAR-T ATMPs have also made significant strides, and are therefore, the main focus of this report.

Regulatory Frameworks and Approvals
The regulatory landscape for ATMPs varies widely across South and Central American countries (1). According to the Regulation Tracker of the Genetic Literacy Project website (2), regulations for gene editing of adult human cells, including gene therapy and stem cell therapy in most of the countries of our region are vague. Brazil is currently taking the lead, since this country is highly regulated for ATMP research and commercial approvals. Other countries such as Chile, México and Argentina are still developing regulations that take into account some, -but unfortunately not all-, cell and gene therapies.

The Brazilian Health Regulatory Agency (ANVISA) has been at the forefront of ATMP regulation in the region. It has established a comprehensive regulatory framework that supports the development, approval, and commercialization of ATMPs. Outside of CAR-T therapies, ANVISA has approved only two advanced gene therapies (Zolgensma and Luxturna) for the treatment of specific genetic disorders. Zolgensma is intended to treat spinal muscular atrophy (SMA), caused by mutations in the SMN1 gene, providing a single-dose treatment option for children under two years old. It is specifically indicated for SMA patients with bi-allelic mutations of the SMN1 gene or those with up to three copies of the SMN2 gene. On the other hand, Luxturna is used to treat inherited retinal dystrophy caused by mutations in the RPE65 gene. This therapy is indicated for patients with confirmed biallelic RPE65 mutations who have sufficient viable retinal cells. Also, Brazil has been active in the development and approval of MSC therapies for conditions like graft-versus-host disease (GvHD), osteoarthritis, and autoimmune diseases. However, to date, there is no authorized MSC therapies beyond some trial use.

Argentina has been committed to aligning its regulatory processes with global standards. Its regulatory framework already defines ‘biological medicinal products’ as ‘products derived from living organisms like cells or tissues’. This definition includes stem cell preparations, classifies them as ATMPs and requires them to be registered and approved before commercialization. Still, challenges regarding clarity and harmonization of regulations specific to advanced therapies remain (3). Also, Argentina is advancing in stem cell research and therapies, with several ongoing clinical trials exploring their use in treating neurological disorders, cardiovascular diseases, and autoimmune conditions. A full list of these trials can be found in the following link: http://www.celulasmadre.mincyt.gob.ar/tratamientos.php. Despite that, the National Administration of Drugs, Food, and Medical Technology (ANMAT) in Argentina has only approved the gene therapy Luxturna. No cell therapy treatments can be commercially used yet.

Recent efforts from Argentina are focused on improving its regulatory landscape to promote innovation. ANMAT's proactive approach in approving the gene therapy Luxturna demonstrated the importance of having a regulatory body that is willing to embrace innovation and collaborate with global experts and institutions. On top of that, ANMAT focused their efforts to negotiate pricing and provide financial support to make Luxturna accessible to a broader patient population.

Emerging potential countries such as Mexico and Chile have shown an increasing interest in regulating and approved ATMPs, although its framework is still far from being fully developed, compared to Brazil or even Argentina. Mexico has made strides in the research of stem cell therapies, particularly MSC-based treatments for inflammatory and degenerative diseases. However, the laws and standards in the country do not consider any definition nor classification of ATMPs. Regulatory framework is still being discussed by legislators and, unfortunately, they are only considering hematopoietic stem cells and blood transplants in the picture. Moreover, the regulatory oversight from the Mexican Federal Commission for the Protection against Sanitary Risk (COFEPRIS) remains weak. Because of this, numerous non-regulated clinics have appeared. Although Mexico’s potential in gene therapy development is growing, supported by research institutions like the National Institute of Genomic Medicine (INMEGEN) and partnerships with international biotech companies, there is only one RNA therapy (not quite considered as ATMP) in the country:  Kynamro, an antisense oligonucleotide inhibitor of apolipoprotein B used to treat homozygous familial hypercholesterolemia.

On the other hand, recent efforts from different Mexican institutions have built or are in the process of building GMP facilities for the research and development of cell therapies: the Biomedical Sciences Institute from Universidad Nacional Autónoma de México (https://www.biomedicas.unam.mx/wp-content/pdf/plan-desarrollo-2023-2027-iibo), the Research and Development of Biotherapeutics Unit from Instituto Politécnico Nacional (https://udibi.com.mx/) and the Hematology Unit in the University Hospital of Universidad Autónoma de Nuevo León (https://www.medigraphic.com/cgi-bin/new/resumen.cgi?IDARTICULO=107039). These study groups are paving the way for the deployment of ATMPs in the country.

Chile is actively participating in clinical trials involving gene therapies and stem cell research, with a focus on rare diseases and regenerative medicine. This country has approved some products only for compassionate use, such is the case of TAPCells, the dendritic cell vaccine against melanoma and prostate cancer that is currently under clinical trials for its commercialization in Brazil. Even when the Public Health Institute is aware about the results obtained in the research studies of the Faculty of Medicine and the Clinical Hospital of the University of Chile with this therapy, TAPCells is not approved for commercial use, and it is allowed only as a complementary treatment under the supervision of an oncologist or an immunologist. No ATMP has been approved yet and the lack of a regulatory pathway had hindered the development of these therapies in the country.

Peru, Ecuador, and Uruguay are exploring the potential for ATMPs, with ongoing research and the development of preliminary regulatory frameworks. However, the hurdle of the regulations in most of the countries of the region had hindered and delayed the possibility that any ATMP could be available for commercial use. 

Challenges in the Region
The major significant but not insurmountable challenge that has slowed down and impacted the availability, adoption, and implementation of these therapies across South and Central America region is the regulatory hurdles. Not all the countries that comprise the region include ATMPs in their regulations nor have plans to regulate them, while others are still in the process of developing regulatory guidelines. This process includes changes in guidelines or requirements, leading to inconsistencies in approval processes. 

Moreover, the established guidelines are not harmonized among countries. In some cases, the regulatory body requires additional studies and data from the same product already approved in another country. This fragmentation and evolving landscape have located our region in a disadvantageous position in the eyes of multinational companies looking to bring innovative treatments to market, because they must navigate multiple regulatory environments to be able to sell their products. This can discourage international companies from entering the market. Further, most of the countries in the region have regulatory processes with long approval times with lengthy and complex processes. The lack of established protocols can result in even longer review periods, leading to even more delays. 

Local innovation is not promoted or encouraged either. Without clear and harmonized regulatory pathways, there is a greater risk of delays, increased costs for clinical trials, and product approvals. Therefore, investors are hesitant in supporting local research and development that can lead to homegrown innovations, slowing down the overall growth of the industry. On top of that, ambiguous or absent regulations hinder the public awareness and understanding of the importance of evaluating quality, effectiveness and safety of these therapies. People buy any so-called “regenerative medicine” or “stem cell therapy” without asking for appropriate facilities, evidence, or quality controls. As there is no pressure to meet any standard, investors are discouraged to impulse or support biotech startups and research institutions to develop science-based, ethical treatments manufactured in specialized facilities and equipment that will raise their cost. There is no public demand for those. 

Probably, the main cause of the regulatory delay in our region is that it remains difficult for all actors -including regulatory agencies- to count on a cadre of well trained professionals with the expertise or resources needed to competently assess these advanced therapies, causing lengthy review times or the imposition of additional, sometimes ambiguous, requirements. We need well-trained personnel with specific expertise in cell and gene therapies, GMP rules, quality control, clinical trials, etc. As the role of industry in the development of ATMPs is poor in the region, there is no room for training outside of academia, with the limitations that this implies. 

Opportunities for Improvement
The future of cell and gene therapies in South and Central America looks uphill, but both promising and rewarding. Ongoing clinical trials and research initiatives are paving the way for new treatments and approvals in the region. Collaborative efforts between governments, academic institutions, and biotech companies among all the countries of the region will be key to overcoming existing challenges and expanding access to these life-changing therapies. Some strategies that could facilitate the approval and commercialization of more advanced therapy products include:

Harmonization of Standards: Regional cooperation to harmonize regulatory standards and processes across countries in the region could help streamline approvals, make it easier for therapies to be introduced and makes the region more appealing for investors and large companies.
Capacity Building: Investing in infrastructure and expertise development can help address gaps in regulatory and oversight capacity. In addition, the existence of an established regional ecosystem for the development of ATMPs saves time and money for future companies that enter the market.
Public-Private Partnerships: Collaborations between government agencies, industry, and research institutions can help overcome economic, knowledge, and logistical barriers.

Patient Advocacy and Education: Increased awareness and advocacy for cell and gene therapies can help drive regulatory changes and support access to these innovative treatments.

Adopting International Guidelines: Adopting and adapting international regulatory guidelines can provide a framework for local regulatory bodies, ensuring safety and efficacy while expediting approvals. This also gives the region the opportunity to compete for the attention of multinational companies because harmonization with the benchmarks makes easier the submission of their products for commercialization using the same data in each country. 
Innovative Financing: Innovative financing models, such as outcome-based pricing and government subsidies, can make these therapies more affordable. Collaboration with global health organizations can also provide funding support.

Support to Local Innovations: Investing in local research and development can lead to homegrown innovations. Governments and the private sector should work together to support biotech startups and research institutions.

Role of International Societies: In the absence of strong local industry stakeholders, international societies such as ISCT play a crucial role by providing guidance, fostering collaboration, and facilitating knowledge exchange among stakeholders. These societies help bridge gaps between local regulatory bodies, researchers, and industry by offering platforms for discussion on best practices, safety standards, and regulatory frameworks. Additionally, they can provide training and resources to local regulators and industry professionals, helping to build capacity and expertise in evaluating complex therapies. It is vital for the evolution of our region that stakeholders from different countries actively participate in the activities and platforms that this society offers.

Public Awareness: One vital piece for the development of the ATMPs ecosystem is the general population. Researchers, governments, and industry need to organize campaigns aimed at educating patients and healthcare providers with the aim to teach them to discriminate safe, science-based from unethical products. If the population demands better products and therapies, biotech pharma owners and investors could be motivated to invest in the development of ethical and legal ATMPs.

The approval and adoption of cell and gene therapies in South and Central America represents a significant advancement in the region’s healthcare landscape. However, it involves navigating a complex landscape of regulatory hurdles, including varying standards, infrastructure limitations, high costs, and ethical concerns. While challenges remain, the potential benefits of these therapies for patients with genetic and rare diseases are immense. Addressing these challenges requires a concerted effort from regulatory agencies, industry stakeholders, and policymakers to create a more streamlined and supportive environment for the introduction of these life-changing therapies.

From the Legal and Regulatory Affairs Committee: South & Central America we invite all stakeholders across the region —regulators, industry leaders, academic researchers, healthcare professionals, and patient advocates— to join our committee to collaborate strategically and drive the growth of ATMPs in our markets. With the ISCT’s endorsement, we can participate in roundtables, working groups, and strategic collaborations that address the unique challenges faced in the region, from regulatory hurdles to market access and patient education. Together, we can share insights, develop harmonized frameworks, and create actionable solutions that accelerate the approval and adoption of ATMPs, ultimately bringing innovative therapies to patients across South and Central America who need them most. Let’s work together to shape a more cohesive and supportive environment for the development and commercialization of cell and gene therapies in our region.

References:

1. Orozco-Solares, et al. Allogeneic Mesenchymal Stem Cell-Based Treatment Legislation in Latin America: The Need for Standardization in a Medical Tourism Context. Stem Cells Dev. 2022 Apr;31(7-8):143-162. doi: 10.1089/scd.2022.0013
2. Genetic Literacy Project Human/Health Gene Editing Index Compare Regulatory Restrictions Country-to-Country. https://crispr-gene-editing-regs-tracker.geneticliteracyproject.org/
3. Arzuaga F. A Governance Framework for Advanced Therapies in Argentina: Regenerative Medicine, Advanced Therapies, Foresight, Regulation and Governance. In: Laurie G, Dove E, Ganguli-Mitra A, et al., eds. The Cambridge Handbook of Health Research Regulation. Cambridge Law Handbooks. Cambridge University Press; 2021:324-332.