Stem Cell - Legislation Throughout Latin America
The Need for Standardization in a Medical Tourism Context
Legislation Within Latin America
To our knowledge, there are only a few published studies focusing on the cell therapy policies or regulations within Latin America. This knowledge gap limits the understanding of the pros and cons of the industry and obstructs the ability to generate policies favoring health-centered outcomes. Brazil, Mexico, and Costa Rica are among the top 10 medical tourism destinations worldwide. Latin America is comparable with other medical tourism destinations in terms of socioeconomic development, absence of/or direct regulation, low operating costs, and policies prioritizing provider discretion.
According to the Regulation Tracker of the Genetic Literacy Project website, most Latin American countries do not have precise regulations regarding current or future cell therapies. As in other countries, limited funding, resources, and religious background could be hampering cell therapy policymaking. Awareness of the current legislation status in this region and efforts to standardize cell treatments and harmonize the regulations with the leading health agencies are critical.
As we observed before in the regulations of leading agencies, some Latin American countries reviewed in this study consider cell-based products outside of hematopoietic stem cells as a biological medicinal product and regulate them as drugs. Despite differences in the definition of cell therapies, the Latin American agencies agree in the necessity for authorization or licensing of health establishments manipulating cell products.
We confirm that, while some countries in the region have a more straightforward path than others, several countries are doing efforts at a national level to regulate the therapeutic application of cells. However, the discrepancy in the laws creates an inconsistent regulatory landscape that could favor new regulations based on competition, leaving aside ethical and scientific values. Most Latin American laws recognize autologous or allogeneic cell transplants, but do not consider any allogeneic ATMP. Despite its limitations, Latin American regulation does have a regulatory framework that can be used to restrain unauthorized or unproven therapies. This framework must be considered by patients seeking these treatments and by the owners of the clinics that want to establish a cell therapy business in the following Latin American Countries.
México
Mexico, is the world’s second largest medical tourism market because of its proximity to the United States and the open understanding of seeking actual cures, not just treatments as per it’s regulations. It attracts over a million medical tourists a year, especially for regenerative medicine and cell therapies. Many clinics are advertised and based in the United States, but provide their treatments in Mexico due to the permissive regulations for several innovative practices.
The health agency in this country is the Federal Commission for the Protection against Sanitary Risks (COFEPRIS, “Comisión Federal de Protección contra Riesgos Sanitarios”). In contrast to Brazil and Argentina, there is no regulatory framework regarding cell-based treatments. For these, policy makers have presented a draft standard for the implantation of progenitor cells for therapeutic and research purposes. However, it does not consider or classify cell therapies other than hematopoietic stem cells or blood components, and until now, it has not been officially released.
COFEPRIS does not officially regulate cell-based therapies as procedures or drugs; nevertheless, according to the arisen needs with the emergence of “regenerative medicine” clinics and several establishments processing cells and tissues, it issues licenses for procurement, isolation, or preserving stem and progenitor cells. Another license, called “Regenerative Medicine,” allows the application of platelet-rich plasma and other autologous procedures. However, it does not forbid any specific application, creating an ambiguity abused by many. According to several studies, clinics in Mexico are more likely to offer allogeneic therapies, probably using the Regenerative Medicine license. Yet, there are still an important number of clinics that are unlicensed by COFEPRIS offering these treatments.
Health establishments should satisfy the Statutes of the General Health Law and the guidelines published by the Transplant National Center (CENATRA, “Centro Nacional de Transplantes”) before tissue procurement and cell transplantation. Furthermore, the National Center for Blood Transfusion (CNTS, “Centro Nacional de Transfusión Sanguínea”) requires a monthly report of every cell donation, preservation, and transplant.
Although the authority requests it, these requirements are not established in any regulation or standard and are not legally required. Also, these principles seem contradictory since cell transplantation is not considered a blood transfusion. CENATRA, in the Statutes of the Control of Organs, excludes progenitor cells without explaining which cells are “progenitor.” We found this confusion as an improvement opportunity within the Mexican regulation that requires the attention and collaboration of stakeholders and researchers.
Currently, COFEPRIS demands the health establishments processing cells to adhere to the Official Norms designed for blood or tissue management for the clinical and laboratory screening of the donor: NOM-253-SSA2-2012, for the manipulation of human blood and its components for therapeutic purposes; and NOM-039-SSA2-2014, for the prevention and control of sexually transmitted infections. In addition, every new medical product should be subjected to clinical trials before authorization as a therapy, according to NOM-012-SSA3-2012 criteria for the execution of research projects for human health and the Statutes of the General Health Law in matters of Research for Health. COFEPRIS is also suggesting the use of other standards initially designed for drugs to simulate a regulatory framework resembling the benchmarks.
If the establishment wants to administer the MSC product in a patient, it should request the license for the industry or laboratory of medicines or biological products for human use and a Certification of GMP for Health Supplies to manufacture allogeneic MSC-based products, and its manufacture must be performed following NOM-059-SSA1-2015, good manufacturing practices for medicine, and NOM-164-SSA1-2015, good manufacturing practices for drugs. However, all these are mere suggestions and therefore are not routinely required when asking for a Regenerative Medicine or Stem Cell Bank license.
Mexican cell therapy-related regulations need further efforts such as cell therapy definitions, classification, and considering additional quality controls in every step of the manufacturing process. Continuous inspections are critical to avoid using the licenses mentioned above for cell therapy administration without proper testing. COFEPRIS has declared that one of the primary oversight tools is the patient’s reports to regulatory authorities. However, this is an unpopular practice. First, because many patients do not have the tools to assess scientific legitimacy, and second, many seek experimental procedures that are broadly prohibited.
Argentina
Initially, no regulation in Argentina discriminated between different cell types, manipulation, or risk levels. The National Administration of Drugs, Food and Medical Technology (ANMAT, “Administración Nacional de Medicamentos, Alimentos y Tecnología Médica”) resolved that cell therapies were a procedure regulated by the Professional Practice of Medicine Act and not a medical product. It also designated itself to authorize any new experimental procedure involving autologous or allogeneic human cells. Furthermore, the Ministry of Health regulated human cell isolation, preservation, and implantation.
It determined that all activities regarding transplantation of human cells are a matter for the Unique Central National Institute for Ablation and Implant Coordination (INCUCAI, “Instituto Nacional Central Único Coordinador de Ablación e Implante”), managed according to the Transplant Act.
In 2006, Argentina created the Advisory Committee on Cell Therapies and Regenerative Medicine (CATCMR, “Comisión Asesora en Terapias Celulares y Medicina Regenerativa”) constituted by biologists, medical doctors, bioethicists, lawyers, and regulators to advise the Argentinian government on issues regarding cell therapies and to lobby against nonproven cell treatment, And more recently, ANMAT defined and recognized “Somatic Cell Therapy Drugs” (SCTDs) in Disposition No. 7075/11 for biological medicine.
As of now, the production, registration, authorization, and surveillance of industrially produced ATPs are regulated through Disposition No. 179/18, in which every SCTD (including MSCs) is considered allogeneic and is subjected to the same regulation as biological or biotechnology drugs, while clinical trials for obtaining sufficient data involving any kind of medical product or procedure must adhere to the Resolution No. 1480/11, in which the Guide for Investigations with Human Beings is approved. Although there is a clear orientation toward international globalization, there is still much work to be done in Argentinian legislation. Furthermore, given the type of legislation in Argentina, federal rules do not apply to the treatments used inside the jurisdiction of a province. Therefore, there is no effective control over these interventions, and this legal loophole has led to an incrementation in experimental treatments.
Brazil
Until 2016, religious opposition and a constitutional prohibition for the commercialization of tissues and cells in Brazil had kept the development of a regulatory framework in cell-based therapies. However, to date, the National Health Surveillance Agency (ANVISA, “Agência Nacional de Vigilância Sanitária”) has reacted to the development of innovative cell-based practices and is the only country in Latin America that has authorized a legal framework comparable with the ones in the United States, EU, or Japan. Brazil classifies cell therapies as ATPs, and allogeneic MSC products are defined as extensive manipulated cells.
The regulatory framework for cell therapy manufacturing, marketing, product registration, and application in Brazil consists of two rules. The Resolution of the College Board (RDC) No. 338/2020 provides for ATP registration and other measures and RDC No. 214/2018 guarantees the Good Practices in Human Cells for Therapeutic Use and Clinical Research, provides guidelines for ATP processing, and demands a specific license for cell processing and the installation of a Quality Management System.
Similar to Australia, Brazil requires a complete application, including a full characterization of the cell product and preclinical safety data according to the product risk and manipulation for clinical trial authorization before starting. During the trial and early marketing authorization, the sponsor is responsible for the safety monitoring through adverse event notifications. Finally, for clinical application, the manufacturer must submit the comprehensive information of product fabrication and quality to be registered and authorized by ANVISA. As these are the most complete and detailed legal framework for cell therapies in the region, we suggest Brazil could guide Latin America.
Chile
In Chile, the Bulletin 11230-11 presents a Bill to the Congress for the modification of the Sanitary Code to establish a legal framework, to promote the scientific research in cell therapy and stem cells. This Bulletin was created because of the concern of researchers of the high number of clinics offering unproven cell therapy treatments through medical tourism.
Colombia
Colombian National Institute of Drug and Food Surveillance (INVIMA, “Instituto Nacional de Vigilancia de Medicamentos y Alimentos”) is the regulatory agency in charge of supervising drugs and biological products, as well as blood banks and blood derivates. Like other Latin American countries, the Colombian regulatory framework does not consider any specification for cell therapy other than blood and its derivates. However, despite its limitations, Colombian regulation does have a framework that includes CTP described below, which patients must consider when seeking or establishing these treatments.
Decree No. 2493/04 evaluates the procurement, donation, preservation, storage, transport, and disposal of human cell and tissue products for tissue and bone marrow banking. Resolution No. 5108/05 describes the Manual of Good Practices for tissue and bone marrow banks and the procedure to obtain the certificate of Good Practices. The standards for the research of new therapeutic resources and drugs, as well as the ethics and safety in the research in human beings, organs, tissues, and corpses are supervised through Resolution No. 8430/93. Resolution No. 2378/08 establishes the Good Clinical Practices in clinical trials.
Every trial for safety and efficacy of a new drug should be justified, and every drug must be registered by INVIMA before it starts. Last, the commercialization of CTP is regulated under Decree 1782/14, for the evaluations of biological drugs in the process of health registration, and the Resolution No. 5402/15 of Good Manufacturing Practices for Biological Medicines.
Costa Rica
In 2016, the Costa Rican Executive Order N° 39986-S authorized the Adult Stem Cells for Regenerative Therapies, establishing the requirements to apply cell-based treatments as well as the conditions for tissue procurement and cell isolation procedures. However, to administer cell treatments, there are essential requisites to follow. Only medical practitioners can prescribe cell-based therapies. Allogeneic MSC-based products are regulated as biological medicine and must follow all applicable regulation for drugs, in agreement with the Executive Order N° 37006-S. For its registration and commercialization, cell-based products should demonstrate efficacy and safety in clinical and nonclinical studies, following the requisites on the Biomedical Research Regulatory Law (N° 9234) and its Statute (N° 39061-S).
Also, Regulation of Good Pharmacovigilance Practices (N° 39417-S) demands the clinics to notify the adverse reactions to the Pharmacovigilance Center and take care of the medical and psychological needs resulting from these. In order an establishment can offer cell-based treatments, it must have the appropriate license. Licensing and requirements for the health establishments offering these products are determined by the General Regulation for the Qualification of Health Services (N° 41045-S).
With this legal framework, Costa Rica assures the proper manufacture and administration of cell therapies, as well as the clinical following of the patients and the certificate of training for cell therapy of the personnel. As in other countries, although these laws are not specifically for cell-based products, they can be used as a guide for future legislation.
Dominican Republic
The Dominican Ministry of Public Health considers cell therapy as a medicinal or biological product and it is concerned that all cell therapy service, treatment, technique, or medical innovation are innocuous. The Advisory Commission on Cell Therapies and Regenerative Medicine identifies regulatory needs regarding cell therapy and regenerative medicine, promotes intersectoral and multidisciplinary interactions, presents regulatory proposals, and designs instruments and strategies to keep the population sufficiently informed. As there is no legislation for donor screening, living donor informed consent, and transplant regulations, the General Health Law (No. 42-01) and the Donation and Transplantation of Organs and Tissues Law (No. 329-98) could apply for cell therapies as well.
The General Board of Medicines, Food and Health Products (DIGEMAPS “Dirección General de Medicamentos, Alimentos y Productos Sanitarios”) regulates the administration and authorization of cell therapies, including cosmetic procedures under Resolution No. 000018 from 2017. A characteristic that makes the Dominican Republic regulations stand out among its peers is that it does not allow the administration of treatments by doctors who are not specialists associated with the disease treated. It also includes marketing guidelines with the prohibition to concede that the cell therapy is infallible or any kind of mislead information. Other nations in the region could adopt these measures.
Ecuador
In this country, the National Institute of Donation and Organ Transplantation (INDOT, “Instituto Nacional de Donación y Trasplante de Órganos”) and the Academic community composed in 2019 the first Technical Advisory Committee for Cellular Therapy to supervise all matters related to the research and administration of cell therapy and the surveillance, monitoring, and follow-up of unproven cell-based treatments. Donation and Transplantation of Organs, Tissues, and Cells Organic Act and its Statute define stem cells, and considers the terms of cell therapy or regenerative medicine, tissue engineering, and xenotransplantation.
In those regulations, it is established that every facility offering these treatments should be authorized by INDOT. The standards for donor selection, storage, recovery costs, distribution of tissues, and quality management system are stated in the Technical Standard for Living Tissue Donation. Outside of this, no specific regulation has been established yet.
Panamá
Similar to Chile, the Draft Bill No. 300, Bill No. 179, was presented to the National Assembly, which establishes the Guidelines for Cultivation, Development, Reproduction and Administration of MSCs and their Derivatives in the Republic of Panamá. This is the first regulation specifically targeted at MSCs in the region. To date, the regulatory framework for cell therapy was under the jurisdiction of The Transplant Law, and none of the licenses considered applies to a laboratory or clinic for cell-based treatments.
This Draft Bill is intended to govern licensing for establishments, and all processes for donation, extraction, evaluation, processing, reproduction, expansion, differentiation, storage, and administration of MSCs and its derivatives independently. The MSC therapy is not considered there as a pharmaceutical drug, but the draft requires more stringent quality tests for the administration of allogeneic-based therapies. If approved, the Draft Bill could be a milestone and influence for the regulatory framework for MSCs in Latin America.
Peru
Decree No. 016-2011-SA in Peru approved the Regulation for the Registration, Control, and Sanitary Surveillance of Pharmaceutical Products, Medical Devices, and Sanitary Products, includes the requirements for commercialization of biological products, but does not consider any type of cell therapy. Decree No. 014-2005-SA is the only regulation we found to address cell therapy, through the creation of the National Organization for Donation and Transplants (ONDT, “Organización Nacional de Donación y Trasplantes”) and approval of the Regulation of the General Law of Donation and Transplantation of Human Organs and/or Tissues. However, no allogeneic treatment is considered in this or any other regulation.
Uruguay
In Uruguay, the Creation and Development of Cell Therapy and Regenerative Medicine Area is responsible for the development of Regenerative Medicine and Cell Therapy. Regardless, this country only recognizes the use of hematopoietic stem cells in bone marrow transplants and hematological and oncological diseases. Outside those, all regenerative medicine treatments are categorized as experimental or “research only”, although the Ministry of Public Health does regulate all critical processes for cell therapy.
